Objective: Striatins(STRNs) family, which contains three multi-domain scaffolding proteins, are cornerstones of the striatins interacting phosphatase and kinase(STRIPAK) complex. Although the role of the STRIPAK compl...Objective: Striatins(STRNs) family, which contains three multi-domain scaffolding proteins, are cornerstones of the striatins interacting phosphatase and kinase(STRIPAK) complex. Although the role of the STRIPAK complex in cancer has become recognized in recent years, its clinical significance in breast cancer has not been fully established.Methods: Using a freshly frozen breast cancer tissue cohort containing both cancerous and adjacent normal mammary tissues, we quantitatively evaluated the transcript-level expression of all members within the STRIPAK complex along with some key interacting and regulatory proteins of STRNs. The expression profile of each molecule and the integrated pattern of the complex members were assessed against the clinical-pathological factors of the patients. The Cancer Genome Atlas(TCGA) dataset was used to evaluate the breast cancer patients’ response to chemotherapies. Four human breast cancer cell lines, MDA-MB-231, MDA-MB-361, MCF-7, and SKBR-3, were subsequently adopted for in vitro work.Results: Here we found that high-level expressions of STRIP2, calmodulin, CCM3, MINK1 and SLMAP were respectively associated with shorter overall survival(OS) of patients. Although the similar pattern observed for STRN3, STRN4 and a contrary pattern observed for PPP2CA, PPP2CB and PPPR1A were not significant, the integrated expression profile of STRNs group and PPP2 group members constitutes a highly significant prognostic indicator for OS [P<0.001, hazard ratio(HR)=2.04, 95% confidence interval(95% CI), 1.36-3.07] and disease-free survival(DFS)(P=0.003, HR=1.40, 95% CI, 1.12-1.75). Reduced expression of STRN3 has an influence on the biological functions including adhesiveness and migration. In line with our clinical findings, the breast cancer cells responded to STRN3 knockdown with changes in their chemo-sensitivity, of which the response is also breast cancer subtype dependent.Conclusions: Our results suggest a possible role of the STRIPAK complex in breast cancer development and prognosis. Among the members, the expression profile of STRN3 presents a valuable factor for assessing patients’ responses to drug treatment.展开更多
Mast cells are a subtype of white blood cells and are involved in the immune system.These cells contain many chemical substances called mediators,which are involved in the allergic response.The fact that mast cells pl...Mast cells are a subtype of white blood cells and are involved in the immune system.These cells contain many chemical substances called mediators,which are involved in the allergic response.The fact that mast cells play a role in many events that require urgent intervention,especially anaphylaxis,has led to a more detailed study of these cells.The diseases also caused by dysfunctions of mast cells have been examined in many circumstances.For instance,mast cell activation syndrome is known as an augmented number of cells due to decreased cell death,resulting in clinical symptoms affecting many systems.The main common symptoms include flushing,hypotension,urticaria,angioedema,headache,vomiting and diarrhea.Although the underlying mechanism is not yet clearly known,we aim to review the literature in a broad perspective and bring together the existing knowledge in the light of the literature due to the diversity of its involvement in the body and the fact that it is a little known syndrome.展开更多
Cystic fibrosis transmembrane conductance regulator(CFTR), a glycoprotein with 1480 amino acids, has been well established as a chloride channel mainly expressed in the epithelial cells of various tissues and organs s...Cystic fibrosis transmembrane conductance regulator(CFTR), a glycoprotein with 1480 amino acids, has been well established as a chloride channel mainly expressed in the epithelial cells of various tissues and organs such as lungs, sweat glands, gastrointestinal system, and reproductive organs. Although defective CFTR leads to cystic fibrosis, a common genetic disorder in the Caucasian population, there is accumulating evidence that suggests a novel role of CFTR in various cancers, especially in gastroenterological cancers, such as pancreatic cancer and colon cancer. In this review, we summarize the emerging findings that link CFTR with various cancers, with focus on the association between CFTR defects and gastrointestinal cancers as well as the underlying mechanisms. Further study of CFTR in cancer biology may help pave a new way for the diagnosis and treatment of gastrointestinal cancers.展开更多
Members of the receptor tyrosine kinase family, that include EGFR, ErbB-2/HER-2, ErbB-3/HER-3 and ErbB-4/ HER-4, are frequently implicated in experimental models of epithelial cell neoplasia as well as in human cancer...Members of the receptor tyrosine kinase family, that include EGFR, ErbB-2/HER-2, ErbB-3/HER-3 and ErbB-4/ HER-4, are frequently implicated in experimental models of epithelial cell neoplasia as well as in human cancers. Therefore, interference with the activation of these growth factor receptors represents a promising strategy for de- velopment of novel and selective anticancer therapies. Indeed, a number of inhibitors that target either EGFR or HER-2, with the exception of a few that target both; have been developed for treatment of epithelial cancers. Since most solid tumors express different ErbB receptors and/or their ligands, identification of inhibitor(s), targeting multiple EGFR family members may provide a therapeutic benefit to a broader patient population. Here we describe the significance of an ErbB family of receptors in epithelial cancers, and summarize different available therapeutics targeting these receptors. It also emphasizes the need to develop pan-ErbB inhibitors and discusses EGF-Receptor Related Protein, a recently isolated negative regulator of EGFR as a potential pan-ErbB therapeutic for a wide vari- ety of epithelial cancers.展开更多
AIM To investigate the anticancer effect of a recombinant adenovirus-mediated p53(r Ad-p53) combined with 5-fluorouracil(5-FU) in human colon cancer resistant to 5-FU in vivo and the mechanism of r Ad-p53 in reversal ...AIM To investigate the anticancer effect of a recombinant adenovirus-mediated p53(r Ad-p53) combined with 5-fluorouracil(5-FU) in human colon cancer resistant to 5-FU in vivo and the mechanism of r Ad-p53 in reversal of 5-FU resistance.METHODS nude mice bearing human colon cancer SW480/5-FU(5-FU resistant) were randomly assigned to four groups(n = 25 each): control group, 5-FU group, r Ad-p53 group, and r Ad-p53 + 5-FU group. At 24 h, 48 h, 72 h, 120 h and 168 h after treatment, 5 mice were randomly selected from each group and sacrificed using an overdose of anesthetics. The tumors were removed and the protein expressions of p53, protein kinase C(PKC), permeability-glycoprotein(P-gp) and multidrug resistance-associated protein 1(MRP1)(Western blot) and apoptosis(TUNEL) were determined.RESULTS The area ratios of tumor cell apoptosis were larger in the r Ad/p53 + 5-FU group than that in the control, 5-FU and r Ad/p53 groups(P < 0.05), and were larger in the r Ad/p53 group than that of the control group(P < 0.05) and the 5-FU group at more than 48 h(P < 0.05). The p53 expression was higher in the r Ad/p53 and the r Ad/p53 + 5-FU groups than that of the control and 5-FU groups(P < 0.05), and were higher in the r Ad/p53 + 5-FU group than that of the r Ad/p53 group(P < 0.05). Overexpression of PKC, P-gp and MRP1 was observed in the 5-FU and control groups. In the r Ad/p53 + 5-FU group, the expression of P-gp and MRP1 was lower that of the control and 5-FU groups(P < 0.05), and the expression of PKC was lower than that of the control, 5-FU and r Ad/p53 groups at more than 48 h(P < 0.05). In the r Ad/p53 group, the expression of P-gp and MRP1 was lower that of the control and 5-FU groups at more than 48 h(P < 0.05), and the expression of PKC was lower than that of the control and 5-FU groups at more than 120 h(P < 0.05).CONCLUSION5-FU combined with r Ad-p53 has a synergistic anticancer effect in SW480/5-FU(5-FU resistance), which contributes to reversal of 5-FU resistance.展开更多
AIM To determine whether and to what extent the gut microbiome is involved in regulating racial disparity in colorectal cancer(CRC). METHODS All patients were recruited and experiments were performed in accordance wit...AIM To determine whether and to what extent the gut microbiome is involved in regulating racial disparity in colorectal cancer(CRC). METHODS All patients were recruited and experiments were performed in accordance with the relevant guidelines and regulations by the Institutional Review Boards (IRB), committees of the John D. Dingell VAMC and Wayne State University guidelines. African American (AA) and Caucasian American (CA) patients were scheduled for an outpatient screening for colonoscopy, and no active malignancy volunteer patients were doubly consented, initially by the gastroenterologist and later by the study coordinator, for participation in the study. The gut microbial communities in colonic effluents from AAs and CAs were examined using 16 sRNA profiling, and bacterial identifications were validated by performing SYBR-based Real Time PCR. For metagenomic analysis to characterize the microbial communities, multiple software/tools were used, including Metastats and R statistical software.RESULTS It is generally accepted that the incidence and mortality of CRC is higher in AAs than in CAs. However, the reason for this disparity is not well understood. We hypothesize that the gut microbiome plays a role in regulating this disparity. Indeed, we found significant differences in species richness and diversity between AAs and CAs. Bacteroidetes was more abundant in AAs than in CAs. In particular, the pro-inflammatory bacteria Fusobacterium nucleatum and Enterobacter species were significantly higher in AAs, whereas probiotic Akkermansia muciniphila and Bifidobacterium were higher in CAs. The polyphyletic Clostridia class showed a divergent pattern, with Clostridium XI elevated in AAs, and Clostridium IV, known for its beneficial function, higher in CAs. Lastly, the AA group had decreased microbial diversity overall in comparison to the CA group. In summary, there were significant differences in pro-inflammatory bacteria and microbial diversity between AA and CA, which may help explain the CRC disparity between groups.CONCLUSION Our current investigation, for the first time, demonstrates microbial dysbiosis between AAs and CAs, which could contribute to the racial disparity of CRC.展开更多
Colorectal cancer(CRC) that comprises about 50% of estimated gastrointestinal cancers remains a high mortality malignancy. It is estimated that CRC will result in 9% of all cancer related deaths. CRC is the third lead...Colorectal cancer(CRC) that comprises about 50% of estimated gastrointestinal cancers remains a high mortality malignancy. It is estimated that CRC will result in 9% of all cancer related deaths. CRC is the third leading malignancy affecting both males and females equally; with 9% of the estimated new cancer cases and 9% cancer related deaths. Sporadic CRC, whose incidence increases markedly with advancing age, occurs in 80%-85% patients diagnosed with CRC. Little is known about the precise biochemical mechanisms responsible for the rise in CRC with aging. However, many probable reasons for this increase have been suggested; among others they include altered carcinogen metabolism and the cumulative effects of long-term exposure to cancer-causing agents. Herein, we propose a role for self-renewing, cancer stem cells(CSCs) in regulating these cellular events. In this editorial, we have briefly described the recent work on the evolution of CSCs in gastro-intestinal track especially in the colon, and how they are involved in the age-related rise in CRC. Focus of this editorial is to provide a description of(1) CSC;(2) epigenetic and genetic mechanisms giving rise to CSCs;(3) markers of CSC;(4) characteristics; and(5) age-related increase in CSC in the colonic crypt.展开更多
For cancer patients on Phase I trials, one of the most important physician decisions is whether or not patients are deriving benefit from therapy. With an increasing number of cytostatic treatment agents, the criteria...For cancer patients on Phase I trials, one of the most important physician decisions is whether or not patients are deriving benefit from therapy. With an increasing number of cytostatic treatment agents, the criteria to determine patient response to Phase I treatment has become harder to define. Physicians are increasingly looking to patient-reported outcomes (PROs) such as quality of life (QOL) to help evaluate treatment response. Electronic daily diary (EDD) devices can be used by patients to report their QOL over extended periods of time, thereby providing a more accurate picture of how patients are affected by treatment on a daily basis. However, questions remain about how to integrate this patient-reported information into decisions about Phase I treatment. This study investigated how physicians use patients’ daily QOL reports to evaluate patient response to Phase I treatment. Data were collected over a 4-month period from Phase I patients (N = 30) and physicians (N = 3) in an NCI-designated comprehensive cancer center. Patients completed daily QOL reports using EDD devices and physicians were provided with a summary of patients’ QOL before each visit. After the visit, doctors recorded their treatment decision and also rated the importance of four biomedical factors (Toxicity, Imaging, Labs, and Performance Status) and QOL in their treatment decision for that visit. Although physicians rated QOL as being very important in evaluating treatment response, in practice, when predictors of their decisions were analyzed, results showed they relied exclusively on biomedical data (Toxicity, Imaging) to make Phase I treatment decisions. Questions remain about the utility and effective integration of QOL and biomedical data in clinical decision-making processes in Phase I clinical trials.展开更多
Over the past two decades there has been remarkable progress in cancer diagnosis, treatment and screening. The basic mechanisms leading to pathogenesis of various types of cancers are also understood better and some p...Over the past two decades there has been remarkable progress in cancer diagnosis, treatment and screening. The basic mechanisms leading to pathogenesis of various types of cancers are also understood better and some patients, if diagnosed at a particular stage go on to lead a normal pre-diagnosis life. Despite these achievements, racial disparity in some cancers remains a mystery. The higher incidence, aggressiveness and mortality of breast, prostate and colorectal cancers(CRCs) in AfricanAmericans as compared to Caucasian-Americans are now well documented. The polyp-carcinoma sequence in CRC and easy access to colonic epithelia or colonic epithelial cells through colonoscopy/colonic effluent provides the opportunity to study colonic stem cells early in course of natural history of the disease. With the advent of metagenomic sequencing, uncultivable organisms can now be identified in stool and their numbers correlated with the effects on colonic epithelia. It would be expected that these techniques would revolutionize our understanding of the racial disparity in CRC and pave a way for the same in other cancers as well. Unfortunately, this has not happened. Our understanding of the underlying factors responsible in African-Americans for higher incidence and mortality from colorectal carcinoma remains minimal. In this review, we aim to summarize the available data on role of microbiome and cancer stem cells in racial disparity in CRC. This will provide a platform for further research on this topic.展开更多
Objective:Sorafenib is a first-line drug for advanced hepatocellular carcinoma(HCC).Unfortunately,most patients with HCC do not respond to sorafenib,mainly because of the frequent development of drug resistance.Biliru...Objective:Sorafenib is a first-line drug for advanced hepatocellular carcinoma(HCC).Unfortunately,most patients with HCC do not respond to sorafenib,mainly because of the frequent development of drug resistance.Bilirubin is an end metabolite of heme catabolism and an indicator of liver function,but its direct role in regulating the anticancer activity of sorafenib in HCC cells is unclear.In the current study,we aimed to investigate the mechanism of action of bilirubin in sorafenib-mediated tumor suppression in HCC.Methods:A retrospective observational cohort of 100 patients receiving sorafenib was conducted to evaluate the potential role of bilirubin in predicting the prognosis of patients with HCC.Human HCC cell lines were treated with sorafenib in the absence or presence of bilirubin,and cell proliferation,apoptosis,and signaling pathways were assayed.The antagonistic effect of bilirubin toward sorafenib was assessed in nude mice bearing HCC xenografts.Results:Serum levels of bilirubin(including total,direct,and indirect bilirubin)negatively correlated with the overall survival of patients with HCC treated with sorafenib(P<0.05).Both in vitro and in vivo analyses demonstrated that bilirubin significantly abrogated sorafenib-mediated proliferation inhibition and apoptosis induction in HCC cells(P<0.05).Mechanically,bilirubin inhibited sorafenib-induced activation of GSK-3βand subsequent downstream MCL-1 degradation.Conclusions:Our study provides experimental evidence of the antagonistic effect of bilirubin toward sorafenib-mediated anticancer activity in HCC,and it suggests that bilirubin could be used to predict the efficacy of sorafenib treatment.展开更多
The article published recently in Cell Stem Cell from the laboratory of Dr Tang showed the existence and molecular fingerprints of prostate cancer stem cells (CSCs), and this report opens newer ave- nues for develop...The article published recently in Cell Stem Cell from the laboratory of Dr Tang showed the existence and molecular fingerprints of prostate cancer stem cells (CSCs), and this report opens newer ave- nues for developing and designing novel therapeutic strategies for targeted elimina- tion of these CSCs toward prostate cancer therapy.展开更多
AIM: To determine whether folic acid supplementation will reduce the recurrence of colorectal adenomas, the precursors of colorectal cancer, we performed a double-blind placebo-controlled trial in patients with adenom...AIM: To determine whether folic acid supplementation will reduce the recurrence of colorectal adenomas, the precursors of colorectal cancer, we performed a double-blind placebo-controlled trial in patients with adenomatous polyps. METHODS: In the current double-blind, placebo-controlled trial at this VA Medical Center, patients with colorectal adenomas were randomly assigned to receive either a daily 5 mg dose of folic acid or a matched identical placebo for 3 years. All polyps were removed at baseline colonoscopy and each patient had a follow up colonoscopy at 3 years. The primary endpoint was a reduction in the number of recurrent adenomas at 3 years. RESULTS: Of 137 subjects, who were eligible after confirmation of polyp histology and run-in period to conform compliance, 94 completed the study; 49 in folic acid group and 45 in placebo group. Recurrence of adenomas at 3-year was compared between the two groups. The mean number of recurrent polyps at 3-year was 0.36 (SD, 0.69) for folic acid treated patients compared to 0.82 (SD, 1.17) for placebo treated subjects, resulting in a 3-fold increase in polyp recurrence in the placebo group. Patients below 70 years of age and those with left-sided colonicadenomas or advanced adenomas responded better to folic acid supplementation. CONCLUSION: High dose folic acid supplementation is associated with a signif icant reduction in the recurrence of colonic adenomas suggesting that folic acid may be an effective chemopreventive agent for colorectal neoplasia.展开更多
Recurrence of colon cancer still remains a major issue which affects nearly 50% of patients treated by conventional therapeutics. Although the underlying causative factor(s) is not fully understood, development of dru...Recurrence of colon cancer still remains a major issue which affects nearly 50% of patients treated by conventional therapeutics. Although the underlying causative factor(s) is not fully understood, development of drug-resistance has been associated with induction of cancer stem or stem-like cells (CSCs) which constitute a small sub-population of tumor cells known to be highly resistant to chemotherapy. In fact, the discovery of CSCs in a variety of tumors (including colon cancer) has changed the view of carcinogenesis and therapeutic strategies. Emerging reports have indicated that to improve patient outcomes, conventional anticancer therapies should be replaced with specifi c approaches targeting CSCs. Thus, therapeutic strategies that specifically target CSCs are being sought to reduce the risk of relapse and metastasis. In order to specifi cally target colon CSCs (while sparing somatic intestinal stem cells), it is critical to identify unique deregulated pathways responsible for self-renewal of CSCs and colon cancer recurrence. Colon CSCs present a unique opportunity to better understand the biology of solid tumors. Thus, a better understanding of the clinical signs and symptoms of colon cancer patients (under-going surgery or chemotherapy) during perioperative periods, along with the underlying regulatory events affecting the stem/progenitor cell self-renewal and differentiation of colon epithelial cells, is of immense importance. In this review we discuss the implication of clinical factors and the emerging role of CSCs during recurrence of colon cancer along with the development of new therapeutic strategies involving the use of natural agents.展开更多
A rapid, sensitive, and robust reversed-phase liquid chromatography with tandem mass spectrometry method was developed and validated for the determination of total and unbound ceritinib, a secondgeneration ALK inhibit...A rapid, sensitive, and robust reversed-phase liquid chromatography with tandem mass spectrometry method was developed and validated for the determination of total and unbound ceritinib, a secondgeneration ALK inhibitor, in patient plasma and brain tumor tissue samples. Sample preparation involved simple protein precipitation with acetonitrile. Chromatographic separation was achieved on a Waters ACQUITY UPLC BEH C_(18) column using a 4-min gradient elution consisting of mobile phase A(0.1% formic acid in water) and mobile phase B(0.1% formic acid in acetonitrile), at a flow rate of 0.4 m L/min. Ceritinib and the internal standard([^(13)C_6]ceritinib) were monitored using multiple reaction monitoring mode under positive electrospray ionization. The lower limit of quantitation(LLOQ) was 1 n M of ceritinib in plasma. The calibration curve was linear over ceritinib concentration range of 1–2000 n M in plasma. The intra-and interday precision and accuracy were within the generally accepted criteria for bioanalytical method( o15%).The method was successfully applied to assess ceritinib brain tumor penetration, as assessed by the unbound drug brain concentration to unbound drug plasma concentration ratio, in patients with brain tumors.展开更多
By manipulating the phase map of a wavefront of light using a spatial light modulator,the scattered light can be sharply focused on a specific target.Several iterative optimization algo-rithrns for obtaining the optim...By manipulating the phase map of a wavefront of light using a spatial light modulator,the scattered light can be sharply focused on a specific target.Several iterative optimization algo-rithrns for obtaining the optimumn phase map have been explored.However,there has not been a comparative study on the performance of these algorithms.In this paper,six optimization algorithms for wavefront shaping inchuding continuous sequential,partitioning algorithm,transmission matrix estimation method,particle swarm optimization,genetic algorithm(GA),and simulated annealing(SA)are discussed and compared based on their efficiency when introduced with various measurement noise levels.展开更多
基金supported by the Cardiff University China Medical Scholarship。
文摘Objective: Striatins(STRNs) family, which contains three multi-domain scaffolding proteins, are cornerstones of the striatins interacting phosphatase and kinase(STRIPAK) complex. Although the role of the STRIPAK complex in cancer has become recognized in recent years, its clinical significance in breast cancer has not been fully established.Methods: Using a freshly frozen breast cancer tissue cohort containing both cancerous and adjacent normal mammary tissues, we quantitatively evaluated the transcript-level expression of all members within the STRIPAK complex along with some key interacting and regulatory proteins of STRNs. The expression profile of each molecule and the integrated pattern of the complex members were assessed against the clinical-pathological factors of the patients. The Cancer Genome Atlas(TCGA) dataset was used to evaluate the breast cancer patients’ response to chemotherapies. Four human breast cancer cell lines, MDA-MB-231, MDA-MB-361, MCF-7, and SKBR-3, were subsequently adopted for in vitro work.Results: Here we found that high-level expressions of STRIP2, calmodulin, CCM3, MINK1 and SLMAP were respectively associated with shorter overall survival(OS) of patients. Although the similar pattern observed for STRN3, STRN4 and a contrary pattern observed for PPP2CA, PPP2CB and PPPR1A were not significant, the integrated expression profile of STRNs group and PPP2 group members constitutes a highly significant prognostic indicator for OS [P<0.001, hazard ratio(HR)=2.04, 95% confidence interval(95% CI), 1.36-3.07] and disease-free survival(DFS)(P=0.003, HR=1.40, 95% CI, 1.12-1.75). Reduced expression of STRN3 has an influence on the biological functions including adhesiveness and migration. In line with our clinical findings, the breast cancer cells responded to STRN3 knockdown with changes in their chemo-sensitivity, of which the response is also breast cancer subtype dependent.Conclusions: Our results suggest a possible role of the STRIPAK complex in breast cancer development and prognosis. Among the members, the expression profile of STRN3 presents a valuable factor for assessing patients’ responses to drug treatment.
文摘Mast cells are a subtype of white blood cells and are involved in the immune system.These cells contain many chemical substances called mediators,which are involved in the allergic response.The fact that mast cells play a role in many events that require urgent intervention,especially anaphylaxis,has led to a more detailed study of these cells.The diseases also caused by dysfunctions of mast cells have been examined in many circumstances.For instance,mast cell activation syndrome is known as an augmented number of cells due to decreased cell death,resulting in clinical symptoms affecting many systems.The main common symptoms include flushing,hypotension,urticaria,angioedema,headache,vomiting and diarrhea.Although the underlying mechanism is not yet clearly known,we aim to review the literature in a broad perspective and bring together the existing knowledge in the light of the literature due to the diversity of its involvement in the body and the fact that it is a little known syndrome.
基金Supported by American Cancer Society Institutional Research to Li C,No.11-053-01-IRGNational Institutes of Health grant HL128647
文摘Cystic fibrosis transmembrane conductance regulator(CFTR), a glycoprotein with 1480 amino acids, has been well established as a chloride channel mainly expressed in the epithelial cells of various tissues and organs such as lungs, sweat glands, gastrointestinal system, and reproductive organs. Although defective CFTR leads to cystic fibrosis, a common genetic disorder in the Caucasian population, there is accumulating evidence that suggests a novel role of CFTR in various cancers, especially in gastroenterological cancers, such as pancreatic cancer and colon cancer. In this review, we summarize the emerging findings that link CFTR with various cancers, with focus on the association between CFTR defects and gastrointestinal cancers as well as the underlying mechanisms. Further study of CFTR in cancer biology may help pave a new way for the diagnosis and treatment of gastrointestinal cancers.
基金Supported by grants from the National Institute of Aging (5RO1 AG14343) (APNM) and the Department of Veterans Affairs(APNM and AKR) and from The Susan G. Komen Foundation forBreast Cancer Research (AKR)
文摘Members of the receptor tyrosine kinase family, that include EGFR, ErbB-2/HER-2, ErbB-3/HER-3 and ErbB-4/ HER-4, are frequently implicated in experimental models of epithelial cell neoplasia as well as in human cancers. Therefore, interference with the activation of these growth factor receptors represents a promising strategy for de- velopment of novel and selective anticancer therapies. Indeed, a number of inhibitors that target either EGFR or HER-2, with the exception of a few that target both; have been developed for treatment of epithelial cancers. Since most solid tumors express different ErbB receptors and/or their ligands, identification of inhibitor(s), targeting multiple EGFR family members may provide a therapeutic benefit to a broader patient population. Here we describe the significance of an ErbB family of receptors in epithelial cancers, and summarize different available therapeutics targeting these receptors. It also emphasizes the need to develop pan-ErbB inhibitors and discusses EGF-Receptor Related Protein, a recently isolated negative regulator of EGFR as a potential pan-ErbB therapeutic for a wide vari- ety of epithelial cancers.
基金Supported by the Natural Science Foundation of Guangdong,No.2015A030313732
文摘AIM To investigate the anticancer effect of a recombinant adenovirus-mediated p53(r Ad-p53) combined with 5-fluorouracil(5-FU) in human colon cancer resistant to 5-FU in vivo and the mechanism of r Ad-p53 in reversal of 5-FU resistance.METHODS nude mice bearing human colon cancer SW480/5-FU(5-FU resistant) were randomly assigned to four groups(n = 25 each): control group, 5-FU group, r Ad-p53 group, and r Ad-p53 + 5-FU group. At 24 h, 48 h, 72 h, 120 h and 168 h after treatment, 5 mice were randomly selected from each group and sacrificed using an overdose of anesthetics. The tumors were removed and the protein expressions of p53, protein kinase C(PKC), permeability-glycoprotein(P-gp) and multidrug resistance-associated protein 1(MRP1)(Western blot) and apoptosis(TUNEL) were determined.RESULTS The area ratios of tumor cell apoptosis were larger in the r Ad/p53 + 5-FU group than that in the control, 5-FU and r Ad/p53 groups(P < 0.05), and were larger in the r Ad/p53 group than that of the control group(P < 0.05) and the 5-FU group at more than 48 h(P < 0.05). The p53 expression was higher in the r Ad/p53 and the r Ad/p53 + 5-FU groups than that of the control and 5-FU groups(P < 0.05), and were higher in the r Ad/p53 + 5-FU group than that of the r Ad/p53 group(P < 0.05). Overexpression of PKC, P-gp and MRP1 was observed in the 5-FU and control groups. In the r Ad/p53 + 5-FU group, the expression of P-gp and MRP1 was lower that of the control and 5-FU groups(P < 0.05), and the expression of PKC was lower than that of the control, 5-FU and r Ad/p53 groups at more than 48 h(P < 0.05). In the r Ad/p53 group, the expression of P-gp and MRP1 was lower that of the control and 5-FU groups at more than 48 h(P < 0.05), and the expression of PKC was lower than that of the control and 5-FU groups at more than 120 h(P < 0.05).CONCLUSION5-FU combined with r Ad-p53 has a synergistic anticancer effect in SW480/5-FU(5-FU resistance), which contributes to reversal of 5-FU resistance.
基金Supported by Department of Veteran Affairs,No.1I101BX001927National Institutes of Health,No.1R21CA175916
文摘AIM To determine whether and to what extent the gut microbiome is involved in regulating racial disparity in colorectal cancer(CRC). METHODS All patients were recruited and experiments were performed in accordance with the relevant guidelines and regulations by the Institutional Review Boards (IRB), committees of the John D. Dingell VAMC and Wayne State University guidelines. African American (AA) and Caucasian American (CA) patients were scheduled for an outpatient screening for colonoscopy, and no active malignancy volunteer patients were doubly consented, initially by the gastroenterologist and later by the study coordinator, for participation in the study. The gut microbial communities in colonic effluents from AAs and CAs were examined using 16 sRNA profiling, and bacterial identifications were validated by performing SYBR-based Real Time PCR. For metagenomic analysis to characterize the microbial communities, multiple software/tools were used, including Metastats and R statistical software.RESULTS It is generally accepted that the incidence and mortality of CRC is higher in AAs than in CAs. However, the reason for this disparity is not well understood. We hypothesize that the gut microbiome plays a role in regulating this disparity. Indeed, we found significant differences in species richness and diversity between AAs and CAs. Bacteroidetes was more abundant in AAs than in CAs. In particular, the pro-inflammatory bacteria Fusobacterium nucleatum and Enterobacter species were significantly higher in AAs, whereas probiotic Akkermansia muciniphila and Bifidobacterium were higher in CAs. The polyphyletic Clostridia class showed a divergent pattern, with Clostridium XI elevated in AAs, and Clostridium IV, known for its beneficial function, higher in CAs. Lastly, the AA group had decreased microbial diversity overall in comparison to the CA group. In summary, there were significant differences in pro-inflammatory bacteria and microbial diversity between AA and CA, which may help explain the CRC disparity between groups.CONCLUSION Our current investigation, for the first time, demonstrates microbial dysbiosis between AAs and CAs, which could contribute to the racial disparity of CRC.
基金Supported by The National Institutes of Health AG014343,1R21CA175916-01the Department of Veterans Affairs(I101BX001927)the Metropolitan Detroit Research and Education Foundation(to Adhip PN Majumdar)
文摘Colorectal cancer(CRC) that comprises about 50% of estimated gastrointestinal cancers remains a high mortality malignancy. It is estimated that CRC will result in 9% of all cancer related deaths. CRC is the third leading malignancy affecting both males and females equally; with 9% of the estimated new cancer cases and 9% cancer related deaths. Sporadic CRC, whose incidence increases markedly with advancing age, occurs in 80%-85% patients diagnosed with CRC. Little is known about the precise biochemical mechanisms responsible for the rise in CRC with aging. However, many probable reasons for this increase have been suggested; among others they include altered carcinogen metabolism and the cumulative effects of long-term exposure to cancer-causing agents. Herein, we propose a role for self-renewing, cancer stem cells(CSCs) in regulating these cellular events. In this editorial, we have briefly described the recent work on the evolution of CSCs in gastro-intestinal track especially in the colon, and how they are involved in the age-related rise in CRC. Focus of this editorial is to provide a description of(1) CSC;(2) epigenetic and genetic mechanisms giving rise to CSCs;(3) markers of CSC;(4) characteristics; and(5) age-related increase in CSC in the colonic crypt.
文摘For cancer patients on Phase I trials, one of the most important physician decisions is whether or not patients are deriving benefit from therapy. With an increasing number of cytostatic treatment agents, the criteria to determine patient response to Phase I treatment has become harder to define. Physicians are increasingly looking to patient-reported outcomes (PROs) such as quality of life (QOL) to help evaluate treatment response. Electronic daily diary (EDD) devices can be used by patients to report their QOL over extended periods of time, thereby providing a more accurate picture of how patients are affected by treatment on a daily basis. However, questions remain about how to integrate this patient-reported information into decisions about Phase I treatment. This study investigated how physicians use patients’ daily QOL reports to evaluate patient response to Phase I treatment. Data were collected over a 4-month period from Phase I patients (N = 30) and physicians (N = 3) in an NCI-designated comprehensive cancer center. Patients completed daily QOL reports using EDD devices and physicians were provided with a summary of patients’ QOL before each visit. After the visit, doctors recorded their treatment decision and also rated the importance of four biomedical factors (Toxicity, Imaging, Labs, and Performance Status) and QOL in their treatment decision for that visit. Although physicians rated QOL as being very important in evaluating treatment response, in practice, when predictors of their decisions were analyzed, results showed they relied exclusively on biomedical data (Toxicity, Imaging) to make Phase I treatment decisions. Questions remain about the utility and effective integration of QOL and biomedical data in clinical decision-making processes in Phase I clinical trials.
基金Supported by National Institutes of Health,No.1R21 CA175916Department of Veteran Affairs,No.I101BX001927Metro-politan Detroit Research and Education Fund(MDREF) grants to Dr.Majumdar
文摘Over the past two decades there has been remarkable progress in cancer diagnosis, treatment and screening. The basic mechanisms leading to pathogenesis of various types of cancers are also understood better and some patients, if diagnosed at a particular stage go on to lead a normal pre-diagnosis life. Despite these achievements, racial disparity in some cancers remains a mystery. The higher incidence, aggressiveness and mortality of breast, prostate and colorectal cancers(CRCs) in AfricanAmericans as compared to Caucasian-Americans are now well documented. The polyp-carcinoma sequence in CRC and easy access to colonic epithelia or colonic epithelial cells through colonoscopy/colonic effluent provides the opportunity to study colonic stem cells early in course of natural history of the disease. With the advent of metagenomic sequencing, uncultivable organisms can now be identified in stool and their numbers correlated with the effects on colonic epithelia. It would be expected that these techniques would revolutionize our understanding of the racial disparity in CRC and pave a way for the same in other cancers as well. Unfortunately, this has not happened. Our understanding of the underlying factors responsible in African-Americans for higher incidence and mortality from colorectal carcinoma remains minimal. In this review, we aim to summarize the available data on role of microbiome and cancer stem cells in racial disparity in CRC. This will provide a platform for further research on this topic.
基金supported by the National Funds for Developing Local Colleges and Universities(Grant No.B16056001),NSFC(Grant No.81602427)Natural Science Foundation research team of Guangdong Province(Grant Nos.2021A1515011382,2018B030312001,2017A030310151,and 2016A030310281)+3 种基金Science and Technology Program of Guangzhou(Grant No.201604020001)Innovative Academic Team of Guangzhou Education System(Grant No.1201610014)Research Team of Department of Education of Guangdong Province(Grant No.2017KCXTD027),open research funds from the Sixth Affiliated Hospital of Guangzhou Medical University,Qingyuan People’s Hospital(Grant No.202011-106),GZMU(Grant No.A2020262)the Medical Scientific Research Foundation of Guangdong Province,China(Grant No.A2022231).
文摘Objective:Sorafenib is a first-line drug for advanced hepatocellular carcinoma(HCC).Unfortunately,most patients with HCC do not respond to sorafenib,mainly because of the frequent development of drug resistance.Bilirubin is an end metabolite of heme catabolism and an indicator of liver function,but its direct role in regulating the anticancer activity of sorafenib in HCC cells is unclear.In the current study,we aimed to investigate the mechanism of action of bilirubin in sorafenib-mediated tumor suppression in HCC.Methods:A retrospective observational cohort of 100 patients receiving sorafenib was conducted to evaluate the potential role of bilirubin in predicting the prognosis of patients with HCC.Human HCC cell lines were treated with sorafenib in the absence or presence of bilirubin,and cell proliferation,apoptosis,and signaling pathways were assayed.The antagonistic effect of bilirubin toward sorafenib was assessed in nude mice bearing HCC xenografts.Results:Serum levels of bilirubin(including total,direct,and indirect bilirubin)negatively correlated with the overall survival of patients with HCC treated with sorafenib(P<0.05).Both in vitro and in vivo analyses demonstrated that bilirubin significantly abrogated sorafenib-mediated proliferation inhibition and apoptosis induction in HCC cells(P<0.05).Mechanically,bilirubin inhibited sorafenib-induced activation of GSK-3βand subsequent downstream MCL-1 degradation.Conclusions:Our study provides experimental evidence of the antagonistic effect of bilirubin toward sorafenib-mediated anticancer activity in HCC,and it suggests that bilirubin could be used to predict the efficacy of sorafenib treatment.
文摘The article published recently in Cell Stem Cell from the laboratory of Dr Tang showed the existence and molecular fingerprints of prostate cancer stem cells (CSCs), and this report opens newer ave- nues for developing and designing novel therapeutic strategies for targeted elimina- tion of these CSCs toward prostate cancer therapy.
文摘AIM: To determine whether folic acid supplementation will reduce the recurrence of colorectal adenomas, the precursors of colorectal cancer, we performed a double-blind placebo-controlled trial in patients with adenomatous polyps. METHODS: In the current double-blind, placebo-controlled trial at this VA Medical Center, patients with colorectal adenomas were randomly assigned to receive either a daily 5 mg dose of folic acid or a matched identical placebo for 3 years. All polyps were removed at baseline colonoscopy and each patient had a follow up colonoscopy at 3 years. The primary endpoint was a reduction in the number of recurrent adenomas at 3 years. RESULTS: Of 137 subjects, who were eligible after confirmation of polyp histology and run-in period to conform compliance, 94 completed the study; 49 in folic acid group and 45 in placebo group. Recurrence of adenomas at 3-year was compared between the two groups. The mean number of recurrent polyps at 3-year was 0.36 (SD, 0.69) for folic acid treated patients compared to 0.82 (SD, 1.17) for placebo treated subjects, resulting in a 3-fold increase in polyp recurrence in the placebo group. Patients below 70 years of age and those with left-sided colonicadenomas or advanced adenomas responded better to folic acid supplementation. CONCLUSION: High dose folic acid supplementation is associated with a signif icant reduction in the recurrence of colonic adenomas suggesting that folic acid may be an effective chemopreventive agent for colorectal neoplasia.
基金Acknowledgments This work was supported by the National High Technol- ogy Research and Development Program of China (Project 2006AA02Z4B5), the National Natural Science Foundation of China (Project 2010), and a Key Project (9251018201002) of Guangdong Province Natural Science Foundation (to JL). It was also supported in part by Grants HL072166, HL085629, and HL068936 of the NIH and an Established Investigator Award (0740025N) of the American Heart Association (to XW).
文摘由 ubiquitin-proteasome 系统的细胞内部的蛋白质降级是 ATP 依赖者,和最佳的 ATP 集中激活 proteasome 在 vitro 的功能是 ~ 100 渭 M。细胞内部的 ATP 层次在在这个范围以内的水平通常在低 millimolar 范围,而是 ATP 被显示在 vitro 禁止 proteasome peptidase 活动。这里,我们报导支持在生理的层次的细胞内部的 ATP 双向地调整的一个假设的新证据 26S proteasome 在房间的解朊的功能。首先,我们证实 ATP 在 vitro 在 26S proteasome 上施加了双向规定,与最佳的 ATP 集中(在 50 和 100 渭 M 之间) 刺激 proteasome 像糜蛋白酶的活动。第二,我们发现操作细胞内部的 ATP 层次也在有教养的房间在 proteasome 特定的蛋白质底层的层次导致了双向变化。最后,测量增加提高的细胞内部的 ATP,当减少的细胞内部的 ATP 稀释了导致房间死亡的 proteasome 抑制的能力时。这些数据强烈建议在生理的集中范围以内的内长的 ATP 能在 proteasome 活动施加否定影响,允许房间到很快,在应力下面的 ATP 减小上的 upregulate proteasome 活动调节。
基金Supported by The National Institutes of Health/National Institute on Aging, AG014343the Department of Veterans Affairs, to Adhip PN Majumdar
文摘Recurrence of colon cancer still remains a major issue which affects nearly 50% of patients treated by conventional therapeutics. Although the underlying causative factor(s) is not fully understood, development of drug-resistance has been associated with induction of cancer stem or stem-like cells (CSCs) which constitute a small sub-population of tumor cells known to be highly resistant to chemotherapy. In fact, the discovery of CSCs in a variety of tumors (including colon cancer) has changed the view of carcinogenesis and therapeutic strategies. Emerging reports have indicated that to improve patient outcomes, conventional anticancer therapies should be replaced with specifi c approaches targeting CSCs. Thus, therapeutic strategies that specifically target CSCs are being sought to reduce the risk of relapse and metastasis. In order to specifi cally target colon CSCs (while sparing somatic intestinal stem cells), it is critical to identify unique deregulated pathways responsible for self-renewal of CSCs and colon cancer recurrence. Colon CSCs present a unique opportunity to better understand the biology of solid tumors. Thus, a better understanding of the clinical signs and symptoms of colon cancer patients (under-going surgery or chemotherapy) during perioperative periods, along with the underlying regulatory events affecting the stem/progenitor cell self-renewal and differentiation of colon epithelial cells, is of immense importance. In this review we discuss the implication of clinical factors and the emerging role of CSCs during recurrence of colon cancer along with the development of new therapeutic strategies involving the use of natural agents.
基金supported by the United States Public Health Service Cancer Center Support Grant P30 CA022453Novartis for providing the study drug and isotope-labeled internal standard and providing financial support for the clinical study
文摘A rapid, sensitive, and robust reversed-phase liquid chromatography with tandem mass spectrometry method was developed and validated for the determination of total and unbound ceritinib, a secondgeneration ALK inhibitor, in patient plasma and brain tumor tissue samples. Sample preparation involved simple protein precipitation with acetonitrile. Chromatographic separation was achieved on a Waters ACQUITY UPLC BEH C_(18) column using a 4-min gradient elution consisting of mobile phase A(0.1% formic acid in water) and mobile phase B(0.1% formic acid in acetonitrile), at a flow rate of 0.4 m L/min. Ceritinib and the internal standard([^(13)C_6]ceritinib) were monitored using multiple reaction monitoring mode under positive electrospray ionization. The lower limit of quantitation(LLOQ) was 1 n M of ceritinib in plasma. The calibration curve was linear over ceritinib concentration range of 1–2000 n M in plasma. The intra-and interday precision and accuracy were within the generally accepted criteria for bioanalytical method( o15%).The method was successfully applied to assess ceritinib brain tumor penetration, as assessed by the unbound drug brain concentration to unbound drug plasma concentration ratio, in patients with brain tumors.
文摘By manipulating the phase map of a wavefront of light using a spatial light modulator,the scattered light can be sharply focused on a specific target.Several iterative optimization algo-rithrns for obtaining the optimumn phase map have been explored.However,there has not been a comparative study on the performance of these algorithms.In this paper,six optimization algorithms for wavefront shaping inchuding continuous sequential,partitioning algorithm,transmission matrix estimation method,particle swarm optimization,genetic algorithm(GA),and simulated annealing(SA)are discussed and compared based on their efficiency when introduced with various measurement noise levels.