Insulin-like growth factor binding protein-3 (IGFBP-3), a secretory protein, is the most abundant IGF binding protein present in human serum among all IGF binding proteins. IGFBP-3 shows decreased level of expression ...Insulin-like growth factor binding protein-3 (IGFBP-3), a secretory protein, is the most abundant IGF binding protein present in human serum among all IGF binding proteins. IGFBP-3 shows decreased level of expression in cancerous cells but has been known to be present in significant amounts in normal or non-cancerous cells. IGFBP-3 can induce apoptosis in prostate cancer cells either in an IGF-dependent manner or independently of IGF binding. Although putative cell death specific Insulin-like growth factor binding protein-3 (IGFBP-3R) receptor(s) has recently been identified by which IGFBP-3 may induce its anti-tumor effects, IGFBP-3 has also been known to activate various downstream intracellular signaling molecules via a different mechanistic pathway. Stat-1 has been known to be one of the candidate molecules activated by IGFBP-3. IGFBP-3 can also inhibit Akt/IGF-1 survival pathway in MCF-7 breast cancer cells which ultimately leads to the induction of apoptosis in these cells. All these studies clearly demonstrate that IGFBP-3 regulates cell proliferation and promotes its pro-apoptotic effects in cancer cells in two different pathways: 1) sequester IGF-I to bind to IGF-I receptor to inhibit cell proliferation and induce apoptosis, 2) independent of IGF-I pathway, IGFBP-3 binds to some putative receptor and activate various downstream pro-apoptotic molecules involved in cell death.展开更多
At present the publishing of case reports or case series involving small numbers of cases is controversial. While in the past they were commonly published by most journals, recently a number of prominent journals have...At present the publishing of case reports or case series involving small numbers of cases is controversial. While in the past they were commonly published by most journals, recently a number of prominent journals have either stopped publishing them or markedly reduced the numbers published. However, recently an increasing case is being made for their value and a number of new journals have been started devoted specifically to their publication. One of the arguments used for their value is their prominent role in rare diseases either in their recognition, full description or development of treatments. However this aspect has not been specifically studied. In this editorial this aspect is specifically examined using their role in neuroendocrine tumors as an example. Furthermore, the background of the controversy is briefly reviewed to better understand the context of this editorial.展开更多
Our previous results indicated that both the secreted and the intracellular form of full length and 1-97 N-terminal fragment of IGFBP-3 induce apoptosis in PC-3 human prostate cancer cells in an IGF-dependent and inde...Our previous results indicated that both the secreted and the intracellular form of full length and 1-97 N-terminal fragment of IGFBP-3 induce apoptosis in PC-3 human prostate cancer cells in an IGF-dependent and independent manner. This study was undertaken to delineate possible down-stream signaling pathways that are involved in this process. Intact IGFBP-3 and its N-terminal 1-97 fragments with or without a signal propeptide were fused to YFP and expressed in PC-3 human prostate cancer cells. In some cases, the putative IGF-binding site was presented in full length IGFBP-3 and its N-terminal fragment was also mutated. Extent of apoptosis was quantified using FACS. Up-regulation of total Stat-1 and activation of phospho-Stat-1 were shown by western blot. TGF-β signal was measured by luciferase reporter assay. Results from inhibitor studies indicated that both the Caspase 8 and caspase 9 pathways are involved in IGFBP-3 (non-secreted form) which induced apoptosis in PC-3 cells. Exogenous addition of IGFBP-3 to PC-3 cells increased Stat-1 protein expression/tyrosine phosphorylation. Interestingly, results also showed that knockdown of Stat-1 by siRNA potentiated the IGFBP-3 induced apoptosis in PC-3 cells. In addition, both full-length IGFBP-3 and its 1-97 Nterminal fragments inhibited TGF-β signaling in these cells. This is the first report that compares the signal transduction pathways involved in apoptotic pathways mediated by IGFBP-3 in PC-3 human prostate cancer cells. Non-secreted form of full length IGFBP-3 and its N-terminal fragments induced apoptosis in PC-3 cells via activation of caspase 8 and caspase 9. Although, only non-secreted form of IGFBP-3 is involved in inducing apoptosis in PC-3 cells via caspase 8 and caspase 9 activation pathways but both secreted and non-secreted forms of IGFBP-3 are involved in modulating Stat-1 and TGF-β pathways to induce apoptotic actions in PC-3 cells. Non-secreted intact IGFBP-3 and its N-terminal fragments induced apoptosis in PC-3 cells via activation of caspase 8 and caspase 9 pathways. Modulation in STAT-1 and TGF-β pathways may also be important for IGFBP-3 induced apoptosis in PC-3 cells in general. These studies clearly demonstrate that secreted and non-secreted FL and 1-97 N-terminal fragments induce apoptosis in PC-3 cells by regulating different mechanistic pathways.展开更多
Although the natural history of autoimmune hepatitis (AIH) has been characterized, little is known about patients who present asymptomatically. Consequently, whether they require immunosuppressive therapy with its ass...Although the natural history of autoimmune hepatitis (AIH) has been characterized, little is known about patients who present asymptomatically. Consequently, whether they require immunosuppressive therapy with its associated complications is unclear. To compare the natural history of asymptomatic AIH with symptomatic AIH, a large cohort of patients from a single center was examined. All patients with a clinical diagnosis of AIH were reassessed using the revised criteria of the International Autoimmune Hepatitis Group. Liver histology, response to therapy, and survival were assessed. Patients asymptomatic at presentation (n = 31) had lower serum aminotransferase, bilirubin, and immunoglobulin G (IgG) values at baseline. Half of the asymptomatic patients received no therapy, and their survival was no different from that of the total cohort. Ten-year survival was 80.0%(62.5%-97.5%) in the asymptomatic group and 83.8%(75.1%-92.6%) in the symptomatic patients (P = NS). Survival to liver-related endpoints at 10 years was similar in both groups: 89.5%(75.7%-100%) asymptomatic and 83.8%(75.1%-92.6%) symptomatic patients (P = NS). Patients with cirrhosis at baseline had poorer 10-year survival (61.9%[CI 44.9%-78.9%]) than those without cirrhosis at presentation (94.0%[CI 87.4%-100%]) (P = .003) regardless of whether they presented with symptoms or whether they received immunosuppressive therapy. In conclusion, patients with AIH who are asymptomatic at presentation have a good prognosis and may not require immunosuppressive therapy. Cirrhosis on initial liver biopsy portends a poor prognosis in all patients with AIH.展开更多
Parallel DNA helices with reverse WatsonCrick pairing have been described in several papers.It has been pointed out,however,that the parallel structures may also be in equilibrium with antiparallel WatsonCrick helices...Parallel DNA helices with reverse WatsonCrick pairing have been described in several papers.It has been pointed out,however,that the parallel structures may also be in equilibrium with antiparallel WatsonCrick helices due to their closely similar properties.To avoid the problem we have prepared and characterized DNA helices which are constrained to possess parallel polarity by two dC residues,or CC+clamps,at both the ends of AT oligomer chains.The residues are hemiprotonated below neutral pH,forming two stable CC+base pairs with three hydrogen bonds at each end of the helix.The physical properties of these constructs can then be used to calibrate those of duplexes having the same sequences but lacking the terminal C residues.Though recent studies indicate that dC acid selfstructures are fourstranded with intercalated bases,gel electrophoresis indicates that these structures are not present in the molecules described here.展开更多
AIM: To investigate whether assigning young, healthy and motivated lay volunteer partners("buddies") to adolescents with type 2 diabetes improves hemoglobin A1c(HbA 1c). METHODS: Adolescents with type 2 diab...AIM: To investigate whether assigning young, healthy and motivated lay volunteer partners("buddies") to adolescents with type 2 diabetes improves hemoglobin A1c(HbA 1c). METHODS: Adolescents with type 2 diabetes were randomized to partnering with a "buddy" or to conventional treatment. During the initial screening visit, which coincided with a routine outpatient diabetes clinic visit, patients with type 2 diabetes underwent a physical examination, detailed medical history, laboratory measurement of HbA 1c, and completed two questionnaires(Pediatric Quality of Life Inventory and Children's Depression Inventory) to assess their overall quality of life and the presence of depressive symptoms. Patients were then randomized to the intervention(the buddy system) or conventional treatment(standard care). All patients were scheduled to return for followup at 3- and 6-mo after their initial visit. Hb A1 c was determined at all visits(i.e., at screening and at the 3- and 6-mo follow-up visits) and quality of life and depressive symptoms were evaluated at the screening visit and were reassessed at the 6-mo visit. RESULTS: Ten adolescents, recruited from a pool of approximately 200 adolescents, enrolled over a twoyear time period, leading to premature termination of the study. In contrast, we easily recruited motivated lay volunteers. We found no change in HbA 1c from the initial to the 6-mo visit in either group, yet our small sample size limited systematic assessment of this outcome. Participants repeatedly missed clinic appointments, failed to conduct self-glucose-monitoring and rarely brought their glucometers to clinic visits. Total quality of life scores(72.6 ± 6.06) at screening were similar to previously reported scores in adolescents with type 2 diabetes(75.7 ± 15.0) and lower than scores reported in normal-weight(81.2 ± 0.9), overweight(83.5 ± 1.8), and obese youths without diabetes(78.5 ± 1.8) or in adolescents with type 1 diabetes(80.5 ± 13.1). Among adolescents who returned for their 6-mo visit, there were no differences in total quality of life scores(70.2 ± 9.18) between screening and follow-up.CONCLUSION: Our approach, effective in adults with type 2 diabetes, was unsuccessful among adolescents and emphasizes the need for innovative strategies for diabetes treatment in adolescent patients.展开更多
The incidence of obesity and diabetes has been increased with alarming rate in recent years and became a common problem around the globe including developing as well as in developed countries with incalculable social ...The incidence of obesity and diabetes has been increased with alarming rate in recent years and became a common problem around the globe including developing as well as in developed countries with incalculable social costs. Obesity and type 2 diabetes are two common co-morbidities occur together. Obesity and diabetes is closely associated with many diseases, osteoarthritis, hypertension, certain form of cancer, sleep-breathing disorders and coronary heart disease. Impacts of obesity and diabetes (insulin resistance) on arthritis have been seen in patients that we associated with combination of various factors like increased availability of high-energy foods, genetic susceptibility and decreased physical activity in modern society. Arthritis is becoming pandemic around the globe and its occurrence with obesity and diabetes has been observed more common than ever. Combination of these two chronic conditions makes these diseases more vulnerable for human health. Till now very limited information is established about the pathological and mechanistic correlation among these health ailments. In this review article we aimed to survey the literature covering the influence of obesity and diabetes on arthritis pathology and tried to establish correlation with these diseases.展开更多
Human hematopoiesis was evaluated using the techniques of controlled stem cell differentiation, two-dimensional gel electrophoresis-based proteomics, and functional genomics. We provide the first report that glia matu...Human hematopoiesis was evaluated using the techniques of controlled stem cell differentiation, two-dimensional gel electrophoresis-based proteomics, and functional genomics. We provide the first report that glia maturation factor gamma （GMFG） is a cytokine-responsive protein in erythropoietin-induced and granulocyte-colony stimulating factor-induced hematopoietic lineage development. Results from global functional genomics analysis indicate that GMFG possesses several other features： hematopoietic tissue-specific gene expression, a promoter concentrated with high-score hematopoiesis-specific transcription factors, and possible molecular coevolution with a rudimentary blood/immune system. On the basis of our findings, we hypothesize that GMFG is a hematopoietic-specific protein that may mediate the pluripotentiality and lineage commitment of human hematopoietic stem cells.展开更多
Criteria for diagnosing nephropathy and urothelial neoplasms induced by botanicals containing aristolochic acids(AAs) are well established. Highlights of recent research on AAs include mechanisms of AA intrarenal tran...Criteria for diagnosing nephropathy and urothelial neoplasms induced by botanicals containing aristolochic acids(AAs) are well established. Highlights of recent research on AAs include mechanisms of AA intrarenal transport and metabolism and vigorous debate on whether AAs may also cause liver cancers. Many other botanicals may also cause renal injury, but a generalized framework for diagnosing botanical-induced kidney injury(BIKI) is lacking. Based on what we have learnt about the wide spectrum of phenotypes of BIKI attributed to AAs and a recently published standardized phenotypic framework of drug-induced kidney disease, we propose that BIKI may be categorized into six phenotypes(acute kidney injury, tubular dysfunction, glomerular disorders, nephrolithiasis, chronic kidney disease, and neoplasms) and four mechanistic types(A, predictable;B, idiosyncratic;C, chronic;and D, delayed). We call for international cooperation assembling a task force to develop, refine, and regularly appraise an online BIKI database, documenting botanical use, phenotypes, mechanisms, and levels of evidence. Once established, such a database may be linked with electronic patient records and pharmacovigilance channels to generate alerts, guide clinical decision-making, direct future research, and support evidence-based regulation of herbal medicines and education of healthcare professionals and the public. Finally, to prevent BIKI, we propose that a proactive approach integrating the triad of botanicals, users, and stakeholders will be needed.展开更多
文摘Insulin-like growth factor binding protein-3 (IGFBP-3), a secretory protein, is the most abundant IGF binding protein present in human serum among all IGF binding proteins. IGFBP-3 shows decreased level of expression in cancerous cells but has been known to be present in significant amounts in normal or non-cancerous cells. IGFBP-3 can induce apoptosis in prostate cancer cells either in an IGF-dependent manner or independently of IGF binding. Although putative cell death specific Insulin-like growth factor binding protein-3 (IGFBP-3R) receptor(s) has recently been identified by which IGFBP-3 may induce its anti-tumor effects, IGFBP-3 has also been known to activate various downstream intracellular signaling molecules via a different mechanistic pathway. Stat-1 has been known to be one of the candidate molecules activated by IGFBP-3. IGFBP-3 can also inhibit Akt/IGF-1 survival pathway in MCF-7 breast cancer cells which ultimately leads to the induction of apoptosis in these cells. All these studies clearly demonstrate that IGFBP-3 regulates cell proliferation and promotes its pro-apoptotic effects in cancer cells in two different pathways: 1) sequester IGF-I to bind to IGF-I receptor to inhibit cell proliferation and induce apoptosis, 2) independent of IGF-I pathway, IGFBP-3 binds to some putative receptor and activate various downstream pro-apoptotic molecules involved in cell death.
基金Supported by Intramural Research Funds of NIDDK,NIH
文摘At present the publishing of case reports or case series involving small numbers of cases is controversial. While in the past they were commonly published by most journals, recently a number of prominent journals have either stopped publishing them or markedly reduced the numbers published. However, recently an increasing case is being made for their value and a number of new journals have been started devoted specifically to their publication. One of the arguments used for their value is their prominent role in rare diseases either in their recognition, full description or development of treatments. However this aspect has not been specifically studied. In this editorial this aspect is specifically examined using their role in neuroendocrine tumors as an example. Furthermore, the background of the controversy is briefly reviewed to better understand the context of this editorial.
文摘Our previous results indicated that both the secreted and the intracellular form of full length and 1-97 N-terminal fragment of IGFBP-3 induce apoptosis in PC-3 human prostate cancer cells in an IGF-dependent and independent manner. This study was undertaken to delineate possible down-stream signaling pathways that are involved in this process. Intact IGFBP-3 and its N-terminal 1-97 fragments with or without a signal propeptide were fused to YFP and expressed in PC-3 human prostate cancer cells. In some cases, the putative IGF-binding site was presented in full length IGFBP-3 and its N-terminal fragment was also mutated. Extent of apoptosis was quantified using FACS. Up-regulation of total Stat-1 and activation of phospho-Stat-1 were shown by western blot. TGF-β signal was measured by luciferase reporter assay. Results from inhibitor studies indicated that both the Caspase 8 and caspase 9 pathways are involved in IGFBP-3 (non-secreted form) which induced apoptosis in PC-3 cells. Exogenous addition of IGFBP-3 to PC-3 cells increased Stat-1 protein expression/tyrosine phosphorylation. Interestingly, results also showed that knockdown of Stat-1 by siRNA potentiated the IGFBP-3 induced apoptosis in PC-3 cells. In addition, both full-length IGFBP-3 and its 1-97 Nterminal fragments inhibited TGF-β signaling in these cells. This is the first report that compares the signal transduction pathways involved in apoptotic pathways mediated by IGFBP-3 in PC-3 human prostate cancer cells. Non-secreted form of full length IGFBP-3 and its N-terminal fragments induced apoptosis in PC-3 cells via activation of caspase 8 and caspase 9. Although, only non-secreted form of IGFBP-3 is involved in inducing apoptosis in PC-3 cells via caspase 8 and caspase 9 activation pathways but both secreted and non-secreted forms of IGFBP-3 are involved in modulating Stat-1 and TGF-β pathways to induce apoptotic actions in PC-3 cells. Non-secreted intact IGFBP-3 and its N-terminal fragments induced apoptosis in PC-3 cells via activation of caspase 8 and caspase 9 pathways. Modulation in STAT-1 and TGF-β pathways may also be important for IGFBP-3 induced apoptosis in PC-3 cells in general. These studies clearly demonstrate that secreted and non-secreted FL and 1-97 N-terminal fragments induce apoptosis in PC-3 cells by regulating different mechanistic pathways.
文摘Although the natural history of autoimmune hepatitis (AIH) has been characterized, little is known about patients who present asymptomatically. Consequently, whether they require immunosuppressive therapy with its associated complications is unclear. To compare the natural history of asymptomatic AIH with symptomatic AIH, a large cohort of patients from a single center was examined. All patients with a clinical diagnosis of AIH were reassessed using the revised criteria of the International Autoimmune Hepatitis Group. Liver histology, response to therapy, and survival were assessed. Patients asymptomatic at presentation (n = 31) had lower serum aminotransferase, bilirubin, and immunoglobulin G (IgG) values at baseline. Half of the asymptomatic patients received no therapy, and their survival was no different from that of the total cohort. Ten-year survival was 80.0%(62.5%-97.5%) in the asymptomatic group and 83.8%(75.1%-92.6%) in the symptomatic patients (P = NS). Survival to liver-related endpoints at 10 years was similar in both groups: 89.5%(75.7%-100%) asymptomatic and 83.8%(75.1%-92.6%) symptomatic patients (P = NS). Patients with cirrhosis at baseline had poorer 10-year survival (61.9%[CI 44.9%-78.9%]) than those without cirrhosis at presentation (94.0%[CI 87.4%-100%]) (P = .003) regardless of whether they presented with symptoms or whether they received immunosuppressive therapy. In conclusion, patients with AIH who are asymptomatic at presentation have a good prognosis and may not require immunosuppressive therapy. Cirrhosis on initial liver biopsy portends a poor prognosis in all patients with AIH.
文摘Parallel DNA helices with reverse WatsonCrick pairing have been described in several papers.It has been pointed out,however,that the parallel structures may also be in equilibrium with antiparallel WatsonCrick helices due to their closely similar properties.To avoid the problem we have prepared and characterized DNA helices which are constrained to possess parallel polarity by two dC residues,or CC+clamps,at both the ends of AT oligomer chains.The residues are hemiprotonated below neutral pH,forming two stable CC+base pairs with three hydrogen bonds at each end of the helix.The physical properties of these constructs can then be used to calibrate those of duplexes having the same sequences but lacking the terminal C residues.Though recent studies indicate that dC acid selfstructures are fourstranded with intercalated bases,gel electrophoresis indicates that these structures are not present in the molecules described here.
基金Supported by The Intramural Research Program of the National Institutes of Healththe National Institute of Diabetes,Digestive+2 种基金Kidney Diseases in collaboration with the Division of EndocrinologyDiabetes at the Children’s National Medical Center(Washington,DC)provided by the Endocrine Fellows Foundation Marilyn Fishman Grant for Diabetes Research
文摘AIM: To investigate whether assigning young, healthy and motivated lay volunteer partners("buddies") to adolescents with type 2 diabetes improves hemoglobin A1c(HbA 1c). METHODS: Adolescents with type 2 diabetes were randomized to partnering with a "buddy" or to conventional treatment. During the initial screening visit, which coincided with a routine outpatient diabetes clinic visit, patients with type 2 diabetes underwent a physical examination, detailed medical history, laboratory measurement of HbA 1c, and completed two questionnaires(Pediatric Quality of Life Inventory and Children's Depression Inventory) to assess their overall quality of life and the presence of depressive symptoms. Patients were then randomized to the intervention(the buddy system) or conventional treatment(standard care). All patients were scheduled to return for followup at 3- and 6-mo after their initial visit. Hb A1 c was determined at all visits(i.e., at screening and at the 3- and 6-mo follow-up visits) and quality of life and depressive symptoms were evaluated at the screening visit and were reassessed at the 6-mo visit. RESULTS: Ten adolescents, recruited from a pool of approximately 200 adolescents, enrolled over a twoyear time period, leading to premature termination of the study. In contrast, we easily recruited motivated lay volunteers. We found no change in HbA 1c from the initial to the 6-mo visit in either group, yet our small sample size limited systematic assessment of this outcome. Participants repeatedly missed clinic appointments, failed to conduct self-glucose-monitoring and rarely brought their glucometers to clinic visits. Total quality of life scores(72.6 ± 6.06) at screening were similar to previously reported scores in adolescents with type 2 diabetes(75.7 ± 15.0) and lower than scores reported in normal-weight(81.2 ± 0.9), overweight(83.5 ± 1.8), and obese youths without diabetes(78.5 ± 1.8) or in adolescents with type 1 diabetes(80.5 ± 13.1). Among adolescents who returned for their 6-mo visit, there were no differences in total quality of life scores(70.2 ± 9.18) between screening and follow-up.CONCLUSION: Our approach, effective in adults with type 2 diabetes, was unsuccessful among adolescents and emphasizes the need for innovative strategies for diabetes treatment in adolescent patients.
文摘The incidence of obesity and diabetes has been increased with alarming rate in recent years and became a common problem around the globe including developing as well as in developed countries with incalculable social costs. Obesity and type 2 diabetes are two common co-morbidities occur together. Obesity and diabetes is closely associated with many diseases, osteoarthritis, hypertension, certain form of cancer, sleep-breathing disorders and coronary heart disease. Impacts of obesity and diabetes (insulin resistance) on arthritis have been seen in patients that we associated with combination of various factors like increased availability of high-energy foods, genetic susceptibility and decreased physical activity in modern society. Arthritis is becoming pandemic around the globe and its occurrence with obesity and diabetes has been observed more common than ever. Combination of these two chronic conditions makes these diseases more vulnerable for human health. Till now very limited information is established about the pathological and mechanistic correlation among these health ailments. In this review article we aimed to survey the literature covering the influence of obesity and diabetes on arthritis pathology and tried to establish correlation with these diseases.
文摘Human hematopoiesis was evaluated using the techniques of controlled stem cell differentiation, two-dimensional gel electrophoresis-based proteomics, and functional genomics. We provide the first report that glia maturation factor gamma （GMFG） is a cytokine-responsive protein in erythropoietin-induced and granulocyte-colony stimulating factor-induced hematopoietic lineage development. Results from global functional genomics analysis indicate that GMFG possesses several other features： hematopoietic tissue-specific gene expression, a promoter concentrated with high-score hematopoiesis-specific transcription factors, and possible molecular coevolution with a rudimentary blood/immune system. On the basis of our findings, we hypothesize that GMFG is a hematopoietic-specific protein that may mediate the pluripotentiality and lineage commitment of human hematopoietic stem cells.
基金Kidney Research UK,Innovation China UK,European Union and the Intramural Research Program,NIDDK,NIH for funding of this important line of research
文摘Criteria for diagnosing nephropathy and urothelial neoplasms induced by botanicals containing aristolochic acids(AAs) are well established. Highlights of recent research on AAs include mechanisms of AA intrarenal transport and metabolism and vigorous debate on whether AAs may also cause liver cancers. Many other botanicals may also cause renal injury, but a generalized framework for diagnosing botanical-induced kidney injury(BIKI) is lacking. Based on what we have learnt about the wide spectrum of phenotypes of BIKI attributed to AAs and a recently published standardized phenotypic framework of drug-induced kidney disease, we propose that BIKI may be categorized into six phenotypes(acute kidney injury, tubular dysfunction, glomerular disorders, nephrolithiasis, chronic kidney disease, and neoplasms) and four mechanistic types(A, predictable;B, idiosyncratic;C, chronic;and D, delayed). We call for international cooperation assembling a task force to develop, refine, and regularly appraise an online BIKI database, documenting botanical use, phenotypes, mechanisms, and levels of evidence. Once established, such a database may be linked with electronic patient records and pharmacovigilance channels to generate alerts, guide clinical decision-making, direct future research, and support evidence-based regulation of herbal medicines and education of healthcare professionals and the public. Finally, to prevent BIKI, we propose that a proactive approach integrating the triad of botanicals, users, and stakeholders will be needed.
