Fibrous dysplasia(FD)is a rare,disabling skeletal disease for which there are no established treatments.Growing evidence supports inhibiting the osteoclastogenic factor receptor activator of nuclear kappa-B ligand(RAN...Fibrous dysplasia(FD)is a rare,disabling skeletal disease for which there are no established treatments.Growing evidence supports inhibiting the osteoclastogenic factor receptor activator of nuclear kappa-B ligand(RANKL)as a potential treatment strategy.In this study,we investigated the mechanisms underlying RANKL inhibition in FD tissue and its likely indirect effects on osteoprogenitors by evaluating human FD tissue pre-and post-treatment in a phase 2 clinical trial of denosumab(NCT03571191)and in murine in vivo and ex vivo preclinical models.Histological analysis of human and mouse tissue demonstrated increased osteogenic maturation,reduced cellularity,and reduced expression of the pathogenic Gαs variant in FD lesions after RANKL inhibition.RNA sequencing of human and mouse tissue supported these findings.The interaction between osteoclasts and mutant osteoprogenitors was further assessed in an ex vivo lesion model,which indicated that the proliferation of abnormal FD osteoprogenitors was dependent on osteoclasts.The results from this study demonstrated that,in addition to its expected antiosteoclastic effect,denosumab reduces FD lesion activity by decreasing FD cell proliferation and increasing osteogenic maturation,leading to increased bone formation within lesions.These findings highlight the unappreciated role of cellular crosstalk between osteoclasts and preosteoblasts/osteoblasts as a driver of FD pathology and demonstrate a novel mechanism of action of denosumab in the treatment of bone disease.展开更多
Purpose: Although controversial, assessment of epidermal growth factor receptor (EGFR) expression is required for the approved indications of Cetuximab in metastatic colorectal cancer (mCRC). With the objective of imp...Purpose: Although controversial, assessment of epidermal growth factor receptor (EGFR) expression is required for the approved indications of Cetuximab in metastatic colorectal cancer (mCRC). With the objective of improving patient selection, “ERBITUX-OUEST” study aimed at analyzing EGFR status in a large cohort of mCRC patients who received cetuximab without preliminary EGFR screening, and assessing the correlation between EGFR status and response to treatment retrospectively. Patients and methods: 332 patients treated with Irinotecan Cetuximab based regimen after progression on irinotecan or oxaliplatin therapy were included. EGFR status was assessed using three available immunohistochemistry (IHC) tests and in situ hybridization in case of negativity. Clinical outcomes of EGFR-positive and EGFR-non-detected (or considered as negative with at least one test) patients were compared. Results: Of the 332 samples centrally screened, 194 were classified as full-positive (i.e., EGFR-positive for all three tests), 86 as full-negative, and 52 as discordant. One third of the 131 negative samples with FDA approved test should be reclassified as positive with at least one of the two others tests. Regarding results from FDA approved test only, neither objective response rate (ORR), progression-free survival (PFS) nor overall survival (OS) differed significantly between EGFR-negative and EGFR-positive patients (P = 0.788, 0.326 and 0.888, respectively). Similarly, comparison of full-negative to other groups did not show any significant difference in terms of ORR (P = 0.507), PFS (P = 0.222) or OS (P = 0.686). Conclusion: These data strongly argue against mCRC patients selection for Cetuximab treatment based on EGFR expression as measured by currently available IHC technics.展开更多
Hepatitis B virus(HBV) infection is a global health problem. It is estimated there are more than 2 billion individuals exposed to the virus and 250 million are chronically infected. Hepatitis B is the cause of more th...Hepatitis B virus(HBV) infection is a global health problem. It is estimated there are more than 2 billion individuals exposed to the virus and 250 million are chronically infected. Hepatitis B is the cause of more than 600000 annual deaths due to cirrhosis and hepatocellular carcinoma. An effective vaccine exists and preventative initiatives center around universal vaccination especially in those at highest risk. Effective vaccination algorithms have led to a significant decline in the development of new infections and its devastating consequences. The vaccine is administered intramuscularly in three doses, with 95% showing long lasting serologic immunity. An additional fourth dose or a repeated higher dose three course regimen is given to those that fail to show immunity. Despite these additional regimens, some remain vulnerable to hepatitis B and are deemed nonresponders. Individuals with chronic disease states such as kidney disease, liver disease, diabetes mellitus, as well as those with a genetic predisposition, and those on immunomodulation therapy, have the highest likelihood of non-response. Various strategies have been developed to elicit an immune response in these individuals. These include increased vaccination dose, intradermal administration, alternative adjuvants, alternative routes of administration, co-administration with other vaccines, and other novel therapies. These alternative strategies can show improved response and lasting immunity. In summary, HBV vaccination is a major advance of modern medicine and all individuals at risk should be sought and vaccinated with subsequent adequate titers demonstrated.展开更多
Background: The impact of perioperative intravenous fluid administration on surgical outcomes has been documented in literature, but not specifically studied in the context of hepato-pancreato-biliary(HPB) surgery. Th...Background: The impact of perioperative intravenous fluid administration on surgical outcomes has been documented in literature, but not specifically studied in the context of hepato-pancreato-biliary(HPB) surgery. This study aimed to investigate the impact of postoperative intravenous fluid administration on intensive care unit(ICU), in this subgroup of patients. Methods: A single-center retrospective cohort of 241 HPB patients was assessed, focusing on intravenous fluid administration in ICU, during the first 24 h. Intravenous fluid variables were compared to hospital stay and postoperative complications. Data were assessed using Spearman's correlation test for bivariate correlations and logistic regression for multivariate analysis. Results: The median volume of intravenous fluid administered in the first 24 h postoperatively was 4380 mL, of which 2200 mL was crystalloid, 1500 mL colloid and 680 mL "other" fluid. Patients with one or more complications had a higher median total intravenous fluid input(4790 vs. 4300 mL), higher colloid volume(20 0 0 vs. 150 0 mL), lower urine output(1595 vs. 1900 mL) and greater overall fluid balance( + 3040 vs. + 2553 mL) than those without complications. There were correlations between total intravenous fluid volume administered( r = 0.278, P < 0.001), intravenous colloid input( r = 0.278, P < 0.001), urine output( r =-0.295, P < 0.001), positive fluid balance( r = 0.344, P < 0.001) and length of hospital stay. Logistic regression model was constructed to predict the occurrence of one or more complications; total intravenous fluid volume and overall fluid balance were both independent significant predictors(OR = 2.463, P = 0.007; OR = 1.001, P = 0.011; respectively). Conclusions: Administration of high volumes of intravenous fluids in the first 24 hours post-HPB surgery, along with higher positive fluid balance is associated with a higher rate of complications and longer hospital stay. Moreover, lower urine output is associated with longer hospital stay. Whether these are the cause of complications or the result of them remains unclear.展开更多
It is now widely suggested that people who are dependent on nicotine should switch from ordinary tobacco smoking to alternative products, which at least reduce the overall harm from smoking. A number of alternatives a...It is now widely suggested that people who are dependent on nicotine should switch from ordinary tobacco smoking to alternative products, which at least reduce the overall harm from smoking. A number of alternatives are now popular, including electronic cigarettes and heatsticks. In this work comparative analysis of the smoke/aerosol emission from 3R4F standard cigarettes and iQOS heatsticks was undertaken. For this, gas chromatography-mass spectrometry (GC-MS) analysis was applied, to measure the non-volatile compounds of smoke/aerosol emission from individual samples, with the specific aim to determine their content of nicotine and selected other main components. All measurement data were collected under the Health Canada Intense (HCI) puffing regime. The most relevant findings of the present investigation can be summarized as follows. First, the number of measured aerosol components in the iQOS samples, with respect to those of 3R4F samples, was significantly lower (notably 37 versus 12 components). Second, the analysis of the iQOS and 3R4F GC-MS chromatographic fingerprints indicated a non-nicotine global component reduction (number and areas excluding nicotine) of larger than 80% for the iQOS samples in comparison to 3R4F samples. Third, the nicotine content of the iQOS aerosol was less than half that contained in the 3R4F smoke. The results from the present investigation indicate that—except for nicotine—smokers are exposed to a largely reduced number and amount of non-volatile, non-nicotine components in the iQOS heatstick aerosol, in comparison to those in the 3R4F cigarette smoke.展开更多
Editor’s Note:The Vermont School of Colombia is one of the few middle schools in the country that teaches Chinese as the second foreign language.In early June 2013,a 77-member student delegation came to China to atte...Editor’s Note:The Vermont School of Colombia is one of the few middle schools in the country that teaches Chinese as the second foreign language.In early June 2013,a 77-member student delegation came to China to attend a summer camp jointly hosted by the Chinese People’s Association for Friendship with Foreign Countries(CPAFFC)and the North China University of Technology(NCUT).The following is an essay written in Chinese by a Colombian student recording his tour in China.展开更多
基金supported by the Intramural Research Program of the NIDCR, NICHD,and Clinical Center, National Institutes of Healthsupported by Amgen, Inc.+2 种基金supported in part by the NIDCR Genomics and Computational Biology Core:ZIC DC000086Veterinary Resources Core:ZIC DE000740-05supported by the Research on Women’s Health(ORWH)through the Bench to Bedside Program award#884515.
文摘Fibrous dysplasia(FD)is a rare,disabling skeletal disease for which there are no established treatments.Growing evidence supports inhibiting the osteoclastogenic factor receptor activator of nuclear kappa-B ligand(RANKL)as a potential treatment strategy.In this study,we investigated the mechanisms underlying RANKL inhibition in FD tissue and its likely indirect effects on osteoprogenitors by evaluating human FD tissue pre-and post-treatment in a phase 2 clinical trial of denosumab(NCT03571191)and in murine in vivo and ex vivo preclinical models.Histological analysis of human and mouse tissue demonstrated increased osteogenic maturation,reduced cellularity,and reduced expression of the pathogenic Gαs variant in FD lesions after RANKL inhibition.RNA sequencing of human and mouse tissue supported these findings.The interaction between osteoclasts and mutant osteoprogenitors was further assessed in an ex vivo lesion model,which indicated that the proliferation of abnormal FD osteoprogenitors was dependent on osteoclasts.The results from this study demonstrated that,in addition to its expected antiosteoclastic effect,denosumab reduces FD lesion activity by decreasing FD cell proliferation and increasing osteogenic maturation,leading to increased bone formation within lesions.These findings highlight the unappreciated role of cellular crosstalk between osteoclasts and preosteoblasts/osteoblasts as a driver of FD pathology and demonstrate a novel mechanism of action of denosumab in the treatment of bone disease.
文摘Purpose: Although controversial, assessment of epidermal growth factor receptor (EGFR) expression is required for the approved indications of Cetuximab in metastatic colorectal cancer (mCRC). With the objective of improving patient selection, “ERBITUX-OUEST” study aimed at analyzing EGFR status in a large cohort of mCRC patients who received cetuximab without preliminary EGFR screening, and assessing the correlation between EGFR status and response to treatment retrospectively. Patients and methods: 332 patients treated with Irinotecan Cetuximab based regimen after progression on irinotecan or oxaliplatin therapy were included. EGFR status was assessed using three available immunohistochemistry (IHC) tests and in situ hybridization in case of negativity. Clinical outcomes of EGFR-positive and EGFR-non-detected (or considered as negative with at least one test) patients were compared. Results: Of the 332 samples centrally screened, 194 were classified as full-positive (i.e., EGFR-positive for all three tests), 86 as full-negative, and 52 as discordant. One third of the 131 negative samples with FDA approved test should be reclassified as positive with at least one of the two others tests. Regarding results from FDA approved test only, neither objective response rate (ORR), progression-free survival (PFS) nor overall survival (OS) differed significantly between EGFR-negative and EGFR-positive patients (P = 0.788, 0.326 and 0.888, respectively). Similarly, comparison of full-negative to other groups did not show any significant difference in terms of ORR (P = 0.507), PFS (P = 0.222) or OS (P = 0.686). Conclusion: These data strongly argue against mCRC patients selection for Cetuximab treatment based on EGFR expression as measured by currently available IHC technics.
文摘Hepatitis B virus(HBV) infection is a global health problem. It is estimated there are more than 2 billion individuals exposed to the virus and 250 million are chronically infected. Hepatitis B is the cause of more than 600000 annual deaths due to cirrhosis and hepatocellular carcinoma. An effective vaccine exists and preventative initiatives center around universal vaccination especially in those at highest risk. Effective vaccination algorithms have led to a significant decline in the development of new infections and its devastating consequences. The vaccine is administered intramuscularly in three doses, with 95% showing long lasting serologic immunity. An additional fourth dose or a repeated higher dose three course regimen is given to those that fail to show immunity. Despite these additional regimens, some remain vulnerable to hepatitis B and are deemed nonresponders. Individuals with chronic disease states such as kidney disease, liver disease, diabetes mellitus, as well as those with a genetic predisposition, and those on immunomodulation therapy, have the highest likelihood of non-response. Various strategies have been developed to elicit an immune response in these individuals. These include increased vaccination dose, intradermal administration, alternative adjuvants, alternative routes of administration, co-administration with other vaccines, and other novel therapies. These alternative strategies can show improved response and lasting immunity. In summary, HBV vaccination is a major advance of modern medicine and all individuals at risk should be sought and vaccinated with subsequent adequate titers demonstrated.
文摘Background: The impact of perioperative intravenous fluid administration on surgical outcomes has been documented in literature, but not specifically studied in the context of hepato-pancreato-biliary(HPB) surgery. This study aimed to investigate the impact of postoperative intravenous fluid administration on intensive care unit(ICU), in this subgroup of patients. Methods: A single-center retrospective cohort of 241 HPB patients was assessed, focusing on intravenous fluid administration in ICU, during the first 24 h. Intravenous fluid variables were compared to hospital stay and postoperative complications. Data were assessed using Spearman's correlation test for bivariate correlations and logistic regression for multivariate analysis. Results: The median volume of intravenous fluid administered in the first 24 h postoperatively was 4380 mL, of which 2200 mL was crystalloid, 1500 mL colloid and 680 mL "other" fluid. Patients with one or more complications had a higher median total intravenous fluid input(4790 vs. 4300 mL), higher colloid volume(20 0 0 vs. 150 0 mL), lower urine output(1595 vs. 1900 mL) and greater overall fluid balance( + 3040 vs. + 2553 mL) than those without complications. There were correlations between total intravenous fluid volume administered( r = 0.278, P < 0.001), intravenous colloid input( r = 0.278, P < 0.001), urine output( r =-0.295, P < 0.001), positive fluid balance( r = 0.344, P < 0.001) and length of hospital stay. Logistic regression model was constructed to predict the occurrence of one or more complications; total intravenous fluid volume and overall fluid balance were both independent significant predictors(OR = 2.463, P = 0.007; OR = 1.001, P = 0.011; respectively). Conclusions: Administration of high volumes of intravenous fluids in the first 24 hours post-HPB surgery, along with higher positive fluid balance is associated with a higher rate of complications and longer hospital stay. Moreover, lower urine output is associated with longer hospital stay. Whether these are the cause of complications or the result of them remains unclear.
文摘It is now widely suggested that people who are dependent on nicotine should switch from ordinary tobacco smoking to alternative products, which at least reduce the overall harm from smoking. A number of alternatives are now popular, including electronic cigarettes and heatsticks. In this work comparative analysis of the smoke/aerosol emission from 3R4F standard cigarettes and iQOS heatsticks was undertaken. For this, gas chromatography-mass spectrometry (GC-MS) analysis was applied, to measure the non-volatile compounds of smoke/aerosol emission from individual samples, with the specific aim to determine their content of nicotine and selected other main components. All measurement data were collected under the Health Canada Intense (HCI) puffing regime. The most relevant findings of the present investigation can be summarized as follows. First, the number of measured aerosol components in the iQOS samples, with respect to those of 3R4F samples, was significantly lower (notably 37 versus 12 components). Second, the analysis of the iQOS and 3R4F GC-MS chromatographic fingerprints indicated a non-nicotine global component reduction (number and areas excluding nicotine) of larger than 80% for the iQOS samples in comparison to 3R4F samples. Third, the nicotine content of the iQOS aerosol was less than half that contained in the 3R4F smoke. The results from the present investigation indicate that—except for nicotine—smokers are exposed to a largely reduced number and amount of non-volatile, non-nicotine components in the iQOS heatstick aerosol, in comparison to those in the 3R4F cigarette smoke.
文摘Editor’s Note:The Vermont School of Colombia is one of the few middle schools in the country that teaches Chinese as the second foreign language.In early June 2013,a 77-member student delegation came to China to attend a summer camp jointly hosted by the Chinese People’s Association for Friendship with Foreign Countries(CPAFFC)and the North China University of Technology(NCUT).The following is an essay written in Chinese by a Colombian student recording his tour in China.
