Background:Thimerosal is a mercury-containing preservative widely used in vaccines.This study aimed to investigate its potential antitumor effects and mechanisms in solid malignancies,particularly colorectal cancer(CR...Background:Thimerosal is a mercury-containing preservative widely used in vaccines.This study aimed to investigate its potential antitumor effects and mechanisms in solid malignancies,particularly colorectal cancer(CRC)and melanoma.Methods:A combination of in vitro and in vivo approaches was employed.Cell proliferation,apoptosis,migration,and invasion were assessed using Cell Counting Kit-8(CCK-8),colony formation,ATP viability,Western blotting,flow cytometry,wound-healing and Transwell assays.Subcutaneous,lung metastases,and Azoxymethane/Dextran Sulfate Sodium Salt(AOM/DSS)-induced colitis-associated CRC models were established to examine antitumor efficacy and safety.The functional role of mercury ions was validated using structural analogues.Mechanistic studies included RNA sequencing,Western blot,and immunohistochemical analysis of CD8^(+)T cell infiltration.The synergistic effect with programmed cell death protein 1(PD-1)antibody therapy was also evaluated.Results:Thimerosal potently inhibited tumor growth(with IC50 values ranging from 0.1 to 1μM in vitro)and significantly prolonged survival without overt toxicity in vivo.Mechanistically,mercury ions were identified as critical functional sites mediating Thimerosal’s antitumor effects.Specifically,Thimerosal inhibited the phosphorylation of Janus kinase 1(JAK1)and signal transducer and activator of transcription 3(STAT3).Furthermore,it enhanced the infiltration of CD8^(+)T cells into the tumor microenvironment and synergistically augmented the efficacy of anti-PD-1 therapy.Conclusion:Thimerosal exerts dual antitumor roles by direct JAK1/STAT3 inhibition and immune modulation via CD8^(+)T cell recruitment.It represents a promising repurposed drug and immunotherapeutic adjuvant for CRC and melanoma.展开更多
Background:Autism spectrum disorder(ASD)is defined by standardized criteria of qualitative impairments in social interaction,qualitative impairments in communication,and restricted and stereotyped patterns of behavior...Background:Autism spectrum disorder(ASD)is defined by standardized criteria of qualitative impairments in social interaction,qualitative impairments in communication,and restricted and stereotyped patterns of behavior,interests,and activities.A significant number of children diagnosed with ASD suffer a loss of previously-acquired skills,which is suggestive of neurodegeneration or a type of progressive encephalopathy with an etiological pathogenic basis occurring after birth.To date,the etiology of ASD remains under debate,however,many studies suggest toxicity,especially from mercury(Hg),in individuals diagnosed with an ASD.The present study evaluated concerns about the toxic effects of organic-Hg exposure from Thimerosal(49.55%Hg by weight)in childhood vaccines by conducting a two-phased(hypothesis generating/hypothesis testing)study with documented exposure to varying levels of Thimerosal from vaccinations.Methods:A hypothesis generating cohort study was undertaken to evaluate the relationship between exposure to organic-Hg from a Thimerosal-containing Diphtheria-Tetanus-acellular-Pertussis(DTaP)vaccine in comparison to a Thimerosal-free DTaP vaccine administered,from 1998 through 2000,for the risk of ASD as reported in the Vaccine Adverse Event Reporting System(VAERS)database(phase I).A hypothesis testing case–control study was undertaken to evaluate the relationship between organic-Hg exposure from Thimerosal-containing hepatitis B vaccines administered at specific intervals in the first six months of life among cases diagnosed with an ASD and controls born between 1991 through 1999 in the Vaccine Safety Datalink(VSD)database(phase II).Results:In phase I,it was observed that there was a significantly increased risk ratio for the incidence of ASD reported following the Thimerosal-containing DTaP vaccine in comparison to the Thimerosal-free DTaP vaccine.In phase II,it was observed that cases diagnosed with an ASD were significantly more likely than controls to receive increased organic-Hg from Thimerosal-containing hepatitis B vaccine administered within the first,second,and sixth month of life.Conclusions:Routine childhood vaccination is an important public health tool to reduce the morbidity and mortality associated with infectious diseases,but the present study provides new epidemiological evidence supporting an association between increasing organic-Hg exposure from Thimerosal-containing childhood vaccines and the subsequent risk of an ASD diagnosis.展开更多
When any type of product has been ordered to be removed from the marketplace by a governmental regulatory body, that action is a powerful indicator that the product has been determined to be unsafe for further use, th...When any type of product has been ordered to be removed from the marketplace by a governmental regulatory body, that action is a powerful indicator that the product has been determined to be unsafe for further use, thereby branding the product as defective and opening up the possibility of product liability litigation. When the product is a drug or medical device, it is especially serious since the possibility of personal injury (acute and/or chronic) or death may occur. Needless to say, in these situations, product injury litigation will almost surely follow. We review the definition and requisite claims needed to establish drug product liability, and the role that the medical literature, clinical trial data, and even experimental research data can play in product (drug)-injury litigation. We show how each of these resources played a significant role in two well-known cases: Fen-Phen and thimerosal. The ultimate goal of such knowledge is to make better informed decisions about drug safety.展开更多
Background: The objective of this study is to determine whether analyze of the infant’s pain associated with diphtheria-pertussis-tetanus (DPT) immunization is useful for vaccination in children. It is not known whet...Background: The objective of this study is to determine whether analyze of the infant’s pain associated with diphtheria-pertussis-tetanus (DPT) immunization is useful for vaccination in children. It is not known whether the immunization pain can be prevented with the adequate choice of DPT vaccines among several manufacturers in Japan. Further, it is not clear whether the difference of the reaction during vaccination between gender and age. Design: Three manufacturer’s Japanese DPT vaccines were used in this study. The parents assessed their infant’s pain on a modified visual analogue scale (MVAS), the start of the crying and total crying time during the immunization. Results: The A manufacturer’s DPT vaccine was significantly lower on the proportion of crying, the duration of crying and MVAS score than the other two manufacturer’s DPT vaccines. The proportion of crying, the duration of crying and MVAS score was lower in the boy than in the girl. On the other hand, it had not found the difference of their reactions with age. Conclusions: Our studies have found that the adequate choice of DPT vaccine decreased vaccination pain. The studies also indicate that some tendencies with vaccinations were shown in children. To consider these tendencies was useful in performing less painful vaccination.展开更多
基金supported by the National Natural Science Foundation of China(82441036)Ganzhou Municipal Science and Technology Project(2022-RC1342)+3 种基金Guangdong Basic and Applied Basic Research Foundation(2022B1515130004)Key-Area Research and Development Program of Guangdong Province(2019B020234003)Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Cancer(2020B121201004)Open Project Fund Project of Guangdong Academy of Medical Sciences(YKY-KF202210).
文摘Background:Thimerosal is a mercury-containing preservative widely used in vaccines.This study aimed to investigate its potential antitumor effects and mechanisms in solid malignancies,particularly colorectal cancer(CRC)and melanoma.Methods:A combination of in vitro and in vivo approaches was employed.Cell proliferation,apoptosis,migration,and invasion were assessed using Cell Counting Kit-8(CCK-8),colony formation,ATP viability,Western blotting,flow cytometry,wound-healing and Transwell assays.Subcutaneous,lung metastases,and Azoxymethane/Dextran Sulfate Sodium Salt(AOM/DSS)-induced colitis-associated CRC models were established to examine antitumor efficacy and safety.The functional role of mercury ions was validated using structural analogues.Mechanistic studies included RNA sequencing,Western blot,and immunohistochemical analysis of CD8^(+)T cell infiltration.The synergistic effect with programmed cell death protein 1(PD-1)antibody therapy was also evaluated.Results:Thimerosal potently inhibited tumor growth(with IC50 values ranging from 0.1 to 1μM in vitro)and significantly prolonged survival without overt toxicity in vivo.Mechanistically,mercury ions were identified as critical functional sites mediating Thimerosal’s antitumor effects.Specifically,Thimerosal inhibited the phosphorylation of Janus kinase 1(JAK1)and signal transducer and activator of transcription 3(STAT3).Furthermore,it enhanced the infiltration of CD8^(+)T cells into the tumor microenvironment and synergistically augmented the efficacy of anti-PD-1 therapy.Conclusion:Thimerosal exerts dual antitumor roles by direct JAK1/STAT3 inhibition and immune modulation via CD8^(+)T cell recruitment.It represents a promising repurposed drug and immunotherapeutic adjuvant for CRC and melanoma.
基金This study was financially supported by the Dwoskin Family Foundation and the Selz Foundation.
文摘Background:Autism spectrum disorder(ASD)is defined by standardized criteria of qualitative impairments in social interaction,qualitative impairments in communication,and restricted and stereotyped patterns of behavior,interests,and activities.A significant number of children diagnosed with ASD suffer a loss of previously-acquired skills,which is suggestive of neurodegeneration or a type of progressive encephalopathy with an etiological pathogenic basis occurring after birth.To date,the etiology of ASD remains under debate,however,many studies suggest toxicity,especially from mercury(Hg),in individuals diagnosed with an ASD.The present study evaluated concerns about the toxic effects of organic-Hg exposure from Thimerosal(49.55%Hg by weight)in childhood vaccines by conducting a two-phased(hypothesis generating/hypothesis testing)study with documented exposure to varying levels of Thimerosal from vaccinations.Methods:A hypothesis generating cohort study was undertaken to evaluate the relationship between exposure to organic-Hg from a Thimerosal-containing Diphtheria-Tetanus-acellular-Pertussis(DTaP)vaccine in comparison to a Thimerosal-free DTaP vaccine administered,from 1998 through 2000,for the risk of ASD as reported in the Vaccine Adverse Event Reporting System(VAERS)database(phase I).A hypothesis testing case–control study was undertaken to evaluate the relationship between organic-Hg exposure from Thimerosal-containing hepatitis B vaccines administered at specific intervals in the first six months of life among cases diagnosed with an ASD and controls born between 1991 through 1999 in the Vaccine Safety Datalink(VSD)database(phase II).Results:In phase I,it was observed that there was a significantly increased risk ratio for the incidence of ASD reported following the Thimerosal-containing DTaP vaccine in comparison to the Thimerosal-free DTaP vaccine.In phase II,it was observed that cases diagnosed with an ASD were significantly more likely than controls to receive increased organic-Hg from Thimerosal-containing hepatitis B vaccine administered within the first,second,and sixth month of life.Conclusions:Routine childhood vaccination is an important public health tool to reduce the morbidity and mortality associated with infectious diseases,but the present study provides new epidemiological evidence supporting an association between increasing organic-Hg exposure from Thimerosal-containing childhood vaccines and the subsequent risk of an ASD diagnosis.
文摘When any type of product has been ordered to be removed from the marketplace by a governmental regulatory body, that action is a powerful indicator that the product has been determined to be unsafe for further use, thereby branding the product as defective and opening up the possibility of product liability litigation. When the product is a drug or medical device, it is especially serious since the possibility of personal injury (acute and/or chronic) or death may occur. Needless to say, in these situations, product injury litigation will almost surely follow. We review the definition and requisite claims needed to establish drug product liability, and the role that the medical literature, clinical trial data, and even experimental research data can play in product (drug)-injury litigation. We show how each of these resources played a significant role in two well-known cases: Fen-Phen and thimerosal. The ultimate goal of such knowledge is to make better informed decisions about drug safety.
文摘Background: The objective of this study is to determine whether analyze of the infant’s pain associated with diphtheria-pertussis-tetanus (DPT) immunization is useful for vaccination in children. It is not known whether the immunization pain can be prevented with the adequate choice of DPT vaccines among several manufacturers in Japan. Further, it is not clear whether the difference of the reaction during vaccination between gender and age. Design: Three manufacturer’s Japanese DPT vaccines were used in this study. The parents assessed their infant’s pain on a modified visual analogue scale (MVAS), the start of the crying and total crying time during the immunization. Results: The A manufacturer’s DPT vaccine was significantly lower on the proportion of crying, the duration of crying and MVAS score than the other two manufacturer’s DPT vaccines. The proportion of crying, the duration of crying and MVAS score was lower in the boy than in the girl. On the other hand, it had not found the difference of their reactions with age. Conclusions: Our studies have found that the adequate choice of DPT vaccine decreased vaccination pain. The studies also indicate that some tendencies with vaccinations were shown in children. To consider these tendencies was useful in performing less painful vaccination.
