Treatment of advanced hepatocellular carcinoma remains unsatisfying and so far only prognostic biomarkers like α-fetoprotein have been established. No clear predictive biomarker is currently available for standard of...Treatment of advanced hepatocellular carcinoma remains unsatisfying and so far only prognostic biomarkers like α-fetoprotein have been established. No clear predictive biomarker is currently available for standard of care therapies, including targeted therapies like sorafenib. Novel therapeutic options like immune checkpoint inhibitors may pose new challenges to identification and validation of such markers. Currently, PD-L1 expression via immunohistochemistry and tumor mutational burden via next-generation sequencing are explored as predictive biomarkers for these novel treatments. Limited tissue availability due to lack of biopsies still restricts the use of tissue based approaches. Novel methods exploring circulating or cell free nucleic acids(DNA, RNA or miRNAcontaining exosomes) could provide a new opportunity to establish predictive biomarkers. Epigenetic profiling and next-generation sequencing approaches from liquid biopsies are under development. Sample size, etiologic and geographical background need to be carefully addressed in such studies to achieve meaningful results that could be translated into clinical practice. Proteomics, metabolomics and molecular imaging are further emerging technologies.展开更多
BACKGROUND Gastrointestinal bleeding(GIB)is a common and potentially life-threatening clinical event.To date,the literature on the long-term global epidemiology of GIB has not been systematically reviewed.AIM To syste...BACKGROUND Gastrointestinal bleeding(GIB)is a common and potentially life-threatening clinical event.To date,the literature on the long-term global epidemiology of GIB has not been systematically reviewed.AIM To systematically review the published literature on the worldwide epidemiology of upper and lower GIB.METHODS EMBASE®and MEDLINE were queried from 01 January 1965 to September 17,2019 to identify population-based studies reporting incidence,mortality,or casefatality rates of upper GIB(UGIB)or lower GIB(LGIB)in the general adult population,worldwide.Relevant outcome data were extracted and summarized(including data on rebleeding following initial occurrence of GIB when available).All included studies were assessed for risk of bias based upon reporting guidelines.RESULTS Of 4203 retrieved database hits,41 studies were included,comprising a total of around 4.1 million patients with GIB worldwide from 1980–2012.Thirty-three studies reported rates for UGIB,four for LGIB,and four presented data on both.Incidence rates ranged from 15.0 to 172.0/100000 person-years for UGIB,and from 20.5 to 87.0/100000 person-years for LGIB.Thirteen studies reported on temporal trends,generally showing an overall decline in UGIB incidence over time,although a slight increase between 2003 and 2005 followed by a decline was shown in 5/13 studies.GIB-related mortality data were available from six studies for UGIB,with rates ranging from 0.9 to 9.8/100000 person-years,and from three studies for LGIB,with rates ranging from 0.8 to 3.5/100000 person-years.Casefatality rate ranged from 0.7%to 4.8%for UGIB and 0.5%to 8.0%for LGIB.Rates of rebleeding ranged from 7.3%to 32.5%for UGIB and from 6.7%to 13.5%for LGIB.Two main areas of potential bias were the differences in the operational GIB definition used and inadequate information on how missing data were handled.CONCLUSION Wide variation was seen in estimates of GIB epidemiology,likely due to high heterogeneity between studies however,UGIB showed a decreasing trend over the years.Epidemiological data were more widely available for UGIB than for LGIB.展开更多
Hepatocellular carcinoma(HCC)remains a global medical burden with rising incidence due to chronic viral hepatitis and non-alcoholic fatty liver diseases.Treatment of advanced disease stages is still unsatisfying.Besid...Hepatocellular carcinoma(HCC)remains a global medical burden with rising incidence due to chronic viral hepatitis and non-alcoholic fatty liver diseases.Treatment of advanced disease stages is still unsatisfying.Besides first and second generation tyrosine kinase inhibitors,immune checkpoint inhibitors have become central for the treatment of HCC.New modalities like epigenetic therapy using histone deacetylase inhibitors(HDACi)and cell therapy approaches with chimeric antigen receptor T cells(CAR-T cells)are currently under investigation in clinical trials.Development of such novel drugs is closely linked to the availability and improvement of novel preclinical and animal models and the identification of predictive biomarkers.The current status of treatment options for advanced HCC,emerging novel therapeutic approaches and different preclinical models for HCC drug discovery and development are reviewed here.展开更多
Hypromellose acetate succinate(HPMCAS) microparticles containing the poorly-water soluble drug celecoxib(CEL) were prepared by electrospraying intended for oral drug delivery. Various solvent mixtures with different s...Hypromellose acetate succinate(HPMCAS) microparticles containing the poorly-water soluble drug celecoxib(CEL) were prepared by electrospraying intended for oral drug delivery. Various solvent mixtures with different solubility for CEL and HPMCAS were used to induce changes in the polymer structural conformation of the microparticles. The performance of the prepared microparticles was evaluated by studying the solid state from, particle size and morphology, radial drug distribution and drug release. CEL was amorphous in all electrosprayed HPMCAS microparticles. The particle size and morphology was dependent on the solubility of HPMCAS in the solvent mixture used with poorer solvents resulting in smaller microparticles with rougher appearance. The CEL distribution on the particles surface was relatively homogeneous and similar for all microparticles. Drug release from the microparticles was observed at a higher rate depending on the solubility of HPMCAS in the solvent used for electrospraying, and in all cases an at least 4-fold higher rate was observed compared with the crystalline drug. Drug precipitation from the supersaturated solution was inhibited by HPMCAS for all microparticles based on its parachute effect while crystalline CEL did not reach supersaturation. This study demonstrated that electrospraying can be used to produce microparticles with tailored properties for pharmaceutical application by adjusting solvent selection.展开更多
An improvement in pancreatic cancer treatment represents an urgent medical goal. Late diagnosis and high intrinsic resistance to conventional chemotherapy has led to a dismal overall prognosis that has remained unchan...An improvement in pancreatic cancer treatment represents an urgent medical goal. Late diagnosis and high intrinsic resistance to conventional chemotherapy has led to a dismal overall prognosis that has remained unchanged during the past decades. Increasing knowledge about the molecular pathogenesis of the disease has shown that genetic alterations, such as mutations of K-ras, and especially epigenetic dysregulation of tumor-associated genes, such as silencing of the tumor suppressor p16<sup>ink4a</sup>, are hallmarks of pancreatic cancer. Here, we describe genes that are commonly affected by epigenetic dysregulation in pancreatic cancer via DNA methylation, histone acetylation or miRNA (microRNA) expression, and review the implications on pancreatic cancer biology such as epithelial-mesenchymal transition, morphological pattern formation, or cancer stem cell regulation during carcinogenesis from PanIN (pancreatic intraepithelial lesions) to invasive cancer and resistance development. Epigenetic drugs, such as DNA methyltransferases or histone deactylase inhibitors, have shown promising preclinical results in pancreatic cancer and are currently in early phases of clinical development. Combinations of epigenetic drugs with established cytotoxic drugs or targeted therapies are promising approaches to improve the poor response and survival rate of pancreatic cancer patients.展开更多
The deletion of the C-terminal arginine of the anaphylatoxin protein C5a reduces it receptor binding affinity.Understanding how C-terminal arginine affects the structure and bioactivity of C5a is important for the dev...The deletion of the C-terminal arginine of the anaphylatoxin protein C5a reduces it receptor binding affinity.Understanding how C-terminal arginine affects the structure and bioactivity of C5a is important for the development of C5a C-terminal mimics as drug candidates.Herein,we report the total chemical synthesis of rat C5a and its D-enantiomer with its C-terminal arginine deleted,namely L-rC5a-desArg and D-rC5a-desArg.The structure of rC5a-desArg was then determined by racemic crystallography for the first time.The C-terminal residues of rC5a-Arg were found to expand from the fourth helix in a continuous helical confo rmation.This C-terminal conformation is significantly different from that of the previously reported full-length of C5a,indicating that the deletion of C-terminal arginine residue could result in the destruction of a positively charged surface formed by two adjacent Arg residues in C5a.展开更多
BACKGROUND Data on non-drug related risk-factors for gastrointestinal bleeding(GIB)in the general population are limited,especially for life-style factors,clinical measurements and laboratory parameters.AIM To identif...BACKGROUND Data on non-drug related risk-factors for gastrointestinal bleeding(GIB)in the general population are limited,especially for life-style factors,clinical measurements and laboratory parameters.AIM To identify and investigate non-drug risk factors for major GIB in the general population of Finland.METHODS We performed a retrospective cohort study using data from the FINRISK health examination surveys,which have been conducted every 5 years across Finland from 1987 to 2007.Participants were adults aged 25 years to 74 years,excluding those with a previous hospitalization for GIB.Follow-up from enrollment was performed through linkage to national electronic health registers and ended at an event of GIB that led to hospitalization/death,death due to any other cause,or after 10 years.Covariates included demographics,socioeconomic and lifestyle factors,clinical measurements,laboratory parameters and comorbidities.Variable selection was undertaken using Least Absolute Shrinkage and Selection Operator(LASSO)and factors associated with GIB were identified using Cox regression.RESULTS Among 33,508 participants,403(1.2%)experienced GIB[256 men(63.5%);mean age,56.0 years(standard deviation(SD)±12.1)]and 33105 who did not experience GIB[15768 men(47.6%);mean age,46.8(SD±13)years],within 10 years of follow-up.Factors associated with a significantly increased risk of GIB were baseline age[per 10-year increase;hazard ratio(HR)1.62,95%confidence interval(CI):1.42-1.86],unemployment(HR:1.70,95%CI:1.11-2.59),body mass index(BMI)(HR:1.15,95%CI:1.01-1.32),gamma-glutamyl transferase(GGT)(HR:1.05,95%CI:1.02-1.09),precursors of GIB(HR:1.90,95%CI:1.37-2.63),cancer(HR:1.47,95%CI:1.10-1.97),psychiatric disorders(HR:1.32,95%CI:1.01-1.71),heart failure(HR:1.46,95%CI:1.04-2.05),and liver disorders(HR:3.20,95%CI:2.06-4.97).Factors associated with a significantly decreased risk of GIB were systolic blood pressure(SBP)(HR:0.78,95%CI:0.64-0.96),6-10 cups of coffee a day(HR:0.67,95%CI:0.46-0.99),or>10 cups(HR:0.43,95%CI:0.23-0.81).CONCLUSION Our study confirms established risk-factors for GIB and identifies potential risk-factors not previously reported such as unemployment,BMI,GGT,SBP and coffee consumption.展开更多
Upper respiratory tract infections or common colds are a multi-symptom disease which is usually symptomatically treated with fixed dose multi-active ingredient medicinal products which are commonly used as non-prescri...Upper respiratory tract infections or common colds are a multi-symptom disease which is usually symptomatically treated with fixed dose multi-active ingredient medicinal products which are commonly used as non-prescription and over the counter. However, the active ingredients combined require a particular and clinically sound justification. Analgesics and decongestant can be combined to treat simultaneously the prominent symptoms cold-related pain (e.g. headache, muscle aches and pains), fever, inflammationand nasal/sinus congestion. This overview provides a summary of the evidence supporting the combination of acetylsalicylic acid (aspirin) and pseudoephedrine available in the common cold product Aspirin? Complex.展开更多
Aim: We assessed bleeding pattern, tolerance and patient satisfaction of an oral contraceptive containing 3 mg drospirenone and 30 mcg ethinyl estradiol (DRSP/EE) under real-life conditions. Study Design: We performed...Aim: We assessed bleeding pattern, tolerance and patient satisfaction of an oral contraceptive containing 3 mg drospirenone and 30 mcg ethinyl estradiol (DRSP/EE) under real-life conditions. Study Design: We performed a multicenter, prospective, 6-cycle, observational study in Canada, Europe and the Middle East. Detailed analyses of the three Middle East countries, Jordan, Lebanon andSyriawere presented here. The efficacy variables included an assessment of bleeding patterns, premenstrual symptoms of water retention and patient satisfaction, as determined by a visual analogue scale. Results: A total of 914 women were enrolled. The percentage of women with intermenstrual bleeding decreased from 37.4%, 48.7% and 32.2% at baseline to 9.7%, 6.1% and 10.9% at the end of cycle6 inJordan, Lebanon and Syria, respectively (creased sharply in all three countries (p Amenorrhea decreased significantly in Lebanon and Syria (p < 0.005). In addition, signs of water retention like abdominal bloating, breast tenderness and swelling of extremities decreased significantly over the course of 6 treatment cycles (p < 0.001). Patient satisfaction increased for all investigated items. Upon completion of the study, 82.7% of women answered “Yes” to continue treatment with this oral contraceptive. Conclusion: The oral contraceptive containing 3 mg drospirenone and 30 mcg ethinyl estradiol has beneficial effects on bleeding pattern, symptoms of water retention and patient satisfaction.展开更多
Insect pest damage to crops is a threat to global food security(Tilman et al.,2011).Climate change,the evolution of insecticide resistance,and the phasing out of insecticides due to environmental and safety concerns e...Insect pest damage to crops is a threat to global food security(Tilman et al.,2011).Climate change,the evolution of insecticide resistance,and the phasing out of insecticides due to environmental and safety concerns exacerbate this problem.Farmers urgently need safe and effective crop protection tools to sustainably generate yields that meet ever-increasing global demand.展开更多
文摘Treatment of advanced hepatocellular carcinoma remains unsatisfying and so far only prognostic biomarkers like α-fetoprotein have been established. No clear predictive biomarker is currently available for standard of care therapies, including targeted therapies like sorafenib. Novel therapeutic options like immune checkpoint inhibitors may pose new challenges to identification and validation of such markers. Currently, PD-L1 expression via immunohistochemistry and tumor mutational burden via next-generation sequencing are explored as predictive biomarkers for these novel treatments. Limited tissue availability due to lack of biopsies still restricts the use of tissue based approaches. Novel methods exploring circulating or cell free nucleic acids(DNA, RNA or miRNAcontaining exosomes) could provide a new opportunity to establish predictive biomarkers. Epigenetic profiling and next-generation sequencing approaches from liquid biopsies are under development. Sample size, etiologic and geographical background need to be carefully addressed in such studies to achieve meaningful results that could be translated into clinical practice. Proteomics, metabolomics and molecular imaging are further emerging technologies.
文摘BACKGROUND Gastrointestinal bleeding(GIB)is a common and potentially life-threatening clinical event.To date,the literature on the long-term global epidemiology of GIB has not been systematically reviewed.AIM To systematically review the published literature on the worldwide epidemiology of upper and lower GIB.METHODS EMBASE®and MEDLINE were queried from 01 January 1965 to September 17,2019 to identify population-based studies reporting incidence,mortality,or casefatality rates of upper GIB(UGIB)or lower GIB(LGIB)in the general adult population,worldwide.Relevant outcome data were extracted and summarized(including data on rebleeding following initial occurrence of GIB when available).All included studies were assessed for risk of bias based upon reporting guidelines.RESULTS Of 4203 retrieved database hits,41 studies were included,comprising a total of around 4.1 million patients with GIB worldwide from 1980–2012.Thirty-three studies reported rates for UGIB,four for LGIB,and four presented data on both.Incidence rates ranged from 15.0 to 172.0/100000 person-years for UGIB,and from 20.5 to 87.0/100000 person-years for LGIB.Thirteen studies reported on temporal trends,generally showing an overall decline in UGIB incidence over time,although a slight increase between 2003 and 2005 followed by a decline was shown in 5/13 studies.GIB-related mortality data were available from six studies for UGIB,with rates ranging from 0.9 to 9.8/100000 person-years,and from three studies for LGIB,with rates ranging from 0.8 to 3.5/100000 person-years.Casefatality rate ranged from 0.7%to 4.8%for UGIB and 0.5%to 8.0%for LGIB.Rates of rebleeding ranged from 7.3%to 32.5%for UGIB and from 6.7%to 13.5%for LGIB.Two main areas of potential bias were the differences in the operational GIB definition used and inadequate information on how missing data were handled.CONCLUSION Wide variation was seen in estimates of GIB epidemiology,likely due to high heterogeneity between studies however,UGIB showed a decreasing trend over the years.Epidemiological data were more widely available for UGIB than for LGIB.
文摘Hepatocellular carcinoma(HCC)remains a global medical burden with rising incidence due to chronic viral hepatitis and non-alcoholic fatty liver diseases.Treatment of advanced disease stages is still unsatisfying.Besides first and second generation tyrosine kinase inhibitors,immune checkpoint inhibitors have become central for the treatment of HCC.New modalities like epigenetic therapy using histone deacetylase inhibitors(HDACi)and cell therapy approaches with chimeric antigen receptor T cells(CAR-T cells)are currently under investigation in clinical trials.Development of such novel drugs is closely linked to the availability and improvement of novel preclinical and animal models and the identification of predictive biomarkers.The current status of treatment options for advanced HCC,emerging novel therapeutic approaches and different preclinical models for HCC drug discovery and development are reviewed here.
基金the Danish Council for Inde-pendent Research(Grant No.DFF-12-131927)for financial sup-port of this project
文摘Hypromellose acetate succinate(HPMCAS) microparticles containing the poorly-water soluble drug celecoxib(CEL) were prepared by electrospraying intended for oral drug delivery. Various solvent mixtures with different solubility for CEL and HPMCAS were used to induce changes in the polymer structural conformation of the microparticles. The performance of the prepared microparticles was evaluated by studying the solid state from, particle size and morphology, radial drug distribution and drug release. CEL was amorphous in all electrosprayed HPMCAS microparticles. The particle size and morphology was dependent on the solubility of HPMCAS in the solvent mixture used with poorer solvents resulting in smaller microparticles with rougher appearance. The CEL distribution on the particles surface was relatively homogeneous and similar for all microparticles. Drug release from the microparticles was observed at a higher rate depending on the solubility of HPMCAS in the solvent used for electrospraying, and in all cases an at least 4-fold higher rate was observed compared with the crystalline drug. Drug precipitation from the supersaturated solution was inhibited by HPMCAS for all microparticles based on its parachute effect while crystalline CEL did not reach supersaturation. This study demonstrated that electrospraying can be used to produce microparticles with tailored properties for pharmaceutical application by adjusting solvent selection.
文摘An improvement in pancreatic cancer treatment represents an urgent medical goal. Late diagnosis and high intrinsic resistance to conventional chemotherapy has led to a dismal overall prognosis that has remained unchanged during the past decades. Increasing knowledge about the molecular pathogenesis of the disease has shown that genetic alterations, such as mutations of K-ras, and especially epigenetic dysregulation of tumor-associated genes, such as silencing of the tumor suppressor p16<sup>ink4a</sup>, are hallmarks of pancreatic cancer. Here, we describe genes that are commonly affected by epigenetic dysregulation in pancreatic cancer via DNA methylation, histone acetylation or miRNA (microRNA) expression, and review the implications on pancreatic cancer biology such as epithelial-mesenchymal transition, morphological pattern formation, or cancer stem cell regulation during carcinogenesis from PanIN (pancreatic intraepithelial lesions) to invasive cancer and resistance development. Epigenetic drugs, such as DNA methyltransferases or histone deactylase inhibitors, have shown promising preclinical results in pancreatic cancer and are currently in early phases of clinical development. Combinations of epigenetic drugs with established cytotoxic drugs or targeted therapies are promising approaches to improve the poor response and survival rate of pancreatic cancer patients.
基金supported by the National Key R&D Program of China(No.2017YFA0505200)the National Natural Science Foundation of China(Nos.21532004,21807001,91753205,81621002,21621003)。
文摘The deletion of the C-terminal arginine of the anaphylatoxin protein C5a reduces it receptor binding affinity.Understanding how C-terminal arginine affects the structure and bioactivity of C5a is important for the development of C5a C-terminal mimics as drug candidates.Herein,we report the total chemical synthesis of rat C5a and its D-enantiomer with its C-terminal arginine deleted,namely L-rC5a-desArg and D-rC5a-desArg.The structure of rC5a-desArg was then determined by racemic crystallography for the first time.The C-terminal residues of rC5a-Arg were found to expand from the fourth helix in a continuous helical confo rmation.This C-terminal conformation is significantly different from that of the previously reported full-length of C5a,indicating that the deletion of C-terminal arginine residue could result in the destruction of a positively charged surface formed by two adjacent Arg residues in C5a.
文摘BACKGROUND Data on non-drug related risk-factors for gastrointestinal bleeding(GIB)in the general population are limited,especially for life-style factors,clinical measurements and laboratory parameters.AIM To identify and investigate non-drug risk factors for major GIB in the general population of Finland.METHODS We performed a retrospective cohort study using data from the FINRISK health examination surveys,which have been conducted every 5 years across Finland from 1987 to 2007.Participants were adults aged 25 years to 74 years,excluding those with a previous hospitalization for GIB.Follow-up from enrollment was performed through linkage to national electronic health registers and ended at an event of GIB that led to hospitalization/death,death due to any other cause,or after 10 years.Covariates included demographics,socioeconomic and lifestyle factors,clinical measurements,laboratory parameters and comorbidities.Variable selection was undertaken using Least Absolute Shrinkage and Selection Operator(LASSO)and factors associated with GIB were identified using Cox regression.RESULTS Among 33,508 participants,403(1.2%)experienced GIB[256 men(63.5%);mean age,56.0 years(standard deviation(SD)±12.1)]and 33105 who did not experience GIB[15768 men(47.6%);mean age,46.8(SD±13)years],within 10 years of follow-up.Factors associated with a significantly increased risk of GIB were baseline age[per 10-year increase;hazard ratio(HR)1.62,95%confidence interval(CI):1.42-1.86],unemployment(HR:1.70,95%CI:1.11-2.59),body mass index(BMI)(HR:1.15,95%CI:1.01-1.32),gamma-glutamyl transferase(GGT)(HR:1.05,95%CI:1.02-1.09),precursors of GIB(HR:1.90,95%CI:1.37-2.63),cancer(HR:1.47,95%CI:1.10-1.97),psychiatric disorders(HR:1.32,95%CI:1.01-1.71),heart failure(HR:1.46,95%CI:1.04-2.05),and liver disorders(HR:3.20,95%CI:2.06-4.97).Factors associated with a significantly decreased risk of GIB were systolic blood pressure(SBP)(HR:0.78,95%CI:0.64-0.96),6-10 cups of coffee a day(HR:0.67,95%CI:0.46-0.99),or>10 cups(HR:0.43,95%CI:0.23-0.81).CONCLUSION Our study confirms established risk-factors for GIB and identifies potential risk-factors not previously reported such as unemployment,BMI,GGT,SBP and coffee consumption.
文摘Upper respiratory tract infections or common colds are a multi-symptom disease which is usually symptomatically treated with fixed dose multi-active ingredient medicinal products which are commonly used as non-prescription and over the counter. However, the active ingredients combined require a particular and clinically sound justification. Analgesics and decongestant can be combined to treat simultaneously the prominent symptoms cold-related pain (e.g. headache, muscle aches and pains), fever, inflammationand nasal/sinus congestion. This overview provides a summary of the evidence supporting the combination of acetylsalicylic acid (aspirin) and pseudoephedrine available in the common cold product Aspirin? Complex.
文摘Aim: We assessed bleeding pattern, tolerance and patient satisfaction of an oral contraceptive containing 3 mg drospirenone and 30 mcg ethinyl estradiol (DRSP/EE) under real-life conditions. Study Design: We performed a multicenter, prospective, 6-cycle, observational study in Canada, Europe and the Middle East. Detailed analyses of the three Middle East countries, Jordan, Lebanon andSyriawere presented here. The efficacy variables included an assessment of bleeding patterns, premenstrual symptoms of water retention and patient satisfaction, as determined by a visual analogue scale. Results: A total of 914 women were enrolled. The percentage of women with intermenstrual bleeding decreased from 37.4%, 48.7% and 32.2% at baseline to 9.7%, 6.1% and 10.9% at the end of cycle6 inJordan, Lebanon and Syria, respectively (creased sharply in all three countries (p Amenorrhea decreased significantly in Lebanon and Syria (p < 0.005). In addition, signs of water retention like abdominal bloating, breast tenderness and swelling of extremities decreased significantly over the course of 6 treatment cycles (p < 0.001). Patient satisfaction increased for all investigated items. Upon completion of the study, 82.7% of women answered “Yes” to continue treatment with this oral contraceptive. Conclusion: The oral contraceptive containing 3 mg drospirenone and 30 mcg ethinyl estradiol has beneficial effects on bleeding pattern, symptoms of water retention and patient satisfaction.
基金supported by the Science and Technology Innovation Project of the Chinese Academy of Agricultural Sciences(CAAS-2060302).
文摘Insect pest damage to crops is a threat to global food security(Tilman et al.,2011).Climate change,the evolution of insecticide resistance,and the phasing out of insecticides due to environmental and safety concerns exacerbate this problem.Farmers urgently need safe and effective crop protection tools to sustainably generate yields that meet ever-increasing global demand.
