Drug metabolism and pharmacokinetics(DMPK) is an important branch of pharmaceutical sciences.The nature of ADME(absorption,distribution,metabolism,excretion) and PK(pharmacokinetics) inquiries during drug discovery an...Drug metabolism and pharmacokinetics(DMPK) is an important branch of pharmaceutical sciences.The nature of ADME(absorption,distribution,metabolism,excretion) and PK(pharmacokinetics) inquiries during drug discovery and development has evolved in recent years from being largely descriptive to seeking a more quantitative and mechanistic understanding of the fate of drug candidates in biological systems.Tremendous progress has been made in the past decade,not only in the characterization of physiochemical properties of drugs that influence their ADME,target organ exposure,and toxicity,but also in the identification of design principles that can minimize drug-drug interaction(DDI) potentials and reduce the attritions.The importance of membrane transporters in drug disposition,efficacy,and safety,as well as the interplay with metabolic processes,has been increasingly recognized.Dramatic increases in investments on new modalities beyond traditional small and large molecule drugs,such as peptides,oligonucleotides,and antibody-drug conjugates,necessitated further innovations in bioanalytical and experimental tools for the characterization of their ADME properties.In this review,we highlight some of the most notable advances in the last decade,and provide future perspectives on potential major breakthroughs and innovations in the translation of DMPK science in various stages of drug discovery and development.展开更多
The global physical and biogeochemical environment has been substantially altered in response to increased atmospheric greenhouse gases from human activities.In 2023,the sea surface temperature(SST)and upper 2000 m oc...The global physical and biogeochemical environment has been substantially altered in response to increased atmospheric greenhouse gases from human activities.In 2023,the sea surface temperature(SST)and upper 2000 m ocean heat content(OHC)reached record highs.The 0–2000 m OHC in 2023 exceeded that of 2022 by 15±10 ZJ(1 Zetta Joules=1021 Joules)(updated IAP/CAS data);9±5 ZJ(NCEI/NOAA data).The Tropical Atlantic Ocean,the Mediterranean Sea,and southern oceans recorded their highest OHC observed since the 1950s.Associated with the onset of a strong El Niño,the global SST reached its record high in 2023 with an annual mean of~0.23℃ higher than 2022 and an astounding>0.3℃ above 2022 values for the second half of 2023.The density stratification and spatial temperature inhomogeneity indexes reached their highest values in 2023.展开更多
Based on an analysis of 51-year (1965 2015) data, the influence of El Ni o Southern Oscillation (ENSO) events on tropical cyclone (TC) activity is examined over the western North Pacific (WNP). The total number of TCs...Based on an analysis of 51-year (1965 2015) data, the influence of El Ni o Southern Oscillation (ENSO) events on tropical cyclone (TC) activity is examined over the western North Pacific (WNP). The total number of TCs formed in the entire WNP reduces by about 3.4 TCs per year in La Ni a years, whereas TCs have an equivalent genesis number between El Ni o years and climatology. During El Ni o years, the frequency of TC formation increases remarkably in the southeast quadrant (140 E 180 , 0 17 N) and decreases in the northwest quadrant (120 140 E, 17 30 N). During La Ni a years, TCs tend to form in the northwest and southwest quadrants (120 140 E, 0 17 N) quadrants. TCs tend to become long-lived in the peak season (from July to Septem- ber) of El Ni o years and during strong El Ni o events. TC genesis shows a southeastward positive shift in terms of lifetime and intensity during El Ni o years, thus more super TCs (winds ≥ 58.64 m s 1) are formed in the southeast quadrant. Further analysis using the genesis potential index (GPI) indicates that the interannual variations in the TC genesis and track are significantly influenced by a combination of large-scale dynamic and thermodynamic conditions.展开更多
Background:Postoperative chylous ascites is an infrequent condition after colorectal surgery and is easily treatable.However,its effect on the long-term oncological prognosis is not well established.This study aimed t...Background:Postoperative chylous ascites is an infrequent condition after colorectal surgery and is easily treatable.However,its effect on the long-term oncological prognosis is not well established.This study aimed to investigate the short-term and long-term impact of chylous ascites treated with neoadjuvant therapy followed by rectal cancer surgery and to evaluate the incidence of chylous ascites after different surgical approaches.Methods:A total of 898 locally advanced rectal cancer patients treated with neoadjuvant chemoradiotherapy followed by surgery between January 2010 and December 2018 were included.The clinicopathological data and outcomes of the patients with chylous ascites were compared with those of the patients without chylous ascites.The primary endpoint was recurrence-free survival(RFS).To balance baseline confounders between groups,propensity score matching(PSM)was performed for each patient with a logistic regression model.Results:Chylous ascites was detected in 3.8%(34/898)of the patients.The incidence of chylous ascites was highest after robotic surgery(6.9%,6/86),followed by laparoscopic surgery(4.2%,26/618)and open surgery(1.0%,2/192,P=0.021).The patients with chylous ascites had a significantly higher number of lymph nodes harvested(15.6 vs.12.8,P=0.009)and a 3-day longer postoperative hospital stay(P=0.017).The 5-year RFS rate was 64.5%in the chylous ascites group,which was significantly lower than the rate in the no chylous ascites group(79.9%;P=0.007).The results remained unchanged after PSM was performed.The chylous ascites group showed a nonsignificant trend towards a higher peritoneal metastasis risk(5.9%vs.1.6%,P=0.120).Univariate analysis and multivariate analysis confirmed chylous ascites(hazard ratio=3.038,P<0.001)as an independent negative prognostic factor for RFS.Conclusions:Considering the higher incidence of chylous ascites after laparoscopic and robotic surgery and its adverse prognosis,we recommend sufficient coagulation of the lymphatic tissue near the vessel origins,esp展开更多
Background:Pre-operative assessment with high-resolution magnetic resonance imaging(MRI)is useful for assessing the risk of local recurrence(LR)and survival in rectal cancer.However,few studies have explored the clini...Background:Pre-operative assessment with high-resolution magnetic resonance imaging(MRI)is useful for assessing the risk of local recurrence(LR)and survival in rectal cancer.However,few studies have explored the clinical importance of the morphology of the anterior mesorectum,especially in patients with anterior cancer.Hence,the study aimed to investigate the impact of the morphology of the anterior mesorectum on LR in patients with primary rectal cancer.Methods:A retrospective study was performed on 176 patients who underwent neoadjuvant treatment and curative-intent surgery.Patients were divided into two groups according to the morphology of the anterior mesorectum on sagittal MRI:(1)linear type:the anterior mesorectum was thin and linear;and(2)triangular type:the anterior mesorectum was thick and had a unique triangular shape.Clinicopathological and LR data were compared between patients with linear type anterior mesorectal morphology and patients with triangular type anterior mesorectal morphology.Results:Morphometric analysis showed that 90(51.1%)patients had linear type anterior mesorectal morphology,while 86(48.9%)had triangular type anterior mesorectal morphology.Compared to triangular type anterior mesorectal morphology,linear type anterior mesorectal morphology was more common in females and was associated with a higher risk of circumferential resection margin involvement measured by MRI(35.6%[32/90]vs.16.3%[14/86],P=0.004)and a higher 5-year LR rate(12.2%vs.3.5%,P=0.030).In addition,the combination of linear type anterior mesorectal morphology and anterior tumors was confirmed as an independent risk factor for LR(odds ratio=4.283,P=0.014).Conclusions:The classification established in this study was a simple way to describe morphological characteristics of the anterior mesorectum.The combination of linear type anterior mesorectal morphology and anterior tumors was an independent risk factor for LR and may act as a tool to assist with LR risk stratification and treatment selection.展开更多
基金supported in part by grants from the National Institutes of Health (CA023074,CA092596,ES004940,ES006694,and ES020867,USA)。
文摘Drug metabolism and pharmacokinetics(DMPK) is an important branch of pharmaceutical sciences.The nature of ADME(absorption,distribution,metabolism,excretion) and PK(pharmacokinetics) inquiries during drug discovery and development has evolved in recent years from being largely descriptive to seeking a more quantitative and mechanistic understanding of the fate of drug candidates in biological systems.Tremendous progress has been made in the past decade,not only in the characterization of physiochemical properties of drugs that influence their ADME,target organ exposure,and toxicity,but also in the identification of design principles that can minimize drug-drug interaction(DDI) potentials and reduce the attritions.The importance of membrane transporters in drug disposition,efficacy,and safety,as well as the interplay with metabolic processes,has been increasingly recognized.Dramatic increases in investments on new modalities beyond traditional small and large molecule drugs,such as peptides,oligonucleotides,and antibody-drug conjugates,necessitated further innovations in bioanalytical and experimental tools for the characterization of their ADME properties.In this review,we highlight some of the most notable advances in the last decade,and provide future perspectives on potential major breakthroughs and innovations in the translation of DMPK science in various stages of drug discovery and development.
基金supported by the National Natural Science Foundation of China (Grant Nos. 42076202, 42122046, 42206208 and 42261134536)the Open Research Cruise NORC2022-10+NORC2022-303 supported by NSFC shiptime Sharing Projects 42149910+7 种基金the new Cornerstone Science Foundation through the XPLORER PRIZE, DAMO Academy Young Fellow, Youth Innovation Promotion Association, Chinese Academy of SciencesNational Key Scientific and Technological Infrastructure project “Earth System Science Numerical Simulator Facility” (EarthLab)sponsored by the US National Science Foundationsupported by NASA Awards 80NSSC17K0565, 80NSSC21K1191, and 80NSSC22K0046by the Regional and Global Model Analysis (RGMA) component of the Earth and Environmental System Modeling Program of the U.S. Department of Energy’s Office of Biological & Environmental Research (BER) via National Science Foundation IA 1947282supported by NOAA (Grant No. NA19NES4320002 to CISESS-MD at the University of Maryland)supported by the Young Talent Support Project of Guangzhou Association for Science and Technologyfunded by the Istituto Nazionale di Geofisica e Vulcanologia (INGV) in agreement between INGV, ENEA, and GNV SpA shipping company that provides hospitality on its commercial vessels
文摘The global physical and biogeochemical environment has been substantially altered in response to increased atmospheric greenhouse gases from human activities.In 2023,the sea surface temperature(SST)and upper 2000 m ocean heat content(OHC)reached record highs.The 0–2000 m OHC in 2023 exceeded that of 2022 by 15±10 ZJ(1 Zetta Joules=1021 Joules)(updated IAP/CAS data);9±5 ZJ(NCEI/NOAA data).The Tropical Atlantic Ocean,the Mediterranean Sea,and southern oceans recorded their highest OHC observed since the 1950s.Associated with the onset of a strong El Niño,the global SST reached its record high in 2023 with an annual mean of~0.23℃ higher than 2022 and an astounding>0.3℃ above 2022 values for the second half of 2023.The density stratification and spatial temperature inhomogeneity indexes reached their highest values in 2023.
基金supported by grants from the National Natural Science Foundation of China (Nos. 41621064 and 41606003)
文摘Based on an analysis of 51-year (1965 2015) data, the influence of El Ni o Southern Oscillation (ENSO) events on tropical cyclone (TC) activity is examined over the western North Pacific (WNP). The total number of TCs formed in the entire WNP reduces by about 3.4 TCs per year in La Ni a years, whereas TCs have an equivalent genesis number between El Ni o years and climatology. During El Ni o years, the frequency of TC formation increases remarkably in the southeast quadrant (140 E 180 , 0 17 N) and decreases in the northwest quadrant (120 140 E, 17 30 N). During La Ni a years, TCs tend to form in the northwest and southwest quadrants (120 140 E, 0 17 N) quadrants. TCs tend to become long-lived in the peak season (from July to Septem- ber) of El Ni o years and during strong El Ni o events. TC genesis shows a southeastward positive shift in terms of lifetime and intensity during El Ni o years, thus more super TCs (winds ≥ 58.64 m s 1) are formed in the southeast quadrant. Further analysis using the genesis potential index (GPI) indicates that the interannual variations in the TC genesis and track are significantly influenced by a combination of large-scale dynamic and thermodynamic conditions.
基金This study was supported by grants from the National Clinical Key Specialty Construction Project(General Surgery)of China(No.2012-649)National Natural Science Foundation of China(No.81902378)+2 种基金Natural Science Foundation of Fujian Province(No.2020J011030)Medical Science Research Foundation of Beijing Medical and Health Foundation(No.B20062DS)Joint Funds for the innovation of Science and Technology,Fujian province(No.2019Y9101).
文摘Background:Postoperative chylous ascites is an infrequent condition after colorectal surgery and is easily treatable.However,its effect on the long-term oncological prognosis is not well established.This study aimed to investigate the short-term and long-term impact of chylous ascites treated with neoadjuvant therapy followed by rectal cancer surgery and to evaluate the incidence of chylous ascites after different surgical approaches.Methods:A total of 898 locally advanced rectal cancer patients treated with neoadjuvant chemoradiotherapy followed by surgery between January 2010 and December 2018 were included.The clinicopathological data and outcomes of the patients with chylous ascites were compared with those of the patients without chylous ascites.The primary endpoint was recurrence-free survival(RFS).To balance baseline confounders between groups,propensity score matching(PSM)was performed for each patient with a logistic regression model.Results:Chylous ascites was detected in 3.8%(34/898)of the patients.The incidence of chylous ascites was highest after robotic surgery(6.9%,6/86),followed by laparoscopic surgery(4.2%,26/618)and open surgery(1.0%,2/192,P=0.021).The patients with chylous ascites had a significantly higher number of lymph nodes harvested(15.6 vs.12.8,P=0.009)and a 3-day longer postoperative hospital stay(P=0.017).The 5-year RFS rate was 64.5%in the chylous ascites group,which was significantly lower than the rate in the no chylous ascites group(79.9%;P=0.007).The results remained unchanged after PSM was performed.The chylous ascites group showed a nonsignificant trend towards a higher peritoneal metastasis risk(5.9%vs.1.6%,P=0.120).Univariate analysis and multivariate analysis confirmed chylous ascites(hazard ratio=3.038,P<0.001)as an independent negative prognostic factor for RFS.Conclusions:Considering the higher incidence of chylous ascites after laparoscopic and robotic surgery and its adverse prognosis,we recommend sufficient coagulation of the lymphatic tissue near the vessel origins,esp
基金National Clinical Key Specialty Construction Project (General Surgery) of China(No. 2012-649)National Natural Science Foundation of China(No. 81902378)+4 种基金Joint Funds for the innovation of Science and Technology, Fujian province(No. 2020Y9071)Medical Science Research Foundation of Beijing Medical and Health Foundation(No. B20062DS)Bethune Charitable Foundation(No. X-J2018-004)Fujian provincial health technology project(Nos. 2020CXA025, 2021GGA013)Natural Science Foundation of Fujian Province(No. 2020J011030)
文摘Background:Pre-operative assessment with high-resolution magnetic resonance imaging(MRI)is useful for assessing the risk of local recurrence(LR)and survival in rectal cancer.However,few studies have explored the clinical importance of the morphology of the anterior mesorectum,especially in patients with anterior cancer.Hence,the study aimed to investigate the impact of the morphology of the anterior mesorectum on LR in patients with primary rectal cancer.Methods:A retrospective study was performed on 176 patients who underwent neoadjuvant treatment and curative-intent surgery.Patients were divided into two groups according to the morphology of the anterior mesorectum on sagittal MRI:(1)linear type:the anterior mesorectum was thin and linear;and(2)triangular type:the anterior mesorectum was thick and had a unique triangular shape.Clinicopathological and LR data were compared between patients with linear type anterior mesorectal morphology and patients with triangular type anterior mesorectal morphology.Results:Morphometric analysis showed that 90(51.1%)patients had linear type anterior mesorectal morphology,while 86(48.9%)had triangular type anterior mesorectal morphology.Compared to triangular type anterior mesorectal morphology,linear type anterior mesorectal morphology was more common in females and was associated with a higher risk of circumferential resection margin involvement measured by MRI(35.6%[32/90]vs.16.3%[14/86],P=0.004)and a higher 5-year LR rate(12.2%vs.3.5%,P=0.030).In addition,the combination of linear type anterior mesorectal morphology and anterior tumors was confirmed as an independent risk factor for LR(odds ratio=4.283,P=0.014).Conclusions:The classification established in this study was a simple way to describe morphological characteristics of the anterior mesorectum.The combination of linear type anterior mesorectal morphology and anterior tumors was an independent risk factor for LR and may act as a tool to assist with LR risk stratification and treatment selection.
