Gastric cancers are caused primarily due to the activation and amplification of the EGFR or HER2 kinases resulting in cell proliferation,adhesion,angiogenesis,and metastasis.Conventional therapies are ineffective due ...Gastric cancers are caused primarily due to the activation and amplification of the EGFR or HER2 kinases resulting in cell proliferation,adhesion,angiogenesis,and metastasis.Conventional therapies are ineffective due to the intra-tumoral heterogeneity and concomitant genetic mutations.Hence,dual inhibition strategies are recommended to increase potency and reduce cytotoxicity.In this study,we have conducted computational high-throughput screening of the ChemBridge library followed by in vitro assays and identified novel selective inhibitors that have a dual impediment of EGFR/HER2 kinase activities.Diversity-based High-throughput Virtual Screening(D-HTVS)was used to screen the whole ChemBridge small molecular library against EGFR and HER2.The atomistic molecular dynamic simulation was conducted to understand the dynamics and stability of the protein-ligand complexes.EGFR/HER2 kinase enzymes,KATOIII,and Snu-5 cells were used for in vitro validations.The atomistic Molecular Dynamics simulations followed by solvent-based Gibbs binding free energy calculation of top molecules,identified compound C3(5-(4-oxo-4H-3,1-benzoxazin-2-yl)-2-[3-(4-oxo-4H-3,1-benzoxazin-2-yl)phenyl]-1H-isoindole-1,3(2H)-dione)to have a good affinity for both EGFR and HER2.The predicted compound,C3,was promising with better binding energy,good binding pose,and optimum interactions with the EGFR and HER2 residues.C3 inhibited EGFR and HER2 kinases with IC50 values of 37.24 and 45.83 nM,respectively.The GI50 values of C3 to inhibit KATOIII and Snu-5 cells were 84.76 and 48.26 nM,respectively.Based on these findings,we conclude that the identified compound C3 showed a conceivable dual inhibitory activity on EGFR/HER2 kinase,and therefore can be considered as a plausible lead-like molecule for treating gastric cancers with minimal side effects,though testing in higher models with pharmacokinetic approach is required.展开更多
Detecting target echo in the existence of self-screen jamming is a challenging work for radar system, especially when digital radio frequency memory(DRFM) technique is employed that mixes the jamming and target echo b...Detecting target echo in the existence of self-screen jamming is a challenging work for radar system, especially when digital radio frequency memory(DRFM) technique is employed that mixes the jamming and target echo both in spatial and time-frequency domain. The conventional way to solve this problem would suffer from performance degradation when physical target(PT) and false target(FT) are superposed in time. In this paper, we propose a new spatial filter according to the different correlation characteristic between PT and FT. The filter takes the ratio of expected signal power to expected jamming and noise power as the objective function under the constant filter modulus constraint. The optimal filter coefficients are derived with a generalized rayleigh quotient approach. Moreover, we analytically compute the target detection probability and demonstrate the applicability of the proposed method to the correlation coefficient. Monte Carlo simulations are provided to corroborate the proposed studies. Furthermore, the proposed method has simple architecture and low computation complexity, making it easily applied in modern radar system.展开更多
Background:Dual vision and hearing loss or dual sensory impairment(DSI)negatively impacts a person’s ability to communicate,acquire information,and perform daily activities.Because the incidence of DSI is higher in o...Background:Dual vision and hearing loss or dual sensory impairment(DSI)negatively impacts a person’s ability to communicate,acquire information,and perform daily activities.Because the incidence of DSI is higher in older adults(65+),and the fact that most developed countries are aging,there is expected increase in DSI prevalence.The detection and evaluation of DSI is of utmost importance because several aspects of health care delivery,and communication with health professionals,depend on it.Identifying DSI in older adults can be more difficult when they present with mild cognitive impairment(MCI),which may limit their ability to report sensory loss,potentially resulting on medical professionals failing to detect DSI.The interRAI CHA is the only standardized interview instrument for adults(18+)that helps first-line health care providers to identify and assess DSI.This study evaluated this instrument’s sensitivity and specificity for detecting vision and or hearing loss in older adults with and without risk of MCI.Methods:The study sample consisted of 200 adults aged 64+that were receiving rehabilitation services for either vision loss only,hearing loss only,or DSI.Two measurements were collected:(I)interRAI CHA,which consists of roughly 150 closed-ended questions,two of which are used to identify DSI;(II)Montreal Cognitive Assessment(MoCA),a 10-minute screening test that assess cognitive function and identifies individuals at risk of MCI.The interRA CHA sensitivity and specificity for identifying DSI was calculated in comparison to gold standard objective measurements of vision and hearing obtained from participants’medical records.Sensitivity and specificity results were stratified based on risk of MCI,as assessed by the MoCA.Results:Sensitivity for DSI was slightly better for respondents that were not at risk of MCI(97.4%)compared to those who were at risk of MCI(96.2%).Likewise,sensitivity for HL only was slightly better for respondents that were not at risk of MCI(97.4%)compared to those who were at risk of MCI(96.8%).Because sensitivity was 100%for VL only,the potential impact of MCI risk on the interRAI CHA’s sensitivity for detecting VL only cannot be studied in this sample.Specificity for DSI and HL were higher for participants not at risk of MCI(HI:96.2%,DSI:94.8%),compared to those at risk of MCI(HI:90.2%,DSI:91.1%).Dissimilar to this,in the VI group specificity was slightly better in participants at risk of MCI(100%),compared to those not at risk of MCI(98.7%).This was due to a single participant not at risk of MCI who was not classified as VL by the medical record,yet did report difficulties with vision when responding to the interRAI CHA question on vision.Conclusions:The interRAI CHA’s sensitivity and specificity for detecting DSI was lower for older adults at risk of MCI,compared to those not at risk of MCI.Future research should investigate strategies to improve identification of DSI in persons at risk of MCI.展开更多
文摘Gastric cancers are caused primarily due to the activation and amplification of the EGFR or HER2 kinases resulting in cell proliferation,adhesion,angiogenesis,and metastasis.Conventional therapies are ineffective due to the intra-tumoral heterogeneity and concomitant genetic mutations.Hence,dual inhibition strategies are recommended to increase potency and reduce cytotoxicity.In this study,we have conducted computational high-throughput screening of the ChemBridge library followed by in vitro assays and identified novel selective inhibitors that have a dual impediment of EGFR/HER2 kinase activities.Diversity-based High-throughput Virtual Screening(D-HTVS)was used to screen the whole ChemBridge small molecular library against EGFR and HER2.The atomistic molecular dynamic simulation was conducted to understand the dynamics and stability of the protein-ligand complexes.EGFR/HER2 kinase enzymes,KATOIII,and Snu-5 cells were used for in vitro validations.The atomistic Molecular Dynamics simulations followed by solvent-based Gibbs binding free energy calculation of top molecules,identified compound C3(5-(4-oxo-4H-3,1-benzoxazin-2-yl)-2-[3-(4-oxo-4H-3,1-benzoxazin-2-yl)phenyl]-1H-isoindole-1,3(2H)-dione)to have a good affinity for both EGFR and HER2.The predicted compound,C3,was promising with better binding energy,good binding pose,and optimum interactions with the EGFR and HER2 residues.C3 inhibited EGFR and HER2 kinases with IC50 values of 37.24 and 45.83 nM,respectively.The GI50 values of C3 to inhibit KATOIII and Snu-5 cells were 84.76 and 48.26 nM,respectively.Based on these findings,we conclude that the identified compound C3 showed a conceivable dual inhibitory activity on EGFR/HER2 kinase,and therefore can be considered as a plausible lead-like molecule for treating gastric cancers with minimal side effects,though testing in higher models with pharmacokinetic approach is required.
文摘Detecting target echo in the existence of self-screen jamming is a challenging work for radar system, especially when digital radio frequency memory(DRFM) technique is employed that mixes the jamming and target echo both in spatial and time-frequency domain. The conventional way to solve this problem would suffer from performance degradation when physical target(PT) and false target(FT) are superposed in time. In this paper, we propose a new spatial filter according to the different correlation characteristic between PT and FT. The filter takes the ratio of expected signal power to expected jamming and noise power as the objective function under the constant filter modulus constraint. The optimal filter coefficients are derived with a generalized rayleigh quotient approach. Moreover, we analytically compute the target detection probability and demonstrate the applicability of the proposed method to the correlation coefficient. Monte Carlo simulations are provided to corroborate the proposed studies. Furthermore, the proposed method has simple architecture and low computation complexity, making it easily applied in modern radar system.
文摘目的探讨在HPV阳性女性中,液基细胞学、DNA倍体分析及P16/Ki-67双染检测对宫颈癌前病变的分流作用。方法回顾性分析2021年5月至2022年12月在我院妇科行阴道镜及宫颈活检的妇女590例。患者高危人乳头瘤病毒(human papilloma virus,HPV)检测阳性,且行液基细胞学(liquid-based cytology,LBC)、DNA倍体分析、P16/Ki-67双染3种检查,对上述3种方法的灵敏度、特异性、受试者工作特征(receiver operating characteristic,ROC)曲线进行统计分析。结果液基细胞学、DNA倍体分析和P16/Ki-67双染3种筛查方法对宫颈癌前病变的灵敏度分别为84.2%、77.5%、76.4%,特异性分别为40.7%、49.2%、70.1%,曲线下面积(area under the curve,AUC)分别是0.625、0.634、0.733,其中,P16/Ki-67双染检测显著优于液基细胞学检查及DNA倍体分析(P<0.0001)。结论本研究认为,在HPV阳性女性中,P16/Ki-67双染检测的分流效果最佳。
文摘Background:Dual vision and hearing loss or dual sensory impairment(DSI)negatively impacts a person’s ability to communicate,acquire information,and perform daily activities.Because the incidence of DSI is higher in older adults(65+),and the fact that most developed countries are aging,there is expected increase in DSI prevalence.The detection and evaluation of DSI is of utmost importance because several aspects of health care delivery,and communication with health professionals,depend on it.Identifying DSI in older adults can be more difficult when they present with mild cognitive impairment(MCI),which may limit their ability to report sensory loss,potentially resulting on medical professionals failing to detect DSI.The interRAI CHA is the only standardized interview instrument for adults(18+)that helps first-line health care providers to identify and assess DSI.This study evaluated this instrument’s sensitivity and specificity for detecting vision and or hearing loss in older adults with and without risk of MCI.Methods:The study sample consisted of 200 adults aged 64+that were receiving rehabilitation services for either vision loss only,hearing loss only,or DSI.Two measurements were collected:(I)interRAI CHA,which consists of roughly 150 closed-ended questions,two of which are used to identify DSI;(II)Montreal Cognitive Assessment(MoCA),a 10-minute screening test that assess cognitive function and identifies individuals at risk of MCI.The interRA CHA sensitivity and specificity for identifying DSI was calculated in comparison to gold standard objective measurements of vision and hearing obtained from participants’medical records.Sensitivity and specificity results were stratified based on risk of MCI,as assessed by the MoCA.Results:Sensitivity for DSI was slightly better for respondents that were not at risk of MCI(97.4%)compared to those who were at risk of MCI(96.2%).Likewise,sensitivity for HL only was slightly better for respondents that were not at risk of MCI(97.4%)compared to those who were at risk of MCI(96.8%).Because sensitivity was 100%for VL only,the potential impact of MCI risk on the interRAI CHA’s sensitivity for detecting VL only cannot be studied in this sample.Specificity for DSI and HL were higher for participants not at risk of MCI(HI:96.2%,DSI:94.8%),compared to those at risk of MCI(HI:90.2%,DSI:91.1%).Dissimilar to this,in the VI group specificity was slightly better in participants at risk of MCI(100%),compared to those not at risk of MCI(98.7%).This was due to a single participant not at risk of MCI who was not classified as VL by the medical record,yet did report difficulties with vision when responding to the interRAI CHA question on vision.Conclusions:The interRAI CHA’s sensitivity and specificity for detecting DSI was lower for older adults at risk of MCI,compared to those not at risk of MCI.Future research should investigate strategies to improve identification of DSI in persons at risk of MCI.