Current research on robot calibration can be roughly classified into two categories,and both of them have certain inherent limitations.Model-based methods are difficult to model and compensate the pose errors arising ...Current research on robot calibration can be roughly classified into two categories,and both of them have certain inherent limitations.Model-based methods are difficult to model and compensate the pose errors arising from configuration-dependent geometric and non-geometric source errors,whereas the accuracy of data-driven methods depends on a large amount of measurement data.Using a 5-DOF(degrees of freedom)hybrid machining robot as an exemplar,this study presents a model data-driven approach for the calibration of robotic manipulators.An f-DOF realistic robot containing various source errors is visualized as a 6-DOF fictitious robot having error-free parameters,but erroneous actuated/virtual joint motions.The calibration process essentially involves four steps:(1)formulating the linear map relating the pose error twist to the joint motion errors,(2)parameterizing the joint motion errors using second-order polynomials in terms of nominal actuated joint variables,(3)identifying the polynomial coefficients using the weighted least squares plus principal component analysis,and(4)compensating the compensable pose errors by updating the nominal actuated joint variables.The merit of this approach is that it enables compensation of the pose errors caused by configuration-dependent geometric and non-geometric source errors using finite measurement configurations.Experimental studies on a prototype machine illustrate the effectiveness of the proposed approach.展开更多
Background:Constitutional mismatch repair deficiency(CMMRD)is a rare disorder resulting from biallelic germline pathogenic variants in mismatch repair genes.This study described the molecular profile of two metachrono...Background:Constitutional mismatch repair deficiency(CMMRD)is a rare disorder resulting from biallelic germline pathogenic variants in mismatch repair genes.This study described the molecular profile of two metachronous brain tumors and a patient-derived xenograft(PDX)from a Brazilian child with CMMRD.Methods:After PDX development,methylation array,whole exome sequencing,and Nano String techniques were applied to describe the genetic landscape of CMMRD.Results:A 6½-year-old girl was diagnosed with Sonic Hedgehog(SHH)-activated medulloblastoma and somatic TP53-mutant.After surgery and radiochemotherapy,she remained free of disease progression.At 10 years and 3 months,she developed a diffuse pediatric-type high-grade glioma(dp HGG).The child had a family history of cancer,and subsequent investigation revealed a biallelic germline variant on MSH6(c.3556+1G>A)with the absence of protein expression in both normal and tumor tissue.A PDX model of the dp HGG was developed.The methylation profile confirmed the diagnosis of both brain tumors and PDX,refining the classification of dp HGG,Rtk1 subtype,subclass A,with an actionable alteration on Platelet-derived growth factor receptor A(PDGFRA).Exome analysis showed high tumor mutational burden,with 3019,540,and 1049 pathogenic variants in the medulloblastoma,dp HGG,and PDX,respectively.Only the medulloblastoma exhibited microsatellite instability.The CD24,CD47,and CD276 immune checkpoints had elevated messenger RNA levels,yet no programmed death ligand 1 expression was observed in CMMRD-derived tumors.Conclusion:We report an extensive molecular profile of a CMMRD patient,and the developed PDX model can be applied to explore new therapeutic approaches for CMMRD-associated brain tumors.展开更多
BACKGROUND Mismatch repair deficient/microsatellite instability-high(MMR-D/MSI-H)colorectal cancers(CRCs)possess a distinctive genomic profile that results in a spectrum of phenotypic attributes setting them apart fro...BACKGROUND Mismatch repair deficient/microsatellite instability-high(MMR-D/MSI-H)colorectal cancers(CRCs)possess a distinctive genomic profile that results in a spectrum of phenotypic attributes setting them apart from their mismatch repair proficient(MMR-P)or microsatellite stable(MSS)counterparts.CRCs have several prognostic factors,including stage,tumor differentiation,location,lymphovascular and perineural invasion,tumor budding,tumor infiltrating lymphocytes,lymph node yield(LNY),and lymph node ratio(LNR).AIM To determine the unique phenotypic characteristics of MMR-D/MSI-H CRCs and leverage the conventional wisdom of LNY and LNR with the distinctive characteristics of MMR-D/MSI-H CRCs.METHODS This retrospective analysis involved 223 stage I-III CRC patients who underwent surgical resection without neoadjuvant treatment.Clinical and histological features were obtained from patient records and by re-examining the hematoxylin and eosin-stained slides.MMR/MSI status was evaluated for all patients using either MMR immunohistochemistry or MSI testing.RESULTS Of the 223 patients in our study,87(39.01%)were MMR-D/MSI-H CRCs while 136(60.99%)were MMR-P/MSS CRCs.The MMR-D/MSI-H CRCs exhibited significant statistical differences compared to the MMR-P/MSS CRCs in several factors,including location,stage,tumor budding,lymphovascular and perineural invasion,lymphocytic response,LNY,LNR,and size of uninvolved lymph nodes.LNY and LNR were significantly higher in MMR-D/MSI-H group compared with the MMR-P/MSS group(P=0.003 and P<0.001,respectively).Also,the interquartile range of the largest uninvolved lymph node was 1 cm(0.8 cm-1.2 cm)in MMR-D/MSI-H CRCs compared to 0.7 cm(0.6 cm-0.97 cm)in MMRP/MSS CRCs.The overall survival for the MMR-P/MSS CRC group was 71%at five years,and the MMR-D/MSIH CRC group was 92%at five years(P<0.001).CONCLUSION MMR-D/MSI-H CRCs possess a unique genomic profile that leads to distinct phenotypic characteristics,including an enhanced immune response.This distinctive profile underscores the substantial prognostic and predictive value of MMR-D/MSI-H status in CRC.展开更多
Gastric cancer(GC)remains a major global health challenge,because of its poor prognosis and limited treatment options in advanced stages1,2.Recent advancements in immunotherapy,highlighted by the findings of the CHECK...Gastric cancer(GC)remains a major global health challenge,because of its poor prognosis and limited treatment options in advanced stages1,2.Recent advancements in immunotherapy,highlighted by the findings of the CHECKMATE-649,ORIENT-16,and KEYNOTE-859 trials,have markedly transformed the treatment paradigm for advanced gastric cancer(AGC)3-5.展开更多
BACKGROUND Colorectal cancer is one of the malignant tumors with a high incidence and mortality rate globally,and the occurrence of liver metastasis significantly affects patient survival prognosis.In recent years,the...BACKGROUND Colorectal cancer is one of the malignant tumors with a high incidence and mortality rate globally,and the occurrence of liver metastasis significantly affects patient survival prognosis.In recent years,the application of immune checkpoint inhibitors(ICIs)in cancer treatment has made important progress,especially showing good therapeutic effects in patients with high microsatellite instability or mismatch repair deficiency.However,for the majority of patients with microsatellite stable(MSS)or proficient mismatch repair(pMMR)colorectal cancer,the efficacy of ICIs is limited,prompting researchers to explore combination therapy strategies to improve efficacy.Targeted drugs such as tyrosine kinase inhibitors(TKIs)and radiotherapy are believed to work synergistically with ICIs by modifying the tumor microenvironment and enhancing antigen presentation.AIM To investigate the efficacy and safety of the combination therapy of radiotherapy,ICIs,and TKIs in patients with MSS or pMMR colorectal cancer liver metastasis(CCLM),in order to provide new clinical treatment references.METHODS A retrospective analysis was conducted on the clinical data of 43 MSS or pMMR CCLM patients treated at our hospital from September 2021 to July 2024.Based on the treatment interventions received,the patients were divided into a control group(n=21,receiving ICIs and TKIs combination therapy)and an observation group(n=22,receiving radiotherapy,ICIs,and TKIs triple therapy).The therapeutic effects,serum tumor markers(carcinoembryonic antigen and RESULTS The disease control rate in the observation group(63.64%)was significantly higher than that of the control group(23.81%)(P<0.05)).Both groups showed a decrease in carcinoembryonic antigen and carbohydrate antigen 199 levels post-treatment,with the observation group demonstrating a more significant change(P<0.05).The median progression-free survival and median overall survival in the control group were 5.1 months and 7.6 months,respectively,while the observation group had a median progression-free survival and overall survival of 4.3 months and 6.9 months,respectively.The control group had longer survival times than the observation group,but the differences were not statistically significant(P>0.05).The incidence of adverse reactions,including nausea and vomiting,gastrointestinal reactions,skin reactions,bone marrow suppression,liver and kidney function impairment,neurotoxicity,leukopenia,neutropenia,and thrombocytopenia,showed no significant differences between the two groups(P>0.05).CONCLUSION Compared to the ICIs and TKIs combination therapy,the radiotherapy,ICIs,and TKIs triple therapy can further improve the disease control rate and serum tumor marker levels in MSS or pMMR CCLM patients without increasing the risk of related adverse reactions,making it a treatment regimen worthy of further validation.展开更多
The rapid urbanization and structural imbalances in Chinese megacities have exacerbated the housing supplydemand mismatch,creating an urgent need for fine-scale diagnostic tools.This study addresses this critical gap ...The rapid urbanization and structural imbalances in Chinese megacities have exacerbated the housing supplydemand mismatch,creating an urgent need for fine-scale diagnostic tools.This study addresses this critical gap by developing the Housing Contradiction Evaluation Weighted Index(HCEWI)model,making three key contributions to high-resolution housing monitoring.First,we establish a tripartite theoretical framework integrating dynamic population pressure(PPI),housing supply potential(HSI),and functional diversity(HHI).The PPI innovatively combines mobile signaling data with principal component analysis to capture real-time commuting patterns,while the HSI introduces a novel dual-criteria system based on Local Climate Zones(LCZ),weighted by building density and residential function ratio.Second,we develop a spatiotemporal coupling architecture featuring an entropy-weighted dynamic integration mechanism with self-correcting modules,demonstrating robust performance against data noise.Third,our 25-month longitudinal analysis in Shenzhen reveals significant findings,including persistent bipolar clustering patterns,contrasting volatility between peripheral and core areas,and seasonal policy responsiveness.Methodologically,we advance urban diagnostics through 500-meter grid monthly monitoring and process-oriented temporal operators that reveal“tentacle-like”spatial restructuring along transit corridors.Our findings provide a replicable framework for precision housing governance and demonstrate the transformative potential of mobile signaling data in implementing China’s“city-specific policy”approach.We further propose targeted intervention strategies,including balance regulation for high-contradiction zones,Transit-Oriented Development(TOD)activation for low-contradiction clusters,and dynamic land conversion mechanisms for transitional areas.展开更多
为提高零中频接收机中正交(in-phase quadrature,IQ)失配信号校正的收敛速度与鲁棒性,本文将Kalman滤波算法与盲源分离结构结合,提出了一种基于双通道Kalman滤波的校正算法。该算法通过状态空间建模与协方差自适应更新,能够在动态环境...为提高零中频接收机中正交(in-phase quadrature,IQ)失配信号校正的收敛速度与鲁棒性,本文将Kalman滤波算法与盲源分离结构结合,提出了一种基于双通道Kalman滤波的校正算法。该算法通过状态空间建模与协方差自适应更新,能够在动态环境下实现更高效、稳定的参数估计,从而实现对IQ失配信号的有效补偿。将本文算法与最小均方算法(least mean square,LMS)、归一化最小均方算法(normalized least mean square,NLMS)和仿射投影算法(affine projection algorithm,APA)进行对比仿真,结果显示,校正后信号的镜像抑制比(image rejection ratio,IRR)均达到约45 dB,但双通道Kalman滤波算法对应的IRR曲面图更加平滑,同时,16QAM和16PSK调制方式下该算法的误符号率最低,表明本文算法能够有效实现IQ失配校正,具有较好的稳定性。本文算法迭代约50次时,均方误差收敛趋近于0,而LMS、NLMS和APA算法则分别需要迭代约500次、400次和200次才能够收敛,表明该算法具有较好的收敛性。通过参数的敏感性仿真分析,在较大的参数范围内本文算法达到的IRR差别甚微,具有良好的鲁棒性。展开更多
AIM:To investigate gene mutations and DNA mismatch repair(MMR) protein abnormality in Chinese colorectalcarcinoma(CRC) patients and their correlations with clinicopathologic features.METHODS:Clinical and pathological ...AIM:To investigate gene mutations and DNA mismatch repair(MMR) protein abnormality in Chinese colorectalcarcinoma(CRC) patients and their correlations with clinicopathologic features.METHODS:Clinical and pathological information for 535 patients including 538 tumors was reviewed and recorded.Mutation analyses for exon 2 of KRAS gene and exon 15 of BRAF gene were performed by Sanger sequencing except that in 9 tumors amplification refractory mutation system PCR was used.Expression of MMR proteins including MHL1,MSH2,MSH6 and PMS2 was evaluated by immunohistochemistry.Correlations of KRAS and BRAF mutation status and the expression status of MMR proteins with age,gender,cancer stage,location,and histology were analyzed.Correlations between KRAS or BRAF mutations and MMR protein expression were also explored.RESULTS:The overall frequencies of KRAS and BRAF mutations were 37.9% and 4.4%,respectively.KRAS mutations were more common in patients ≥ 50 years old(39.8% vs 22% in patients < 50 years old,P < 0.05).The frequencies of BRAF mutants were higher in tumors from females(6.6% vs males 2.8%,P < 0.05),located in the right colon(9.6% vs 2.1% in the left colon,1.8% in the rectum,P < 0.01),with mucinous differentiation(9.8% vs 2.8% without mucinous differentiation,P < 0.01),or being poorly differentiated(9.5% vs 3.4% well/moderately differentiated,P < 0.05).MMR deficiency was strongly associated with proximal location(20.5% in the right colon vs 9.2% in the left colon and 5.1% in the rectum,P < 0.001),early cancer stage(15.0% in stages Ⅰ-Ⅱ vs 7.7% in stages Ⅲ-Ⅳ,P < 0.05),and mucinous differentiation(20.2% vs 9.2% without mucin,P < 0.01).A higher frequency of MLH1/PMS2 loss was found in females(9.2% vs 4.4% in males,P < 0.05),and MSH2/MSH6 loss tended to be seen in younger(<50 years old) patients(12.0% vs 4.0% ≥ 50 years old,P < 0.05).MMR deficient tumors were less likely to have KRAS mutations(18.8% vs 41.7% in MMR proficient tumors,P < 0.05) and tumorswith abnormal MLH1/PMS2 tended to harbor BRAF mutations(15.4% vs 4.2% in MMR proficient tumors,P < 0.05).CONCLUSION:The frequency of sporadic CRCs having BRAF mutation,MLH1 deficiency and MSI in Chinese population may be lower than that in the Western population.展开更多
In recent decades, event-related potentials have been used for the clinical electrophysiological assessment of patients with disorders of consciousness （DOCs）. In this paper, an oddball paradigm with two types of fr...In recent decades, event-related potentials have been used for the clinical electrophysiological assessment of patients with disorders of consciousness （DOCs）. In this paper, an oddball paradigm with two types of frequencydeviant stimulus （standard stimuli were pure tones of 1000 Hz; small deviant stimuli were pure tones of 1050 Hz; large deviant stimuli were pure tones of 1200 Hz） was applied to elicit mismatch negativity （MMN） in 30 patients with DOCs diagnosed using the JFK Coma Recovery Scale- Revised （CRS-R）. The results showed that the peak amplitudes of MMN elicited by both large and small deviant stimuli were significantly different from baseline. In terms of the spatial properties of MMN, a significant interaction effect between conditions （small and large deviant stimuli） and electrode nodes was centered at the frontocentral area. Furthermore, correlation coefficients were calculated between MMN amplitudes and CRS-R scores for each electrode among all participants to generate topographic maps. Meanwhile, a significant negative correlation between the MMN amplitudes elicited by large deviant stimuli and the CRS-R scores was also found at the frontocentral area. In consequence, our results combine the above spatial properties of MMN in patients with DOCs, and provide a more precise location （frontocentral area） at which to evaluate the correlation between clinical electrophysiological assessment and the level of consciousness.展开更多
AIM:To analyze the mismatch repair(MMR)status and the ARID1A expression as well as their clinicopathological significance in gastric adenocarcinomas.METHODS:We examined the expressions of MMR proteins and ARID1A by im...AIM:To analyze the mismatch repair(MMR)status and the ARID1A expression as well as their clinicopathological significance in gastric adenocarcinomas.METHODS:We examined the expressions of MMR proteins and ARID1A by immunohistochemistry in consecutive 489 primary gastric adenocarcinomas.The results were further correlated with clinicopathological variables.RESULTS:The loss of any MMR protein expression,indicative of MMR deficiency,was observed in 38cases(7.8%)and was significantly associated with an older age(68.6±9.2 vs 60.4±11.7,P<0.001),a female sex(55.3%vs 31.3%,P=0.004),an antral location(44.7%vs 25.7%,P=0.021),and a differentiated histology(57.9%vs 39.7%,P=0.023).Abnormal ARID1A expression,including reduced or loss of ARID1A expression,was observed in 109 cases(22.3%)and was significantly correlated with lymphatic invasion(80.7%vs 69.5%,P=0.022)and lymph node metastasis(83.5%vs 73.7%,P=0.042).The tumors with abnormal ARID1A expression more frequently indicated MMR deficiency(47.4%vs 20.2%,P<0.001).A multivariate analysis identified abnormal ARID1A expression as an independent poor prognostic factor(HR=1.36,95%CI:1.01-1.84;P=0.040).CONCLUSION:Our observations suggest that the AIRD1A inactivation is associated with lymphatic invasion,lymph node metastasis,poor prognosis,and MMR deficiency in gastric adenocarcinomas.展开更多
AIM:To determine the prognostic significance of deficient mismatch repair(d MMR) and BRAF V600 E in Thai sporadic colorectal cancer(CRC) patients.METHODS:We studied a total of 211 out of 405 specimens obtained from ne...AIM:To determine the prognostic significance of deficient mismatch repair(d MMR) and BRAF V600 E in Thai sporadic colorectal cancer(CRC) patients.METHODS:We studied a total of 211 out of 405 specimens obtained from newly diagnosed CRC patients between October 1,2006 and December 31,2007 at Siriraj Hospital,Mahidol University.Formalinfixed paraffin-embedded blocks of CRC tissue samples w e re a n a l y ze d fo r d M M R b y d e t e c t i o n o f M M R protein expression loss by immunohistochemistry or microsatellite instability using polymerase chain reaction(PCR)-DHPLC.BRAF V600 E mutational analysis was performed in DNA extracted from the same archival tissues by two-round allele-specific PCR and analyzed by high sensitivity DHPLC.Associations between patient characteristics,MMR and BRAF status with diseasefree survival(DFS) and overall survival(OS) were determined by Kaplan-Meier survival plots and log-rank test together with Cox's proportional hazard regression.RESULTS:d MMR and BRAF V600 E mutations were identified in 31 of 208(14.9%) and 23 of 211(10.9%) tumors,respectively.d MMR was more commonly found in patients with primary colon tumors rather than rectal cancer(20.4% vs 7.6%,P =0.01),but there was no difference in MMR status between the right-sided and left-sided colon tumors(20.8% vs 34.6%,P = 0.24).d MMR was associated with early-stage rather than metastatic disease(17.3% vs 0%,P = 0.015).No clinicopathological features such primary site or tumor differentiation were associated with the BRAF mutation.Six of 31(19.3%) samples with d MMR carried the BRAFmutation,while 17 of 177(9.6%) with proficient MMR(p MMR) harbored the mutation(P = 0.11).Notably,patients with d MMR tumors had significantly superior DFS(HR = 0.30,95%CI:0.15-0.77; P = 0.01) and OS(HR = 0.29,95%CI:0.10-0.84; P = 0.02) compared with patients with p MMR tumors.By contrast,the BRAF V600 E mutation had no prognostic impact on DFS and OS.CONCLUSION:The prevalence of d MMR and BRAF V600 E in Thai sporadic CRC patients was 15% and 11%,respectively.The d MMR phenotype was associated with a favorable outcome.展开更多
In this experiment, 97 patients with obstructive sleep apnea hypopnea syndrome were divided into three groups （mild, moderate, severe） according to minimum oxygen saturation, and 35 healthy subjects were examined as...In this experiment, 97 patients with obstructive sleep apnea hypopnea syndrome were divided into three groups （mild, moderate, severe） according to minimum oxygen saturation, and 35 healthy subjects were examined as controls. Cognitive function was determined using the mismatch negativity paradigm and the Montreal Cognitive Assessment. The results revealed that as the disease worsened, the mismatch negativity latency was gradually extended, and the amplitude gradually declined in patients with obstructive sleep apnea hypopnea syndrome. Importantly, mismatch negativity latency in severe patients with a persistent time of minimum oxygen saturation 〈 60 seconds was significantly shorter than that with a persistent time of minimum oxygen saturation 〉 60 seconds. Correlation analysis revealed a negative correlation between minimum oxygen saturation latency and Montreal Cognitive Assessment scores. These findings indicate that intermittent night-time hypoxemia affects mismatch negativity waveforms and Montrea Cognitive Assessment scores. As indicators for detecting the cognitive functional status of obstructive sleep apnea hypopnea syndrome patients, the sensitivity of mismatch negativity is 82.93%, the specificity is 73.33%, the accuracy rate is 81.52%, the positive predictive value is 85.00%, the negative predictive value is 70.21%, the positive likelihood ratio is 3, and the negative likelihood ratio is 0.23. These results indicate that mismatch negativity can be used as an effective tool for diagnosis of cognitive dysfunction in obstructive sleep apnea hypopnea syndrome patients.展开更多
To develop a quantitative method for methylation analysis of the p16 gene based on mismatch hybridization and chemiluminescence. Methods Genomic DNA was modified by sodium bisulfite to convert all unmethylated but no...To develop a quantitative method for methylation analysis of the p16 gene based on mismatch hybridization and chemiluminescence. Methods Genomic DNA was modified by sodium bisulfite to convert all unmethylated but not methylated cytosines to uracil, and subsequently a pair of primer having no CpG sites was designed for amplification target DNA containing methylated or unmethylated CpG sites. The PCR product spanning CpG sites were hybridized with two oligonucleotide probes which perfectly matched the methylated and unmethylated CpG sequences respectively, and the hybrids were detected by chemiluminescent method. The percentage of methylated target sequences could be estimated by calculating the ratio of signals obtained with two probes. Results The percentage of methylation of artificial mixtures DNA showed a linear relation. There was a negative correlation between the methyaltion index with p16 transcriptional mRNA of p16 gene in tumor cell lines. Conclusion Compared with existing methods, this assay is nonisotopic, rapid, simple, and can be widely applied to the study of DNA methylation.展开更多
基金Supported by National Natural Science Foundation of China(Grant Nos.52325501,U24B2047).
文摘Current research on robot calibration can be roughly classified into two categories,and both of them have certain inherent limitations.Model-based methods are difficult to model and compensate the pose errors arising from configuration-dependent geometric and non-geometric source errors,whereas the accuracy of data-driven methods depends on a large amount of measurement data.Using a 5-DOF(degrees of freedom)hybrid machining robot as an exemplar,this study presents a model data-driven approach for the calibration of robotic manipulators.An f-DOF realistic robot containing various source errors is visualized as a 6-DOF fictitious robot having error-free parameters,but erroneous actuated/virtual joint motions.The calibration process essentially involves four steps:(1)formulating the linear map relating the pose error twist to the joint motion errors,(2)parameterizing the joint motion errors using second-order polynomials in terms of nominal actuated joint variables,(3)identifying the polynomial coefficients using the weighted least squares plus principal component analysis,and(4)compensating the compensable pose errors by updating the nominal actuated joint variables.The merit of this approach is that it enables compensation of the pose errors caused by configuration-dependent geometric and non-geometric source errors using finite measurement configurations.Experimental studies on a prototype machine illustrate the effectiveness of the proposed approach.
基金Brazilian National Program of Genomics and Precision Health-Genomas Brasil,Grant/Award Number:MS-SECTICS-Decit/CNPq 16/2023São Paulo Research Foundation,Grant/Award Number:FAPESP-2021/07957-5+5 种基金Barretos Cancer Hospital,Grant/Award Number:13/2021National Oncology Care Support Program (PRONON),CNPq,Grant/Award Number:444217/2023-1Public Ministry of Labor Campinas (Research, Prevention, and Education of Occupational Cancer)Brazilian Ministry of Health (MoH)National Council for Scientific and Technological DevelopmentCNPq Productivity
文摘Background:Constitutional mismatch repair deficiency(CMMRD)is a rare disorder resulting from biallelic germline pathogenic variants in mismatch repair genes.This study described the molecular profile of two metachronous brain tumors and a patient-derived xenograft(PDX)from a Brazilian child with CMMRD.Methods:After PDX development,methylation array,whole exome sequencing,and Nano String techniques were applied to describe the genetic landscape of CMMRD.Results:A 6½-year-old girl was diagnosed with Sonic Hedgehog(SHH)-activated medulloblastoma and somatic TP53-mutant.After surgery and radiochemotherapy,she remained free of disease progression.At 10 years and 3 months,she developed a diffuse pediatric-type high-grade glioma(dp HGG).The child had a family history of cancer,and subsequent investigation revealed a biallelic germline variant on MSH6(c.3556+1G>A)with the absence of protein expression in both normal and tumor tissue.A PDX model of the dp HGG was developed.The methylation profile confirmed the diagnosis of both brain tumors and PDX,refining the classification of dp HGG,Rtk1 subtype,subclass A,with an actionable alteration on Platelet-derived growth factor receptor A(PDGFRA).Exome analysis showed high tumor mutational burden,with 3019,540,and 1049 pathogenic variants in the medulloblastoma,dp HGG,and PDX,respectively.Only the medulloblastoma exhibited microsatellite instability.The CD24,CD47,and CD276 immune checkpoints had elevated messenger RNA levels,yet no programmed death ligand 1 expression was observed in CMMRD-derived tumors.Conclusion:We report an extensive molecular profile of a CMMRD patient,and the developed PDX model can be applied to explore new therapeutic approaches for CMMRD-associated brain tumors.
文摘BACKGROUND Mismatch repair deficient/microsatellite instability-high(MMR-D/MSI-H)colorectal cancers(CRCs)possess a distinctive genomic profile that results in a spectrum of phenotypic attributes setting them apart from their mismatch repair proficient(MMR-P)or microsatellite stable(MSS)counterparts.CRCs have several prognostic factors,including stage,tumor differentiation,location,lymphovascular and perineural invasion,tumor budding,tumor infiltrating lymphocytes,lymph node yield(LNY),and lymph node ratio(LNR).AIM To determine the unique phenotypic characteristics of MMR-D/MSI-H CRCs and leverage the conventional wisdom of LNY and LNR with the distinctive characteristics of MMR-D/MSI-H CRCs.METHODS This retrospective analysis involved 223 stage I-III CRC patients who underwent surgical resection without neoadjuvant treatment.Clinical and histological features were obtained from patient records and by re-examining the hematoxylin and eosin-stained slides.MMR/MSI status was evaluated for all patients using either MMR immunohistochemistry or MSI testing.RESULTS Of the 223 patients in our study,87(39.01%)were MMR-D/MSI-H CRCs while 136(60.99%)were MMR-P/MSS CRCs.The MMR-D/MSI-H CRCs exhibited significant statistical differences compared to the MMR-P/MSS CRCs in several factors,including location,stage,tumor budding,lymphovascular and perineural invasion,lymphocytic response,LNY,LNR,and size of uninvolved lymph nodes.LNY and LNR were significantly higher in MMR-D/MSI-H group compared with the MMR-P/MSS group(P=0.003 and P<0.001,respectively).Also,the interquartile range of the largest uninvolved lymph node was 1 cm(0.8 cm-1.2 cm)in MMR-D/MSI-H CRCs compared to 0.7 cm(0.6 cm-0.97 cm)in MMRP/MSS CRCs.The overall survival for the MMR-P/MSS CRC group was 71%at five years,and the MMR-D/MSIH CRC group was 92%at five years(P<0.001).CONCLUSION MMR-D/MSI-H CRCs possess a unique genomic profile that leads to distinct phenotypic characteristics,including an enhanced immune response.This distinctive profile underscores the substantial prognostic and predictive value of MMR-D/MSI-H status in CRC.
基金supported by The National Key Research and Development Program of China(Grant no.2021YFA0910100)Healthy Zhejiang One Million People Cohort(Grant no.K-20230085)+5 种基金Post-doctoral Innovative Talent Support Program(Grant no.BX2023375)Lingyan Project of Zhejiang Provincial Department of Science and Technology(Grant no.2025C02059)the National Natural Science Foundation of China(Grant nos.82304946,82473489,and 82403546)Natural Science Foundation of Zhejiang Province(Grant nos.LR21H280001,LGF22H160056,ZCLQN25H1602,and LMS25H160006)Medicine and Health Science Fund of Zhejiang Province Health Commission(Grant nos.2025KY047 and 2022KY658)Traditional Chinese Medicine Science and Technology Project of Zhejiang Provincial Health Commission(Grant no.2022ZA023).
文摘Gastric cancer(GC)remains a major global health challenge,because of its poor prognosis and limited treatment options in advanced stages1,2.Recent advancements in immunotherapy,highlighted by the findings of the CHECKMATE-649,ORIENT-16,and KEYNOTE-859 trials,have markedly transformed the treatment paradigm for advanced gastric cancer(AGC)3-5.
文摘BACKGROUND Colorectal cancer is one of the malignant tumors with a high incidence and mortality rate globally,and the occurrence of liver metastasis significantly affects patient survival prognosis.In recent years,the application of immune checkpoint inhibitors(ICIs)in cancer treatment has made important progress,especially showing good therapeutic effects in patients with high microsatellite instability or mismatch repair deficiency.However,for the majority of patients with microsatellite stable(MSS)or proficient mismatch repair(pMMR)colorectal cancer,the efficacy of ICIs is limited,prompting researchers to explore combination therapy strategies to improve efficacy.Targeted drugs such as tyrosine kinase inhibitors(TKIs)and radiotherapy are believed to work synergistically with ICIs by modifying the tumor microenvironment and enhancing antigen presentation.AIM To investigate the efficacy and safety of the combination therapy of radiotherapy,ICIs,and TKIs in patients with MSS or pMMR colorectal cancer liver metastasis(CCLM),in order to provide new clinical treatment references.METHODS A retrospective analysis was conducted on the clinical data of 43 MSS or pMMR CCLM patients treated at our hospital from September 2021 to July 2024.Based on the treatment interventions received,the patients were divided into a control group(n=21,receiving ICIs and TKIs combination therapy)and an observation group(n=22,receiving radiotherapy,ICIs,and TKIs triple therapy).The therapeutic effects,serum tumor markers(carcinoembryonic antigen and RESULTS The disease control rate in the observation group(63.64%)was significantly higher than that of the control group(23.81%)(P<0.05)).Both groups showed a decrease in carcinoembryonic antigen and carbohydrate antigen 199 levels post-treatment,with the observation group demonstrating a more significant change(P<0.05).The median progression-free survival and median overall survival in the control group were 5.1 months and 7.6 months,respectively,while the observation group had a median progression-free survival and overall survival of 4.3 months and 6.9 months,respectively.The control group had longer survival times than the observation group,but the differences were not statistically significant(P>0.05).The incidence of adverse reactions,including nausea and vomiting,gastrointestinal reactions,skin reactions,bone marrow suppression,liver and kidney function impairment,neurotoxicity,leukopenia,neutropenia,and thrombocytopenia,showed no significant differences between the two groups(P>0.05).CONCLUSION Compared to the ICIs and TKIs combination therapy,the radiotherapy,ICIs,and TKIs triple therapy can further improve the disease control rate and serum tumor marker levels in MSS or pMMR CCLM patients without increasing the risk of related adverse reactions,making it a treatment regimen worthy of further validation.
基金National Natural Science Foundation of China(No.42101346)Undergraduate Training Programs for Innovation and Entrepreneurship of Wuhan University(GeoAI Special Project)(No.202510486196).
文摘The rapid urbanization and structural imbalances in Chinese megacities have exacerbated the housing supplydemand mismatch,creating an urgent need for fine-scale diagnostic tools.This study addresses this critical gap by developing the Housing Contradiction Evaluation Weighted Index(HCEWI)model,making three key contributions to high-resolution housing monitoring.First,we establish a tripartite theoretical framework integrating dynamic population pressure(PPI),housing supply potential(HSI),and functional diversity(HHI).The PPI innovatively combines mobile signaling data with principal component analysis to capture real-time commuting patterns,while the HSI introduces a novel dual-criteria system based on Local Climate Zones(LCZ),weighted by building density and residential function ratio.Second,we develop a spatiotemporal coupling architecture featuring an entropy-weighted dynamic integration mechanism with self-correcting modules,demonstrating robust performance against data noise.Third,our 25-month longitudinal analysis in Shenzhen reveals significant findings,including persistent bipolar clustering patterns,contrasting volatility between peripheral and core areas,and seasonal policy responsiveness.Methodologically,we advance urban diagnostics through 500-meter grid monthly monitoring and process-oriented temporal operators that reveal“tentacle-like”spatial restructuring along transit corridors.Our findings provide a replicable framework for precision housing governance and demonstrate the transformative potential of mobile signaling data in implementing China’s“city-specific policy”approach.We further propose targeted intervention strategies,including balance regulation for high-contradiction zones,Transit-Oriented Development(TOD)activation for low-contradiction clusters,and dynamic land conversion mechanisms for transitional areas.
文摘为提高零中频接收机中正交(in-phase quadrature,IQ)失配信号校正的收敛速度与鲁棒性,本文将Kalman滤波算法与盲源分离结构结合,提出了一种基于双通道Kalman滤波的校正算法。该算法通过状态空间建模与协方差自适应更新,能够在动态环境下实现更高效、稳定的参数估计,从而实现对IQ失配信号的有效补偿。将本文算法与最小均方算法(least mean square,LMS)、归一化最小均方算法(normalized least mean square,NLMS)和仿射投影算法(affine projection algorithm,APA)进行对比仿真,结果显示,校正后信号的镜像抑制比(image rejection ratio,IRR)均达到约45 dB,但双通道Kalman滤波算法对应的IRR曲面图更加平滑,同时,16QAM和16PSK调制方式下该算法的误符号率最低,表明本文算法能够有效实现IQ失配校正,具有较好的稳定性。本文算法迭代约50次时,均方误差收敛趋近于0,而LMS、NLMS和APA算法则分别需要迭代约500次、400次和200次才能够收敛,表明该算法具有较好的收敛性。通过参数的敏感性仿真分析,在较大的参数范围内本文算法达到的IRR差别甚微,具有良好的鲁棒性。
基金Supported by Grant from the Xinjiang Uygur Autonomous Region Natural Science Fund,No.201233146-14(partly)
文摘AIM:To investigate gene mutations and DNA mismatch repair(MMR) protein abnormality in Chinese colorectalcarcinoma(CRC) patients and their correlations with clinicopathologic features.METHODS:Clinical and pathological information for 535 patients including 538 tumors was reviewed and recorded.Mutation analyses for exon 2 of KRAS gene and exon 15 of BRAF gene were performed by Sanger sequencing except that in 9 tumors amplification refractory mutation system PCR was used.Expression of MMR proteins including MHL1,MSH2,MSH6 and PMS2 was evaluated by immunohistochemistry.Correlations of KRAS and BRAF mutation status and the expression status of MMR proteins with age,gender,cancer stage,location,and histology were analyzed.Correlations between KRAS or BRAF mutations and MMR protein expression were also explored.RESULTS:The overall frequencies of KRAS and BRAF mutations were 37.9% and 4.4%,respectively.KRAS mutations were more common in patients ≥ 50 years old(39.8% vs 22% in patients < 50 years old,P < 0.05).The frequencies of BRAF mutants were higher in tumors from females(6.6% vs males 2.8%,P < 0.05),located in the right colon(9.6% vs 2.1% in the left colon,1.8% in the rectum,P < 0.01),with mucinous differentiation(9.8% vs 2.8% without mucinous differentiation,P < 0.01),or being poorly differentiated(9.5% vs 3.4% well/moderately differentiated,P < 0.05).MMR deficiency was strongly associated with proximal location(20.5% in the right colon vs 9.2% in the left colon and 5.1% in the rectum,P < 0.001),early cancer stage(15.0% in stages Ⅰ-Ⅱ vs 7.7% in stages Ⅲ-Ⅳ,P < 0.05),and mucinous differentiation(20.2% vs 9.2% without mucin,P < 0.01).A higher frequency of MLH1/PMS2 loss was found in females(9.2% vs 4.4% in males,P < 0.05),and MSH2/MSH6 loss tended to be seen in younger(<50 years old) patients(12.0% vs 4.0% ≥ 50 years old,P < 0.05).MMR deficient tumors were less likely to have KRAS mutations(18.8% vs 41.7% in MMR proficient tumors,P < 0.05) and tumorswith abnormal MLH1/PMS2 tended to harbor BRAF mutations(15.4% vs 4.2% in MMR proficient tumors,P < 0.05).CONCLUSION:The frequency of sporadic CRCs having BRAF mutation,MLH1 deficiency and MSI in Chinese population may be lower than that in the Western population.
基金supported by the National Natural Science Foundation of China (81471742, 91748105)Fundamental Research Funds for the Central Universities [DUT16JJ(G)03] in Dalian University of Technology, China
文摘In recent decades, event-related potentials have been used for the clinical electrophysiological assessment of patients with disorders of consciousness （DOCs）. In this paper, an oddball paradigm with two types of frequencydeviant stimulus （standard stimuli were pure tones of 1000 Hz; small deviant stimuli were pure tones of 1050 Hz; large deviant stimuli were pure tones of 1200 Hz） was applied to elicit mismatch negativity （MMN） in 30 patients with DOCs diagnosed using the JFK Coma Recovery Scale- Revised （CRS-R）. The results showed that the peak amplitudes of MMN elicited by both large and small deviant stimuli were significantly different from baseline. In terms of the spatial properties of MMN, a significant interaction effect between conditions （small and large deviant stimuli） and electrode nodes was centered at the frontocentral area. Furthermore, correlation coefficients were calculated between MMN amplitudes and CRS-R scores for each electrode among all participants to generate topographic maps. Meanwhile, a significant negative correlation between the MMN amplitudes elicited by large deviant stimuli and the CRS-R scores was also found at the frontocentral area. In consequence, our results combine the above spatial properties of MMN in patients with DOCs, and provide a more precise location （frontocentral area） at which to evaluate the correlation between clinical electrophysiological assessment and the level of consciousness.
文摘AIM:To analyze the mismatch repair(MMR)status and the ARID1A expression as well as their clinicopathological significance in gastric adenocarcinomas.METHODS:We examined the expressions of MMR proteins and ARID1A by immunohistochemistry in consecutive 489 primary gastric adenocarcinomas.The results were further correlated with clinicopathological variables.RESULTS:The loss of any MMR protein expression,indicative of MMR deficiency,was observed in 38cases(7.8%)and was significantly associated with an older age(68.6±9.2 vs 60.4±11.7,P<0.001),a female sex(55.3%vs 31.3%,P=0.004),an antral location(44.7%vs 25.7%,P=0.021),and a differentiated histology(57.9%vs 39.7%,P=0.023).Abnormal ARID1A expression,including reduced or loss of ARID1A expression,was observed in 109 cases(22.3%)and was significantly correlated with lymphatic invasion(80.7%vs 69.5%,P=0.022)and lymph node metastasis(83.5%vs 73.7%,P=0.042).The tumors with abnormal ARID1A expression more frequently indicated MMR deficiency(47.4%vs 20.2%,P<0.001).A multivariate analysis identified abnormal ARID1A expression as an independent poor prognostic factor(HR=1.36,95%CI:1.01-1.84;P=0.040).CONCLUSION:Our observations suggest that the AIRD1A inactivation is associated with lymphatic invasion,lymph node metastasis,poor prognosis,and MMR deficiency in gastric adenocarcinomas.
基金Supported by Siriraj Research Development Fund No.459/2554(EC2)
文摘AIM:To determine the prognostic significance of deficient mismatch repair(d MMR) and BRAF V600 E in Thai sporadic colorectal cancer(CRC) patients.METHODS:We studied a total of 211 out of 405 specimens obtained from newly diagnosed CRC patients between October 1,2006 and December 31,2007 at Siriraj Hospital,Mahidol University.Formalinfixed paraffin-embedded blocks of CRC tissue samples w e re a n a l y ze d fo r d M M R b y d e t e c t i o n o f M M R protein expression loss by immunohistochemistry or microsatellite instability using polymerase chain reaction(PCR)-DHPLC.BRAF V600 E mutational analysis was performed in DNA extracted from the same archival tissues by two-round allele-specific PCR and analyzed by high sensitivity DHPLC.Associations between patient characteristics,MMR and BRAF status with diseasefree survival(DFS) and overall survival(OS) were determined by Kaplan-Meier survival plots and log-rank test together with Cox's proportional hazard regression.RESULTS:d MMR and BRAF V600 E mutations were identified in 31 of 208(14.9%) and 23 of 211(10.9%) tumors,respectively.d MMR was more commonly found in patients with primary colon tumors rather than rectal cancer(20.4% vs 7.6%,P =0.01),but there was no difference in MMR status between the right-sided and left-sided colon tumors(20.8% vs 34.6%,P = 0.24).d MMR was associated with early-stage rather than metastatic disease(17.3% vs 0%,P = 0.015).No clinicopathological features such primary site or tumor differentiation were associated with the BRAF mutation.Six of 31(19.3%) samples with d MMR carried the BRAFmutation,while 17 of 177(9.6%) with proficient MMR(p MMR) harbored the mutation(P = 0.11).Notably,patients with d MMR tumors had significantly superior DFS(HR = 0.30,95%CI:0.15-0.77; P = 0.01) and OS(HR = 0.29,95%CI:0.10-0.84; P = 0.02) compared with patients with p MMR tumors.By contrast,the BRAF V600 E mutation had no prognostic impact on DFS and OS.CONCLUSION:The prevalence of d MMR and BRAF V600 E in Thai sporadic CRC patients was 15% and 11%,respectively.The d MMR phenotype was associated with a favorable outcome.
基金supported by the National Natural Science Foundation of China,No. 30973309
文摘In this experiment, 97 patients with obstructive sleep apnea hypopnea syndrome were divided into three groups （mild, moderate, severe） according to minimum oxygen saturation, and 35 healthy subjects were examined as controls. Cognitive function was determined using the mismatch negativity paradigm and the Montreal Cognitive Assessment. The results revealed that as the disease worsened, the mismatch negativity latency was gradually extended, and the amplitude gradually declined in patients with obstructive sleep apnea hypopnea syndrome. Importantly, mismatch negativity latency in severe patients with a persistent time of minimum oxygen saturation 〈 60 seconds was significantly shorter than that with a persistent time of minimum oxygen saturation 〉 60 seconds. Correlation analysis revealed a negative correlation between minimum oxygen saturation latency and Montreal Cognitive Assessment scores. These findings indicate that intermittent night-time hypoxemia affects mismatch negativity waveforms and Montrea Cognitive Assessment scores. As indicators for detecting the cognitive functional status of obstructive sleep apnea hypopnea syndrome patients, the sensitivity of mismatch negativity is 82.93%, the specificity is 73.33%, the accuracy rate is 81.52%, the positive predictive value is 85.00%, the negative predictive value is 70.21%, the positive likelihood ratio is 3, and the negative likelihood ratio is 0.23. These results indicate that mismatch negativity can be used as an effective tool for diagnosis of cognitive dysfunction in obstructive sleep apnea hypopnea syndrome patients.
基金This work was supported by the National Natural Science Foundation of China (Grant No. 39990570).
文摘To develop a quantitative method for methylation analysis of the p16 gene based on mismatch hybridization and chemiluminescence. Methods Genomic DNA was modified by sodium bisulfite to convert all unmethylated but not methylated cytosines to uracil, and subsequently a pair of primer having no CpG sites was designed for amplification target DNA containing methylated or unmethylated CpG sites. The PCR product spanning CpG sites were hybridized with two oligonucleotide probes which perfectly matched the methylated and unmethylated CpG sequences respectively, and the hybrids were detected by chemiluminescent method. The percentage of methylated target sequences could be estimated by calculating the ratio of signals obtained with two probes. Results The percentage of methylation of artificial mixtures DNA showed a linear relation. There was a negative correlation between the methyaltion index with p16 transcriptional mRNA of p16 gene in tumor cell lines. Conclusion Compared with existing methods, this assay is nonisotopic, rapid, simple, and can be widely applied to the study of DNA methylation.
