In this paper,6 mm thick 2219-T6 aluminum alloy was joined by means of variable polarity tungsten-arc welding( VP-TIG) and the influence of gradient mismatches on VP-TIG joints is investigated. The average tensile str...In this paper,6 mm thick 2219-T6 aluminum alloy was joined by means of variable polarity tungsten-arc welding( VP-TIG) and the influence of gradient mismatches on VP-TIG joints is investigated. The average tensile strength of the joints reduces 32%,53% and 59%,when the mismatch of the joint was 0. 635 mm,1. 44 mm,1. 83 mm,respectively.Incomplete penetration,additional bending moment( Ma) and decrease of effective load region area are considered to explain this phenomenon. The fracture location of tensile specimens occurred at the weld zone( WZ) close to partial melt zone( PMZ),corresponding to a sharp decline of microhardness from PMZ to WZ. The original position of fracture is found at weld toe,where incomplete penetration forms due to the introduction of gradient mismatches.展开更多
G-A mismatches are non-canonical base pairs that widely occur in native nucleic acids. They have been found to be functionally important in adopting unusual structures. In this paper, G-A mispairing was studied by Ram...G-A mismatches are non-canonical base pairs that widely occur in native nucleic acids. They have been found to be functionally important in adopting unusual structures. In this paper, G-A mispairing was studied by Raman spectral characterization of Polyadenylic acid （PolyA）, Polyguanylic acid （PolyG） and their equimolar mixture in solution of 0.08 mol/L Na^＋, pH7.0. The experiment showed the following three results. （1） At the experimental conditions used in the present work, PolyA and G A complexes existed as single-stranded and double-stranded helix of A form, respectively. And PolyG mainly occurred to be anti-parallel quadruplex conformers. （2） The formation of G A complexes, on one hand strengthened parts of base stacking interactions especially for PolyG, leading to Raman hypochromism effect with some corresponding bands shifting, and on the other hand weakened other base stacking interactions especially for PolyA to a certain degree. During this process, the backbone of PolyG underwent a significant change, but PolyA still conserved its main chain conformation. （3） The formation of G A complexes was stabilized by two interbase hydrogen- bond interactions （i.e. N6H2（A）-N3 （G） and N7 （A）--N2H2（G）） and a third hydrogen bond between O2^＋ （G） and N6 （A）. The third hydrogen bond was responsible for the remarkable changes of PolyG backbone conformation.展开更多
A correlation-based digital background calibration algorithm for pipelined Analog-to- Digital Converters (ADCs) is presented in this paper. The merit of the calibration algorithm is that the main errors information, w...A correlation-based digital background calibration algorithm for pipelined Analog-to- Digital Converters (ADCs) is presented in this paper. The merit of the calibration algorithm is that the main errors information, which include the capacitor mismatches and residue amplifier distortion, are extracted integrally. A modified 1st pipelined stage is adopted to solve the signal overflow caused by the Pseudo-random Noise (PN) sequences. Behavioral simulation results verify the effectiveness of the algorithm. It improves the Signal-to-Noise-plus-Distortion Ratio (SNDR) and Spurious-Free-Dynamic-Range (SFDR) of the pipelined ADC from 41.8 dB to 78.3 dB and 55.6 dB to 98.6 dB, respectively, which is comparable to the prior arts.展开更多
Event-related potential (ERP) studies demonstrated that emotional state immediately affects the processing of different linguistic mismatches (e.g., semantic and syntactic mismatches) in sentences. Furthermore, mood h...Event-related potential (ERP) studies demonstrated that emotional state immediately affects the processing of different linguistic mismatches (e.g., semantic and syntactic mismatches) in sentences. Furthermore, mood has been shown to impact discourse processing. In these studies, a strong expectancy was evoked by a linguistic context. In the present study, a strong expectancy was induced by a visual (non-linguistic) context paired with a sentence. A spatial array was followed by a sentence that matched (□○—The square stands in front of the circle) or mismatched the picture (intra-dimensional mismatch: □○—The square stands behind the circle;extra-dimensional mismatch: □○—The square stands above the circle). The main question was whether mood effects on the processing of visually induced expectancies are similar or different from mood effects on the processing of linguistically induced expectancies. To this aim, we presented conceptual (mis)matches that differed in saliency: intra-dimensional vs. extra-dimensional mismatches which are both reported to elicit an N2b/N400 and P600, reflecting reanalysis. EEG was recorded while participants read for comprehension. Mood (happy vs. sad) was effectively induced by film clips. Neither for N2b/N400 nor for P600, an interaction between mood and match was observed. Thus, in contrast with studies investigating the effects of pure linguistic mismatches (linguistic context paired with unexpected lexical item), mood did not modulate the processing of conceptual mismatches. However, a main effect of match revealed different ERP patterns for the two mismatches. While an increase in N2b/ N400 occurred for the intra-dimensional and extra-dimensional mismatches, a P600 only occurred to the extra-dimensional (more salient) mismatches. This finding is taken as support that being in an emotional state (positive or negative mood) influences processes of reanalysis. That is, when being in an emotional state, a reanalysis (monitoring) process is exclusively triggered by salient mismatches.展开更多
The effect of system mismatches on an adaptive linear constrained generalized sidelobe canceller （LC-GSC） is discussed in this paper. Based on the array gain index, two classic system mismatches, the direction of ar...The effect of system mismatches on an adaptive linear constrained generalized sidelobe canceller （LC-GSC） is discussed in this paper. Based on the array gain index, two classic system mismatches, the direction of arrival （DOA） mismatch and the mismatches arising from array disturbance, are studied, respectively. To obtain the effective methods for compensating for the system mismatches, we analyze the performance of the improved LC-GSC with the diagonal loading and additional constraints （such as the directional constraints and derivative constraints）. The computer simulations show that the techniques of diagonal loading and additional constraints can effectively compensate for the system mismatches. The loss of array gains can be controlled within 3 dB in the presence of 20% of array disturbances or DOA mismatch when the signal-to-noise ratio is less than 10 dB. The analysis illustrates that the proposed compensation methods are valid and feasible.展开更多
Mismatches in spatial scales,or spatial disconnections between causes and effects of ecosystem degradation,can reduce resilience in social–ecological systems.These mismatches can be particularly disruptive in coastal...Mismatches in spatial scales,or spatial disconnections between causes and effects of ecosystem degradation,can reduce resilience in social–ecological systems.These mismatches can be particularly disruptive in coastal and marine areas,where multiple social and ecological systems are multi-layered.Scotland’s Western Isles have a history of local resource exploitation to meet extra-regional,larger-scale demands,which has resulted in a long process of socio-demographic decline.Salmon aquaculture is a major and expanding industry in the area,often linked to“Blue Growth”.The expansion of this industry operates within and contributes to create several scale mismatches.Combining a systems approach across nested scales with a classification of scale mismatches,this work analyses the characteristics of the Western Isles salmon aquaculture industry,and it explores effects on social–ecological resilience.An extent scale mismatch between the global stocks of fishmeal species and the local capacity to respond to fluctuations is identified.The implications for this mismatch for the Western Isles are discussed.Some potential policy arrangements for incorporating matched spatial scales are considered.展开更多
Objective To analyze allele mismatches of HLA-A,-B,-C,-DRB1,-DQB1 and haplotype mismatch of donor-recipient pairs on the outcome of haploidentical transplantation combined with a third part cord blood unit.Methods 230...Objective To analyze allele mismatches of HLA-A,-B,-C,-DRB1,-DQB1 and haplotype mismatch of donor-recipient pairs on the outcome of haploidentical transplantation combined with a third part cord blood unit.Methods 230 pairs of donor-recipient were performed HLA-A,B,C,DRB1,DQB1 typing using展开更多
High microsatellite instability(MSI-H)colorectal cancer(CRC),caused by deficient mismatch repair,accounts for about 15%of all CRC cases and is more common in right-sided tumors.While early-stage MSI-H CRC has a relati...High microsatellite instability(MSI-H)colorectal cancer(CRC),caused by deficient mismatch repair,accounts for about 15%of all CRC cases and is more common in right-sided tumors.While early-stage MSI-H CRC has a relatively good prognosis,advanced cases often respond poorly to standard chemotherapy.Immune checkpoint inhibitors,such as pembrolizumab,have shown strong and lasting effects in MSI-H CRC.Pembrolizumab is now approved as a first-line treatment for metastatic MSI-H CRC due to its superior outcomes compared to traditional chemotherapy.CASE SUMMARY A 44-year-old male with MSI-H transverse colon cancer presented with hematochezia,abdominal pain,and significant weight loss.Imaging revealed a bulky tumor with invasion of adjacent structures and multiple liver lesions.A diverting ileostomy was performed followed by 36 cycles of pembrolizumab.The patient achieved a clinical and radiologic complete response.One month after completing the treatment,the patient underwent laparoscopic right hemicolectomy.A spontaneous transection of the colon at the original tumor site was unexpectedly identified.Final pathology confirmed pathological complete response(ypT0N0)with fibrosis.The patient recovered well after surgery,and follow-up showed no evidence of recurrence.CONCLUSION Immune checkpoint inhibitors may cause delayed structural damage to bowel tissue even after apparent complete tumor regression.展开更多
BACKGROUND Immunotherapy is an approved treatment for metastatic rectal cancer in patients with defective mismatch repair(MMR).AIM To examine the clinical efficacy of neoadjuvant immunotherapy combined with radiothera...BACKGROUND Immunotherapy is an approved treatment for metastatic rectal cancer in patients with defective mismatch repair(MMR).AIM To examine the clinical efficacy of neoadjuvant immunotherapy combined with radiotherapy and chemotherapy for the treatment of locally advanced rectal cancer(LARC),with a focus on patients with proficient MMR(pMMR)and mic-rosatellite stability.METHODS Two researchers searched multiple databases for publications up to September 2024.All included publications examined neoadjuvant immunotherapy for LARC,and reported major pathological response(MPR),pathological complete response(pCR),clinical complete response(CCR),and rates of R0 resection and anus-pre-serving surgery.Meta-analysis,subgroup analysis,sensitivity analysis,and ana-lysis of publication bias were performed.RESULTS We included 15 publications(796 patients).The MPR,pCR,and CCR were sig-nificantly better in the group that received immunotherapy(all P<0.05),espe-cially for patients with pMMR.In addition,the rate of R0 resection and anus-preserving surgery were also significantly greater in the group that received neoadjuvant immunotherapy(both P<0.05).Hematological toxicity and abnormal liver function were the most common clinical adverse events above grade 3.Most patients successfully completed the immunotherapy treatment.The incidence of immune-related adverse reactions was 0%-13.5%,and the severities of these events were generally considered acceptable.CONCLUSION The addition of neoadjuvant immunotherapy improved the clinical remission rate of patients who had LARC with pMMR,and the treatment-related adverse reactions were generally acceptable.Neoadjuvant immunotherapy combined with radiotherapy and chemotherapy should be considered for patients with LARC.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 Endoscopy allows for the direct observation of primary tumor characteristics and responses after neoadjuvant treatment.However,reports on endoscopic evaluation following neoadjuvant immunotherapy remain lim...BACKGROUND Endoscopy allows for the direct observation of primary tumor characteristics and responses after neoadjuvant treatment.However,reports on endoscopic evaluation following neoadjuvant immunotherapy remain limited.AIM To examine the predictive value of endoscopic findings of primary tumors for responses to neoadjuvant immunotherapy.METHODS This retrospective study,conducted at a tertiary center in China,evaluated 74 patients with colorectal cancer,including 17 with deficient mismatch repair(dMMR)and 15 with proficient mismatch repair(pMMR)tumors.Patients underwent neoadjuvant immunotherapy followed by surgery.Endoscopic findings before and after neoadjuvant immunotherapy were reviewed and compared with the pathology of the resected specimens.RESULTS In the pMMR group(n=57 evaluable patients),endoscopy identified 11/17 patients who achieved a complete response(CR),while misidentifying 1/40 patients with residual disease as CR(64.7%vs 2.5%,P<0.01).Conversely,22/40 patients with residual disease were accurately identified as achieving a partial response(PR),with 1/17 patients who achieved CR misclassified as PR(55.0%vs 5.9%,P<0.01).The sensitivity,specificity,and accuracy of endoscopic diagnosis for pathological CR were 64.7%,97.5%,and 87.7%,respectively.In the dMMR cohort,endoscopy classified 9/17 patients as CR and 2 of the remaining patients with residual tumors as PR(64.3%vs 66.7%,P=0.73).The method demonstrated 100%sensitivity and 82.4%accuracy in diagnosing pathological CR.CONCLUSION Endoscopic evidence of CR or PR was well correlated with postoperative pathological outcomes in the pMMR cohort.Despite endoscopic indications of tumor residue,a complete pathological response post-surgery was possible in the dMMR cohort.展开更多
BACKGROUND Hereditary factors are more prevalent in early-onset colorectal cancers(EOCRC)etiology.Lynch syndrome(LS)is the most common hereditary colorectal cancer(CRC)syndrome that results from mutations in DNA misma...BACKGROUND Hereditary factors are more prevalent in early-onset colorectal cancers(EOCRC)etiology.Lynch syndrome(LS)is the most common hereditary colorectal cancer(CRC)syndrome that results from mutations in DNA mismatch repair(MMR)genes.This phenomenon is defined as microsatellite instability(MSI).Immunohistochemistry(IHC)is a widely used,practical,and cost-effective method for the screening of MSI.However,using IHC alone may be insufficient to identify patients with MSI and LS.AIM To determine the clinicopathological features in EOCRC,IHC performance,and the frequency of genetic testing for EOCRC patients.METHODS A retrospective review was conducted on patients with CRC aged≤50 years who underwent surgery at our center between January 2014 and July 2021.MMR proteins were screened using IHC.Of the 131 patients included,IHC was performed on 130.Patients were classified as MSI or microsatellite-stable(MSS),and their features were compared.Additionally,data from patients who received genetic counseling were analyzed.RESULTS Thirty patients with MSI were designated as group 1,whereas 100 with MSS were defined as group 2.The mean age in group 1 was the lowest(median age:42 vs 46,P<0.05).Group 1 exhibited a higher frequency of tumors in the right colon and a lower frequency in the rectum.Lymph node involvement and distant metastases were less common in group 1,and in group 2,tumors were generally diagnosed at a more advanced stage.Genetic testing was performed in 53 patients(40%),with a definitive LS diagnosis established in 13/17 patients(76.4%)in group 1 and 1/36(2.7%)patients in group 2,resulting in a total of 14 patients(26.4%)with confirmed LS.CONCLUSION MSI tumors show a better prognosis.IHC is very effective for screening MSI,but may not be sufficient alone.Low genetic counseling rates highlight the need for hospital-based surveillance programs.展开更多
This study explores the relationship between corporate environmental,social,and governance(ESG)disagreements and corporate debt maturity.By examining panel samples from Chinese non-financial listed companies covering ...This study explores the relationship between corporate environmental,social,and governance(ESG)disagreements and corporate debt maturity.By examining panel samples from Chinese non-financial listed companies covering 2007 to 2020,we find that ESG disagreements negatively influence corporate debt maturity.Even after conducting a series of robustness tests and addressing endogeneity concerns,the adverse effects of ESG disagreements persisted.A heterogeneity analysis shows that this negative impact is more significant for non-state-owned enterprises,small enterprises,enterprises with high capital intensity,enterprises with low analyst attention,and enterprises in high-tech industries.Through a mechanism analysis,we discovered that ESG disagreements can lead to information asymmetry and heightened default risk,subsequently affecting the maturity of corporate debt.Further analysis confirms that the negative impact of ESG on the debt structure inhibits long-term investment and exacerbates the mismatch between investment and financing terms.展开更多
Colon cancer(CC)laterality(right vs left)is recognized as a key determinant of clinical outcomes and treatment decisions in metastatic CC.Right-sided CC(RCC)often presents in older individuals and is associated with h...Colon cancer(CC)laterality(right vs left)is recognized as a key determinant of clinical outcomes and treatment decisions in metastatic CC.Right-sided CC(RCC)often presents in older individuals and is associated with higher rates of Kirsten rat sarcoma viral oncogene homolog and v-raf murine sarcoma viral oncogene homolog B1 mutations and deficient mismatch repair,leading to microsatellite instability-high status.Left-sided CC typically presents in younger individuals,demonstrates a more favorable prognosis,and is often Kirsten rat sarcoma viral oncogene homolog/neuroblastoma RAS viral oncogene homolog/v-raf murine sarcoma viral oncogene homolog B1 wild-type,making it more responsive to antiepidermal growth factor receptor therapy.RCC typically responds poorly to antiepidermal growth factor receptor agents;however,it may benefit from triplet chemotherapy(5-fluorouracil+leucovorin+oxaliplatin+irinotecan)with or without anti-angiogenic agents.Comprehensive molecular profiling remains challenging in low-resource settings due to limited access to advanced diagnostic tools.This review explores key epidemiological and molecular differences between RCC and left-sided CC.In the absence of complete genomic data,tumor sidedness can be a helpful guide for making treatment decisions.Here,we propose a practical algorithm that integrates basic immunohistochemistry to assess a tumor’s mismatch repair status and laterality,potentially facilitating therapy selection in resource-constrained environments.Recognizing laterality-specific trends in prognosis and treatment response can improve personalized care and outcomes for patients with CC in these environments,highlighting the essential role of cost-effective biomarker strategies.展开更多
Accurately correlating the sweating rate and the concentration of biomarkers in sweat is essential in many sweat-based diagnostic applications.These two measurements are always done simultaneously in wearable sweat se...Accurately correlating the sweating rate and the concentration of biomarkers in sweat is essential in many sweat-based diagnostic applications.These two measurements are always done simultaneously in wearable sweat sensing platforms.However,concentration measurements of biomarkers are always delayed on the timeline compared with their production,whereas there is no such delay for sweating rate.Thus,a timeline mismatch exists between these two measurements.This means that the concentration vs rate correlation constructed on the basis of such measurements will deviate from the actual correlation.This study demonstrates the existence of this mismatch and explains its cause using sweat Na^(+)measurements.It also proposes an effective approach that applies a point-by-point compensation for the delay between Na+measurements and the real-time sweating rates,such that the data on the repositioned concentration vs time curve correspond to exactly the same point on the timeline as their production.A vison sensor is developed to measure the sweating rate with high accuracy at a frequency of more than 0.1 Hz.Off-body and on-body measurements of sweating rate and Na^(+)concentration are carried out,and concentration–rate correlations are constructed using both measured and repositioned concentration curves.The least squares and random forest methods are employed to fit the constructed correlations and evaluate the reliability of the proposed approach.The use of the repositioned concentration curve gives a constructed correlation that is much closer to the actual one.This study indicates the necessity to rearrange sensor-measured biomarker concentration vs time curves when correlations of concentration with sweating rate need to be constructed and proposes a practical point-by-point data repositioning strategy for doing so.The results presented here will benefit the study of sweat biomarkers with unclear correlations with sweating rate,as well as providing a basis for the development of more reliable sweat-based diagnostic methods.展开更多
Industrial data mining usually deals with data from different sources.These heterogeneous datasets describe the same object in different views.However,samples from some of the datasets may be lost.Then the remaining s...Industrial data mining usually deals with data from different sources.These heterogeneous datasets describe the same object in different views.However,samples from some of the datasets may be lost.Then the remaining samples do not correspond one-to-one correctly.Mismatched datasets caused by missing samples make the industrial data unavailable for further machine learning.In order to align the mismatched samples,this article presents a cooperative iteration matching method(CIMM)based on the modified dynamic time warping(DTW).The proposed method regards the sequentially accumulated industrial data as the time series.Mismatched samples are aligned by the DTW.In addition,dynamic constraints are applied to the warping distance of the DTW process to make the alignment more efficient.Then a series of models are trained with the cumulated samples iteratively.Several groups of numerical experiments on different missing patterns and missing locations are designed and analyzed to prove the effectiveness and the applicability of the proposed method.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
Copper matrix composites prepared via traditional methods face mechanical property and electrical conductivity trade-off problems.In this study,TiB_(2)/Cu−Cu heterogeneous laminated composites with submicron lamellar ...Copper matrix composites prepared via traditional methods face mechanical property and electrical conductivity trade-off problems.In this study,TiB_(2)/Cu−Cu heterogeneous laminated composites with submicron lamellar thicknesses were prepared via flake powder metallurgy(FPM)using gas-atomized in situ composite powders as raw material.By thermal mismatch strengthening,and the geometrically necessary dislocations(GNDs)generated by mechanically incompatible deformation between adjacent heterogeneous lamellae and their interaction with statistically stored dislocations(SSDs),the as-prepared TiB_(2)/Cu−Cu submicron laminated composites(SLCs)exhibit significantly enhanced mechanical properties.At the same time,the interaction and propagation of multimode cracks provide extrinsic toughening for SLCs.The pure Cu lamellae with low density grain boundaries and dislocations and no TiB_(2)particles provide a channel with little electron scattering for the rapid transport of carriers,thereby ensuring high electrical conductivity.展开更多
基金supported by the National Natural Science Foundation of China(No.50904020)the Fundamental Research Funds for the Central Universities(No.HIT.NSRIF.2012007)
文摘In this paper,6 mm thick 2219-T6 aluminum alloy was joined by means of variable polarity tungsten-arc welding( VP-TIG) and the influence of gradient mismatches on VP-TIG joints is investigated. The average tensile strength of the joints reduces 32%,53% and 59%,when the mismatch of the joint was 0. 635 mm,1. 44 mm,1. 83 mm,respectively.Incomplete penetration,additional bending moment( Ma) and decrease of effective load region area are considered to explain this phenomenon. The fracture location of tensile specimens occurred at the weld zone( WZ) close to partial melt zone( PMZ),corresponding to a sharp decline of microhardness from PMZ to WZ. The original position of fracture is found at weld toe,where incomplete penetration forms due to the introduction of gradient mismatches.
基金Project supported by the Natural Science Foundation of Guangdong Province, China （Grant No 021093） and Key-stone Science and Technology Foundation of Guangdong Province, China （Grant No 2KM04502S）.
文摘G-A mismatches are non-canonical base pairs that widely occur in native nucleic acids. They have been found to be functionally important in adopting unusual structures. In this paper, G-A mispairing was studied by Raman spectral characterization of Polyadenylic acid （PolyA）, Polyguanylic acid （PolyG） and their equimolar mixture in solution of 0.08 mol/L Na^＋, pH7.0. The experiment showed the following three results. （1） At the experimental conditions used in the present work, PolyA and G A complexes existed as single-stranded and double-stranded helix of A form, respectively. And PolyG mainly occurred to be anti-parallel quadruplex conformers. （2） The formation of G A complexes, on one hand strengthened parts of base stacking interactions especially for PolyG, leading to Raman hypochromism effect with some corresponding bands shifting, and on the other hand weakened other base stacking interactions especially for PolyA to a certain degree. During this process, the backbone of PolyG underwent a significant change, but PolyA still conserved its main chain conformation. （3） The formation of G A complexes was stabilized by two interbase hydrogen- bond interactions （i.e. N6H2（A）-N3 （G） and N7 （A）--N2H2（G）） and a third hydrogen bond between O2^＋ （G） and N6 （A）. The third hydrogen bond was responsible for the remarkable changes of PolyG backbone conformation.
基金Supported by the Doctoral Program Foundation of Institutions of Higher Education of China (No.20120111120008)State Key Lab of ASIC & System(Fudan University) (No. 11KF001)Special Fund for Doctoral Program (Hefei University of Technology) (No.2011HGBZ0953)
文摘A correlation-based digital background calibration algorithm for pipelined Analog-to- Digital Converters (ADCs) is presented in this paper. The merit of the calibration algorithm is that the main errors information, which include the capacitor mismatches and residue amplifier distortion, are extracted integrally. A modified 1st pipelined stage is adopted to solve the signal overflow caused by the Pseudo-random Noise (PN) sequences. Behavioral simulation results verify the effectiveness of the algorithm. It improves the Signal-to-Noise-plus-Distortion Ratio (SNDR) and Spurious-Free-Dynamic-Range (SFDR) of the pipelined ADC from 41.8 dB to 78.3 dB and 55.6 dB to 98.6 dB, respectively, which is comparable to the prior arts.
文摘Event-related potential (ERP) studies demonstrated that emotional state immediately affects the processing of different linguistic mismatches (e.g., semantic and syntactic mismatches) in sentences. Furthermore, mood has been shown to impact discourse processing. In these studies, a strong expectancy was evoked by a linguistic context. In the present study, a strong expectancy was induced by a visual (non-linguistic) context paired with a sentence. A spatial array was followed by a sentence that matched (□○—The square stands in front of the circle) or mismatched the picture (intra-dimensional mismatch: □○—The square stands behind the circle;extra-dimensional mismatch: □○—The square stands above the circle). The main question was whether mood effects on the processing of visually induced expectancies are similar or different from mood effects on the processing of linguistically induced expectancies. To this aim, we presented conceptual (mis)matches that differed in saliency: intra-dimensional vs. extra-dimensional mismatches which are both reported to elicit an N2b/N400 and P600, reflecting reanalysis. EEG was recorded while participants read for comprehension. Mood (happy vs. sad) was effectively induced by film clips. Neither for N2b/N400 nor for P600, an interaction between mood and match was observed. Thus, in contrast with studies investigating the effects of pure linguistic mismatches (linguistic context paired with unexpected lexical item), mood did not modulate the processing of conceptual mismatches. However, a main effect of match revealed different ERP patterns for the two mismatches. While an increase in N2b/ N400 occurred for the intra-dimensional and extra-dimensional mismatches, a P600 only occurred to the extra-dimensional (more salient) mismatches. This finding is taken as support that being in an emotional state (positive or negative mood) influences processes of reanalysis. That is, when being in an emotional state, a reanalysis (monitoring) process is exclusively triggered by salient mismatches.
基金supported by the Aviation Science Foundation of China under Grant No. 20112080014
文摘The effect of system mismatches on an adaptive linear constrained generalized sidelobe canceller （LC-GSC） is discussed in this paper. Based on the array gain index, two classic system mismatches, the direction of arrival （DOA） mismatch and the mismatches arising from array disturbance, are studied, respectively. To obtain the effective methods for compensating for the system mismatches, we analyze the performance of the improved LC-GSC with the diagonal loading and additional constraints （such as the directional constraints and derivative constraints）. The computer simulations show that the techniques of diagonal loading and additional constraints can effectively compensate for the system mismatches. The loss of array gains can be controlled within 3 dB in the presence of 20% of array disturbances or DOA mismatch when the signal-to-noise ratio is less than 10 dB. The analysis illustrates that the proposed compensation methods are valid and feasible.
文摘Mismatches in spatial scales,or spatial disconnections between causes and effects of ecosystem degradation,can reduce resilience in social–ecological systems.These mismatches can be particularly disruptive in coastal and marine areas,where multiple social and ecological systems are multi-layered.Scotland’s Western Isles have a history of local resource exploitation to meet extra-regional,larger-scale demands,which has resulted in a long process of socio-demographic decline.Salmon aquaculture is a major and expanding industry in the area,often linked to“Blue Growth”.The expansion of this industry operates within and contributes to create several scale mismatches.Combining a systems approach across nested scales with a classification of scale mismatches,this work analyses the characteristics of the Western Isles salmon aquaculture industry,and it explores effects on social–ecological resilience.An extent scale mismatch between the global stocks of fishmeal species and the local capacity to respond to fluctuations is identified.The implications for this mismatch for the Western Isles are discussed.Some potential policy arrangements for incorporating matched spatial scales are considered.
文摘Objective To analyze allele mismatches of HLA-A,-B,-C,-DRB1,-DQB1 and haplotype mismatch of donor-recipient pairs on the outcome of haploidentical transplantation combined with a third part cord blood unit.Methods 230 pairs of donor-recipient were performed HLA-A,B,C,DRB1,DQB1 typing using
文摘High microsatellite instability(MSI-H)colorectal cancer(CRC),caused by deficient mismatch repair,accounts for about 15%of all CRC cases and is more common in right-sided tumors.While early-stage MSI-H CRC has a relatively good prognosis,advanced cases often respond poorly to standard chemotherapy.Immune checkpoint inhibitors,such as pembrolizumab,have shown strong and lasting effects in MSI-H CRC.Pembrolizumab is now approved as a first-line treatment for metastatic MSI-H CRC due to its superior outcomes compared to traditional chemotherapy.CASE SUMMARY A 44-year-old male with MSI-H transverse colon cancer presented with hematochezia,abdominal pain,and significant weight loss.Imaging revealed a bulky tumor with invasion of adjacent structures and multiple liver lesions.A diverting ileostomy was performed followed by 36 cycles of pembrolizumab.The patient achieved a clinical and radiologic complete response.One month after completing the treatment,the patient underwent laparoscopic right hemicolectomy.A spontaneous transection of the colon at the original tumor site was unexpectedly identified.Final pathology confirmed pathological complete response(ypT0N0)with fibrosis.The patient recovered well after surgery,and follow-up showed no evidence of recurrence.CONCLUSION Immune checkpoint inhibitors may cause delayed structural damage to bowel tissue even after apparent complete tumor regression.
基金Supported by Start-up Fund for Doctor's Scientific Research in Shanxi Cancer Hospital,No.Dr202314and Natural Exploration Category of Shanxi Basic Research Plan,No.202203021221284.
文摘BACKGROUND Immunotherapy is an approved treatment for metastatic rectal cancer in patients with defective mismatch repair(MMR).AIM To examine the clinical efficacy of neoadjuvant immunotherapy combined with radiotherapy and chemotherapy for the treatment of locally advanced rectal cancer(LARC),with a focus on patients with proficient MMR(pMMR)and mic-rosatellite stability.METHODS Two researchers searched multiple databases for publications up to September 2024.All included publications examined neoadjuvant immunotherapy for LARC,and reported major pathological response(MPR),pathological complete response(pCR),clinical complete response(CCR),and rates of R0 resection and anus-pre-serving surgery.Meta-analysis,subgroup analysis,sensitivity analysis,and ana-lysis of publication bias were performed.RESULTS We included 15 publications(796 patients).The MPR,pCR,and CCR were sig-nificantly better in the group that received immunotherapy(all P<0.05),espe-cially for patients with pMMR.In addition,the rate of R0 resection and anus-preserving surgery were also significantly greater in the group that received neoadjuvant immunotherapy(both P<0.05).Hematological toxicity and abnormal liver function were the most common clinical adverse events above grade 3.Most patients successfully completed the immunotherapy treatment.The incidence of immune-related adverse reactions was 0%-13.5%,and the severities of these events were generally considered acceptable.CONCLUSION The addition of neoadjuvant immunotherapy improved the clinical remission rate of patients who had LARC with pMMR,and the treatment-related adverse reactions were generally acceptable.Neoadjuvant immunotherapy combined with radiotherapy and chemotherapy should be considered for patients with LARC.
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.
基金Supported by the National Natural Science Foundation of China,No.82072732.
文摘BACKGROUND Endoscopy allows for the direct observation of primary tumor characteristics and responses after neoadjuvant treatment.However,reports on endoscopic evaluation following neoadjuvant immunotherapy remain limited.AIM To examine the predictive value of endoscopic findings of primary tumors for responses to neoadjuvant immunotherapy.METHODS This retrospective study,conducted at a tertiary center in China,evaluated 74 patients with colorectal cancer,including 17 with deficient mismatch repair(dMMR)and 15 with proficient mismatch repair(pMMR)tumors.Patients underwent neoadjuvant immunotherapy followed by surgery.Endoscopic findings before and after neoadjuvant immunotherapy were reviewed and compared with the pathology of the resected specimens.RESULTS In the pMMR group(n=57 evaluable patients),endoscopy identified 11/17 patients who achieved a complete response(CR),while misidentifying 1/40 patients with residual disease as CR(64.7%vs 2.5%,P<0.01).Conversely,22/40 patients with residual disease were accurately identified as achieving a partial response(PR),with 1/17 patients who achieved CR misclassified as PR(55.0%vs 5.9%,P<0.01).The sensitivity,specificity,and accuracy of endoscopic diagnosis for pathological CR were 64.7%,97.5%,and 87.7%,respectively.In the dMMR cohort,endoscopy classified 9/17 patients as CR and 2 of the remaining patients with residual tumors as PR(64.3%vs 66.7%,P=0.73).The method demonstrated 100%sensitivity and 82.4%accuracy in diagnosing pathological CR.CONCLUSION Endoscopic evidence of CR or PR was well correlated with postoperative pathological outcomes in the pMMR cohort.Despite endoscopic indications of tumor residue,a complete pathological response post-surgery was possible in the dMMR cohort.
文摘BACKGROUND Hereditary factors are more prevalent in early-onset colorectal cancers(EOCRC)etiology.Lynch syndrome(LS)is the most common hereditary colorectal cancer(CRC)syndrome that results from mutations in DNA mismatch repair(MMR)genes.This phenomenon is defined as microsatellite instability(MSI).Immunohistochemistry(IHC)is a widely used,practical,and cost-effective method for the screening of MSI.However,using IHC alone may be insufficient to identify patients with MSI and LS.AIM To determine the clinicopathological features in EOCRC,IHC performance,and the frequency of genetic testing for EOCRC patients.METHODS A retrospective review was conducted on patients with CRC aged≤50 years who underwent surgery at our center between January 2014 and July 2021.MMR proteins were screened using IHC.Of the 131 patients included,IHC was performed on 130.Patients were classified as MSI or microsatellite-stable(MSS),and their features were compared.Additionally,data from patients who received genetic counseling were analyzed.RESULTS Thirty patients with MSI were designated as group 1,whereas 100 with MSS were defined as group 2.The mean age in group 1 was the lowest(median age:42 vs 46,P<0.05).Group 1 exhibited a higher frequency of tumors in the right colon and a lower frequency in the rectum.Lymph node involvement and distant metastases were less common in group 1,and in group 2,tumors were generally diagnosed at a more advanced stage.Genetic testing was performed in 53 patients(40%),with a definitive LS diagnosis established in 13/17 patients(76.4%)in group 1 and 1/36(2.7%)patients in group 2,resulting in a total of 14 patients(26.4%)with confirmed LS.CONCLUSION MSI tumors show a better prognosis.IHC is very effective for screening MSI,but may not be sufficient alone.Low genetic counseling rates highlight the need for hospital-based surveillance programs.
基金STU Scientific Research Initiation Grant[Grant No.STF24004T]Natural Science Foundation of Guangdong Province of China[Grant No.2021B1515020103].
文摘This study explores the relationship between corporate environmental,social,and governance(ESG)disagreements and corporate debt maturity.By examining panel samples from Chinese non-financial listed companies covering 2007 to 2020,we find that ESG disagreements negatively influence corporate debt maturity.Even after conducting a series of robustness tests and addressing endogeneity concerns,the adverse effects of ESG disagreements persisted.A heterogeneity analysis shows that this negative impact is more significant for non-state-owned enterprises,small enterprises,enterprises with high capital intensity,enterprises with low analyst attention,and enterprises in high-tech industries.Through a mechanism analysis,we discovered that ESG disagreements can lead to information asymmetry and heightened default risk,subsequently affecting the maturity of corporate debt.Further analysis confirms that the negative impact of ESG on the debt structure inhibits long-term investment and exacerbates the mismatch between investment and financing terms.
文摘Colon cancer(CC)laterality(right vs left)is recognized as a key determinant of clinical outcomes and treatment decisions in metastatic CC.Right-sided CC(RCC)often presents in older individuals and is associated with higher rates of Kirsten rat sarcoma viral oncogene homolog and v-raf murine sarcoma viral oncogene homolog B1 mutations and deficient mismatch repair,leading to microsatellite instability-high status.Left-sided CC typically presents in younger individuals,demonstrates a more favorable prognosis,and is often Kirsten rat sarcoma viral oncogene homolog/neuroblastoma RAS viral oncogene homolog/v-raf murine sarcoma viral oncogene homolog B1 wild-type,making it more responsive to antiepidermal growth factor receptor therapy.RCC typically responds poorly to antiepidermal growth factor receptor agents;however,it may benefit from triplet chemotherapy(5-fluorouracil+leucovorin+oxaliplatin+irinotecan)with or without anti-angiogenic agents.Comprehensive molecular profiling remains challenging in low-resource settings due to limited access to advanced diagnostic tools.This review explores key epidemiological and molecular differences between RCC and left-sided CC.In the absence of complete genomic data,tumor sidedness can be a helpful guide for making treatment decisions.Here,we propose a practical algorithm that integrates basic immunohistochemistry to assess a tumor’s mismatch repair status and laterality,potentially facilitating therapy selection in resource-constrained environments.Recognizing laterality-specific trends in prognosis and treatment response can improve personalized care and outcomes for patients with CC in these environments,highlighting the essential role of cost-effective biomarker strategies.
基金support from the National Natural Science Foundation of China(Grant No.61901295)the Nanchang Microsystem Institute of Tianjin University.
文摘Accurately correlating the sweating rate and the concentration of biomarkers in sweat is essential in many sweat-based diagnostic applications.These two measurements are always done simultaneously in wearable sweat sensing platforms.However,concentration measurements of biomarkers are always delayed on the timeline compared with their production,whereas there is no such delay for sweating rate.Thus,a timeline mismatch exists between these two measurements.This means that the concentration vs rate correlation constructed on the basis of such measurements will deviate from the actual correlation.This study demonstrates the existence of this mismatch and explains its cause using sweat Na^(+)measurements.It also proposes an effective approach that applies a point-by-point compensation for the delay between Na+measurements and the real-time sweating rates,such that the data on the repositioned concentration vs time curve correspond to exactly the same point on the timeline as their production.A vison sensor is developed to measure the sweating rate with high accuracy at a frequency of more than 0.1 Hz.Off-body and on-body measurements of sweating rate and Na^(+)concentration are carried out,and concentration–rate correlations are constructed using both measured and repositioned concentration curves.The least squares and random forest methods are employed to fit the constructed correlations and evaluate the reliability of the proposed approach.The use of the repositioned concentration curve gives a constructed correlation that is much closer to the actual one.This study indicates the necessity to rearrange sensor-measured biomarker concentration vs time curves when correlations of concentration with sweating rate need to be constructed and proposes a practical point-by-point data repositioning strategy for doing so.The results presented here will benefit the study of sweat biomarkers with unclear correlations with sweating rate,as well as providing a basis for the development of more reliable sweat-based diagnostic methods.
基金the Key National Natural Science Foundation of China(No.U1864211)the National Natural Science Foundation of China(No.11772191)the Natural Science Foundation of Shanghai(No.21ZR1431500)。
文摘Industrial data mining usually deals with data from different sources.These heterogeneous datasets describe the same object in different views.However,samples from some of the datasets may be lost.Then the remaining samples do not correspond one-to-one correctly.Mismatched datasets caused by missing samples make the industrial data unavailable for further machine learning.In order to align the mismatched samples,this article presents a cooperative iteration matching method(CIMM)based on the modified dynamic time warping(DTW).The proposed method regards the sequentially accumulated industrial data as the time series.Mismatched samples are aligned by the DTW.In addition,dynamic constraints are applied to the warping distance of the DTW process to make the alignment more efficient.Then a series of models are trained with the cumulated samples iteratively.Several groups of numerical experiments on different missing patterns and missing locations are designed and analyzed to prove the effectiveness and the applicability of the proposed method.
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supported by the National Natural Science Foundation of China(Nos.52127802,52322409,52271137)the Scientific Research Program of Education Department of Shaanxi Province,China(No.22JY050)the Science and Technology Project of Xi’an,China(No.2021SFGX0004).
文摘Copper matrix composites prepared via traditional methods face mechanical property and electrical conductivity trade-off problems.In this study,TiB_(2)/Cu−Cu heterogeneous laminated composites with submicron lamellar thicknesses were prepared via flake powder metallurgy(FPM)using gas-atomized in situ composite powders as raw material.By thermal mismatch strengthening,and the geometrically necessary dislocations(GNDs)generated by mechanically incompatible deformation between adjacent heterogeneous lamellae and their interaction with statistically stored dislocations(SSDs),the as-prepared TiB_(2)/Cu−Cu submicron laminated composites(SLCs)exhibit significantly enhanced mechanical properties.At the same time,the interaction and propagation of multimode cracks provide extrinsic toughening for SLCs.The pure Cu lamellae with low density grain boundaries and dislocations and no TiB_(2)particles provide a channel with little electron scattering for the rapid transport of carriers,thereby ensuring high electrical conductivity.
