Integrating machine learning algorithms and multiple immunohistochemistry validation to unveil novel diagnostic markers based on costimulatory molecules for predicting immune microenvironment status in triple-negative breast cancer.

Introduction: Costimulatory molecules are putative novel targets or potential additions to current available immunotherapy, but their expression patterns and clinical value in triple-negative breast cancer (TNBC) are to be clarified. Methods: The gene expression profiles datasets of TNBC patients were obtained from The Cancer Genome Atlas and the Gene Expression Omnibus databases. Diagnostic biomarkers for stratifying individualized tumor immune microenvironment (TIME) were identified using the Least Absolute Shrinkage and Selection Operator (LASSO) and Support Vector Machine-Recursive Feature Elimination (SVM-RFE) algorithms. Additionally, we explored their associations with response to immunotherapy via the multiplex immunohistochemistry (mIHC). Results: A total of 60 costimulatory molecule genes (CMGs) were obtained, and we determined two different TIME subclasses ("hot" and "cold") through the K-means clustering method. The "hot" tumors presented a higher infiltration of activated immune cells, i.e., CD4 memory-activated T cells, resting NK cells, M1 macrophages, and CD8 T cells, thereby enriched in the B cell and T cell receptor signaling pathways. LASSO and SVM-RFE algorithms identified three CMGs (CD86, TNFRSF17 and TNFRSF1B) as diagnostic biomarkers. Following, a novel diagnostic nomogram was constructed for predicting individualized TIME status and was validated with good predictive accuracy in TCGA, GSE76250 and GSE58812 databases. Further mIHC conformed that TNBC patients with high CD86, TNFRSF17 and TNFRSF1B levels tended to respond to immunotherapy. Conclusion: This study supplemented evidence about the value of CMGs in TNBC. In addition, CD86, TNFRSF17 and TNFRSF1B were found as potential biomarkers, significantly promoting TNBC patient selection for immunotherapeutic guidance.

Decoding N400m Evoked Component: A Tutorial on Multivariate Pattern Analysis for OP-MEG Data.

Multivariate pattern analysis (MVPA) has played an extensive role in interpreting brain activity, which has been applied in studies with modalities such as functional Magnetic Resonance Imaging (fMRI), Magnetoencephalography (MEG) and Electroencephalography (EEG). The advent of wearable MEG systems based on optically pumped magnetometers (OPMs), i.e., OP-MEG, has broadened the application of bio-magnetism in the realm of neuroscience. Nonetheless, it also raises challenges in temporal decoding analysis due to the unique attributes of OP-MEG itself. The efficacy of decoding performance utilizing multimodal fusion, such as MEG-EEG, also remains to be elucidated. In this regard, we investigated the impact of several factors, such as processing methods, models and modalities, on the decoding outcomes of OP-MEG. Our findings indicate that the number of averaged trials, dimensionality reduction (DR) methods, and the number of cross-validation folds significantly affect the decoding performance of OP-MEG data. Additionally, decoding results vary across modalities and fusion strategy. In contrast, decoder type, resampling frequency, and sliding window length exert marginal effects. Furthermore, we introduced mutual information (MI) to investigate how information loss due to OP-MEG data processing affect decoding accuracy. Our study offers insights for linear decoding research using OP-MEG and expand its application in the fields of cognitive neuroscience.

CCL17 and CCL19 are markers of disease progression in alveolar echinococcosis.

OBJECTIVES: Alveolar echinococcosis (AE) represents one of the deadliest helminthic infections, characterized by an insidious onset and high lethality. METHODS: This study utilized the Gene Expression Omnibus (GEO) database, applied Weighted Correlation Network Analysis (WGCNA) and Differential Expression Analysis (DEA), and employed the Matthews Correlation Coefficient (MCC) to identify CCL17 and CCL19 as key genes in AE. Immunohistochemistry and immunofluorescence co-localization techniques were used to examine the expression of CCL17 and CCL19 in liver tissue lesions of AE patients. Additionally, a mouse model of multilocular echinococcus larvae infection was developed to study the temporal expression patterns of these genes, along with liver fibrosis and inflammatory responses. RESULTS: The in vitro model simulating echinococcal larva infection mirrored the hepatic microenvironment post-infection with multilocular echinococcal tapeworms. Quantitative RT-PCR analysis showed that liver fibrosis occurred in AE patients, with proximal activation and increased expression of CCL17 and CCL19 over time post-infection. Notably, expression peaked during the late stages of infection. Similarly, F4/80, a macrophage marker, exhibited corresponding trends in expression. Upon stimulation of normal hepatocytes by vesicular larvae in cellular experiments, there was a significant increase in CCL17 and CCL19 expression at 12 h post-infection, mirroring the upregulation observed with F4/80. CONCLUSION: CCL17 and CCL19 facilitate macrophage aggregation via the chemokine pathway and their increased expression correlates with the progression of infection, suggesting their potential as biomarkers for AE progression.

A Multivariate analysis on evoked components of Chinese semantic congruity: an OP-MEG study with EEG.

The application of wearable magnetoencephalography using optically-pumped magnetometers has drawn extensive attention in the field of neuroscience. Electroencephalogram system can cover the whole head and reflect the overall activity of a large number of neurons. The efficacy of optically-pumped magnetometer in detecting event-related components can be validated through electroencephalogram results. Multivariate pattern analysis is capable of tracking the evolution of neurocognitive processes over time. In this paper, we adopted a classical Chinese semantic congruity paradigm and separately collected electroencephalogram and optically-pumped magnetometer signals. Then, we verified the consistency of optically-pumped magnetometer and electroencephalogram in detecting N400 using mutual information index. Multivariate pattern analysis revealed the difference in decoding performance of these two modalities, which can be further validated by dynamic/stable coding analysis on the temporal generalization matrix. The results from searchlight analysis provided a neural basis for this dissimilarity at the magnetoencephalography source level and the electroencephalogram sensor level. This study opens a new avenue for investigating the brain's coding patterns using wearable magnetoencephalography and reveals the differences in sensitivity between the two modalities in reflecting neuron representation patterns.

OPM-MEG Measuring Phase Synchronization on Source Time Series: Application in Rhythmic Median Nerve Stimulation.

The magnetoencephalogram (MEG) based on array optically pumped magnetometers (OPMs) has the potential of replacing conventional cryogenic superconducting quantum interference device. Phase synchronization is a common method for measuring brain oscillations and functional connectivity. Verifying the feasibility and fidelity of OPM-MEG in measuring phase synchronization will help its widespread application in the study of aforementioned neural mechanisms. The analysis method on source-level time series can weaken the influence of instantaneous field spread effect. In this paper, the OPM-MEG was used for measuring the evoked responses of 20Hz rhythmic and arrhythmic median nerve stimulation, and the inter-trial phase synchronization (ITPS) and inter-reginal phase synchronization (IRPS) of primary somatosensory cortex (SI) and secondary somatosensory cortex (SII) were analysed. The results find that under rhythmic condition, the evoked responses of SI and SII show continuous oscillations and the effect of resetting phase. The values of ITPS and IRPS significantly increase at the stimulation frequency of 20Hz and its harmonic of 40Hz, whereas the arrhythmic stimulation does not exhibit this phenomenon. Moreover, in the initial stage of stimulation, the ITPS and IRPS values are significantly higher at Mu rhythm in the rhythmic condition compared to arrhythmic. In conclusion, the results demonstrate the ability of OPM-MEG in measuring phase pattern and functional connectivity on source-level, and may also prove beneficial for the study on the mechanism of rhythmic stimulation therapy for rehabilitation.

Identification and exploration of a new M2 macrophage marker MTLN in alveolar echinococcosis.

The pathogen of alveolar echinococcosis (AE) is Echinococcus multilocularis (E. multilocularis), which has the characteristics of diffuse infiltration and growth and has a high mortality rate. At present, the role of macrophages in AE infection has attracted more and more attention, but the new biomarkers and polarization mechanisms of macrophages are rarely studied. In this study, CIBERSORT and WGCNA algorithms were used to establish a weighted gene co-expression network, and MTLN was identified as a biological marker of M2-type macrophages, which participated in energy metabolism of macrophages and mediated inflammatory response, but the role of MTLN in AE was not studied. In this study, liver tissue samples from AE patients were collected and immunofluorescence co-localization showed the relationship between MTLN and macrophage distribution. E. multilocularis infected mouse model was established to analyze the expression of MTLN, liver fibrosis, and inflammatory reaction after E. multilocularis infection. The cell experiment simulated the liver microenvironment of E. multilocularis infected human body and analyzed the expression of MTLN by QRT-PCR and western blot in vitro. The data showed that liver fibrosis occurred in AE patients, and MTLN was activated near the focus. After E. multilocularis infected mice, the expression of MTLN increased with time. In the cell experiment, after the antigen of E. multilocularis protoscolex stimulated normal liver cells, the expression of MTLN increased 48 h, at this time, M2 was up-regulated and M1 was down-regulated. Therefore, MTLN may be the key gene to regulate the polarization of M2 macrophages and cause fibrosis.

Fine mapping of powdery mildew resistance gene PmXNM in a Chinese wheat landrace Xiaonanmai.

KEY MESSAGE: Powdery mildew resistance gene PmXNM, originated from the Chinese wheat landrace Xiaonanmai, was delimited to a 300.7-kb interval enriched with resistance genes. Powdery mildew, caused by Blumeria graminis f. sp. tritici (Bgt), is a globally devastating disease threatening the yield and quality of wheat worldwide. The use of broad-spectrum disease resistance genes from wheat landraces is an effective strategy to prevent this pathogen. Chinese wheat landrace Xiaonanmai (XNM) was immune to 23 tested Bgt isolates at the seedling stage. The F1, F2, and F2:4 progenies derived from the cross between XNM and Chinese Spring (CS) were used in this study. Genetic analysis revealed that powdery mildew resistance in XNM was controlled by a single dominant gene, temporarily designated PmXNM. Bulked segregant analysis and molecular mapping delimited PmXNM to the distal terminal region of chromosome 4AL flanked by markers caps213923 and kasp511718. The region carrying the PmXNM locus was approximately 300.7 kb and contained nine high-confidence genes according to the reference genome sequence of CS. Five of these genes, annotated as disease resistance RPP13-like proteins 1, were clustered in the target region. Haplotype analysis using the candidate gene-specific markers indicated that the majority of 267 common wheat accessions (75.3%) exhibited extensive gene losses at the PmXNM locus, as confirmed by aligning the targeted genome sequences of CS with those of other sequenced wheat cultivars. Seven candidate gene-specific markers have proven effective for marker-assisted introgression of PmXNM into modern elite cultivars.

COF-300-AR@CRL as a two-in-one nanocatalyst for one-step chemiluminescent detection of diphenyl ether herbicide residues in vegetable and fruit samples.

A sensitive and accurate chemiluminescence (CL) method was developed for one-step determination of diphenyl ether herbicides at trace level with nitrofen (2,4-dichlorophenyl-p-nitrophenyl ether) as a model analyte. Candida rugosa lipase (CRL) was immobilized on a nanocarrier of amine-linked covalent organic framework (named as COF-300-AR) through a self-assembly strategy. The formed nanocomposite of COF-300-AR@CRL owns dual enzymatic catalytic activities. It can directly catalyze luminol-dissolved oxygen reaction to produce an intense CL emission by virtue of oxidase mimic activity of COF-300-AR but also effectively decompose nitrofen to release phenolic compounds by the immobilized CRL. The released phenolic compounds own strong reducing capacity and in turn decrease the CL signal sharply. Under the optimal conditions, the decreased CL intensity presents a good linear response to nitrofen concentration in the 0.02-50.0 µM range. The limit of detection (LOD, 3sb/S) is 11 nM and the precision is 2.0% for replicate measurements of 50.0 nM nitrofen solution (n = 11). This method has the advantages of rapid analytical efficiency, good selectivity, satisfactory stability, and recyclability. Recovery experiments were conducted on spiked vegetable and fruit samples with the recoveries falling in the range 90.0-107.0%.

Expression of Tim-3/Galectin-9 pathway and CD8+T cells and related factors in patients with cystic echinococcosis.

OBJECTIVE: One of the primary reasons for the successful patriotization of Echinococcus multilocularis in patients is its ability to induce host immune tolerance. This study examined the expression of the immunosuppressive Tim-3/Galectin-9 pathway, CD8+T cells, and related factors in AE patients. The aim was to analyze the relationship between the Tim-3/Galectin-9 pathway and CD8+T cells in this disease and further understand the mechanism of immune tolerance induced by cystic echinococcosis. METHODS: Using flow cytometry, we evaluated the expression of CTL, CD8+CD28-T cells, CD8+CD28 + IFN-γ + T cells, CD8+CD28+perforin + T cells, CD8+CD28+granzyme B + T cells, CD8+CD28-IL-10 + T cells, CD8+CD28-TGF-ß+T cells, and Tim-3 expression on CD8+T cells in the peripheral blood of control (n = 30) and AE patients (n = 33). qRT-PCR was used to measure CD107a and Tim-3/Galectin-9 mRNA levels in PBMCs from the control and AE groups. Immunohistochemistry was employed to detect IL-10, TGF-ß, and Tim-3/Galectin-9 expressions in the infected livers of AE patients. RESULTS: AE patients exhibited a significant decrease in peripheral blood CTL ratio (P < 0.001) and an increase in CD8+CD28+IFN-γ+T cell ratio (P < 0.001). No significant changes were observed in the ratios of CD8+CD28+perforin + T cells (P = 0.720) and CD8+CD28+granzyme B + T cells (P = 0.051). The proportions of CD8+CD28-T cells (P < 0.001), CD8+CD28-IL-10 + T cells (P < 0.001), and CD8+CD28-TGF-ß+T cells (P < 0.001) were notably higher than in the control group. The expression of Tim-3 on CTL and CD8+CD28-T cells in AE patients was significantly upregulated (P < 0.001, P < 0.001). AE patients displayed a substantial decrease in peripheral blood PBMC CD107a mRNA levels (P < 0.001) and significant elevations in Tim-3/Galectin-9 mRNA levels (P < 0.001, P < 0.001). A negative correlation was observed between CD107a mRNA levels and both Tim-3 (r^2 = 0.411, P < 0.001) and Galectin-9 (r2 = 0.180, P = 0.019) mRNA levels. Expressions of IL-10 (P < 0.001), TGF-ß (P < 0.001), and Tim-3/Galectin-9 (P < 0.001, P < 0.001) in AE patient-infected livers were significantly higher than in uninfected regions. IL-10 and TGF-ß expressions showed a positive correlation with Tim-3/Galectin-9. CONCLUSION: This study suggests that the high expression of Tim-3 on CD8+T cell surfaces in AE patients might promote an increase in CD8+CD28-T cells and related factors, while suppressing CTL and related factor expressions. This potentially induces the onset of immune tolerance, which is unfavorable for the clearance of Echinococcus multilocularis in patients, leading to the exacerbation of persistent infections.

C18ORF54 promotes immune infiltration and poor prognosis as a potential biomarker for hepatocellular carcinoma.

OBJECTIVE: The morbidity of hepatocellular carcinoma (HCC) is increasing annually. The aim of this study is to investigate the molecular mechanisms of upregulated genes in HCC using bioinformatic methods, so as to identify new potential biological markers. METHODS: The Gene Expression Omnibus database (GEO database) was mined for HCC datasets, which were screened for hub genes and subjected to (Gene Ontology) GO and (Kyoto Encyclopedia of Genes and Genomes) KEGG enrichment analysis. The hub genes were analyzed in terms of Receiver Operating Characteristic (ROC) and methylation levels. Validation of hub genes was completed through basic pathological alterations based on the protein and gene expression level of hub genes. The correlation of genes with immune infiltration in HCC was analyzed based on the database Timer 2.0, and the prognosis as well as survival of hub genes in HCC was analyzed using R studio software. Finally, we performed a gene combination drug analysis on the potential therapeutic targets in HCC. RESULTS: Expression-up-regulated genes were screened via differential analysis, which were mainly enriched in cell cycles and DNA replication pathways. Five hub genes, BRCA1 associated RING domain 1 (BARD1), Mismatch Repair Protein (MSH2), Recombinant H2A Histone Family, Member X (H2AFX), Recombinant H2A Histone Family, Member z (H2AFZ) and Chromosome 18 Open Reading Frame 54 (C18orf54) were identified using a Protein-Protein Interaction Networks (PPI). After a comprehensive analysis of ROC curves and methylation gene mutation sites, C18orf54 was localized followed by basic experiments, so as to verify the C18orf54 upregulated in HCC. Based on the online database Timer 2.0, the immune infiltration of C18orf54 gene in HCC was analyzed, which was found to be negatively correlated with CD4+ T cells and macrophages in HCC, meanwhile a further refinement of the immune checkpoint correlation analysis revealed that C18orf54 was mainly correlated with Hepatitis A virus cellular receptor 2 (HAVCR2), T cell immunoreceptor with Ig and ITIM domains (TIGIT) and Cytotoxic T lymphocyte associate protein-4 (CTLA4). The prognosis and survival of patients with HCC expressing C18orf54 were also analyzed, and it was found that such patients had a higher incidence of adjacent liver tissue inflammation, a higher child-Pugh grade score and a higher rate of residual tumor recurrence. Similarly, the prognosis was worse in the subset of patients with C18orf54. Finally, we performed a combined genetic analysis, which suggested that cyclosporine, quercetin, testosterone and calcitriol might be effective in reducing C18orf54 mRNA expression. CONCLUSION: C18orf54 is involved in the immune infiltration and promotes the poor prognosis of HCC, which could be a candidate biomarker for HCC.

Systemic Therapy Combined with Locoregional Therapy Improved Survival in Oligometastatic Breast Cancer: A Single-Center Retrospective Cohort Study.

The optimal therapeutic options, adding locoregional therapy (LRT) to systemic therapy (ST) or not, for patients with oligometastatic breast cancer (OMBC) have not been fully elucidated. Hence, we designed a retrospective observational study which enrolled patients with measurable extracranial OMBC having less than 5 metastatic lesions not necessarily in the same organ. We retrospectively reviewed a total of 199 patients diagnosed with extracranial OMBC, including 28 receiving ST followed by LRT (ST to LRT group), 44 receiving LRT followed by ST (LRT to ST group), and 127 receiving ST alone (ST alone group). After a median follow-up of 28.7 months, patients receiving both ST and LRT had a significantly better prognosis than those receiving ST alone: the median progression-free survival (PFS) was 16.3, 14.0, and 9.3 months (P < 0.001) and the median overall survival (OS) was 39.8, 70.5, and 26.7 months (P < 0.001) in the ST to LRT, LRT to ST, and ST alone groups, respectively. Sequence of ST and LRT had no significant impact on survival among patients receiving both. Further exploratory analysis identified ST plus LRT as an independent predictor for longer PFS. In conclusion, we demonstrated that adding LRT to ST was associated with survival benefits for patients with OMBC, and further prospective studies were warranted.

Comparison of noninvasive prenatal screening for defined pathogenic microdeletion/microduplication syndromes and nonsyndromic copy number variations: a large multicenter study.

Background: This retrospective study assessed the precision of noninvasive prenatal testing (NIPT) in detecting microdeletion/microduplication syndromes (MMSs) and nonsyndromic copy number variations (CNVs). Methods: The study included 19,086 singleton pregnancies screened on NIPT using high-throughput sequencing. Pregnancies with CNVs on NIPT underwent amniocentesis for karyotyping and CNV sequencing (CNV-seq). We analyzed pathogenic MMSs and nonsyndromic CNVs separately, dividing the CNVs into subgroups based on fragment size and fetal ultrasound findings. Results: A total of 170 abnormalities were detected by NIPT, of which 113 (66.5%) underwent invasive testing. The positive predictive value (PPV) of CNV-seq for all types of CNV detected by NIPT was 35.4%, with PPVs of 61.5 and 27.6% for pathogenic MMSs and nonsyndromic CNVs, respectively. PPVs for NIPT showed different values depending on gestational characteristics, with the highest PPV for NIPT in the group with increased nuchal thickness (66.7%) and for the abnormal ultrasound group (57.1%). CNVs ≤5 Mb with normal ultrasound findings were generally associated with a healthy fetus. Conclusion: NIPT can detect chromosomal aberrations in the first trimester, with high performance for MMSs. However, due to the low PPV for nonsyndromic CNVs, and the good pregnancy outcome in most cases, the introduction of expanded NIPT would cause an increase in unnecessary invasive procedures and inappropriate terminations of pregnancy.

Expression of chemokine CXCL8/9/10/11/13 and its prognostic significance in head and neck cancer.

BACKGROUND: Head and neck cancer (HNC) is a very popular cancer, with many primary sites and pathological types, at the top of the list of tumors. Chemokines are a class of small molecular basic proteins, whose N-terminal cysteine residues can be divided into four subunits by location and number, which significantly enhances the expression level in all kinds of cancers. However, in HNC, especially in head and neck squamous cell carcinoma, the chemokine CXCL8/9/10/11/13 has not been clearly explored for its diagnosis and prognosis. METHODS: The ONCOMINE database was used to analyze the expression of chemokine family in various cancers. After CXCL8/9/10/11/13 was screened out, the expression of CXCL 8/9/11/13 in patients with HNC/normal people were analyzed by UALCAN database. The expression and pathological stages of CXCL 8/9/10/13 in HNC tissues were analyzed by the GEPIA database, and the relationship between its mRNA expression and the overall survival (OS) time of patients with HNC was analyzed by Kaplan-Meier plotter database. In addition, 171 co-expressed genes significantly related to CXCL8/9/10/11/13 mutation were screened by online tool cBioPortal, and the protein interaction network of these genes was constructed by STRING database. Finally, the potential functions of CXCL8/9/10/11/13 and its 171 co-expressed genes were explored by the enrichment and analysis function of David database. RESULTS: Transcriptional expression of chemokine 8/9/10/11/13 was significantly increased in patients with HNC. Clinical stage of patients with HNC was significantly correlated with overexpression of CXCL9/10/11. In addition, the chemokine CXCL8/9/10/13 was significantly correlated with over-survival of patients with HNC, so it could be distinguished between short-term and long-term survival of patients with HNC. In conclusion, CXCL8/9/10/11/13 closely connected with the expression and prognosis of HNC. CONCLUSION: In this study, our results suggest that chemokine CXCL8/9/10/11/13 may play a critical role in the development of HNC, and, according to relevant data, it may affect the survival and prognosis of patients with HNC.

Fine mapping of Pm58 from Aegilops tauschii conferring powdery mildew resistance.

KEY MESSAGE: The powdery mildew resistance gene Pm58 was traced to a 141.3-kb interval with the co-segregating marker Xkasp68500 in wheat breeding. Pm58 is a powdery mildew resistance gene identified in Aegilops tauschii accession TA1662 and effective in a common wheat background. To finely map Pm58, an F2 population of 676 plants derived from the cross T093 × TA1662 was used for recombinant screening. We obtained 13 recombinants that occurred between the flanking markers Xhnu670 and Xhnu186. Genotyping and phenotyping these recombinant F2:3 families delimited Pm58 to a 0.22-cM interval (Xsts20220-Xkasp61553) on chromosome arm 2DS. The region carrying the Pm58 locus was approximately 141.3-kb, which contained eight annotated genes according to the reference genome sequence of Ae. tauschii AL8/78. Haplotype analysis of 178 Ae. tauschii accessions using the candidate gene-specific markers identified a disease resistance gene AET2Gv20068500 as a candidate for Pm58. Comparative mapping of the Pm58-containing interval revealed two presence/absence variations (PAVs) between AL8/78 and common wheat Chinese Spring. PAV-1 resides in the 3'-end of AET2Gv20068500. The majority of 158 common wheat cultivars (84.8%) displayed the absence of a 14.1-kb fragment in the PAV-1 region, which was confirmed by aligning the targeted genome sequences of the other sequenced Ae. tauschii accessions and common wheat cultivars. A co-segregating marker Xkasp68500 developed from AET2Gv20068500 can distinguish TA1662 from all randomly selected common wheat cultivars and will be instrumental for tracking Pm58 in breeding programs.

The efficacy of human epidermal growth factor receptor 2 (HER2) blockade switching mode in refractory patients with HER2-positive metastatic breast cancer: a phase II, multicenter, single-arm study (SYSUCC-005).

BACKGROUND: Despite significant survival improvement in human epidermal growth factor receptor 2 (HER2) blockade for HER2-positive breast cancer, resistance to anti-HER2 remains inevitable. Subsequent anti-HER2 with continuing trastuzumab beyond progression is acceptable with limited efficacy when other anti-HER2 treatment is unavailable. This single-arm, phase II study (SYSUCC-005) aimed to explore the efficacy of switching mode for HER2-positive refractory metastatic breast cancer. METHODS: Patients with HER2-positive metastatic breast cancer rapidly progressing during pre-trastuzumab from six hospitals in China were designed to switch to lapatinib 1,250 mg orally once per day continuously plus capecitabine (1,000 mg/m2 orally twice per day on days 1-14) or vinorelbine (25 mg/m2 intravenously once per day on days 1 and 8) of each 21-day cycle. The primary endpoint was progression-free survival (PFS). RESULTS: Between January 5, 2015 and May 31, 2020, 159 patients were eligible in this study. The median follow-up was 33.1 months, a median PFS of 8.5 months was achieved. Brain metastases (hazard ratio [HR] = 1.582, 95% confidence interval [CI] 1.019- 2.453, P = 0.041) and ≥ 2 metastatic sites (HR = 1.679, 95% CI 1.151-2.450, P = 0.007) were independent prognostic factors for PFS. The most common grade ≥ 3 adverse events were diarrhea (3.8%) and hand-foot syndrome (9.4%). CONCLUSION: The switching mode showed predominant efficacy, which might be a prior therapeutic option over continuing mode in subsequent anti-HER2 therapy for patients with HER2-positive refractory metastatic breast cancer. TRIAL REGISTRATION: This trial was registered on ClinicalTrials.gov ( NCT02362958 ) on 13/02/2015.

Chemiluminescence resonance energy transfer determination of uric acid with fluorescent covalent organic framework as energy acceptor.

A simple and feasible strategy was developed for the preparation of fluorescent covalent organic frameworks (COFs) TpPa-1@FL. The TpPa-1-1@FL was prepared via a self-assembly strategy by soaking non-fluorescent COFs TpPa-1 into strong fluorescent fluorescein (FL) solution. A chemiluminescence resonance energy transfer (CRET) system was constructed by the combination strong fluorescent TpPa-1@FL with TCPO-hydrogen peroxide (H2O2) reaction. The chemiluminescence (CL) signal of the system was further improved by the addition of bovine serum albumin (BSA). The CRET system can determine H2O2 with a linear range response from 5.0 µmol/L to 20.0 mmol/L and a detection limit of 1.1 µmol/L. The CRET system was further exploited for indirect detection of uric acid with coupling of uricase. A good linear relationship was obtained for uric acid in the 10.0-400.0 µmol/L concentration range with a detection limit of 3.8 µmol/L. The practicability of this method was assessed by the determination of uric acid in real samples of human serum and urine.

Glucose oxidase@zinc-doped zeolitic imidazolate framework-67 as an effective cascade catalyst for one-step chemiluminescence sensing of glucose.

A chemiluminescence (CL) sensor was constructed for the one-step determination of glucose. Glucose oxidase (GOx) was successfully encapsulated into Zn-doped zeolitic imidazolate framework-67 (Zn-ZIF-67) via a simple one-pot strategy. The as-prepared GOx@Zn-ZIF-67 nanocomposite can trigger cascade reactions of glucose oxidation to generate H2O2 and H2O2-mediated luminol reaction to give an intense CL emission. The sensor responds linearly to glucose in the 20.0-400.0 µmol·L-1 range with a limit of detection (LOD) of 4.7 µmol·L-1. Eleven replicated measurements of 200.0 µmol·L-1 glucose solution gives a relative standard deviation (RSD) of 1.7%. The sensor exhibits good selectivity and stability and was successfully applied to the determination of glucose in real human serum samples. Schematic representation of one-step determination of serum glucose with GOx@Zn-ZIF-67 nanocomposite triggering cascade reactions between luminol and glucose.

Magnetic covalent organic framework immobilized gold nanoparticles with high-efficiency catalytic performance for chemiluminescent detection of pesticide triazophos.

Covalent organic frameworks (COFs) are considered to be a promising support material for catalyst due to their highly ordered porous structure. Here, a core-shell structured Fe3O4 magnetic covalent organic framework (Fe3O4@COF) was synthesized and employed to provide basic sites for immobilization of gold nanoparticles (AuNPs). The AuNPs was in-situ immobilized on the shell of Fe3O4@COF via a citrate reducing method. The Fe3O4@COF-AuNP had convenient magnetic separability and exhibited excellent mimicking peroxidase-like activity in catalyzing chemiluminescence (CL) reaction of luminol with hydrogen peroxide (H2O2). With acetylcholine chloride (ACh) as substrate of acetylcholinesterase (AChE), a CL method was exploited for sensitive detection of organophosphorus pesticide triazophos due to its irreversible inhibiting effect on the AChE activity and subsequently influences the production of H2O2 under the condition of choline oxidase (ChOx). This method gave a good linearity for triazophos in the range of 5.0-300.0 nmol L-1, and a limit of detection (LOD) of 1 nmol L-1 was acquired. The applicability of this method was verified by the determination of triazophos in different spiked vegetable samples.

Establishment of Prognostic Nomograms for Predicting the Survival of HR-Positive, HER2-Negative Metastatic Breast Cancer Patients Treated with Everolimus.

BACKGROUND: There are no clinically available prognostic models for patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer treated with everolimus. We aimed to develop a tool to predict the progression-free survival (PFS) and overall survival (OS) of these patients and to identify optimal candidates who would benefit from everolimus-based treatment in this heterogeneous patient population. METHODS: The clinical data of patients with HR+, HER2- metastatic breast cancer receiving everolimus between May 2012 and January 2018 at Sun Yat-sen University Cancer Center were retrospectively retrieved. Based on potential prognostic factors derived from multivariate Cox analysis, we established predictive nomogram models for PFS and OS and evaluated their predictive values by means of the concordance index (C-index). Calibration curves were used to estimate the consistency between the actual observations and the nomogram-predicted probabilities. RESULTS: A total of 116 patients with HR+, HER2- metastatic breast cancer were enrolled in this study. Three independent prognostic factors, including the line of everolimus in the metastatic setting, everolimus clinical benefit rate and number of liver metastatic lesions, were identified from the multivariate Cox analysis. Prognostic models for individual survival prediction were established and graphically presented as nomograms. The C-index was 0.738 (95% confidence interval [CI]: 0.710-0.767) for the PFS nomogram and 0.752 (95% CI: 0.717-0.788) for the OS nomogram, which showed favourable discrimination. The calibration curves for the probabilities of 6-, 9-, and 12-month PFS and 1-, 2-, and 3-year OS suggested satisfactory consistency between the actual observations and the predicted probabilities. CONCLUSION: We constructed convenient nomogram models for patients with HR+, HER2- metastatic breast cancer to individually predict their potential benefits from everolimus in the metastatic setting. The models showed good performance in terms of accuracy, discrimination capacity and clinical application value.

Characterization of PmHHXM, a New Broad-Spectrum Powdery Mildew Resistance Gene in Chinese Wheat Landrace Honghuaxiaomai.

Powdery mildew, caused by fungal pathogen Blumeria graminis f. sp. tritici, is an agronomically important and widespread wheat disease causing severe yield losses. Deployment of broad-spectrum disease resistance genes is the preferred strategy to prevent this pathogen. Chinese wheat landrace Honghuaxiaomai (HHXM) was resistant to all 23 tested B. graminis f. sp. tritici isolates at the seedling stage. The F1, F2, and F2:3 progenies derived from the cross HHXM × Yangmai 158 were used in this study, and genetic analysis revealed that a single dominant gene, designated PmHHXM, conferred resistance to B. graminis f. sp. tritici isolate E09. Bulked segregant analysis and molecular mapping initially located PmHHXM to the distal region of chromosome 4AL. To fine map PmHHXM, we identified two critical recombinants from 592 F2 plants and delimited PmHHXM to a 0.18-cM Xkasp475200 to Xhnu552 interval covering 1.77 Mb, in which a number of disease resistance-related gene clusters were annotated. Comparative mapping of this interval revealed a perturbed synteny among Triticeae species. This study reports the new powdery mildew resistance gene PmHHXM, which seems different from three known quantitative trait loci/genes identified on chromosome 4AL and has significant values for further genetic improvement. Analysis of the polymorphisms of 13 cosegregating markers between HHXM and 170 modern wheat cultivars indicates that Xhnu227 and Xsts478700 developed here are ideal for marker-assisted introgression of this locus in wheat breeding.