Root-to-shoot signaling positively mediates source-sink relation in late growth stages in diploid and tetraploid wheat.

Non-hydraulic root source signaling (nHRS) is a unique positive response to soil drying in the regulation of plant growth and development. However, it is unclear how the nHRS mediates the tradeoff between source and sink at the late growth stages and its adaptive mechanisms in primitive wheat. To address this issue, a root-splitting design was made by inserting solid partition in the middle of the pot culture to induce the occurrence of nHRS using four wheat cultivars (MO1 and MO4, diploid; DM22 and DM31, tetraploid) as materials. Three water treatments were designed as 1) both halves watered (CK), 2) holistic root system watered then droughted (FS), 3) one-half of the root system watered and half droughted (PS). FS and PS were designed to compare the role of the full root system and split root system to induce nHRS. Leaves samples were collected during booting and anthesis to compare the role of nHRS at both growth stages. The data indicated that under PS treatment, ABA concentration was significantly higher than FS and CK, demonstrating the induction of nHRS in split root design and nHRS decreased cytokinin (ZR) levels, particularly in the PS treatment. Soluble sugar and proline accumulation were higher in the anthesis stage as compared to the booting stage. POD activity was higher at anthesis, while CAT was higher at the booting stage. Increased ABA (nHRS) correlated with source-sink relationships and metabolic rate (i.e., leaf) connecting other stress signals. Biomass density showed superior resource acquisition and utilization capabilities in both FS and PS treatment as compared to CK in all plants. Our findings indicate that nHRS-induced alterations in phytohormones and their effect on source-sink relations were allied with the growth stages in primitive wheat.

Two doses of fosaprepitant included prophylactic treatment for the three-day cisplatin-based chemotherapy induced nausea and vomiting.

PURPOSE: Neurokinin 1 receptor antagonists included prophylactic treatment was recommended for patients who receive one-day cisplatin chemotherapy. It is unclear whether the prolonged administration of fosaprepitant is effective for three-day cisplatin-based chemotherapy induced nausea and vomiting (CINV). We aim to explore the prophylactic antiemetic efficacy and safety of two doses of fosaprepitant included regimen in the patients receiving multiple-day cisplatin chemotherapy. METHODS: This randomized, parallel-group, open-labelled study was conducted in nine hospitals between February 2021 and February 2023. Patients diagnosed as lung cancer and chemotherapy naive were screened. Eligible participants were scheduled to be treated with highly emetogenic chemotherapy regimen which including three days of cisplatin. Then they were randomly divided into the experimental group (two doses of fosaprepitant, Group 2DF) and the control group (one dose of fosaprepitant, Group C). The primary endpoints included the safety and the average none CINV days (NCDs). This study was registered on the website of chictr.org.cn, number ChiCTR2100042665. RESULTS: Overall, 204 participants were randomly assigned, and 198 patients were analyzed. No statistical difference in adverse events was found between the two groups. All treatment-related adverse effects for fosaprepitant observed were of grade 1-2. The average NCDs of Group 2DF was significantly more than Group C (18.21 ± 3.40 days vs 16.14 ± 5.20 days, P = 0.001). Furthermore, the better life function score was achieved in Group 2DF according to FLIE questionnaire. CONCLUSION: The administration of two-dose fosaprepitant was safe and more effective than one dose in protecting patients from CINV induced by three-day cisplatin included chemotherapy.

Norcantharidin in cancer therapy - a new approach to overcoming therapeutic resistance: A review.

Therapeutic resistance in cancer remains a dilemma that scientists and oncologists are eager to solve. Despite several preclinical and clinical studies dedicated to overcoming therapeutic resistance, they often do not yield the expected outcomes. This is primarily due to the multifactorial phenomenon of therapeutic resistance. Norcantharidin (NCTD) is an artificial compound derived from cantharidin that has significant anticancer efficacy without incurring serious side effects. Intriguingly, extensive research suggests that NCTD is essential for boosting anticancer efficacy and reversing treatment resistance. This review article presents a full description of how NCTD can effectively overcome cancer resistance to standard treatments such as chemotherapy, radiation, hormone therapy, and targeted therapy. We also discuss the potential prospects and challenges associated with using NCTD as a therapeutic strategy for reversing resistance to cancer therapy. We anticipate that our review will serve as a valuable reference for researchers and clinicians.

Dynamic functional network connectivity analysis in schizophrenia based on a spatiotemporal CPD framework.

Objective.Dynamic functional network connectivity (dFNC), based on data-driven group independent component (IC) analysis, is an important avenue for investigating underlying patterns of certain brain diseases such as schizophrenia. Canonical polyadic decomposition (CPD) of a higher-way dynamic functional connectivity tensor, can offer an innovative spatiotemporal framework to accurately characterize potential dynamic spatial and temporal fluctuations. Since multi-subject dFNC data from sliding-window analysis are also naturally a higher-order tensor, we propose an innovative sparse and low-rank CPD (SLRCPD) for the three-way dFNC tensor to excavate significant dynamic spatiotemporal aberrant changes in schizophrenia.Approach.The proposed SLRCPD approach imposes two constraints. First, the L1regularization on spatial modules is applied to extract sparse but significant dynamic connectivity and avoid overfitting the model. Second, low-rank constraint is added on time-varying weights to enhance the temporal state clustering quality. Shared dynamic spatial modules, group-specific dynamic spatial modules and time-varying weights can be extracted by SLRCPD. The strength of connections within- and between-IC networks and connection contribution are proposed to inspect the spatial modules. K-means clustering and classification are further conducted to explore temporal group difference.Main results.82 subject resting-state functional magnetic resonance imaging (fMRI) dataset and opening Center for Biomedical Research Excellence (COBRE) schizophrenia dataset both containing schizophrenia patients (SZs) and healthy controls (HCs) were utilized in our work. Three typical dFNC patterns between different brain functional regions were obtained. Compared to the spatial modules of HCs, the aberrant connections among auditory network, somatomotor, visual, cognitive control and cerebellar networks in 82 subject dataset and COBRE dataset were detected. Four temporal states reveal significant differences between SZs and HCs for these two datasets. Additionally, the accuracy values for SZs and HCs classification based on time-varying weights are larger than 0.96.Significance.This study significantly excavates spatio-temporal patterns for schizophrenia disease.

Computed tomography-based nomogram of Siewert type II/III adenocarcinoma of esophagogastric junction to predict response to docetaxel, oxaliplatin and S-1.

BACKGROUND: Neoadjuvant chemotherapy (NAC) has become the standard care for advanced adenocarcinoma of esophagogastric junction (AEG), although a part of the patients cannot benefit from NAC. There are no models based on baseline computed tomography (CT) to predict response of Siewert type II or III AEG to NAC with docetaxel, oxaliplatin and S-1 (DOS). AIM: To develop a CT-based nomogram to predict response of Siewert type II/III AEG to NAC with DOS. METHODS: One hundred and twenty-eight consecutive patients with confirmed Siewert type II/III AEG underwent CT before and after three cycles of NAC with DOS, and were randomly and consecutively assigned to the training cohort (TC) (n = 94) and the validation cohort (VC) (n = 34). Therapeutic effect was assessed by disease-control rate and progressive disease according to the Response Evaluation Criteria in Solid Tumors (version 1.1) criteria. Possible prognostic factors associated with responses after DOS treatment including Siewert classification, gross tumor volume (GTV), and cT and cN stages were evaluated using pretherapeutic CT data in addition to sex and age. Univariate and multivariate analyses of CT and clinical features in the TC were performed to determine independent factors associated with response to DOS. A nomogram was established based on independent factors to predict the response. The predictive performance of the nomogram was evaluated by Concordance index (C-index), calibration and receiver operating characteristics curve in the TC and VC. RESULTS: Univariate analysis showed that Siewert type (52/55 vs 29/39, P = 0.005), pretherapeutic cT stage (57/62 vs 24/32, P = 0.028), GTV (47.3 ± 27.4 vs 73.2 ± 54.3, P = 0.040) were significantly associated with response to DOS in the TC. Multivariate analysis of the TC also showed that the pretherapeutic cT stage, GTV and Siewert type were independent predictive factors related to response to DOS (odds ratio = 4.631, 1.027 and 7.639, respectively; all P < 0.05). The nomogram developed with these independent factors showed an excellent performance to predict response to DOS in the TC and VC (C-index: 0.838 and 0.824), with area under the receiver operating characteristic curve of 0.838 and 0.824, respectively. The calibration curves showed that the practical and predicted response to DOS effectively coincided. CONCLUSION: A novel nomogram developed with pretherapeutic cT stage, GTV and Siewert type predicted the response of Siewert type II/III AEG to NAC with DOS.

Response of source-sink relationship to progressive water deficit in the domestication of dryland wheat.

It is crucial to clarify the physiological responses of wheat (T. aestivum) plants to source-sink manipulation and assimilation transportation under drought stress during domestication of dryland wheat. In this research, a two-year field experiment was conducted using nine wheat cultivars in a semiarid site of northwest China. The source-sink manipulation treatments including defoliation of flag leaves and 50% removal of ears were applied at the anthesis stage under two levels of drought stress conditions i.e. progressive water supply (PWS) and rainfed drought treatment (RDT). Our results indicated that drought stress reduced the dry weight of leaves, sheaths and stems, as well as caused a significant yield reduction. High ploidy wheat exhibits a greater capacity to sustain higher grain yields when subjected to drought stress, primarily due to its stronger buffer capacity between source supply and sink demand. All wheat species with different ploidy levels had a certain degree of source limitation and sink restriction. During the domestication of wheat, the type of source and sink might be ploidy-dependent with progressive water deficit, but similar interactive relationships. The source-sink ratio of tetraploid species was the largest, while that of hexaploid species was the lowest.

The Role of Iron Overload in Diabetic Cognitive Impairment: A Review.

It is well documented that diabetes mellitus (DM) is strongly associated with cognitive decline and structural damage to the brain. Cognitive deficits appear early in DM and continue to worsen as the disease progresses, possibly due to different underlying mechanisms. Normal iron metabolism is necessary to maintain normal physiological functions of the brain, but iron deposition is one of the causes of some neurodegenerative diseases. Increasing evidence shows that iron overload not only increases the risk of DM, but also contributes to the development of cognitive impairment. The current review highlights the role of iron overload in diabetic cognitive impairment (DCI), including the specific location and regulation mechanism of iron deposition in the diabetic brain, the factors that trigger iron deposition, and the consequences of iron deposition. Finally, we also discuss possible therapies to improve DCI and brain iron deposition.

Novel chlorin e6-based conjugates of tyrosine kinase inhibitors: Synthesis and photobiological evaluation as potent photosensitizers for photodynamic therapy.

Since tyrosine kinase inhibitor (TKI) could reverse ABCG2-mediated drug-resistance, novel chlorin e6-based conjugates of Dasatinib and Imatinib as photosensitizer (PS) were designed and synthesized. The results demonstrated that conjugate 10b showed strongest phototoxicity against HepG2 and B16-F10 cells, which was more phototoxic than chlorin e6 and Talaporfin. It could reduce efflux of intracellular PS by inhibiting ABCG2 in HepG2 cells, and localize in mitochondria, lysosomes, golgi and ER, resulting in higher cell apoptosis rate and ROS production than Talaporfin. Moreover, it could induce cell autophagy and block cell cycle in S phase, and significantly inhibit tumor growth and prolong survival time on BALB/c nude mice bearing HepG2 xenograft tumor to a greater extent than chlorin e6. Consequently, compound 10b could be applied as a promising candidate PS due to its good water-solubility and stability, low drug-resistance, high quantum yield of 1O2 and excellent antitumor efficacy in vitro and in vivo.

Prediction of radiation pneumonia after radiotherapy for esophageal cancer using a unified fractional dosiomics combined model.

OBJECTIVE: This study aimed to construct an optimal model to predict radiation pneumonia (RP) after radiotherapy for esophageal cancer using unified fractional dosiomics and to investigate the improvements in the prediction efficiency of each model for RP. METHODS: The clinical data, DVH, pre-treatment CT, and dose distribution of 182 patients were retrospectively analyzed.The independent risk factors were screened using univariate and multivariate logistic regression. The mutual information (MI),least absolute shrinkage and selection operator (LASSO), and recursive feature elimination (RFE) methods were used to screen the omics features. The AUC values of ROC, calibration curves, and clinical decision curves were calculated to evaluate the efficacy and trends of each model. RESULTS: The AUC of dosiomics model were 0.783 and 0.760 in the training and test cohorts, higher than 0.585 and 0.579 in the training and test cohorts of the DVH model. The AUC value of the R + D combination was the highest, reaching 0.833. The combined R + D model had a better calibration degree than the other models (mean absolute error = 0.018) and better net benefit in clinical decision-making. CONCLUSIONS: The radiomics combined dosiomics model was the best combined model to predict RP after radiotherapy for esophageal cancer. The dosiomics model could cover the efficiency of the DVH model and significantly improve the efficiency of the combined model.In the future, we will include other centers for further verification. ADVANCES IN KNOWLEDGE: For the first time, this study used CT images combined dose distribution to predict the occurrence of radiation pneumonitis after radiotherapy for esophageal cancer.

A CT-based novel model to predict pathological complete response of locally advanced esophageal squamous cell carcinoma to neoadjuvant PD-1 blockade in combination with chemotherapy.

PURPOSE: To develop a novel CT-based model to predict pathological complete response (pCR) of locally advanced esophageal squamous cell carcinoma (ESCC) to neoadjuvant PD-1 blockade in combination with chemotherapy. METHODS: 117 consecutive patients with locally advanced ESCC were stratified into training cohort (n = 82) and validation cohort (n = 35). All patients underwent non-contrast and contrast-enhanced thoracic and upper abdominal CT before neoadjuvant PD-1 blockade in combination with chemotherapy (CTpre), and after two cycles of the therapy before esophagectomy (CTpost), respectively. Univariate analyses and binary logistic regression analyses of ESCC quantitative and qualitative CT features were performed to determine independent predictors of pCR. Prediction performance of the model developed with independent predictors from training cohort was evaluated by receiver operating characteristic (ROC) analysis, and validated by Kappa test in validation cohort. RESULTS: In training cohort, the difference in CT attenuation between tumor and background normal esophageal wall obtained from CTpre (ΔTNpre), tumoral increased CT attenuation after contrast-enhanced scan from CTpost images (ΔTpost) and gross tumor volume (GTV) from CTpre were independent predictors of pCR (odds ratio = 1.128 (95% confidence interval (CI): 0.997-1.277), 1.113 (95%CI: 0.965-1.239) and 1.133 (95%CI: 1.043-1.231), respectively, all P-values < 0.05). Logistic regression model equation (0.121 × ΔTNpre + 0.107 × ΔTpost + 0.125 × GTV - 9.856) to predict pCR showed the best performance with an area under the ROC of 0.876, compared with each independent predictor. The good performance was confirmed by the Kappa test (K-value = 0.796) in validation cohort. CONCLUSIONS: This novel model can be reliable to predict pCR to neoadjuvant PD-1 blockade in combination with chemotherapy in locally advanced ESCC.

Effects of liraglutide on astrocyte polarization and neuroinflammation in db/db mice: focus on iron overload and oxidative stress.

Neuroinflammation plays a crucial role in the occurrence and development of cognitive impairment in type 2 diabetes mellitus (T2DM), but the specific injury mechanism is not fully understood. Astrocyte polarization has attracted new attention and has been shown to be directly and indirectly involved in neuroinflammation. Liraglutide has been shown to have beneficial effects on neurons and astrocytes. However, the specific protection mechanism still needs to be clarified. In this study, we assessed the levels of neuroinflammation and A1/A2-responsive astrocytes in the hippocampus of db/db mice and examined their relationships with iron overload and oxidative stress. First, in db/db mice, liraglutide alleviated the disturbance of glucose and lipid metabolism, increased the postsynaptic density, regulated the expression of NeuN and BDNF, and partially restored impaired cognitive function. Second, liraglutide upregulated the expression of S100A10 and downregulated the expression of GFAP and C3, and decreased the secretion of IL-1ß, IL-18, and TNF-α, which may confirm that it regulates the proliferation of reactive astrocytes and A1/A2 phenotypes polarize and attenuate neuroinflammation. In addition, liraglutide reduced iron deposition in the hippocampus by reducing the expression of TfR1 and DMT1 and increasing the expression of FPN1; at the same time, liraglutide by up-regulating the levels of SOD, GSH, and SOD2 expression, as well as downregulation of MDA levels and NOX2 and NOX4 expression to reduce oxidative stress and lipid peroxidation. The above may attenuate A1 astrocyte activation. This study preliminarily explored the effect of liraglutide on the activation of different astrocyte phenotypes and neuroinflammation in the hippocampus of a T2DM model and further revealed its intervention effect on cognitive impairment in diabetes. Focusing on the pathological consequences of astrocytes may have important implications for the treatment of diabetic cognitive impairment.

Collagen changes in rabbit conjunctiva after conjunctival crosslinking.

This study aims to determine the ultrastructural changes in collagen fibrils in rabbit conjunctiva after conjunctival crosslinking using riboflavin and ultraviolet A (UVA) light at an irradiation intensity of 45 mW/cm2. Conjunctival crosslinking may increase conjunctival stiffness. The supertemporal quadrants of the right eyes of 24 adult rabbits were treated with a topical riboflavin solution (0.25%) before irradiation with UVA light at 45 mW/cm2 for 4 min. After 3 weeks, the collagen fibrils in fibril bundles were examined by electron microscopy. Immunohistochemical staining was used to detect the expression levels of collagen I and collagen III in the rabbits' conjunctiva. The diameter of the collagen fibrils in the fibril bundles varied slightly, ranging from 30 to 60 nm in the conjunctival stroma of the control group. In the treatment group, the diameter of collagen fibrils ranged from 60 to 90 nm. The thickest collagen fibrils were observed in the treatment group (up to 90 nm in diameter). In contrast, those in the conjunctival stroma of the control group were considerably smaller (up to 60 nm in diameter). However, thicknesses of collagen fibrils displayed a unimodal distribution. Both collagen I and collagen III increased after treatment with riboflavin and UVA light irradiation at 45 mW/cm2. The data indicate that in rabbits, conjunctival crosslinking with riboflavin and UVA light at 45 mW/cm2 for 4 min is safe and does not induce ultrastructural alterations of the conjunctival cells. The conjunctival crosslinking with riboflavin and UVA light at 45 mW/cm2 can increase the diameter of collagen fibrils, but the average densities of collagen I and collagen III have no statistical significance.

Platelet RNA enables accurate detection of ovarian cancer: an intercontinental, biomarker identification study.

Platelets are reprogrammed by cancer via a process called education, which favors cancer development. The transcriptional profile of tumor-educated platelets (TEPs) is skewed and therefore practicable for cancer detection. This intercontinental, hospital-based, diagnostic study included 761 treatment-naïve inpatients with histologically confirmed adnexal masses and 167 healthy controls from nine medical centers (China, n = 3; Netherlands, n = 5; Poland, n = 1) between September 2016 and May 2019. The main outcomes were the performance of TEPs and their combination with CA125 in two Chinese (VC1 and VC2) and the European (VC3) validation cohorts collectively and independently. Exploratory outcome was the value of TEPs in public pan-cancer platelet transcriptome datasets. The AUCs for TEPs in the combined validation cohort, VC1, VC2, and VC3 were 0.918 (95% CI 0.889-0.948), 0.923 (0.855-0.990), 0.918 (0.872-0.963), and 0.887 (0.813-0.960), respectively. Combination of TEPs and CA125 demonstrated an AUC of 0.922 (0.889-0.955) in the combined validation cohort; 0.955 (0.912-0.997) in VC1; 0.939 (0.901-0.977) in VC2; 0.917 (0.824-1.000) in VC3. For subgroup analysis, TEPs exhibited an AUC of 0.858, 0.859, and 0.920 to detect early-stage, borderline, non-epithelial diseases and 0.899 to discriminate ovarian cancer from endometriosis. TEPs had robustness, compatibility, and universality for preoperative diagnosis of ovarian cancer since it withstood validations in populations of different ethnicities, heterogeneous histological subtypes, and early-stage ovarian cancer. However, these observations warrant prospective validations in a larger population before clinical utilities.

The roles of extracellular vesicles in major depressive disorder.

Major depressive disorder (MDD) is a serious mental disease characterized by depressed mood, loss of interest and suicidal ideation. Its rising prevalence has rendered MDD one of the largest contributors to the global disease burden. However, its pathophysiological mechanism is still unclear, and reliable biomarkers are lacking. Extracellular vesicles (EVs) are widely considered important mediators of intercellular communication, playing an important role in many physiological and pathological processes. Most preclinical studies focus on the related proteins and microRNAs in EVs, which can regulate energy metabolism, neurogenesis, neuro-inflammation and other pathophysiological processes in the development of MDD. The purpose of this review is to describe the current research progress of EVs in MDD and highlight their potential roles as biomarkers, therapeutic indicators and drug delivery carriers for the treatment of MDD.

Surgery, adjuvant immunotherapy plus chemotherapy and radiotherapy for primary malignant melanoma of the parotid gland (PGMM): A case report.

Primary malignant melanoma of the parotid gland (PGMM) is extremely rare, with a poor prognosis. Surgery is the main treatment option followed by adjuvant treatments such as radiotherapy, but which adjuvant treatment to be optimal is still controversial. In this case, a 63-year-old male PGMM patient was first misdiagnosed as a "myoepithelial tumor" and then treated with surgery, postoperative immunotherapy (sintilimab), chemotherapy, and radiotherapy successfully. The progression free survival was more than 19 months without signs of metastasis or recurrence to date. To our best knowledge, this is the first report of postoperative immunotherapy combined with chemotherapy and radiotherapy for PGMM. Our case indicated that combination therapy including surgery, adjuvant immunotherapy (sintilimab) combined with chemotherapy and radiotherapy may be a potential treatment option for PGMM, which needs further research.

Endovascular Treatment of Ruptured or Symptomatic Thoracoabdominal and Pararenal Aortic Aneurysms Using Octopus Endograft Technique: Mid-Term Clinical Outcomes.

OBJECTIVE: To evaluate the effectiveness and safety of using off-the-shelf "Octopus" technique to treat ruptured or symptomatic thoracoabdominal aortic aneurysm (TAAA) and pararenal abdominal aortic aneurysm (PRAAA). METHODS AND RESULTS: All cases who underwent "Octopus" technique from May 2016 to May 2019 at our center were retrospectively analyzed. A total of 10 cases (8 males) were included. The mean age was 54.5±14.2 years (range: 31-80 years). Eight cases presented as aneurysm rupture or impending rupture accepted emergency repair. Technical success, defined by placement of all endografts as planned, was achieved in all cases. A total of 30 target visceral branches were successfully cannulated, 9 celiac arteries were covered intentionally. Intraoperative endoleak was observed in 6 patients, all of them were gutter leak. During hospital stay, there was no death, no side branch occlusion or spinal cord ischemia. Median follow-up was 30 months (range: 12-50 months). One patient died of lung cancer at 14-month follow-up. There was no secondary endoleak. The primary endoleak were found spontaneously resolved in 3 cases at 7 days, 3-month, and 1-year imaging. One persistent endoleak totally resolved after sealing of gutter spaces at 4-month follow-up. The other 2 persistent endoleak decreased during follow-up, which are still under observation. The branch patency rate was 90.3% (28/31). All the 3 occluded branches were renal arteries. Branch occlusion occurred in 2 cases at 1-month follow-up and 1 case at 2-year follow-up, but renal insufficiency was not observed in these cases. Obvious aneurysm sac shrinkage (≥5 mm) was observed in all cases. The aneurysm size shrunk from 7.6±1.9 to 5.5±1.4 cm. No spinal cord ischemia occurred during follow-up. CONCLUSION: Treatment of ruptured TAAA and PRAAA with "Octopus" technique is feasible and safe for high surgical risk patients in the absence of fenestrated and branched devices. The long-term clinical outcomes needed to be investigated.

GSCA: an integrated platform for gene set cancer analysis at genomic, pharmacogenomic and immunogenomic levels.

Cancer initiation and progression are likely caused by the dysregulation of biological pathways. Gene set analysis (GSA) could improve the signal-to-noise ratio and identify potential biological insights on the gene set level. However, platforms exploring cancer multi-omics data using GSA methods are lacking. In this study, we upgraded our GSCALite to GSCA (gene set cancer analysis, http://bioinfo.life.hust.edu.cn/GSCA) for cancer GSA at genomic, pharmacogenomic and immunogenomic levels. In this improved GSCA, we integrated expression, mutation, drug sensitivity and clinical data from four public data sources for 33 cancer types. We introduced useful features to GSCA, including associations between immune infiltration with gene expression and genomic variations, and associations between gene set expression/mutation and clinical outcomes. GSCA has four main functional modules for cancer GSA to explore, analyze and visualize expression, genomic variations, tumor immune infiltration, drug sensitivity and their associations with clinical outcomes. We used case studies of three gene sets: (i) seven cell cycle genes, (ii) tumor suppressor genes of PI3K pathway and (iii) oncogenes of PI3K pathway to prove the advantage of GSCA over single gene analysis. We found novel associations of gene set expression and mutation with clinical outcomes in different cancer types on gene set level, while on single gene analysis level, they are not significant associations. In conclusion, GSCA is a user-friendly web server and a useful resource for conducting hypothesis tests by using GSA methods at genomic, pharmacogenomic and immunogenomic levels.

Cloning and functional identification of pmKPI cDNA in Poecilobdella manillensis.

BACKGROUND: Kazal-type serine protease inhibitors play a role in physiological processes such as blood coagulation and fibrinolysis. The amino acid residues at the P1 site are different, and they inhibit different types of proteases. The inhibitory mechanism of the protease in the salivary glands of Poecilobdella manillensis is still unclear. METHODS AND RESULTS: Based on cloning, prokaryotic expression and bioinformatics analysis, we studied the role of Kazal-type serine protease inhibitors in P. manillensis and analyzed their expression by quantitative real-time PCR. The results suggested that the recombinant protein was successfully expressed in the supernatant when a prokaryotic expression vector was constructed and induced with 0.2 mmol/L IPTG at 37 °C for 4 h, and the enzymatic activity was determined. The mature protein encodes 91 amino acids and has a relative molecular weight of 9929.32 Da, and after removing the signal peptide, the theoretical isoelectric point was 8.79. It is an unstable protein without a transmembrane domain. The mature protein contains two Kazal-type domains, in which all P1 residues are Lys, consisting of an α helix and three antiparallel ß sheets. The upregulated expression of the mRNA was induced after a meal was provided, and the results showed an increasing and then decreasing trend. CONCLUSIONS: Taken together, the results indicate that mature proteins from P. manillensis inhibit thrombin activity, laying the foundation for the subsequent in-depth study of the function of genes encoding Kazal-type serine protease inhibitors.

Three Major Gastrointestinal Cancers Could Be Distinguished through Subclass-Specific IgG Glycosylation.

Esophageal cancer (EC), gastric cancer (GC), and colorectal cancer (CRC) are three major digestive tract tumors with higher morbidity and mortality due to significant molecular heterogeneity. Altered IgG glycosylation has been observed in inflammatory activities and disease progression, and the IgG glycome profile could be used for disease stratification. However, IgG N-glycome profiles in these three cancers have not been systematically investigated. Herein, subclass-specific IgG glycosylation in CRC, GC, and EC was comprehensively characterized by liquid chromatography-tandem mass spectrometry. It was found that IgG1 sialylation was decreased in all three cancers, and the alterations in CRC and EC may be subclass-specific. IgG4 mono-galactosylation was increased in all three cancers, which was a subclass-specific change in all of them. Additionally, glycopeptides of IgG1-H5N5, IgG2-H4N3F1, and IgG4-H4N4F1 could distinguish all three cancer groups from controls with fair diagnostic performance. Furthermore, bioinformatics verified the differential expression of relevant glycosyltransferase genes in cancer progression. Significantly, those three gastrointestinal cancers could be distinguished from each other using subclass-specific IgG glycans. These findings demonstrated the spatial and temporal diversity of IgG N-glycome among digestive cancers, increasing our understanding of the molecular mechanisms of EC, GC, and CRC pathogenesis.