The vasculogenic mimicry related signature predicts the prognosis and immunotherapy response in renal clear cell carcinoma.

BACKGROUND: Clear cell carcinoma of the kidney is a common urological malignancy characterized by poor patient prognosis and treatment outcomes. Modulation of vasculogenic mimicry in tumor cells alters the tumor microenvironment and the influx of tumor-infiltrating lymphocytes, and the combination of its inducers and immune checkpoint inhibitors plays a synergistic role in enhancing antitumor effects. METHODS: We downloaded the data from renal clear cell carcinoma samples and vasculogenic mimicry-related genes to establish a new vasculogenic mimicry-related index (VMRI) using a machine learning approach. Based on VMRI, patients with renal clear cell carcinoma were divided into high VMRI and low VMRI groups, and patients' prognosis, clinical features, tumor immune microenvironment, chemotherapeutic response, and immunotherapeutic response were systematically analyzed. Finally, the function of CDH5 was explored in renal clear cell carcinoma cells. RESULTS: VMRI can be used for prognostic and immunotherapy efficacy prediction in a variety of cancers, which consists of four vasculogenic mimicry-related genes (CDH5, MMP9, MAPK1, and MMP13), is a reliable predictor of survival and grade in patients with clear cell carcinoma of the kidney and has been validated in multiple external datasets. We found that the high VMRI group presented higher levels of immune cell infiltration, which was validated by pathological sections. We performed molecular docking prediction of vasculogenic mimicry core target proteins and identified natural small molecule drugs with the highest affinity for the target protein. Knockdown of CDH5 inhibited the proliferation and migration of renal clear cell carcinoma. CONCLUSIONS: The VMRI identified in this study allows for accurate prognosis assessment of patients with renal clear cell carcinoma and identification of patient populations that will benefit from immunotherapy, providing valuable insights for future precision treatment of patients with renal clear cell carcinoma.

Argatroban in Patients With Acute Ischemic Stroke With Early Neurological Deterioration: A Randomized Clinical Trial.

Importance: The effect of argatroban in patients with acute ischemic stroke (AIS) and early neurological deterioration (END) is unknown. Objective: To assess the efficacy of argatroban for END in AIS. Design, Setting, and Participants: This open-label, blinded-end point, randomized clinical trial was conducted from April 4, 2020, through July 31, 2022. The date of final follow-up was October 31, 2022. This was a multicenter trial. Eligible patients were adults with AIS who experienced END, which was defined as an increase of 2 or more points on the National Institutes of Health Stroke Scale within 48 hours from symptom onset. Patients who withdrew consent, experienced duplicate randomization, or were lost to follow-up were excluded from the study. Interventions: Patients were randomly assigned to the argatroban group and control group within 48 hours of symptom onset. Both groups received standard therapy based on guidelines, including oral mono or dual antiplatelet therapy. The argatroban group received intravenous argatroban for 7 days (continuous infusion at a dose of 60 mg per day for 2 days, followed by 20 mg per day for 5 days) in addition to standard therapy. Main Outcome and Measure: The primary end point was good functional outcome at 90 days, defined as a modified Rankin Scale score of 0 to 3. Results: A total of 628 patients (mean [SD] age, 65 [11.9] years; 400 male [63.7%]) were included in this study (argatroban group, 314 [50%] and control group, 314 [50%]). Of these, 18 withdrew consent, 1 had duplicate randomization, and 8 were lost to follow-up. A total of 601 patients with stroke were included in the intention-to-treat analysis. Finally, 564 patients were included in the per-protocol analysis as 6 participants in the argatroban group and 31 participants in the control group did not follow the complete protocol. The number of patients with good functional outcome at 90 days was 240 (80.5%) in the argatroban group and 222 (73.3%) in the control group (risk difference, 7.2%; 95% CI, 0.6%-14.0%; risk ratio, 1.10; 95% CI, 1.01-1.20; P = .04). The proportion of symptomatic intracranial hemorrhage was 3 of 317 (0.9%) in the argatroban group and 2 of 272 (0.7%) in the control group (P = .78). Conclusions and Relevance: Among patients with AIS with END, treatment with argatroban and antiplatelet therapy resulted in a better functional outcome at 90 days. This trial provided evidence to support the use of argatroban in reducing disability for patients with END. Trial Registration: ClinicalTrials.gov Identifier: NCT04275180.

The effect of nursing intervention combined with PD-1 inhibitor on platelets, white blood cells, tumor markers and quality of life in patients with lung cancer.

Tumor immunotherapy has become one of the important directions in the field of anti-tumor research. Among them, programmed death molecule-1 (PD-1) and its ligand (PD-L1) inhibitors have attracted considerable attention. This study analyzed the application effects of PD-1 inhibitors assisted nursing intervention in patients with lung cancer (LC). Sixty-eight patients with LC were divided into research group and control group randomly. Control group was treated with PD-1 inhibitor chemotherapy. Research group was treated with PD-1 inhibitors as auxiliary nursing intervention. Platelets, immune function indexes, tumor markers, and white blood cells were analyzed. Clinical efficacy was evaluated by traditional Chinese medicine (TCM) symptom score, survival quality of karnofsky performance scale (KPS) score, living quality of quality of life (QOL) score, and nausea and vomiting classification. Hemoglobin (HB), platelet (PLT) and serum white blood cells (WBC) levels in the two groups were decreased after treatment. HB, PLT and WBC levels were enhanced in research group versus control group. Moreover, carcino-embryonic antigen (CEA), carbohydrate antigen 199 (CA199) and CA125 levels in both groups were reduced after treatment. Compared with before treatment, the levels of cluster of differentiation (CD)3+, CD4+, CD4+/CD8+ in control group and the research group increased, while the CD8+ content was significantly decreased after treatment. And their content of the research group was significantly higher/lower than that of the control group. TCM symptom score, KPS score, QOL score and nausea and vomiting classification were improved in research group compared to control group. PD-1 inhibitors assisted nursing intervention can improve the living quality of patients with LC after chemotherapy.

Net water uptake, a neuroimaging marker of early brain edema, as a predictor of symptomatic intracranial hemorrhage after acute ischemic stroke.

Objective: We hypothesized that quantitative net water uptake (NWU), a novel neuroimaging marker of early brain edema, can predict symptomatic intracranial hemorrhage (sICH) after acute ischemic stroke (AIS). Methods: We enrolled patients with AIS who completed admission multimodal computed tomography (CT) within 24 h after stroke onset. NWU within the ischemic core and penumbra was calculated based on admission CT, namely NWU-core and NWU-penumbra. sICH was defined as the presence of ICH in the infarct area within 7 days after stroke onset, accompanied by clinical deterioration. The predictive value of NWU-core and NWU-penumbra on sICH was evaluated by logistic regression analyses and the receiver operating characteristic (ROC) curve. A pure neuroimaging prediction model was built considering imaging markers, which has the potential to be automatically quantified with an artificial algorithm on image workstation. Results: 154 patients were included, of which 93 underwent mechanical thrombectomy (MT). The median time from symptom onset to admission CT was 262 min (interquartile range, 198-368). In patients with MT, NWU-penumbra (OR =1.442; 95% CI = 1.177-1.766; P < 0.001) and NWU-core (OR = 1.155; 95% CI = 1.027-1.299; P = 0.016) were independently associated with sICH with adjustments for age, sex, time from symptom onset to CT, hypertension, lesion volume, and admission National Institutes of Health Stroke Scale (NIHSS) score. ROC curve showed that NWU-penumbra had better predictive performance than NWU-core on sICH [area under the curve (AUC): 0.773 vs. 0.673]. The diagnostic efficiency of the predictive model was improved with the containing of NWU-penumbra (AUC: 0.853 vs. 0.760). A pure imaging model also presented stable predictive power (AUC = 0.812). In patients without MT, however, only admission NIHSS score (OR = 1.440; 95% CI = 1.055-1.965; P = 0.022) showed significance in predicting sICH in multivariate analyses. Conclusions: NWU-penumbra may have better predictive performance than NWU-core on sICH after MT. A pure imaging model showed potential value to automatically screen patients with sICH risk by image recognition, which may optimize treatment strategy.

Traditional Chinese Medicine Formula Jian Pi Tiao Gan Yin Reduces Obesity in Mice by Modulating the Gut Microbiota and Fecal Metabolism.

The current study employed the high-fat diet (HFD) induced murine model to assess the relationship between the effect of Jian Pi Tiao Gan Yin (JPTGY) and the alterations of gut microbiota and fecal metabolism. C57BL/6 mice were used to establish an animal model of obesity via HFD induce. Serum biochemical indicators of lipid metabolism were used to evaluate the pharmacodynamics of JPTGY in obese mice. Bacterial communities and metabolites in the feces specimens from the controls, the Group HFD, and the JPTGY-exposed corpulency group were studied by 16s rDNA genetic sequence in combination with liquid chromatography-mass spectrometry (LC-MS) based untargeted fecal metabolomics techniques. Results revealed that JPTGY significantly decreased the levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and elevated high-density lipoprotein cholesterol (HDL-C). Moreover, JPTGY could up-regulate the abundance and diversity of fecal microbiota, which was characterized by the higher phylum of proteobacteria. Consistently, at the genus levels, JPTGY supplementation induced enrichments in Lachnospiraceae NK4A136 group, Oscillibacter, Turicibacter, Clostridium sensu stricto 1, and Intestinimonas, which were intimately related to 14 pivotal fecal metabolins in respond to JPTGY therapy were determined. What is more, metabolomics further analyses show that the therapeutic effect of JPTGY for obesity involves linoleic acid (LA) metabolism paths, alpha-linolenic acid (ALA) metabolism paths, glycerophospholipid metabolism paths, arachidonic acid (AA) metabolism paths, and pyrimidine metabolism paths, which implied the potential mechanism of JPTGY in treating obesity. It was concluded that the linking of corpulency phenotypes with intestinal flora and fecal metabolins unveils the latent causal link of JPTGY in the treatment of hyperlipidemia and obesity.

Shengxuebao Mixture for Iron Deficiency Anemia: A Meta-Analysis and Systematic Review.

OBJECTIVE: Traditional Chinese medicine Shengxuebao Mixture (SXBM) has been approved for treating iron deficiency anemia (IDA) in China. This study aimed to collect evidence and quantify the effect of SXBM on IDA. METHODS: Seven online databases were surveyed up to July 13, 2021. Randomized controlled trials in which SXBM was combined with conventional therapies to treat IDA and compared with placebo or conventional therapies were included in the study. The red blood cell (RBC) count, hemoglobin (Hb) level, serum ferritin (SF) level, and adverse events rate (AER) were evaluated. RESULTS: A total of 1,108 patients from 8 trials were recruited. SXBM plus conventional therapy increased the Hb level (mean difference [MD] = 13.04, 95% confidence interval [CI] 8.37-17.7, p < 0.00001), RBC count (MD = 0.41, 95% CI 0.19-0.62, p = 0.002), SF level (MD = 6.25, 95% CI 2.88-9.62, p = 0.0003), and AER (risk ratio = 0.56, 95% CI 0.36-0.86; p = 0.008). CONCLUSIONS: SXBM combined with conventional treatment seemed to be beneficial for patients with IDA. However, the harmlessness of SXBM was not confirmed due to insufficient trials and low methodological quality. Follow-up clinical studies should be cautiously designed, and more research is needed.

The bZIP73 transcription factor controls rice cold tolerance at the reproductive stage.

Cold temperature during the reproductive stage often causes great yield loss of grain crops in subtropical and temperate regions. Previously we showed that the rice transcription factor bZIP73Jap plays an important role in cold adaptation at the seedling stage. Here we further demonstrate that bZIP73Jap also confers cold stress tolerance at the reproductive stage. bZIP73Jap was up-regulated under cold treatment and predominately expressed in panicles at the early binucleate and flowering stages. bZIP73Jap forms heterodimers with bZIP71, and co-expression of bZIP73Jap and bZIP71 transgenic lines significantly increased seed-setting rate and grain yield under natural cold stress conditions. bZIP73Jap :bZIP71 not only repressed ABA level in anthers, but also enhanced soluble sugar transport from anthers to pollens and improved pollen grain fertility, seed-setting rate, and grain yield. Interestingly, bZIP73Jap :bZIP71 also regulated the expression of qLTG3-1Nip , and qLTG3-1Nip overexpression lines greatly improved rice tolerance to cold stress during the reproductive stage. Therefore, our work establishes a framework for rice cold stress tolerance through the bZIP71-bZIP73Jap -qLTG3-1Nip -sugar transport pathway. Together with our previous work, our results provide a powerful tool for improving rice cold stress tolerance at both the seedling and the reproductive stages.

Assessment of Five Chilling Tolerance Traits and GWAS Mapping in Rice Using the USDA Mini-Core Collection.

Rice (Oryza sativa L.) is often exposed to cool temperatures during spring planting in temperate climates. A better understanding of genetic pathways regulating chilling tolerance will enable breeders to develop varieties with improved tolerance during germination and young seedling stages. To dissect chilling tolerance, five assays were developed; one assay for the germination stage, one assay for the germination and seedling stage, and three for the seedling stage. Based on these assays, five chilling tolerance indices were calculated and assessed using 202 O. sativa accessions from the Rice Mini-Core (RMC) collection. Significant differences between RMC accessions made the five indices suitable for genome-wide association study (GWAS) based quantitative trait loci (QTL) mapping. For young seedling stage indices, japonica and indica subspecies clustered into chilling tolerant and chilling sensitive accessions, respectively, while both subspecies had similar low temperature germinability distributions. Indica subspecies were shown to have chilling acclimation potential. GWAS mapping uncovered 48 QTL at 39 chromosome regions distributed across all 12 rice chromosomes. Interestingly, there was no overlap between the germination and seedling stage QTL. Also, 18 QTL and 32 QTL were in regions discovered in previously reported bi-parental and GWAS based QTL mapping studies, respectively. Two novel low temperature seedling survivability (LTSS)-QTL, qLTSS3-4 and qLTSS4-1, were not in a previously reported QTL region. QTL with strong effect alleles identified in this study will be useful for marker assisted breeding efforts to improve chilling tolerance in rice cultivars and enhance gene discovery for chilling tolerance.

Association between oxytocin and receptor genetic polymorphisms and aggression in a northern Chinese Han population with alcohol dependence.

OBJECTIVE: Alcohol dependence (AD) is a common chronic brain disorder precipitated by complex interactions between biological, genetic, and environmental risk factors. Aggression often occurs in the context of AD. Previous studies have shown that Oxytocin (OXT) and OXT receptor (OXTR) are involved in the regulation of aggression. The present study investigated whether variations and interactions of OXT and OXTR genes were associated with AD-related aggression in a genetically homogeneous northern Chinese Han population. METHODS: Three hundred and twenty-four male AD patients and 510 male healthy controls (HCs) were recruited. A Chinese version of the Buss-Perry Aggression Questionnaire was used as a subjective measurement of aggressive behavior. Three variations, rs2254298, rs53576, and rs6133010 were genotyped using TaqMan and ligase detection reaction for all subjects. Generalized Multifactor Dimensionality Reduction was used to detect interactions between genetic attributes and environmental attributes. RESULTS: The frequencies of alleles and genotypes of rs6133010 were significantly different between AD patients and HCs (p<0.001). In HCs, the effect of genotype GG of rs53576 on hostility aggression was significantly stronger than that of genotype AA and AG (p=0.001 and p=0.004, respectively), and the subjects with the interaction combination of rs6133010AA×rs2254298GG×rs53576AG exhibited significant effect on physical aggression (p=0.0107). CONCLUSION: The present study found that rs6133010 in the OXT gene is associated with AD in the northern Chinese Han population. The polymorphisms of OXT/R may play a key role in the susceptibility of AD-related aggression.

An AT-hook gene is required for palea formation and floral organ number control in rice.

Grasses have highly specialized flowers and their outer floral organ identity remains unclear. In this study, we identified and characterized rice mutants that specifically disrupted the development of palea, one of the outer whorl floral organs. The depressed palea1 (dp1) mutants show a primary defect in the main structure of palea, implying that palea is a fusion between the main structure and marginal tissues on both sides. The sterile lemma at the palea side is occasionally elongated in dp1 mutants. In addition, we found a floral organ number increase in dp1 mutants at low penetration. Both the sterile lemma elongation and the floral organ number increase phenotype are enhanced by the mutation of an independent gene SMALL DEGENERATIVE PALEA1 (SDP1), whose single mutation causes reduced palea size. E function and presumable A function floral homeotic genes were found suppressed in the dp1-2 mutant. We identified the DP1 gene by map-based cloning and found it encodes a nuclear-localized AT-hook DNA binding protein, suggesting a grass-specific role of chromatin architecture modification in flower development. The DP1 enhancer SDP1 was also positional cloned, and was found identical to the recently reported RETARDED PALEA1 (REP1) gene encoding a TCP family transcription factor. We further found that SDP1/REP1 is downstreamly regulated by DP1.

Isolation and functional analysis of LiYAB1, a YABBY family gene, from lily (Lilium longiflorum).

YABBY family proteins are plant-specific transcriptional factors. YABBY genes can be divided into three subfamilies. Within the CRC/DL subfamily, the Arabidopsis CRC (CRABS CLAW) and the rice DL (DROOPING LEAF) have functionally diverged in the control of leaf development. CRC has no function in leaf development, while DL plays an important role in the formation of leaf midribs. In this study LiYAB1, an ortholog of CRC/DL genes from lily (Lilium longiflorum), was isolated by screening a cDNA library derived from young lily flower buds. Subcellular localization analysis indicated that LiYAB1 is nuclear localized. LiYAB1 is expressed strongly in the carpels of the lily flower and weakly in the leaves, which is similar to DL in rice. Ectopic expression of LiYAB1 in the rice dl mutant could rescue the drooping leaf phenotype of dl in some of the transgenic rice plants and cause abnormal leaves in the other transgenic plants. The overexpression of LiYAB1 in the wild-type Arabidopsis caused leaf abnormality. The results suggest that LiYAB1, a member of the CRC/DL subfamily genes, might have an important function in regulating the leaf development in lilies, as DL does in rice.

Adapting rice anther culture to gene transformation and RNA interference.

Anther culture offers a rapid method of generating homozygous lines for breeding program and genetic analysis. To produce homozygous transgenic lines of rice (Oryza sativa L.) in one step, we developed an efficient protocol of anther-callus-based transformation mediated by Agrobacterium after optimizing several factors influencing efficient transformation, including callus induction and Agrobacterium density for co-cultivation. Using this protocol, we obtained 145 independent green transformants from five cultivars of japonica rice by transformation with a binary vector pCXK1301 bearing the rice gene, Xa21 for resistance to bacterial blight, of which 140 were further confirmed by PCR and Southern hybridization analysis, including haploids (32.1%), diploids (62.1%) and mixoploids (7.5%). Fifteen diploids were found to be doubled haploids, which accounted for 10.7% of the total positive lines. Finally, by including 28 from colchicine induced or spontaneous diploidization of haploids later after transformation, a total of 43 doubled haploids (30.7%) of Xa21 transgenic lines were obtained. We also generated two RNAi transgenic haploids of the rice OsMADS2 gene, a putative redundant gene of OsMADS4 based on their sequence similarity, to investigate its possible roles in rice flower development by this method. Flowers from the two OsMADS2 RNAi transgenic haploids displayed obvious homeotic alternations, in which lodicules were transformed into palea/lemma-like tissues, whereas identities of other floral organs were maintained. The phenotypic alternations were proved to result from specific transcriptional suppression of OsMADS2 gene by the introduced RNAi transgene. The results confirmed that OsMADS2 is involved in lodicule development of rice flower and functionally redundant with OsMADS4 gene. Our results demonstrated that rice anther culture could be adapted to gene transformation and RNAi analysis in rice.