bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical course of patients with adrenal incidentalomas and cortisol autonomy: a German retrospective single center cohort study
Authors: Remde Hanna , Kranz Stefanie , Morell Sarah Maria , Altieri Barbara , Kroiss Matthias , Detomas Mario , Fassnacht Martin , Deutschbein Timo
Published: May 2023

Background

Adrenal incidentalomas with cortisol autonomy are associated with increased cardiovascular morbidity and mortality. Specific data on the clinical and biochemical course of affected patients are lacking.

Methods

Retrospective study from a tertiary referral centre in Germany. After exclusion of overt hormone excess, malignancy and glucocorticoid medication, patients with adrenal incidentalomas were stratified according to serum cortisol after 1 mg dexamethasone: autonomous cortisol secretion (ACS), >5.0; possible ACS (PACS), 1.9-5.0; non-functioning adenomas (NFA), ≤1.8 µg/dl.

Results

A total of 260 patients were enrolled (147 women (56.5%), median follow-up 8.8 (2.0-20.8) years). At initial diagnosis, median age was 59.5 (20-82) years, and median tumour size was 27 (10-116) mm. Bilateral tumours were more prevalent in ACS (30.0%) and PACS (21.9%) than in NFA (8.1%). Over time, 40/124 (32.3%) patients had a shift of their hormonal secretion pattern (NFA to PACS/ACS, n=15/53; PACS to ACS, n=6/47; ACS to PACS, n=11/24; PACS to NFA, n=8/47). However, none of the patients developed overt Cushing’s syndrome. Sixty-one patients underwent adrenalectomy (NFA, 17.9%; PACS, 24.0%; ACS, 39.0%). When non-operated patients with NFA were compared to PACS and ACS at last follow-up, arterial hypertension (65.3% vs. 81.9% and 92.0%; p<0.05), diabetes (23.8% vs. 35.6% and 40.0%; p<0.01), and thromboembolic events (PACS: HR 3.43, 95%-CI 0.89-13.29; ACS: HR 5.96, 95%-CI 1.33-26.63; p<0.05) were significantly less frequent, along with a trend towards a higher rate of cardiovascular events in case of cortisol autonomy (PACS: HR 2.23, 95%-CI 0.94-5.32; ACS: HR 2.60, 95%-CI 0.87-7.79; p=0.1). Twenty-five (12.6%) of the non-operated patients died, with higher overall mortality in PACS (HR 2.6, 95%-CI 1.0-4.7; p=0.083) and ACS (HR 4.7, 95%-CI 1.6-13.3; p<0.005) compared to NFA. In operated patients, prevalence of arterial hypertension decreased significantly (77.0% at diagnosis to 61.7% at last follow-up; p<0.05). The prevalence of cardiovascular events and mortality did not differ significantly between operated and non-operated patients, whereas thromboembolic events were significantly less frequent in the surgical treatment group.

Conclusion

Our study confirms relevant cardiovascular morbidity in patients with adrenal incidentalomas (especially those with cortisol autonomy). These patients should therefore be monitored carefully, including adequate treatment of typical cardiovascular risk factors. Adrenalectomy was associated with a significantly decreased prevalence of hypertension. However, more than 30% of patients required reclassification according to repeated dexamethasone suppression tests. Thus, cortisol autonomy should ideally be confirmed before making any relevant treatment decision (e.g. adrenalectomy).
Determination and characterization of molecular heterogeneity and precision medicine strategies of patients with pancreatic cancer and pancreatic neuroendocrine tumor based on oxidative stress and mitochondrial dysfunction-related genes
Authors: Cui Yougang , Yuan Qihang , Chen Junhong , Jiang Jian , Guan Hewen , Zhu Ruiping , Li Ning , Liu Wenzhi , Wang Changmiao
Published: May 2023

Background

Mitochondria are significant both for cellular energy production and reactive oxygen/nitrogen species formation. However, the significant functions of mitochondrial genes related to oxidative stress (MTGs-OS) in pancreatic cancer (PC) and pancreatic neuroendocrine tumor (PNET) are yet to be investigated integrally. Therefore, in pan-cancer, particularly PC and PNET, a thorough assessment of the MTGs-OS is required.

Methods

Expression patterns, prognostic significance, mutation data, methylation rates, and pathway-regulation interactions were studied to comprehensively elucidate the involvement of MTGs-OS in pan-cancer. Next, we separated the 930 PC and 226 PNET patients into 3 clusters according to MTGs-OS expression and MTGs-OS scores. LASSO regression analysis was utilized to construct a novel prognostic model for PC. qRT-PCR(Quantitative real-time PCR) experiments were performed to verify the expression levels of model genes.

Results

The subtype associated with the poorest prognosis and lowerest MTGs-OS scores was Cluster 3, which could demonstrate the vital function of MTGs-OS for the pathophysiological processes of PC. The three clusters displayed distinct variations in the expression of conventional cancer-associated genes and the infiltration of immune cells. Similar molecular heterogeneity was observed in patients with PNET. PNET patients with S1 and S2 subtypes also showed distinct MTGs-OS scores. Given the important function of MTGs-OS in PC, a novel and robust MTGs-related prognostic signature (MTGs-RPS) was established and identified for predicting clinical outcomes for PC accurately. Patients with PC were separated into the training, internal validation, and external validation datasets at random; the expression profile of MTGs-OS was used to classify patients into high-risk (poor prognosis) or low-risk (good prognosis) categories. The variations in the tumor immune microenvironment may account for the better prognoses observed in high-risk individuals relative to low-risk ones.

Conclusions

Overall, our study for the first time identified and validated eleven MTGs-OS remarkably linked to the progression of PC and PNET, and elaborated the biological function and prognostic value of MTGs-OS. Most importantly, we established a novel protocol for the prognostic evaluation and individualized treatment for patients with PC.
Age at diagnosis, diabetes duration and the risk of cardiovascular disease in patients with diabetes mellitus: a cross-sectional study
Authors: Yao Xuelin , Zhang Jie , Zhang Xiaoqian , Jiang Tian , Zhang Yi , Dai Fang , Hu Honglin , Zhang Qiu
Published: May 2023

Background

The purpose of the study was to evaluate characteristics and risk of cardiovascular disease (CVD) according to age at diagnosis and disease duration among adults with diabetes mellitus (DM).

Methods

The association between age at diagnosis, diabetes duration and CVD were examined in 1,765 patients with DM. High risk of estimated ten-year atherosclerotic cardiovascular disease (ASCVD) was performed by the Prediction for ASCVD Risk in China (China-PAR) project. Data were compared with analysis of variance and χ2 test, respectively. Multiple logistic regression was used to determine the risk factors of CVD.

Results

The mean age at diagnosis (± standard deviation) was 52.91 ± 10.25 years and diabetes duration was 8.06 ± 5.66 years. Subjects were divided into early-onset DM group (≤43 years), late-onset DM group (44 to 59 years), elderly-onset DM group (≥60 years) according to age at diagnosis. Diabetes duration was classified by 5 years. Both early-onset and longest diabetes duration (>15 years) had prominent hyperglycaemia. Diabetes duration was associated with the risk of ischemic stroke (odds ratio (OR), 1.091) and coronary artery disease (OR, 1.080). Early-onset group (OR, 2.323), and late-onset group (OR, 5.199), and hypertension (OR, 2.729) were associated with the risk of ischemic stroke. Late-onset group (OR, 5.001), disease duration (OR, 1.080), and hypertension (OR, 2.015) and hyperlipidemia (OR, 1.527) might increase the risk of coronary artery disease. Aged over 65 (OR, 10.192), central obesity (OR, 1.992), hypertension (OR, 18.816), cardiovascular drugs (OR, 5.184), antihypertensive drugs (OR, 2.780), and participants with disease duration >15 years (OR, 1.976) were associated with the high risk of estimated ten-year ASCVD in participants with DM.

Conclusion

Age at diagnosis, diabetes duration, hypertension and hyperlipidemia were independent risks of CVD. Longest (>15 years) diabetes duration increased the high risk of ten-year ASCVD prediction among Chinese patients with DM. It’s urgent to emphasize the importance of age at diagnosis and diabetes duration to improve primary complication of diabetes.
Blood lactate levels are associated with an increased risk of metabolic dysfunction-associated fatty liver disease in type 2 diabetes: a real-world study
Authors: Ma Yi-Lin , Ke Jiang-Feng , Wang Jun-Wei , Wang Yu-Jie , Xu Man-Rong , Li Lian-Xi
Published: May 2023

Aim

To investigate the association between blood lactate levels and metabolic dysfunction-associated fatty liver disease (MAFLD) in type 2 diabetes mellitus (T2DM).

Methods

4628 Chinese T2DM patients were divided into quartiles according to blood lactate levels in this real-world study. Abdominal ultrasonography was used to diagnosis MAFLD. The associations of blood lactate levels and quartiles with MAFLD were analyzed by logistic regression.

Results

There were a significantly increased trend in both MAFLD prevalence (28.9%, 36.5%, 43.5%, and 54.7%) and HOMA2-IR value (1.31(0.80-2.03), 1.44(0.87-2.20), 1.59(0.99-2.36), 1.82(1.15-2.59)) across the blood lactate quartiles in T2DM patients after adjustment for age, sex, diabetic duration, and metformin use (all p<0.001 for trend). After correcting for other confounding factors, not only increased blood lactate levels were obviously associated with MAFLD presence in the patients with (OR=1.378, 95%CI: 1.210-1.569, p<0.001) and without taking metformin (OR=1.181, 95%CI: 1.010-1.381, p=0.037), but also blood lactate quartiles were independently correlated to the increased risk of MAFLD in T2DM patients (p<0.001 for trend). Compared with the subjects in the lowest blood lactate quartiles, the risk of MAFLD increased to 1.436-, 1.473-, and 2.055-fold, respectively, in those from the second to the highest lactate quartiles.

Conclusions

The blood lactate levels in T2DM subjects were independently associated with an increased risk of MAFLD, which was not affected by metformin-taking and might closely related to insulin resistance. Blood lactate levels might be used as a practical indicator for assessing the risk of MAFLD in T2DM patients.
Role of Delta/Notch-like EGF-related receptor in blood glucose homeostasis
Authors: Ruiz-Otero Nelmari , Kuruvilla Rejji
Published: May 2023

Cell-cell interactions are necessary for optimal endocrine functions in the pancreas. β-cells, characterized by the expression and secretion of the hormone insulin, are a major constituent of functional micro-organs in the pancreas known as islets of Langerhans. Cell-cell contacts between β-cells are required to regulate insulin production and glucose-stimulated insulin secretion, which are key determinants of blood glucose homeostasis. Contact-dependent interactions between β-cells are mediated by gap junctions and cell adhesion molecules such as E-cadherin and N-CAM. Recent genome-wide studies have implicated Delta/Notch-like EGF-related receptor (Dner) as a potential susceptibility locus for Type 2 Diabetes in humans. DNER is a transmembrane protein and a proposed Notch ligand. DNER has been implicated in neuron-glia development and cell-cell interactions. Studies herein demonstrate that DNER is expressed in β-cells with an onset during early postnatal life and sustained throughout adulthood in mice. DNER loss in adult β-cells in mice (β-Dner cKO mice) disrupted islet architecture and decreased the expression of N-CAM and E-cadherin. β-Dner cKO mice also exhibited impaired glucose tolerance, defects in glucose- and KCl-induced insulin secretion, and decreased insulin sensitivity. Together, these studies suggest that DNER plays a crucial role in mediating islet cell-cell interactions and glucose homeostasis.
The relationship between polycystic ovary syndrome and coronary heart disease: a bibliometric analysis
Authors: Liang Xuzhi , He Haijing , Zeng Hao , Wei Liuyi , Yang Jiahuang , Wen Yuqi , Fan Siqi , Fan Jiangtao
Published: May 2023

Background

Polycystic ovary syndrome (PCOS) is one of the most common gynecological endocrine diseases for women of puberty and reproductive age. PCOS can affect women’s health for the rest of their lives since the incidence of coronary heart disease (CHD) may increase in the perimenopausal and senile periods among PCOS women compared with non-PCOS women.

Method

A literature retrieval based on the Science Citation Index Expanded (SCI-E) database. All obtained records results were downloaded in plain text format for subsequent analysis. VOSviewer v1.6.10, Citespace and Microsoft Excel 2010 software were utilized for analyzing the following terms: countries, institutions, authors, journals, references and keywords.

Results

There were 312 articles retrieved from January 1, 2000 to February 8, 2023, and the frequency of citations was 23,587. The United States, England, and Italy contributed the majority of the records. Harvard University, the University of Athens, and Monash University were the top 3 most productive institutions with publications on the relationship between PCOS and CHD. Journal of clinical endocrinology & metabolism ranked first with the highest publications (24 records), followed by Fertility and sterility (18 records). The keywords were divided into six clusters in the overlay keywords network: (1) the correlation between CHD risk factors and PCOS women; (2) the relationship between cardiovascular disease and female reproductive system hormone secretion; (3) the interaction between CHD and metabolic syndrome; (4) the relationship between c-reactive protein and endothelial function and oxidative stress in PCOS patients; (5) the potential positive effect of metformin on reducing CHD risk factors in PCOS patients; (6) the study of serum cholesterol and body-fat distribution in patients with CHD in PCOS. Oxidative stress, genome-wide association, obesity, primary prevention, and sex difference were main hotspots in this field in recent five years according to the keyword citation burst analysis.

Conclusion

The article obtained the hotspots and trends and provided a reference for subsequent research on the association between PCOS and CHD. Moreover, it is hypothesized that oxidative stress and genome-wide association were frontier hotspots in studies that explore the relationship between PCOS and CHD, and prevention research may be valued in the future.
Iron overload triggering ECM-mediated Hippo/YAP pathway in follicle development: a hypothetical model endowed with therapeutic implications
Authors: Xia Lingjin , Shen Yupei , Liu Suying , Du Jing
Published: May 2023

Disruption of iron homeostasis plays a negative role in follicle development. The dynamic changes in follicle growth are dependent on Hippo/YAP signaling and mechanical forces. However, little is known about the liaison between iron overload and the Hippo/YAP signalling pathway in term of folliculogenesis. Here, based on the available evidence, we established a hypothesized model linking excessive iron, extracellular matrix (ECM), transforming growth factor-β (TGF-β) and Hippo/Yes-associated protein (YAP) signal regarding follicle development. Hypothetically, the TGF-β signal and iron overload may play a synergistic role in ECM production via YAP. We speculate that the dynamic homeostasis of follicular iron interacts with YAP, increasing the risk of ovarian reserve loss and may enhance the sensitivity of follicles to accumulated iron. Hence, therapeutic interventions targeting iron metabolism disorders, and Hippo/YAP signal may alter the consequences of the impaired developmental process based on our hypothesis, which provides potential targets and inspiration for further drug discovery and development applied to clinical treatment.
Evaluation of efficacy and safety of glucokinase activators—a systematic review and meta-analysis
Authors: Yang Wenjia , Wu Han , Cai Xiaoling , Lin Chu , Jiao Ruoyang , Ji Linong
Published: May 2023

Aims

Glucokinase activators (GKAs) promote the activity of glucokinase (GK) and is under development for the treatment of diabetes. The efficacy and safety of GKAs require evaluation.

Methods

This meta-analysis included randomized controlled trials (RCTs) with a duration of at least 12 weeks conducted in patients with diabetes. The primary objective of this meta-analysis was the difference of hemoglobin A1c (HbA1c) change from baseline to study end between GKA groups and placebo groups. Risk of hypoglycemia and laboratory indicators were also evaluated. Weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated for the continuous outcomes, and odds ratios (ORs) and 95% CI were calculated for the risk of hypoglycemia.

Results

Data from 13 RCTs with 2,748 participants treated with GKAs and 2,681 control participants were analyzed. In type 2 diabetes, the level of HbA1c decreased greater in patients with GKA treatment compared with placebo (WMD = -0.339%, 95% CI -0.524 to -0.154%, P < 0.001). The OR comparing GKA versus placebo was 1.448 for risk of hypoglycemia (95% CI 0.808 to 2.596, P = 0.214). The WMD comparing GKA versus placebo was 0.322 mmol/L for triglyceride (TG) levels (95% CI 0.136 to 0.508 mmol/L, P = 0.001). When stratified by drug type, selectivity, and study duration, a significant difference was found between groups. In type 1 diabetes, the result of HbA1c change and lipid indicators showed no significant difference between the TPP399 group and the placebo group.

Conclusions

In patients with type 2 diabetes, GKA treatment was associated with a better glycemic control but a significant elevation in TG concentration in general. The efficacy and safety varied with drug type and selectivity.

Systematic review registration

International Prospective Register of Systematic Reviews, identifier CRD42022378342.
Epigenetic regulation of SST2 expression in small intestinal neuroendocrine tumors
Authors: Klomp Maria J. , Refardt Julie , van Koetsveld Peter M. , Campana Claudia , Dalm Simone U. , Dogan Fadime , van Velthuysen Marie-Louise F. , Feelders Richard A. , de Herder Wouter W. , Hofland Johannes , Hofland Leo J.
Published: May 2023

Background

Somatostatin receptor type 2 (SST2) expression is critical for the diagnosis and treatment of neuroendocrine tumors and is associated with improved patient survival. Recent data suggest that epigenetic changes such as DNA methylation and histone modifications play an important role in regulating SST2 expression and tumorigenesis of NETs. However, there are limited data on the association between epigenetic marks and SST2 expression in small intestinal neuroendocrine tumors (SI-NETs).

Methods

Tissue samples from 16 patients diagnosed with SI-NETs and undergoing surgical resection of the primary tumor at Erasmus MC Rotterdam were analysed for SST2 expression levels and epigenetic marks surrounding the SST2 promoter region, i.e. DNA methylation and histone modifications H3K27me3 and H3K9ac. As a control, 13 normal SI-tissue samples were included.

Results

The SI-NET samples had high SST2 protein and mRNA expression levels; a median (IQR) of 80% (70-95) SST2-positive cells and 8.2 times elevated SST2 mRNA expression level compared to normal SI-tissue (p=0.0042). In comparison to normal SI-tissue, DNA methylation levels and H3K27me3 levels were significantly lower at five out of the eight targeted CpG positions and at two out of the three examined locations within the SST2 gene promoter region of the SI-NET samples, respectively. No differences in the level of activating histone mark H3K9ac were observed between matched samples. While no correlation was found between histone modification marks and SST2 expression, SST2 mRNA expression levels correlated negatively with DNA methylation within the SST2 promoter region in both normal SI-tissue and SI-NETs (p=0.006 and p=0.04, respectively).

Conclusion

SI-NETs have lower SST2 promoter methylation levels and lower H3K27me3 methylation levels compared to normal SI-tissue. Moreover, in contrast to the absence of a correlation with SST2 protein expression levels, significant negative correlations were found between SST2 mRNA expression level and the mean level of DNA methylation within the SST2 promoter region in both normal SI-tissue and SI-NET tissue. These results indicate that DNA methylation might be involved in regulating SST2 expression. However, the role of histone modifications in SI-NETs remains elusive.
Integrative single-cell RNA and ATAC sequencing reveals that the FOXO1-PRDX2-TNF axis regulates tendinopathy
Authors: Guo Junfeng , Tang Hong , Huang Pan , Ye Xiao , Tang Chuyue , Shu Zhao , Guo Junfeng , Kang Xia , Shi Youxing , Zhou Binghua , Liang Taotao , Tang Kanglai
Published: May 2023

Introduction

Tendinopathy, the most common form of chronic tendon disorder, leads to persistent tendon pain and loss of function. Profiling the heterogeneous cellular composition in the tendon microenvironment helps to elucidate rational molecular mechanisms of tendinopathy.

Methods and results

In this study, through a multi-modal analysis, a single-cell RNA- and ATAC-seq integrated tendinopathy landscape was generated for the first time. We found that a specific cell subpopulation with low PRDX2 expression exhibited a higher level of inflammation, lower proliferation and migration ability, which not only promoted tendon injury but also led to microenvironment deterioration. Mechanistically, a motif enrichment analysis of chromatin accessibility showed that FOXO1 was an upstream regulator of PRDX2 transcription, and we confirmed that functional blockade of FOXO1 activity induced PRDX2 silencing. The TNF signaling pathway was significantly activated in the PRDX2-low group, and TNF inhibition effectively restored diseased cell degradation.

Discussion

We revealed an essential role of diseased cells in tendinopathy and proposed the FOXO1-PRDX2-TNF axis is a potential regulatory mechanism for the treatment of tendinopathy.
Convolutional neural network to predict IDH mutation status in glioma from chemical exchange saturation transfer imaging at 7 Tesla
Authors: Yuan Yifan , Yu Yang , Chang Jun , Chu Ying-Hua , Yu Wenwen , Hsu Yi-Cheng , Patrick Liebig Alexander , Liu Mianxin , Yue Qi
Published: May 2023

Background and goal

Noninvasive prediction of isocitrate dehydrogenase (IDH) mutation status in glioma guides surgical strategies and individualized management. We explored the capability on preoperatively identifying IDH status of combining a convolutional neural network (CNN) and a novel imaging modality, ultra-high field 7.0 Tesla (T) chemical exchange saturation transfer (CEST) imaging.

Method

We enrolled 84 glioma patients of different tumor grades in this retrospective study. Amide proton transfer CEST and structural Magnetic Resonance (MR) imaging at 7T were performed preoperatively, and the tumor regions are manually segmented, leading to the “annotation” maps that offers the location and shape information of the tumors. The tumor region slices in CEST and T1 images were further cropped out as samples and combined with the annotation maps, which were inputted to a 2D CNN model for generating IDH predictions. Further comparison analysis to radiomics-based prediction methods was performed to demonstrate the crucial role of CNN for predicting IDH based on CEST and T1 images.

Results

A fivefold cross-validation was performed on the 84 patients and 4090 slices. We observed a model based on only CEST achieved accuracy of 74.01% ± 1.15%, and the area under the curve (AUC) of 0.8022 ± 0.0147. When using T1 image only, the prediction performances dropped to accuracy of 72.52% ± 1.12% and AUC of 0.7904 ± 0.0214, which indicates no superiority of CEST over T1. However, when we combined CEST and T1 together with the annotation maps, the performances of the CNN model were further boosted to accuracy of 82.94% ± 1.23% and AUC of 0.8868 ± 0.0055, suggesting the importance of a joint analysis of CEST and T1. Finally, using the same inputs, the CNN-based predictions achieved significantly improved performances above those from radiomics-based predictions (logistic regression and support vector machine) by 10% to 20% in all metrics.

Conclusion

7T CEST and structural MRI jointly offer improved sensitivity and specificity of preoperative non-invasive imaging for the diagnosis of IDH mutation status. As the first study of CNN model on imaging acquired at ultra-high field MR, our results could demonstrate the potential of combining ultra-high-field CEST and CNN for facilitating decision-making in clinical practice. However, due to the limited cases and B1 inhomogeneities, the accuracy of this model will be improved in our further study.
The role of imaging and sentinel lymph node biopsy in patients with T3b-T4b melanoma with clinically negative disease
Authors: Papageorge Marianna V. , Maina Renee M. , King Amber Loren O. , Lee Victor , Baumann Raymond , Pucar Darko , Ariyan Stephan , Khan Sajid A. , Weiss Sarah A. , Clune James , Olino Kelly
Published: May 2023

Background

Previous studies demonstrate minimal utility of pre-operative imaging for low-risk melanoma; however, imaging may be more critical for patients with high-risk disease. Our study evaluates the impact of peri-operative cross-sectional imaging in patients with T3b-T4b melanoma.

Methods

Patients with T3b-T4b melanoma who underwent wide local excision were identified from a single institution (1/1/2005 – 12/31/2020). Cross-sectional imaging was defined as body CT, PET and/or MRI in the perioperative period, with the following findings: in-transit or nodal disease, metastatic disease, incidental cancer, or other. Propensity scores were created for the odds of undergoing pre-operative imaging. Recurrence free survival was analyzed using the Kaplan-Meier method and log-rank test.

Results

A total of 209 patients were identified with a median age of 65 (IQR 54-76), of which the majority were male (65.1%), with nodular melanoma (39.7%) and T4b disease (47.9%). Overall, 55.0% underwent pre-operative imaging. There were no differences in imaging findings between the pre- and post-operative cohorts. After propensity-score matching, there was no difference in recurrence free survival. Sentinel node biopsy was performed in 77.5% patients, with 47.5% resulting in a positive result.

Conclusion

Pre-operative cross-sectional imaging does not impact the management of patients with high-risk melanoma. Careful consideration of imaging use is critical in the management of these patients and highlights the importance of sentinel node biopsy for stratification and decision making.
Optimal 18F-FDG PET/CT radiomics model development for predicting EGFR mutation status and prognosis in lung adenocarcinoma: a multicentric study
Authors: Zuo Yan , Liu Qiufang , Li Nan , Li Panli , Zhang Jianping , Song Shaoli
Published: May 2023

Purpose

To develop and interpret optimal predictive models to identify epidermal growth factor receptor (EGFR) mutation status and subtypes in patients with lung adenocarcinoma based on multicentric 18F-FDG PET/CT data, and further construct a prognostic model to predict their clinical outcome.

Methods

The 18F-FDG PET/CT imaging and clinical characters of 767 patients with lung adenocarcinoma from 4 cohorts were collected. Seventy-six radiomics candidates using cross-combination method to identity EGFR mutation status and subtypes were built. Further, Shapley additive explanations and local interpretable model-agnostic explanations were used for optimal models’ interpretation. Moreover, in order to predict the overall survival, a multivariate Cox proportional hazard model based on handcrafted radiomics features and clinical characteristics was constructed. The predictive performance and clinical net benefit of the models were evaluated via area under receiver operating characteristic (AUC), C-index and decision curve analysis.

Results

Among the 76 radiomics candidates, light gradient boosting machine classifier (LGBM) combined with recursive feature elimination wrapped LGBM feature selection method achieved best performance in predicting EGFR mutation status (AUC reached 0.80, 0.61, 0.71 in the internal test cohort and two external test cohorts, respectively). And extreme gradient boosting classifier combined with support vector machine feature selection method achieved best performance in predicting EGFR subtypes (AUC reached 0.76, 0.63, 0.61 in the internal test cohort and two external test cohorts, respectively). The C-index of the Cox proportional hazard model achieved 0.863.

Conclusions

The integration of cross-combination method and the external validation from multi-center data achieved a good prediction and generalization performance in predicting EGFR mutation status and its subtypes. The combination of handcrafted radiomics features and clinical factors achieved good performance in predicting prognosis. With the urgent needs of multicentric 18F-FDG PET/CT trails, robust and explainable radiomics models have great potential in decision making and prognosis prediction of lung adenocarcinoma.
Case Report: Lung adenocarcinoma associated with germline ERCC2 frameshift mutation
Authors: Liu Lili , Cui Jia , Liu Siye , Pan Evenki , Sun Limin
Published: May 2023

Family history is an established risk factor for lung cancer. Previous studies have found that germline genetic alterations, such as those in EGFR, BRCA1, BRCA2, CHEK2, CDKN2A, HER2, MET, NBN, PARK2, RET, TERT, TP53, and YAP1, are associated with an increased risk of developing lung cancer. The study reports the first of a lung adenocarcinoma proband with germline ERCC2 frameshift mutation c.1849dup (p. A617Gfs*32). Her family cancer history review demonstrated that her two healthy sisters, a brother with lung cancer, and three healthy cousins were positive for ERCC2 frameshift mutation, which might contribute to increased cancer risk. Our study highlights the necessity of performing comprehensive genomic profiling in discovering rare genetic alterations, early cancer screening, and monitoring for patients with family cancer history.
Water status and macronutrient concentrations, but not carbon status, of Viscum album ssp. album are determined by its hosts: a study across nine mistletoe–host pairs in central Switzerland
Authors: Wang Ao , Bose Arun K. , Lehmann Marco M. , Rigling Andreas , Gessler Arthur , Yu Longfei , Li Maihe
Published: May 2023

Introduction

European mistletoe,Viscum albumL., is a hemiparasite that can infect various tree species, yet our understanding of its physiological interactions with host species is limited.

Methods

Nine mistletoe–host pairs (i.e.V. albumssp.albumgrowing on nine different broadleaf tree species) under different growth conditions in central Switzerland were selected to examine the carbon, water and nutrient relationships between mistletoe and its hosts. We measured leaf morphological traits, isotopic compositions (δ13C and δ15N), concentrations of non-structural carbohydrates (NSC) and specific compounds (i.e. mobile sugars and starch), and macronutrients (i.e. N, P, K, Ca, Mg, S) in leaf and xylem tissues of both mistletoe and its hosts.

Results and Discussion

There were only non-significant relationships between NSC concentrations in mistletoe and in its host species across the nine mistletoe–host pairs, suggesting the carbon condition ofV. albumssp.albumis determined by both the heterotrophic carbon transfer and self-photosynthetic capacity among different mistletoe-host pairs. However, mistletoe leaf morphological traits (single leaf area and mass, and leaf mass per unit leaf area) did not change across the nine mistletoe–host pairs, and mistletoe leaf δ13C, water content and macronutrient concentrations were linearly correlated with those in the host leaves. Macronutrients showed accumulations in mistletoe across the nine pairs. Further, tissue N concentrations were significantly higher in mistletoe grown on N-fixing hosts than on non-N-fixing hosts. Finally, leaf N:P in mistletoe was significantly correlated with the ratio in the host across the nine mistletoe–host pairs. Overall, our results indicate strong relationships between mistletoe and its hosts for water- and nutrient-related traits, but not for carbon-related traits, which demonstrates thatV. albumssp. album can adjust its physiology to survive on different deciduous tree species hosts and under different site conditions.
Chemical priming of plant defense responses to pathogen attacks
Authors: Hönig Martin , Roeber Venja M. , Schmülling Thomas , Cortleven Anne
Published: May 2023

Plants can acquire an improved resistance against pathogen attacks by exogenous application of natural or artificial compounds. In a process called chemical priming, application of these compounds causes earlier, faster and/or stronger responses to pathogen attacks. The primed defense may persist over a stress-free time (lag phase) and may be expressed also in plant organs that have not been directly treated with the compound. This review summarizes the current knowledge on the signaling pathways involved in chemical priming of plant defense responses to pathogen attacks. Chemical priming in induced systemic resistance (ISR) and systemic acquired resistance (SAR) is highlighted. The roles of the transcriptional coactivator NONEXPRESSOR OF PR1 (NPR1), a key regulator of plant immunity, induced resistance (IR) and salicylic acid signaling during chemical priming are underlined. Finally, we consider the potential usage of chemical priming to enhance plant resistance to pathogens in agriculture.
Fine mapping of a QTL and identification of candidate genes associated with cold tolerance during germination in peanut (Arachis hypogaea L.) on chromosome B09 using whole genome re-sequencing
Authors: Zhang Xin , Zhang Xiaoji , Wang Luhuan , Liu Qimei , Liang Yuying , Zhang Jiayu , Xue Yunyun , Tian Yuexia , Zhang Huiqi , Li Na , Sheng Cong , Nie Pingping , Feng Suping , Liao Boshou , Bai Dongmei
Published: May 2023

Low temperatures significantly affect the growth and yield of peanuts. Temperatures lower than 12 °C are generally detrimental for the germination of peanuts. To date, there has been no report on precise information on the quantitative trait loci (QTL) for cold tolerance during the germination in peanuts. In this study, we developed a recombinant inbred line (RIL) population comprising 807 RILs by tolerant and sensitive parents. Phenotypic frequencies of germination rate low-temperature conditions among RIL population showed normally distributed in five environments. Then, we constructed a high density SNP-based genetic linkage map through whole genome re-sequencing (WGRS) technique and identified a major quantitative trait locus (QTL), qRGRB09, on chromosome B09. The cold tolerance-related QTLs were repeatedly detected in all five environments, and the genetic distance was 6.01 cM (46.74 cM - 61.75 cM) after taking a union set. To further confirm that qRGRB09 was located on chromosome B09, we developed Kompetitive Allele Specific PCR (KASP) markers for the corresponding QTL regions. A regional QTL mapping analysis, which was conducted after taking the intersection of QTL intervals of all environments into account, confirmed that qRGRB09 was between the KASP markers, G22096 and G220967 (chrB09:155637831–155854093), and this region was 216.26 kb in size, wherein a total of 15 annotated genes were detected. This study illustrates the relevance of WGRS-based genetic maps for QTL mapping and KASP genotyping that facilitated QTL fine mapping of peanuts. The results of our study also provided useful information on the genetic architecture underlying cold tolerance during germination in peanuts, which in turn may be useful for those engaged in molecular studies as well as crop improvement in the cold-stressed environment.
Meristem genes are essential for the vegetative reproduction of Kalanchoë pinnata
Authors: Jácome-Blásquez Francisco , Kim Minsung
Published: May 2023

Several Kalanchoë species reproduce asexually by forming plantlets in the leaf crenulations. Some species produce plantlets incessantly via somatic embryogenesis and organogenesis, whereas others exclusively develop plantlets after leaf detachment, presumably through organogenesis. SHOOT MERISTEMLESS (STM), which mediates SAM functions, appears to be involved in Kalanchoë plantlet formation, suggesting that meristem genes may be essential for plantlet formation. However, the genetic regulatory network for establishing and maintaining plantlet primordia in Kalanchoë remains elusive. Here, we showed that meristem genes were differentially expressed in the leaf crenulations of K. pinnata during plantlet development after leaf detachment. The regulatory interactions among these meristem genes are largely conserved in K. pinnata crenulations. Moreover, transgenic antisense (AS) plants with lower expression of these key meristem genes formed significantly fewer plantlets with some morphological defects, suggesting that the meristem genes play an important role in plantlet formation and development. Our research revealed that key meristem genetic pathways were co-opted to the leaf margin to facilitate the unique asexual reproduction mechanism in K. pinnata. This also highlights how evolutionary tinkering invents new structures such as epiphyllous buds and plantlets by rewiring pre-existing genetic pathways.
Inhibition of rice germination by ustiloxin A involves alteration in carbon metabolism and amino acid utilization
Authors: Fu Xiaoxiang , Jin Yu , Paul Matthew J. , Yuan Minxuan , Liang Xingwei , Cui Ruqiang , Huang Yingjin , Peng Wenwen , Liang Xiaogui
Published: May 2023

Ustiloxins are the main mycotoxin in rice false smut, a devastating disease caused by Ustilaginoidea virens. A typical phytotoxicity of ustiloxins is strong inhibition of seed germination, but the physiological mechanism is not clear. Here, we show that the inhibition of rice germination by ustiloxin A (UA) is dose-dependent. The sugar availability in UA-treated embryo was lower while the starch residue in endosperm was higher. The transcripts and metabolites responsive to typical UA treatment were investigated. The expression of several SWEET genes responsible for sugar transport in embryo was down-regulated by UA. Glycolysis and pentose phosphate processes in embryo were transcriptionally repressed. Most of the amino acids detected in endosperm and embryo were variously decreased. Ribosomal RNAs for growth were inhibited while the secondary metabolite salicylic acid was also decreased under UA. Hence, we propose that the inhibition of seed germination by UA involves the block of sugar transport from endosperm to embryo, leading to altered carbon metabolism and amino acid utilization in rice plants. Our analysis provides a framework for understanding of the molecular mechanisms of ustiloxins on rice growth and in pathogen infection.
Annual compost amendments can replace synthetic fertilizer, improve soil moisture, and ensure tree performance during peach orchard establishment in a humid subtropical climate
Authors: Lawrence Brian T. , Melgar Juan Carlos
Published: May 2023

The application of organic matter (OM) to peach orchards is currently uncommon in commercial operations but could potentially replace synthetic fertilizers and improve long-term orchard sustainability. The purpose of the study was to monitor how annual applications of compost to replace synthetic fertilizer would change soil quality, peach tree nutrient and water status, and tree performance during the first four years of orchard establishment within a subtropical climate. Food waste compost was incorporated before planting and added annually over four years with the following treatments: 1) 1x rate, applied as dry weight at 22,417 kg ha-1 (10 tons acre-1) incorporated during the first year and 11,208 kg ha-1 (5 tons acre-1) applied topically each year after; 2) 2x rate, applied as dry weight at 44,834 kg ha-1 (20 tons acre-1) incorporated during the first year and 22,417 kg ha-1 (10 tons acre-1) applied topically each year after; and 3) control, with no compost added. Treatments were applied to a virgin orchard location, where peach trees had never previously been grown, and to a replant location, where peach trees had been grown previously for more than 20 years. Synthetic fertilizer was reduced in the 1x and 2x rates by 80 and 100% during the spring and all treatments received the summer application according to standard practice. Soil OM, phosphorus and sodium all increased with the addition of 2x compost in the replant location at 15 cm depth, but not within the virgin location compared to the control treatment. The 2x rate of compost improved soil moisture during the growing season, but tree water status was similar between treatments. Tree growth was similar between treatments in the replant location, but the 2x treatment had larger trees compared to the control by the third year. Foliar nutrients were similar between treatments over the four years, while 2x compost rate increased fruit yield in the virgin location compared to the control the second year of harvest. The 2x food waste compost rate could be considered as a replacement for synthetic fertilizers and to potentially increase tree growth during orchard establishment.
Perenniality, more than genotypes, shapes biological and chemical rhizosphere composition of perennial wheat lines
Authors: Bertola Marta , Righetti Laura , Gazza Laura , Ferrarini Andrea , Fornasier Flavio , Cirlini Martina , Lolli Veronica , Galaverna Gianni , Visioli Giovanna
Published: May 2023

Perennial grains provide various ecosystem services compared to the annual counterparts thanks to their extensive root system and permanent soil cover. However, little is known about the evolution and diversification of perennial grains rhizosphere and its ecological functions over time. In this study, a suite of -OMICSs - metagenomics, enzymomics, metabolomics and lipidomics - was used to compare the rhizosphere environment of four perennial wheat lines at the first and fourth year of growth in comparison with an annual durum wheat cultivar and the parental species Thinopyrum intermedium. We hypothesized that wheat perenniality has a greater role in shaping the rhizobiome composition, biomass, diversity, and activity than plant genotypes because perenniality affects the quality and quantity of C input – mainly root exudates – hence modulating the plant-microbes crosstalk. In support of this hypothesis, the continuous supply of sugars in the rhizosphere along the years created a favorable environment for microbial growth which is reflected in a higher microbial biomass and enzymatic activity. Moreover, modification in the rhizosphere metabolome and lipidome over the years led to changes in the microbial community composition favoring the coexistence of more diverse microbial taxa, increasing plant tolerance to biotic and abiotic stresses. Despite the dominance of the perenniality effect, our data underlined that the OK72 line rhizobiome distinguished from the others by the increase in abundance of Pseudomonas spp., most of which are known as potential beneficial microorganisms, identifying this line as a suitable candidate for the study and selection of new perennial wheat lines.
Combined analyses of transcriptome and metabolome reveal the mechanism of exogenous strigolactone regulating the response of elephant grass to drought stress
Authors: Zhou Jing , Liu Yijia , Li Yan , Ling Wenqing , Fan Xiaoyu , Feng Qixian , Ming Ray , Yang Fulin
Published: May 2023

Elephant grass is widely used in feed production and ecological restoration because of its huge biomass and low occurrence of diseases and insect pets. However, drought seriously affects growth and development of this grass. Strigolactone (SL), a small molecular phytohormone, reportedly participates in improving resilience to cope with arid environment. But the mechanism of SL regulating elephant grass to response to drought stress remains unknown and needs further investigation. We conducted RNA-seq experiments and identified 84,296 genes including 765 and 2325 upregulated differential expression genes (DEGs) and 622 and 1826 downregulated DEGs, compared drought rehydration with spraying SL in roots and leaves, respectively. Combined with targeted phytohormones metabolite analysis, five hormones including 6-BA, ABA, MeSA, NAA, and JA had significant changes under re-watering and spraying SL stages. Moreover, a total of 17 co-expression modules were identified, of which eight modules had the most significant correlation with all physiological indicators with weighted gene co-expression network analysis. The venn analysis revealed the common genes between Kyoto Encyclopedia of Genes and Genomes enriched functional DEGs and the top 30 hub genes of higher weights in eight modules, respectively. Finally, 44 DEGs had been identified as key genes which played a major role in SL response to drought stress. After verification of its expression level by qPCR, six key genes in elephant grass including PpPEPCK, PpRuBPC, PpPGK, PpGAPDH, PpFBA, and PpSBPase genes regulated photosynthetic capacity under the SL treatment to respond to drought stress. Meanwhile, PpACAT, PpMFP2, PpAGT2, PpIVD, PpMCCA, and PpMCCB regulated root development and phytohormone crosstalk to respond to water deficit conditions. Our research led to a more comprehensive understanding about exogenous SL that plays a role in elephant grass response to drought stress and revealed insights into the SL regulating molecular mechanism in plants to adapt to the arid environment.
Leadership and Service Delivery in Times of Change
Authors: Atiku Sulaiman Olusegun , Kurana Collen Mulife , Ganiyu Idris Olayiwola
Published: May 2023

There has been a growing concern for excellent service delivery in the public sector. The challenges that are hindering service delivery in Town Councils have been attributed to political interference in appointments and ineffective leadership. The residents in the Town Council have been experiencing power outages and water shortages. The livelihoods of the residents and business operations have been hindered by these difficulties. This study investigates the influence of leadership on service delivery in a Town Council in Namibia. A qualitative research approach was adopted to analyse the influence of leadership practices on service delivery in times of change. A total of ten participants were sampled from a population of 117 staff members using a purposive sampling. Face-to-face interviews were conducted using a semi-structured interview guide. Participants views were tape recorded, transcribed into Microsoft Word, and analysed using thematic analysis via NVivo 12. The results showed that logistical difficulties, political interference, lack of human resources, and financial constraints, are the challenges hampering service delivery in the Town Council. The need for managers and supervisors to inspire, coach, mentor, and motivate their subordinates to enhance service delivery using a transformational leadership style is evident in the results. Therefore, the Town Council should prioritise budgeting, foster public-private partnerships, promote innovation, and ensure stakeholder engagement to enhance service delivery in the Town Council.