Salvianolic acid B improves diabetic skin wound repair through Pink1/Parkin-mediated mitophagy.

Diabetic skin wound is a disturbing and rapidly evolving clinical issue. Here, we investigated how salvianolic acid B (Sal B) affected the diabetic wound healing process. Following Sal B administration, histopathological damage was investigated by H&E and Masson staining, and CD34, apoptosis and mitophagy markers were measured by immunofluorescence, immunohistochemistry, and western blotting. Migration, proliferation, and mitochondrial function of high glucose (HG) -induced HMEC-1 cells were measured. The effects of si-Parkin on endothelial cell migration, apoptosis and mitochondrial autophagy were examined. Sal B alleviated inflammatory cell infiltration and promoted angiogenesis in skin wound tissue. Apoptosis and mitophagy were ameliorated by Sal B in diabetic skin wound tissues and HG-induced HMEC-1 cells. Parkin inhibition impaired the migratorypromoted cell apoptosis and inhibited mitophagy of HMEC-1 cells. This finding demonstrated that Sal B promoted diabetic skin wound repair via Pink1/Parkin-mediated mitophagy, improved our understanding of the diabetic wound healing process.

Characterization and Expression Analysis of Sugar Transporters through Partial Least Square Structural Equation Model (PLS-SEM) Revealed Their Role in Pepper (Capsicum annuum L.).

Pepper (Capsicum annuum L.) is one of the most important economic crops in the world. By controlling the transport and distribution of photosynthetic products between cells and organs, sugar transporters are widely involved in growth and development, environmental adaptation, and microbial interactions. The present study was carried out at the genome-wide level to systematically characterize sugar transporters. As a result, 50 MST, 3 SUT, and 29 SWEET genes were identified and classified. The expression pattern of sugar transporters in pepper was analyzed by transcriptomic data. The expression properties of sugar transporters were further explored in pepper varieties with significant differences in weight, shape, and pungency. It was shown that the pepper sugar transporter genes had obvious spatiotemporal specific expression characteristics and exhibited variety-specific expression preferences. We focus on analyzing candidate genes that may be involved in fruit development and expansion. We further explore the response of pepper sugar transporters to adversity stress using a structural equation model. Finally, we found that the MST, SUT, and SWEET families are collectively involved in balancing pepper resistance to abiotic stress by coordinating the expression strengths of different family members. Our study may contribute to the functional study of pepper sugar transporter genes and create the prospect of utilizing sugar transporter gene resources to improve pepper variety.

Simultaneous detection of dental caries and fissure sealant in intraoral photos by deep learning: a pilot study.

BACKGROUND: Deep learning, as an artificial intelligence method has been proved to be powerful in analyzing images. The purpose of this study is to construct a deep learning-based model (ToothNet) for the simultaneous detection of dental caries and fissure sealants in intraoral photos. METHODS: A total of 1020 intraoral photos were collected from 762 volunteers. Teeth, caries and sealants were annotated by two endodontists using the LabelMe tool. ToothNet was developed by modifying the YOLOX framework for simultaneous detection of caries and fissure sealants. The area under curve (AUC) in the receiver operating characteristic curve (ROC) and free-response ROC (FROC) curves were used to evaluate model performance in the following aspects: (i) classification accuracy of detecting dental caries and fissure sealants from a photograph (image-level); and (ii) localization accuracy of the locations of predicted dental caries and fissure sealants (tooth-level). The performance of ToothNet and dentist with 1year of experience (1-year dentist) were compared at tooth-level and image-level using Wilcoxon test and DeLong test. RESULTS: At the image level, ToothNet achieved an AUC of 0.925 (95% CI, 0.880-0.958) for caries detection and 0.902 (95% CI, 0.853-0.940) for sealant detection. At the tooth level, with a confidence threshold of 0.5, the sensitivity, precision, and F1-score for caries detection were 0.807, 0.814, and 0.810, respectively. For fissure sealant detection, the values were 0.714, 0.750, and 0.731. Compared with ToothNet, the 1-year dentist had a lower F1 value (0.599, p < 0.0001) and AUC (0.749, p < 0.0001) in caries detection, and a lower F1 value (0.727, p = 0.023) and similar AUC (0.829, p = 0.154) in sealant detection. CONCLUSIONS: The proposed deep learning model achieved multi-task simultaneous detection in intraoral photos and showed good performance in the detection of dental caries and fissure sealants. Compared with 1-year dentist, the model has advantages in caries detection and is equivalent in fissure sealants detection.

Metabolic pathway-based subtyping reveals distinct microenvironmental states associated with diffuse large B-cell lymphoma outcomes.

Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogeneous disease that requires personalized clinical treatment. Assigning patients to different risk categories and cytogenetic abnormality and genetic mutation groups has been widely applied for prognostic stratification of DLBCL. Increasing evidence has demonstrated that dysregulated metabolic processes contribute to the initiation and progression of DLBCL. Metabolic competition within the tumor microenvironment is also known to influence immune cell metabolism. However, metabolism- and immune-related stratification has not been established. Here, 1660 genes involved in 84 metabolic pathways were selected and tested to establish metabolic clusters (MECs) of DLBCL. MECs established based on independent lymphoma datasets distinguished different survival outcomes. The CIBERSORT algorithm and EcoTyper were applied to quantify the relative abundance of immune cell types and identify variation in cell states for 13 lineages comprising the tumor micro environment among different MECs, respectively. Functional characterization showed that MECs were an indicator of the immune microenvironment and correlated with distinctive mutational characteristics and oncogenic signaling pathways. The novel immune-related MECs exhibited promising clinical prognostic value and potential for informing DLBCL treatment decisions.

Epidemiological features and prognosis for primary gastrointestinal follicular lymphoma.

Primary gastrointestinal follicular lymphoma (PGI-FL) is a rare extra-nodal lymphoma. Its epidemiology and prognosis remain unclear. We performed a retrospective analysis of eligible patients with 1648 PGI-FL and 34 892 nodal FL (N-FL) in the Surveillance, Epidemiology and End Results (SEER) database. The age-adjusted average annual incidence of PGI-FL was 0.111/100000. The median overall survival (OS) for PGI-FL and N-FL patients was 207 and 165 months respectively. The 5-year diffuse large B-cell lymphoma (DLBCL) transformation rates were 2.1% and 2.6% respectively. Age, sex, grade, Ann Arbor stage, primary site and radiation were independent prognostic factors (p < 0.05). Nomograms were constructed to predict 1-, 5- and 10-year OS and disease-specific survival (DSS). The receiver operating characteristic curves and calibration plots showed the established nomograms had robust and accurate performance. Patients were classified into three risk groups according to nomogram score. In conclusion, the incidence of PGI-FL has increased over the past 40 years, and PGI-FL has a better prognosis and a lower DLBCL transformation rate than N-FL. The nomograms were developed and validated as an individualized tool to predict survival. Patients were divided into three risk groups to assist clinicians in identifying high-risk patients and choosing the optimal individualized treatments.

Optimizing nitrogen application position to change root distribution in soil and regulate maize growth and yield formation in a wide-narrow row cropping system: pot and field experiments.

The wide-and narrow-row cropping technology used for maize has the advantages of protecting cultivated soil and improving the population structure in maize fields. However, the relationship between nitrogen application position and root interactions has not been determined. Through pot and field experiments, we evaluated the effects of two nitrogen application positions ((narrow row nitrogen application (RC) and wide row nitrogen application (RN)) and two nitrogen application regimens ((high nitrogen(HN) and low nitrogen(LN)) on root growth and yield composition of wide-narrow row maize during the flowering and harvest stages. In field experiments, RC increased the biomass, length and surface area of competing roots (narrow-row roots, CR) at the flowering stage. The yield and agronomic efficiency of N(AEN) and partial factor productivity of N(PFPN) were increased by RN compared to RC under HN, However, the AEN under LN was significantly lower; There was no significant effect on maize growth and biomass allocation at the same level of application of N. At the flowering stage, the results of CR and non-competing roots (wide-row roots, NCR) was consistent under pot experiments and the field experiments, and the yield under RN was also higher than that under RC, although the difference was not significant. Furthermore, according to the principal component analysis and correlation analysis, the competing roots were the main factor influencing yield and AEN. In conclusion, our study showed that RN is a useful fertilization method to improve overall productivity. All in all, how roots coordinate neighbors and nitrogen spatial heterogeneity is a complex ecological process, and its trophic behavior deserves further study.

Upregulation of tumor suppressor PIAS3 by Honokiol promotes tumor cell apoptosis via selective inhibition of STAT3 tyrosine 705 phosphorylation.

The natural product Honokiol exhibits robust antitumor activity against a range of cancers, and it has also received approval to undergo phase I clinical trial testing. We confrmed that honokiol can promote the apoptotic death of tumor cells through cell experiments. Then siRNA constructs specific for PIAS3, PIAS3 overexpression plasmid and the mutation of the STAT3 Tyr705 residue were used to confirm the mechanism of Honokiol-induced apoptosis. Finally, we confrmed that honokiol can promote PIAS3 upregulation, in turn suppressing STAT3 Tyr705 phosphorylation through the in vivo and in vitro experiments. Honokiol was ultimately found to reduce tumor cell viability by promoting apoptosis through a mechanism dependent on the ability of Honokiol to promote PIAS3 upregulation and the selective inhibition of p-STAT3 (Tyr705) without affecting p-STAT3 (Ser727) or p-STAT1 (Tyr701) levels. PIAS3 knockdown and overexpression in tumor cells altered STAT3 activation and associated DNA binding activity through the control of Tyr705 phosphorylation via PIAS3-STAT3 complex formation, ultimately shaping Honokiol-induced tumor cell apoptosis. Honokiol was also confirmed to significantly prolong the survival of mice bearing xenograft tumors in a PIAS3-dependent fashion. Together, these findings highlight a novel pathway through which Honokiol can promote PIAS3 upregulation, in turn suppressing STAT3 Tyr705 phosphorylation and promoting the apoptotic death of tumor cells.

Integrative genomic and transcriptomic analysis reveals genetic alterations associated with the early progression of follicular lymphoma.

Follicular lymphoma (FL), the most common indolent lymphoma, is a clinically and genetically heterogeneous disease. However, the prognostic value of driver gene mutations and copy number alterations has not been systematically assessed. Here, we analysed the clinical-biological features of 415 FL patients to identify variables associated with disease progression within 24 months of first-line therapy (POD24). Patients with B symptoms, elevated lactate dehydrogenase and ß2-microglobulin levels, unfavourable baseline haemoglobin levels, advanced stage, and high-risk FL International Prognostic Index (FLIPI) scores had an increased risk of POD24, with FLIPI being the most important factor in logistic regression. HIST1H1D, identified as a driver mutation, was correlated with POD24. Gains of 6p22.2 (HIST1H1D) and 18q21.33 (BCL2) and loss of 1p36.13 (NBPF1) predicted POD24 independent of FLIPI. Gene expression profiling of FL samples showed that the POD24 cohort was significantly enriched in the inflammatory response (mediated by interferon and tumour necrosis factor), cell cycle regulation (transcription, replication and proliferation) sets and PI3K-AKT-mTOR signalling. This result was further validated with transcriptome-wide information provided by RNA-seq at single-cell resolution. Our study, performed on a large cohort of FL patients, highlights the importance of distinctive genetic alterations and gene expression relevant to disease diagnosis and early progression.

OX40 shapes an inflamed tumor immune microenvironment and predicts response to immunochemotherapy in diffuse large B-cell lymphoma.

OX40 enhances the T-cell activation via costimulatory signaling. However, its molecular characteristics and value in predicting response to immunochemotherapy in DLBCL remain largely unexplored. Here, we performed an integrative analysis of sequencing and multiplex immunofluorescence staining, and discovered abnormally higher expression of OX40 in DLBCL patients. Elevated OX40 could activate T cells leading to a higher immune score for tumor immune microenvironment (TiME). OX40 upregulation simultaneously happened with immune-related genes including PD-1, CTLA4 and TIGIT et,al. Patients with high OX40 expression exhibited a lower Ann Arbor stage and IPI score and more easily achieved a complete response/partial response. The analysis of infiltrated T-cell subset revealed that patients with a greater number of CD4+/OX40+ or CD8+/OX40+ T cells had a longer OS. Our findings indicated that OX40 shapes an inflamed tumor immune microenvironment and predicts response to immunochemotherapy, providing insights for the application of OX40 agonist in DLBCL patients.

Improved method to stratify lymphoma patients with risk of secondary central nervous system involvement: A multicenter retrospective analysis.

Secondary central nervous system (SCNS) involvement is an infrequent but universally fatal event in diffused large B-cell lymphoma. The occurrence rate of SCNS involvement is approximately 5% but comes with a poor prognosis ever after. However, existing risk models to predict the incidence and prognosis of these patients with SCNS involvement lack both efficiency and accuracy. Controversy has also been reported regarding which risk factor may best identify the population with a high CNS relapse rate. In this study, we retrospectively analyzed 831 patients with diffused large B-cell lymphoma, diagnosed between March 2008 and June 2018 in Tianjin Medical University Cancer Institute and Hospital, Beijing Cancer Hospital, and Cancer Hospital of The University of Chinese Academy of Science. Risk factors and nomogram were identified and established based on Fine and Gray's competing risk analysis. Among these patients, 55 (6.6%) of them eventually developed SCNS involvement. The 1- and 2-year incidence for SCNS involvement were 3.9% and 4.7%, respectively. The median time from de novo diagnosis to CNS relapse was 8 months, and the median overall survival of these patients was 28 months. Considering the competing mortality before SCNS involvement, Fine and Gray's competing risk model was performed to analyze the characteristics related to SCNS involvement, and identified risk factors as the multiple extranodal involvements, elevated LDH and AMC level, and the involvement of breast, adrenal gland/kidney, pulmonary and bone. Corresponding factors were integrated into the competing nomogram for SCNS involvement (c-index = 0.778). In conclusion, we present the first predictive nomogram to evaluate the risk to develop SCNS involvement in de novo DLBCL patients, which may help in both prognostic evaluation and clinical decision for this subgroup.

Prolonged drought regulates the silage quality of maize (Zea mays L.): Alterations in fermentation microecology.

Prolonged drought stress caused by global warming poses a tremendous challenge to silage production of maize. Drought during maize growth and development resulted in altered micro-environment for silage fermentation. How fermentation of silage maize responds to moisture scales remains uncharted territory. In this research, Maize water control trials were conducted and the silage quality and microbial community of drought-affected maize were determined. The results showed that drought stress significantly reduced the dry matter but increased root-to-shoot ratio, soluble sugar and malonaldehyde content in maize. Before fermentation, the crude protein, crude ash and acid detergent fiber contents were significantly increased but the ether extract content was decreased under drought. The crude protein and acid detergent fiber were significantly decreased in the drought affected group after fermentation. Furthermore, water stress at maize maturity stage greatly reduced the number of total bacteria in silage fermentation but increased the proportion of the lactobacillus and lactic acid content of silage. Drought stress alters the microbial ecosystem of the fermentation process and reconstitutes the diversity of the bacterial community and its metabolites. This study provides a theoretical basis for the study of changes in silage fermentation as affected by abiotic stresses.

Clinical features and outcomes of patients with follicular lymphoma: A real-world study of 926 patients in China.

Background: The data about the clinical features and outcomes of Chinese patients with follicular lymphoma (FL) are limited. Here, we conducted a retrospective study to explore the initial treatment strategies and clinical outcomes of Chinese patients with FL in the real world. Method: This study included FL patients who were newly diagnosed in Tianjin Medical University Cancer Institute and Hospital from March 2002 to August 2020. Results: A total of 926 FL patients were enrolled. The median age was 54 years old, and the majority of the Chinese FL patients had advanced-stage disease and Eastern Cooperative Oncology Group(ECOG) <1 but less frequently infiltrated bone marrow. After a median of 38-month follow-up, the 5-year progressive-free survival (PFS) and overall survival (OS) of grade1-3a were 57.8% and 88.7%, respectively, which both are similar to those reported in previous Chinese and Western studies. The co-existence at diagnosis of FL and diffuse large B-cell lymphoma (DLBCL) components (FL/DLBCL) was associated with poor outcomes. The FL grades and proportion of DLBCL component in FL/DLBCL did not have an impact on PFS and OS. The most common regimen with great efficacy and risk-benefit was RCHOP-like followed by R maintenance regimen. The 5-year cumulative hazard of histological transformation (HT) was 4.7% (95% CI, 3.5-5.9); median time to transformation was 23.5 months (range, 2-146 months) after diagnosis. Three-year survival following transformation was 55% (95% CI, 40-70). Patients with stage III-IV, elevated ß2 microglobulin (ß2-MG), and B symptoms seemed to be more prone to progress within 24 months of frontline therapy (POD24). The FLIPI-2 showed the highest specificity to predict POD24, reflecting the prediction of correctly classifying as low-risk patients, but the FLIPI had the highest sensitivity to predict the risk of progression for critical patients. Conclusions: We revealed the clinical characteristics and outcomes of FL patients in the real world in China, which may provide novel data on prognostic factors and primary treatment of FL, applicable to routine clinical practice.

A retrospective analysis of EBV-DNA status with the prognosis of lymphoma.

Epstein-Barr virus (EBV) infection is proved to be associated with clinicopathology of lymphoma. However, little is known about the relationship between EBV-DNA status after treatment and prognosis. In this study, real-time polymerase chain reaction (PCR) was used for quantitative detection of EBV-DNA load in peripheral blood of all 26,527 patients with lymphoma, and the clinical characteristics and prognosis of 202 patients were retrospectively analysed, including 100 patients with positive EBV-DNA and 102 randomly selected patients with negative EBV-DNA. We found that the average rate of EBV-DNA positivity in lymphomas was 0.376%, and EBV-DNA-positive patients presented higher risk with elevated lactate dehydrogenase (LDH) and ß2-MG level, B symptoms, secondary hemophagocytic syndrome and lower objective response rate compared to EBV-DNA-negative patients. Multivariate analysis revealed EBV-DNA-positive patients had inferior progression-free survival (PFS) and overall survival (OS) and EBV-DNA level before treatment was related to PFS but not OS of T/NK cell lymphoma. In T/NK cell lymphoma, EBV-DNA converting negative after treatment was correlated with better PFS but not OS, and second-line therapy could induce more EBV-DNA-negative conversion compared to CHOP-based therapy. In all, EBV-DNA positivity before treatment can be a biomarker representing the tumour burden and an independent prognostic factor. EBV-DNA-negative conversion after treatment is a good prognostic factor for T/NK cell lymphomas.

A novel immune-related epigenetic signature based on the transcriptome for predicting the prognosis and therapeutic response of patients with diffuse large B-cell lymphoma.

Epigenetic modifications contribute to lymphomagenesis. Here, we performed an expression clustering analysis and identified two epigenetic-related clusters (EC1 and EC2). EC1 presented abundant TP53, MYD88, HIST1H1D, HIST1H1C, KMT2D and EZH2 mutations and an inferior prognosis. Pathways involved in the regulation of DNA methylation/demethylation, histone methyltransferase activity, and protein methyltransferase activity were significantly enriched in EC1. However, EC2 was frequently accompanied by B2M, CD70 and MEF2B mutations, which presented with enrichments in DNA damage repair, cytokine-mediated and B-cell activated immune signaling, increased levels of CD8+ T-, γδT- and T helper-cells, as well as immune scores and immunogenic cell death (ICD) modulators. According to the prediction, EC1 was more sensitive to vorinostat, serdemetan and navitoclax. However, ruxolitinib, cytarabine and CP466722 were more suitable treatments for EC2. The novel immune-related epigenetic signature exhibits promising clinical predictive value for diffuse large B-cell lymphoma (DLBCL), particularly for guiding epigenetic therapeutic regimens. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) based combination treatment regimens are suggested.

Risk factors for POD24 in patients with previously untreated follicular lymphoma: a systematic review and meta-analysis.

Progression of disease within 24 months (POD24) is strongly associated with a poor outcome in patients with follicular lymphoma (FL). Our study aimed to identify the potential risk factors for POD24 in patients with FL. Medline, EMBASE and the Cochrane Library were systematically searched from the earliest record to September 2020. Studies investigating the prognostic factors for POD24 in patients with newly diagnosed grade 1-3a FL were included. Among 10,014 pieces of literature, a total of 90 studies investigating 82 risk factors were included for qualitative analysis. Meta-analyses were performed in 31 studies with 11 factors. Results showed that elevated sIL-2R, ß2m and LDH, total metabolic tumour volume > 510 cm3, vitamin D < 20 ng/mL, grade 3a and lymphoma-associated macrophages/high-power field ≥ 15 were significantly associated with an increased risk of POD24. No significant association was found between POD24 and the ALC/AMC ratio, sex, T effector signature or EZH2 genetic alteration. Additionally, minimal residual disease, Ki-67, PD-1 and TP53 were analysed narratively. Overall, this is the first study that comprehensively analysed the prognostic factors associated with POD24 in FL patients. We have confirmed the significance value of several common prognostic factors as well as others not commonly included in clinical study, helping to construct an integrated and more efficient model.

APR-246 triggers ferritinophagy and ferroptosis of diffuse large B-cell lymphoma cells with distinct TP53 mutations.

TP53 mutations correlate with inferior survival in many cancers. APR-246 is a compound to shift mutant p53 and exhibits anti-cancer effects. Among its effects, APR-246 facilitates the binding of restored p53 mutants to target genes and their transcription. A set of 2464 DLBCL cases from multiple cohorts including our center, was integrated to identify the type and localization of TP53 mutations and clinical impacts. APR-246 was applied in TP53-mutated DLBCL cells and xenograft mouse models to explore the anti-tumor effect. TP53 mutations frequency was 16% and TP53 mutations correlated with poor overall survival (OS) and progression-free survival (PFS) in all cases, especially in germinal center B-cell-like (GCB) and unclassified (UNC) subtypes. Notably, TP53 single mutations in the DNA binding domain (DBD) led to poor OS and PFS. Specifically, mutations in exon 7 correlated with poorer OS, while mutations in exons 5 and 6 associated with inferior PFS. APR-246 induces p53-dependent ferritinophagy of DLBCL cells with TP53 missense mutation on exon 7 and ferroptosis of DLBCL cells harboring wild-type TP53 and other TP53 mutations. TP53 mutations on exons 5, 6 and 7 are predictors of progression and survival. Targeting mutant p53 by APR-246 is a promising therapeutic approach for DLBCL patients.

Rupture process of the 2021 M7.4 Maduo earthquake and implication for deformation mode of the Songpan-Ganzi terrane in Tibetan Plateau.

The deformation mode of the Tibetan Plateau is of crucial importance for understanding its construction and extrusion processes, as well as for the assessment of regional earthquake potential. Block motion and viscous flow models have been proposed to describe the deformation field but are not fully supported by modern geophysical observations. The 2021 Mw 7.4 Maduo earthquake, which occurred inside the Songpan-Ganzi terrane (SGT) in central-east Tibet, provides a chance to evaluate the associated deformation mode of the region. We conduct a joint inversion for this earthquake and resolve a bilateral rupture process, which is characterized by super- and subshear rupture velocities, respectively. We interpret this distinct rupture behavior to be the result of the respective slip concentration depths of the two ruptured segments. We analyze geological, seismic, and geodetic evidence and find that the SGT upper crust shows distributed shear deformation and distinct transverse anisotropy, which are associated with folded structures originating from compression of the paleo-Tethys ocean accretional prism realigned by following shear deformation. The SGT receives lateral shear loading from its NS boundary and accommodates a right-step sinistral motion across the terrane boundary faults. The unique tectonic setting of the SGT defines locations and behaviors of internal faulting and strong earthquakes such as the 2021 Maduo earthquake, with the latter occurring on slow-moving faults at intervals of several thousands of years.