Treatment-related pneumonitis after thoracic radiotherapy/chemoradiotherapy combined with anti-PD-1 monoclonal antibodies in advanced esophageal squamous cell carcinoma.

PURPOSE: This study aims to evaluate the risk factors of treatment-related pneumonitis (TRP) following thoracic radiotherapy/chemoradiotherapy combined with anti-PD­1 monoclonal antibodies (mAbs) in patients with advanced esophageal squamous cell carcinoma (ESCC). METHODS: We retrospectively reviewed 97 patients with advanced ESCC who were treated with thoracic radiotherapy/chemoradiotherapy combined with anti-PD­1 mAbs. Among them, 56 patients received concurrent radiotherapy with anti-PD­1 mAbs and 41 patients received sequential radiotherapy with anti-PD­1 mAbs. The median prescribed planning target volume (PTV) dose was 59.4 Gy (range from 50.4 to 66 Gy, 1.8-2.2 Gy/fraction). Clinical characteristics, the percentage of lung volume receiving more than 5-50 Gy in increments of 5 Gy (V5-V50, respectively) and the mean lung dose (MLD) were analyzed as potential risk factors for TRP. RESULTS: 46.4% (45/97), 20.6% (20/97), 20.6% (20/97), 4.1% (4/97), and 1.0% (1/97) of the patients developed any grade of TRP, grade 1 TRP, grade 2 TRP, grade 3 TRP, and fatal (grade 5) TRP, respectively. Anti-PD­1 mAbs administered concurrently with radiotherapy, V5, V10, V15, V25, V30, V35, V40 and MLD were associated with the occurrence of grade 2 or higher TRP. Concurrent therapy (P = 0.010, OR = 3.990) and V5 (P = 0.001, OR = 1.126) were independent risk factors for grade 2 or higher TRP. According to the receiver operating characteristic (ROC) curve analysis, the optimal V5 threshold for predicting grade 2 or higher TRP was 55.7%. CONCLUSION: The combination of thoracic radiotherapy/chemoradiotherapy with anti-PD­1 mAbs displayed a tolerable pulmonary safety profile. Although the incidence of TRP was high, grade 1-2 TRP accounted for the majority. Anti-PD­1 mAbs administered concurrently with radiotherapy and the lung V5 were significantly associated with the occurrence of grade 2 or higher TRP. Therefore, it seems safer to control V5 below 55% in clinical, especially for the high-risk populations receiving concurrent therapy.

Using network pharmacology to discover potential drugs for hypertrophic scars.

BACKGROUND: Hypertrophic scar is a disease of abnormal skin fibrosis caused by excessive fibroblast proliferation, and existing drugs cannot achieve satisfactory therapeutic effects. OBJECTIVES: This study aimed to explore the molecular pathogenesis of hypertrophic scars and screen effective drugs for hypertrophic scars. METHODS: Existing human hypertrophic scar RNA sequencing data were utilized to search for hypertrophic scar-related gene modules and key genes through weighted gene co-expression network analysis (WGCNA). Candidate compounds were screened in a compound library. Potential drugs were screened by molecular docking and verified in human hypertrophic scar fibroblasts and a mouse mechanical force hypertrophic scar model. RESULTS: WGCNA showed that hypertrophic scar-associated gene modules influence focal adhesion, transforming growth factor ß (TGF-ß) signaling pathway, and other biological pathways. Integrin ß1 (ITGB1) is the hub protein. Among the candidate compounds obtained by computer virtual screening and molecular docking, crizotinib, sorafenib, and SU11274 can inhibit the proliferation and migration of human hypertrophic scar fibroblasts and pro-fibrotic gene expression. Crizotinib had the best effect on hypertrophic scar attenuation in mouse models. At the same time, mouse ITGB1 small interfering RNA (siRNA) can also inhibit mouse scar hyperplasia. CONCLUSIONS: ITGB1 and TGF-ß signaling pathways are important for hypertrophic scar formation. Crizotinib could serve as a potential drug for hypertrophic scars.

Shear wave elastography-derived scoring system: application in the detection, subdivision and evaluation of systemic sclerosis.

OBJECTIVES: To locate the most valuable sites for shear wave elastography (SWE) evaluation and to develop a clinically applicable scoring system based on SWE for systemic sclerosis (SSc) and to verify the accuracy for detection and subdivision and the correlation by modified Rodnan total skin score (mRTSS). METHODS: SSc patients with limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc) and symptomatic other rheumatic diseases (ORD) patients were included in this cross-sectional study. We assessed the skin stiffness at forehead, chest, abdomen, and bilateral fingers, hands, forearm, arms, thighs, legs, and feet, by palpation and SWE. Logistic regression was used to screen the most valuable sites for detection of SSc and subdivision of lcSSc and dcSSc, on which a scoring system was developed and verified. RESULTS: A total of 49 lcSSc, 51 dcSSc, and 36 ORD patients were included. The SWE-derived scoring system, including finger, hand, foot, arm, chest, and abdomen, reached a sensitivity and specificity of 80.0% and 94.4%, respectively, for diagnosing SSc at the cut-off value >24. The scoring system, including arm, chest, and abdomen, reached a sensitivity of 72.5% and specificity of 98.0% for subdividing dcSSc at the cut-off value >11. The kappa coefficient between the SWE-derived diagnosis and clinical diagnosis was 0.636 (P<0.001). The SWE-derived total scores of six sites had a strong correlation with mRTSS (r=0.757, p<0.001). CONCLUSIONS: The SWE-derived scoring system can be valuable in detection and evaluation of SSc in clinical application.

Multi-omics analyses uncover metabolic signatures and gene expression profiles of interstitial cystitis/bladder pain syndrome.

BACKGROUND AND OBJECTIVE: We explore molecular and metabolic pathways involved in interstitial cystitis (IC) with integrating multi-omics analysis for identifying potential diagnostic and therapeutic targets. METHODS: Mouse models of IC/bladder pain syndrome (BPS) were established by intraperitoneal injection of cyclophosphamide and bladder tissue samples were collected for metabolomics and transcriptome analysis. RESULTS: We found a total of 82 and 145 differential metabolites in positive ion modes and negative ion modes, respectively. Glycerophospholipid metabolism, choline metabolism in cancer, and nucleotide metabolism pathways were significantly enriched in the IC/BPS group. Transcriptome analysis demonstrated that 1069 upregulated genes and 1087 downregulated genes were detected. Importantly, the stronger enrichment for cell cycle pathway was observed in IC/BPS than that in normal bladder tissue, which may be involved in the process of bladder remodeling. Moreover, the inflammatory response and inflammatory factors related pathways were enriched in the IC/BPS group. CONCLUSIONS: Our findings provide critical directions for further exploration of the molecular pathology underlying IC/BPS.

Differentiating HCC from ICC and prediction of ICC grade based on MRI deep-radiomics: Using lesions and their extended regions.

PURPOSE: This study aimed to evaluate the ability of MRI-based intratumoral and peritumoral radiomics features of liver tumors to differentiate between hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) and to predict ICC differentiation. METHODS: This study retrospectively collected 87 HCC patients and 75 ICC patients who were confirmed pathologically. The standard region of interest (ROI) of the lesion drawn by the radiologist manually shrank inward and expanded outward to form multiple ROI extended regions. A three-step feature selection method was used to select important radiomics features and convolution features from extended regions. The predictive performance of several machine learning classifiers on dominant feature sets was compared. The extended region performance was assessed by area under the curve (AUC), specificity, sensitivity, F1-score and accuracy. RESULTS: The performance of the model is further improved by incorporating convolution features. Compared with the standard ROI, the extended region obtained better prediction performance, among which 6 mm extended region had the best prediction ability (Classification: AUC = 0.96, F1-score = 0.94, Accuracy: 0.94; Grading: AUC = 0.94, F1-score = 0.93, Accuracy = 0.89). CONCLUSION: Larger extended region and fusion features can improve tumor predictive performance and have potential value in tumor radiology.

Biomarkers of peripheral blood neutrophil extracellular traps in the diagnosis and progression of malignant tumors.

BACKGROUND AND AIMS: The mortality rate associated with malignant tumors remains high and there is a lack of effective diagnostic and tumor progression markers. Neutrophil extracellular traps (NETs) can promote tumor-associated thrombosis, invasive metastasis, and inflammatory responses, but there is a lack of research on the value of measuring NETs in the peripheral blood of patients with malignancies. METHODS: We included 263 patients with malignancies (55 gliomas, 101 ovarian, 64 colorectal, and 43 lung cancers) and 75 healthy controls in this study. We compared the levels of citrullinated histone H3 (citH3), cell-free DNA (cfDNA), and systemic inflammation-related parameters, including neutrophils, lymphocytes, monocytes, platelets, neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, platelet-to-lymphocyte ratio, systemic immune inflammation index, and systemic inflammation response index. We assessed the value of changes in NETs in peripheral blood to determine the diagnosis, venous thromboembolism, clinical staging, and systemic inflammatory response in patients with malignancy. RESULTS: The levels of citH3 and cfDNA in peripheral blood can distinguish between healthy controls and tumor patients. The levels of citH3 and cfDNA before clinical intervention did not predict the risk of combined venous thromboembolism in oncology patients in the short-term after clinical intervention. The levels of citH3, cfDNA, and systemic inflammation-related parameters in the peripheral blood of tumor patients increased with the clinical stage. There was a correlation between cfDNA levels in peripheral blood and systemic inflammation-related parameters in tumor patients, and this correlation was more significant in patients with advanced tumors. CONCLUSIONS: Changes in NETs in the peripheral blood differ between healthy controls and patients with malignant tumors. NETs may be involved in tumor-induced systemic inflammatory responses through interaction with circulating inflammatory cells, thus promoting tumor progression. NETs may be used as markers to assist in the diagnosis and progression of tumor malignancy.

Adaptation of Glucose Metabolism to Limb Autotomy and Regeneration in the Chinese Mitten Crab.

Limb autotomy and regeneration represent distinctive responses of crustaceans to environmental stress. Glucose metabolism plays a pivotal role in energy generation for tissue development and regeneration across various species. However, the relationship between glucose metabolism and tissue regeneration in crustaceans remains elusive. Therefore, this study is aimed at analyzing the alterations of glucose metabolic profile during limb autotomy and regeneration in Eriocheir sinensis, while also evaluating the effects of carbohydrate supplementation on limb regeneration. The results demonstrated that limb autotomy triggered a metabolic profile adaption at the early stage of regeneration. Hemolymph glucose levels were elevated, and multiple glucose catabolic pathways were enhanced in the hepatopancreas. Additionally, glucose and ATP levels in the regenerative limb were upregulated, along with increased expression of glucose transporters. Furthermore, the gene expression and activity of enzymes involved in gluconeogenesis were repressed in the hepatopancreas. These findings indicate that limb regeneration triggers metabolic profile adaptations to meet the elevated energy requirements. Moreover, the study observed that supplementation with corn starch enhanced limb regeneration capacity by promoting wound healing and blastema growth. Interestingly, dietary carbohydrate addition influenced limb regeneration by stimulating gluconeogenesis rather than glycolysis in the regenerative limb. Thus, these results underscore the adaptation of glucose metabolism during limb autotomy and regeneration, highlighting its essential role in the limb regeneration process of E. sinensis.

Palladium-Catalyzed Enantioselective Directed C(sp3)-H Functionalization Using C5-Substituted 8-Aminoquinoline Auxiliaries.

8-Aminoquinoline (AQ) has proven to be a highly effective bidentate directing group for palladium-catalyzed C-H functionalization reactions. However, enantiocontrol of AQ-directed C(sp3)-H functionalization reactions has been challenging. Herein, a new protocol is presented for the Pd-catalyzed enantioselective arylation of unactivated ß C(sp3)-H bonds of alkyl carboxamides with aryl iodides using a C5-iodinated 8-aminoquinolines (IQ) auxiliary in conjugation with a BINOL ligand. Additionally, a C5-aryl substituted 8-aminoquinoline auxiliary can facilitate enantioselective alkenylation and alkynylation of benzylic C(sp3)-H bonds of 3-arylpropanamides with the corresponding bromide reagents under similar conditions.

The effects of Mediterranean diet on cardiovascular risk factors, glycemic control and weight loss in patients with type 2 diabetes: a meta-analysis.

To explore the impact of the Mediterranean diet on cardiovascular risk factors, glycemic control and weight loss in patients with type 2 diabetes(T2D) by a meta-analysis of randomized controlled trials (RCTs). We systematically searched PubMed, Cochrance Library, EMBASE and four Chinese databases to identify RCTs that compared the Mediterranean diet with control diets in patients with T2D up to December 2021. The Risk of Bias of the included studies was assessed using the version 2 of the Cochrane risk-of-bias tools for randomized trials (ROB 2). Seven RCTs with 1371 patients met the eligibility criteria and entered into the meta-analysis. Compared to control diets, the beneficial effects of Mediterranean diet were not statistically significant in high-density lipoprotein (MD = 2.33; 95% CI: -0.27 to 4.92), low-density lipoprotein (MD = -2.34; 95% CI -5.67 to 0.99) and total cholesterol (MD = 2.60; 95% CI: -0.95 to 6.15). But Mediterranean diet led to reduce the level of diastolic blood pressure (MD = -1.20; 95% CI: -2.21 to -0.19) and systolic blood pressure (MD = -4.17; 95% CI: -7.12 to -1.22). Meanwhile, Mediterranean diet showed beneficial effects in glycemic control (HbA1[%]: MD = -0.39, 95% CI: -0.58 to -0.20; fasting plasma glucose: MD = -15.12, 95% CI: -24.69 to -5.55) and weight loss (BMI: MD = -0.71, 95% CI: -1.30 to -0.78; WC: MD = -1.69; 95% CI: -3.35 to -0.02) compared to the control diets. The meta-analysis presented evidence supporting the beneficial effects of the Mediterranean diet on blood pressure, glycemic control, and weight loss. However, the impact of the Mediterranean diet on the lipid profile was not found to be significant, warranting further verification. This Meta-analysis was registered on the INPLASY website (Registration number: INPLASY 202160096).

GhVOZ1-AVP1 module positively regulates salt tolerance in upland cotton (Gossypium hirsutum L.).

Vascular Plant One­zinc Finger (VOZ) transcription factor can respond to a variety of abiotic stresses, however its function in cotton and the molecular mechanisms of response to salt tolerance remained unclear. In this study, we found that GhVOZ1 is highly expressed in stamen and stem of cotton under normal conditions. The expression of GhVOZ1 increased significantly after 3 h of salt treatment in three-leaf staged upland cotton. Overexpressed transgenic lines of GhVOZ1 in Arabidopsis and upland cotton were treated with salt stress and we found that GhVOZ1 could respond positively to salt stress. GhVOZ1 can regulate Arabidopsis Vacuolar Proton Pump Pyrophosphatase (H+-PPase) gene (AVP1) expression through specific binding to GCGTCTAAAGTACGC site on GhAVP1 promoter, which was examined through Dual-luciferase assay and Electrophoretic mobility shift assay (EMSA). AVP1 expression was significantly increased in Arabidopsis with GhVOZ1 overexpression, while GhAVP1 expression was decreased in virus induced gene silenced (VIGS) cotton plants of GhVOZ1. Knockdown of GhAVP1 expression in cotton plants by VIGS showed decreased superoxide dismutase (SOD) and peroxidase (POD) activities, whereas an increased malondialdehyde (MDA) content and ultimately decreased salt tolerance. The GhVOZ1-AVP1 module could maintain sodium ion homeostasis through cell ion transport and positively regulate the salt tolerance in cotton, providing new ideas and insights for the study of salt tolerance.

Embryonic diapause due to high glucose is related to changes in glycolysis and oxidative phosphorylation, as well as abnormalities in the TCA cycle and amino acid metabolism.

Introduction: The adverse effects of high glucose on embryos can be traced to the preimplantation stage. This study aimed to observe the effect of high glucose on early-stage embryos. Methods and results: Seven-week-old ICR female mice were superovulated and mated, and the zygotes were collected. The zygotes were randomly cultured in 5 different glucose concentrations (control, 20mM, 40mM, 60mM and 80mM glucose). The cleavage rate, blastocyst rate and total cell number of blastocyst were used to assess the embryo quality. 40 mM glucose was selected to model high glucose levels in this study. 40mM glucose arrested early embryonic development, and the blastocyst rate and total cell number of the blastocyst decreased significantly as glucose concentration was increased. The reduction in the total cell number of blastocysts in the high glucose group was attributed to decreased proliferation and increased cell apoptosis, which is associated with the diminished expression of GLUTs (GLUT1, GLUT2, GLUT3). Furthermore, the metabolic characterization of blastocyst culture was observed in the high-glucose environment. Discussion: The balance of glycolysis and oxidative phosphorylation at the blastocyst stage was disrupted. And embryo development arrest due to high glucose is associated with changes in glycolysis and oxidative phosphorylation, as well as abnormalities in the TCA cycle and amino acid metabolism.