bluuebunny/crossref_metadata_2025 huggingface dataset:
Models predict change in plasma triglyceride concentrations and long-chain n-3 polyunsaturated fatty acid proportions in healthy participants after fish oil intervention
Authors: Potter Tilly I. T. , Horgan Graham W. , Wanders Anne J. , Zandstra Elizabeth H. , Zock Peter L. , Fisk Helena L. , Minihane Anne M. , Calder Philip C. , Mathers John C. , de Roos Baukje
Published: October 2022

Introduction

Substantial response heterogeneity is commonly seen in dietary intervention trials. In larger datasets, this variability can be exploited to identify predictors, for example genetic and/or phenotypic baseline characteristics, associated with response in an outcome of interest.

Objective

Using data from a placebo-controlled crossover study (the FINGEN study), supplementing with two doses of long chain n-3 polyunsaturated fatty acids (LC n-3 PUFAs), the primary goal of this analysis was to develop models to predict change in concentrations of plasma triglycerides (TG), and in the plasma phosphatidylcholine (PC) LC n-3 PUFAs eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA), after fish oil (FO) supplementation. A secondary goal was to establish if clustering of data prior to FO supplementation would lead to identification of groups of participants who responded differentially.

Methods

To generate models for the outcomes of interest, variable selection methods (forward and backward stepwise selection, LASSO and the Boruta algorithm) were applied to identify suitable predictors. The final model was chosen based on the lowest validation set root mean squared error (RMSE) after applying each method across multiple imputed datasets. Unsupervised clustering of data prior to FO supplementation was implemented using k-medoids and hierarchical clustering, with cluster membership compared with changes in plasma TG and plasma PC EPA + DHA.

Results

Models for predicting response showed a greater TG-lowering after 1.8 g/day EPA + DHA with lower pre-intervention levels of plasma insulin, LDL cholesterol, C20:3n-6 and saturated fat consumption, but higher pre-intervention levels of plasma TG, and serum IL-10 and VCAM-1. Models also showed greater increases in plasma PC EPA + DHA with age and female sex. There were no statistically significant differences in PC EPA + DHA and TG responses between baseline clusters.

Conclusion

Our models established new predictors of response in TG (plasma insulin, LDL cholesterol, C20:3n-6, saturated fat consumption, TG, IL-10 and VCAM-1) and in PC EPA + DHA (age and sex) upon intervention with fish oil. We demonstrate how application of statistical methods can provide new insights for precision nutrition, by predicting participants who are most likely to respond beneficially to nutritional interventions.
Case report: ALK-rearranged spindle and epithelioid cell neoplasms with S100 and CD34 co-expression: Additional evidence of kinase fusion–positive soft tissue tumors
Authors: Sheng Shao-Jie , Li Ju-Ming , Fan Qin-He , Liu Yang , Chen Shao-Yu , Zhao Ming , Gong Qi-Xing
Published: October 2022

ALK rearrangements have rarely been reported in S100- and CD34-co-expressing soft tissue neoplasms with lipofibromatosis-like neural tumor (LPFNT) pattern or stromal and perivascular hyalinization, mimicking NTRK-rearranged spindle cell tumors. Here, we reported ALK fusions involving related partner genes in two adult soft tissue tumors with S100 and CD34 co-expression, and conducted a literature review of mesenchymal tumors harboring ALK or other kinase fusions. Case 1 was a 25-year-old female who underwent excision of a soft tissue mass in the anterior thigh region. Morphologically, the tumor was composed of spindle cells adjacent to epithelioid cells embedded in myxedematous and hyalinized stroma, with infiltrative boundary. Spindle cells mixed with inflammatory infiltration resembling inflammatory myofibroblastic tumor (IMT) were seen sporadically. However, brisk mitosis and focal necrosis was also observed, indicating an intermediate-grade sarcoma. In case 2, the left side of the neck of a 34-year-old man was affected. The tumor was composed of monomorphic spindle cells arranged in fascicular growth or patternless pattern, with stromal and perivascular hyalinization. Sparse inflammatory cell infiltration was also observed. Both tumors showed CD34, S100, and ALK-D5F3 immunoreactivity. Next generation sequencing (NGS) test identified a PLEKHH2::ALK fusion in case 1, which was confirmed by RT-PCR and Sanger sequencing, whereas the RT-PCR (ARMS method) test detected an EML4::ALK fusion in case 2. In conclusion, this study expands the morphological and genetic landscape of tumors with S100 and CD34 co-expression harboring kinase fusions, and suggests that kinase fusion–positive mesenchymal neoplasms are becoming an enlarging entity with a variety of morphological patterns.
A novel risk model construction and immune landscape analysis of gastric cancer based on cuproptosis-related long noncoding RNAs
Authors: Wang Yuanhang , Liu Kanghui , Shen Kuan , Xiao Jian , Zhou Xinyi , Cheng Quan , Hu Li , Fan Hao , Ni Peidong , Xu Zekuan , Zhang Diancai , Yang Li
Published: October 2022

Recent studies have identified cuproptosis, a new mechanism of regulating cell death. Accumulating evidence suggests that copper homeostasis is associated with tumorigenesis and tumor progression, however, the clinical significance of cuproptosis in gastric cancer (GC) is unclear. In this study, we obtained 26 prognostic cuproptosis-related lncRNAs (CRLs) based on 19 cuproptosis-related genes (CRGs) via Pearson correlation analysis, differential expression analysis, and univariate Cox analysis. A risk model based on 10 CRLs was established with the least absolute shrinkage and selection operator (LASSO) Cox regression analysis and multivariate Cox proportional hazards model to predict the prognosis and immune landscape of GC patients from The Cancer Genome Atlas (TCGA). The risk model has excellent accuracy and efficiency in predicting prognosis of GC patients (Area Under Curve (AUC) = 0.742, 0.803, 0.806 at 1,3,5 years, respectively, P < 0.05). In addition, we found that the risk score was negatively correlated with the infiltration of natural killer (NK) cells and helper T cells, while positively correlated with the infiltration of monocytes, macrophages, mast cells, and neutrophils. Moreover, we evaluated the difference in drug sensitivity of patients with different risk patterns. Furthermore, low-risk patients showed higher tumor mutation burden (TMB) and better immunotherapy response than high-risk patients. In the end, we confirmed the oncogenic role of AL121748.1 which exhibited the highest Hazard Ratio (HR) value among 10 CRLs in GC via cellular functional experiments. In conclusion, our risk model shows a significant role in tumor immunity and could be applied to predict the prognosis of GC patients.
PAX5 alterations in B-cell acute lymphoblastic leukemia
Authors: Jia Zhilian , Gu Zhaohui
Published: October 2022

PAX5, a master regulator of B cell development and maintenance, is one of the most common targets of genetic alterations in B-cell acute lymphoblastic leukemia (B-ALL). PAX5 alterations consist of copy number variations (whole gene, partial, or intragenic), translocations, and point mutations, with distinct distribution across B-ALL subtypes. The multifaceted functional impacts such as haploinsufficiency and gain-of-function of PAX5 depending on specific variants have been described, thereby the connection between the blockage of B cell development and the malignant transformation of normal B cells has been established. In this review, we provide the recent advances in understanding the function of PAX5 in orchestrating the development of both normal and malignant B cells over the past decade, with a focus on the PAX5 alterations shown as the initiating or driver events in B-ALL. Recent large-scale genomic analyses of B-ALL have identified multiple novel subtypes driven by PAX5 genetic lesions, such as the one defined by a distinct gene expression profile and PAX5 P80R mutation, which is an exemplar leukemia entity driven by a missense mutation. Although altered PAX5 is shared as a driver in B-ALL, disparate disease phenotypes and clinical outcomes among the patients indicate further heterogeneity of the underlying mechanisms and disturbed gene regulation networks along the disease development. In-depth mechanistic studies in human B-ALL and animal models have demonstrated high penetrance of PAX5 variants alone or concomitant with other genetic lesions in driving B-cell malignancy, indicating the altered PAX5 and deregulated genes may serve as potential therapeutic targets in certain B-ALL cases.
High-cutoff hemodialysis in multiple myeloma patients with acute kidney injury
Authors: Xing Yan , Yan Jipeng , Yu Zixian , Zhao Jin , Wang Yuwei , Li Xiayin , Qin Yunlong , Sun Shiren
Published: October 2022

Multiple myeloma (MM), an incurable hematological malignancy with clonal proliferation of plasma cells, is mainly characterized by excessive production of monoclonal immunoglobulins and free light chains (FLCs). Kidney injury is one of the main clinical manifestations and is also a significant predictor of the prognosis of symptomatic MM patients, especially those who require dialysis-supported treatment. Overproduction of FLCs is the trigger for kidney injury, as they can induce the transcription of inflammatory and profibrotic cytokines in the proximal tubule and bind to Tamm–Horsfall protein in the distal tubules to form casts that obstruct the tubules, leading to kidney injury and even renal fibrosis. In addition to traditional antimyeloma treatment, high-cutoff hemodialysis (HCO-HD), which can effectively remove FLCs in vitro, has attracted much attention in recent years. Due to its greater membrane pore size, it has significant advantages in removing larger molecules and can be applied in rhabdomyolysis, sepsis, and even myeloma cast nephropathy. However, mounting questions have recently been raised regarding whether HCO-HD can truly provide clinical benefits in MM patients with acute kidney injury (AKI). Therefore, in this study, we discussed the pathological causes of AKI secondary to MM and summarized the current situation of HCO-HD in MM patients compared with other available extracorporeal techniques. In addition, pivotal clinical trials that reflect the ability of the clearance of FLCs and the side effects of HCO-HD are highlighted, and the relevant protocol of HCO-HD is also provided to assist clinicians in decision-making.
Stratification of malignant renal neoplasms from cystic renal lesions using deep learning and radiomics features based on a stacking ensemble CT machine learning algorithm
Authors: He Quan-Hao , Tan Hao , Liao Fang-Tong , Zheng Yi-Neng , Lv Fa-Jin , Jiang Qing , Xiao Ming-Zhao
Published: October 2022

Using nephrographic phase CT images combined with pathology diagnosis, we aim to develop and validate a fusion feature-based stacking ensemble machine learning model to distinguish malignant renal neoplasms from cystic renal lesions (CRLs). This retrospective research includes 166 individuals with CRLs for model training and 47 individuals with CRLs in another institution for model testing. Histopathology results are adopted as diagnosis criterion. Nephrographic phase CT scans are selected to build the fusion feature-based machine learning algorithms. The pretrained 3D-ResNet50 CNN model and radiomics methods are selected to extract deep features and radiomics features, respectively. Fivefold cross-validated least absolute shrinkage and selection operator (LASSO) regression methods are adopted to identify the most discriminative candidate features in the development cohort. Intraclass correlation coefficients and interclass correlation coefficients are employed to evaluate feature’s reproducibility. Pearson correlation coefficients for normal distribution features and Spearman’s rank correlation coefficients for non-normal distribution features are used to eliminate redundant features. After that, stacking ensemble machine learning models are developed in the training cohort. The area under the receiver operator characteristic curve (ROC), calibration curve, and decision curve analysis (DCA) are adopted in the testing cohort to evaluate the performance of each model. The stacking ensemble machine learning algorithm reached excellent diagnostic performance in the testing dataset. The calibration plot shows good stability when using the stacking ensemble model. Net benefits presented by DCA are higher than the Bosniak 2019 version classification when employing any machine learning algorithm. The fusion feature-based machine learning algorithm accurately distinguishes malignant renal neoplasms from CRLs, which outperformed the Bosniak 2019 version classification, and proves to be more applicable for clinical decision-making.
Predictive value of baseline metabolic tumor burden on 18F-FDG PET/CT for brain metastases in patients with locally advanced non-small-cell lung cancer
Authors: Shang Jingjie , You Huimin , Dong Chenchen , Li Yingxin , Cheng Yong , Tang Yongjin , Guo Bin , Gong Jian , Ling Xueying , Xu Hao
Published: October 2022

Objectives

Brain metastases (BMs) are a major cause leading to the failure of treatment management for non-small-cell lung cancer (NSCLC) patients. The purpose of this study was to evaluate the predictive value of baseline metabolic tumor burden on 18F-FDG PET/CT measured with metabolic tumor volume (MTV) and total lesion glycolysis (TLG) for brain metastases (BMs) development in patients with locally advanced non-small-cell lung cancer (NSCLC) after treatment.

Methods

Forty-seven patients with stage IIB-IIIC NSCLC who underwent baseline 18F-FDG PET/CT examinations were retrospectively reviewed. The maximum standardized uptake value (SUVmax), MTV, and TLG of the primary tumor (SUVmaxT, MTVT, and TLGT), metastatic lymph nodes (SUVmaxN, MTVN, and TLGN), and whole-body tumors (SUVmaxWB, MTVWB, and TLGWB) were measured. The optimal cut-off values of PET parameters to predict brain metastasis-free survival were obtained using Receiver operating characteristic (ROC) analysis, and the predictive value of clinical variables and PET parameters were evaluated using Cox proportional hazards regression analysis.

Results

The median follow-up duration was 25.0 months for surviving patients, and 13 patients (27.7%) developed BM. The optimal cut-off values were 21.1 mL and 150.0 g for MTVT and TLGT, 20.0, 10.9 mL and 55.6 g for SUVmaxN, MTVN and TLGN, and 27.9, 27.4 mL and 161.0 g for SUVmaxWB, MTVWB and TLGWB, respectively. In the Cox proportional hazards models, the risk of BM was significantly associated with MTVN and MTVWB or TLGN and TLGWB after adjusting for histological cell type, N stage, SUVmaxN, and SUVmaxWB.

Conclusions

Baseline metabolic tumor burden (MTV and TLG) evaluated from the level of metastatic lymph nodes and whole-body tumors are significant predictive factors for BM development in patients with locally advanced NSCLC.
Establishment of a prognostic nomogram for patients with locoregionally advanced nasopharyngeal carcinoma incorporating clinical characteristics and dynamic changes in hematological and inflammatory markers
Authors: Liu Qin , Ma Lingyu , Ma Huangrong , Yang Li , Xu Zhiyuan
Published: October 2022

Background

This study aims to investigate the prognostic value of changes in hematological and inflammatory markers during induction chemotherapy (IC) and concurrent chemo-radiation (CCRT), thus construct nomograms to predict progression free survival (PFS) of patients with locally advanced nasopharyngeal carcinoma (LANPC).

Methods

130 patients were included in this prospective analysis. Univariate and multivariate cox regression analyses were conducted to identify prognostic factors. Three multivariate analyses integrating different groups of variables were conducted independently. Concordance indexes (c-index), calibration plots and Kaplan-Meier curves were used to evaluate the nomograms. Bootstrap validation was performed to determine the accuracy of the nomogram using 1000 resamples. The performances of proposed nomograms and TNM staging system were compared to validate the prognostic value of hematological and inflammatory markers.

Results

Pretreatment gross tumor volume of nodal disease (GTVn), Δe/bHGB (hemoglobin count at end of treatment/baseline hemoglobin count), and stage were selected as predictors for 3-year PFS in first multivariate analysis of clinical factors. The second multivariate analysis of clinical factors and all hematological variables demonstrated that ΔminLYM (minimum lymphocyte count during CCRT/lymphocyte count post-IC), pretreatment GTVn and stage were associated with 3-year PFS. Final multivariate analysis, incorporating all clinical factors, hematological variables and inflammatory markers, identified the following prognostic factors: pretreatment GTVn, stage, ΔmaxPLR (maximum platelet-to-lymphocyte ratio (PLR) during CCRT/PLR post-IC), and ΔminPLT (minimum platelet count during CCRT/platelet count post-IC). Calibration plots showed agreement between the PFS predicted by the nomograms and actual PFS. Kaplan–Meier curves demonstrated that patients in the high-risk group had shorter PFS than those in the low-risk group (P ≤ 0.001). The c-indexes of the three nomograms for PFS were 0.742 (95% CI, 0.639-0.846), 0.766 (95% CI, 0.661-0.871) and 0.815 (95% CI,0.737-0.893) respectively, while c-index of current TNM staging system was 0.633 (95% CI, 0.531-0.736).

Conclusion

We developed and validated a nomogram for predicting PFS in patients with LANPC who received induction chemotherapy and concurrent chemo-radiation. Our study confirmed the prognostic value of dynamic changes in hematological and inflammatory markers. The proposed nomogram outperformed the current TNM staging system in predicting PFS, facilitating risk stratification and guiding individualized treatment plans.
Counterclockwise modular laparoscopic anatomical mesohepatectomy using combined glissonean pedicle (Takasaki approach) and hepatic vein-guided approaches
Authors: Zhao Zonglei , Lyu Xiaotong , Lyu Xiaoqin , Kong Lingqun , Zhao Baolei , Zhu Wentao , Wei Qiang , Lin Xutao , Cao Xuefeng , Zhang Xingyuan
Published: October 2022

Background

Although laparoscopic anatomical hepatectomy (LAH) is widely adopted today, laparoscopic anatomic mesohepatectomy (LAMH) for patients with hepatocellular carcinoma (HCC) remains technically challenging.

Methods

In this study, 6 patients suffering from solitary liver tumors located in the middle lobe of the liver underwent counterclockwise modular LAMH using combined Glissonean pedicle (Takasaki approach) and hepatic vein-guided approaches. In this process, the Glissonean pedicle approach (Takasaki approach) was first used to transect the liver pedicles of segment right anterior (G58) and segment 4 (G4). Second, the hepatic vein-guided approach was performed along the umbilical fissure vein (UFV) to sever the liver parenchyma from the caudal to cranial direction, and the middle hepatic vein (MHV) and anterior fissure vein (AFV) were then disconnected at the root. Last, the hepatic vein-guided approach was once more performed along the ventral side of the right hepatic vein (RHV) to transect the liver parenchyma from the cranial to anterior direction, and the middle lobe of the liver, including the tumor, was removed completely. The entire process was applied in a counterclockwise fashion, and the exposure or transection sequence was G58, and G4, followed by UFV, MHV, AFV, and finally, the liver parenchyma along the ventral side of RHV.

Results

The counterclockwise modular LAMH using combined Glissonean pedicle (Takasaki approach) and hepatic vein-guided approaches was feasible in all 6 cases. The median duration of the operation was 275 ± 35.07 min, and the mean estimated blood loss was 283.33 ml. All of the 6 patients recovered smoothly. The Clavien-Dindo Grade I-II complications rate was up to 33.33%, mainly characterized by postoperative pain and a small amount of ascites. No Clavien-Dindo Grade III-V complications occurred, and the mean postoperative hospital stay was 6.83 ± 1.47 days. Follow-up results showed that the average disease-free survival (DFS) was 12.17 months, and the 21-months OS rate, DFS rate and tumor recurrent rate were 100%, 83.33% and 16.67% respectively.

Conclusions

Counterclockwise modular LAMH using combined Glissonean pedicle (Takasaki approach) and hepatic vein-guided approaches takes the advantages of the two approaches, is a novel protocol for LAMH. It is thought to be technically feasible for patients with a centrally located solitary HCC. The oncologic feasibility of this technique needs to be investigated based on long-term follow-up. A multicenter, large-scale, more careful study is necessary.
Randomized phase II study of TX followed by XELOX versus the reverse sequence for chemo-naive patients with metastatic gastric cancer
Authors: Zhao Xiao-Yin , Liu Xin , Li Wen-Hua , Qiu Li-Xin , Huang Ming-Zhu , Wang Chen-Chen , Chen Zhi-Yu , Zhang Wen , Feng Wan-Jing , Guo Wei-Jian , Zhu Xiaodong
Published: October 2022

This research found that the clinical outcomes (PFS, ORR, OS) of the non-platinum-based doublet regimen (docetaxel capecitabine combination) were similar to those of the platinum-based (oxaliplatin capecitabine combination) when used as first line therapy for MGC patients.

Background

Docetaxel, platinum and fluorouracil are the three most important drugs in the treatment of MGC. This study was to compare clinical outcomes of the docetaxel capecitabine combination and the oxaliplatin capecitabine combination as first-line therapy in MGC patients.

Methods

In this phase II trial, MGC patients were randomly assigned and treated with either TX (capecitabine 1000 mg/m2/twice daily/1-14 days and docetaxel 60/75 mg/m2 on the 1st day) (because of toxicity, the dose of docetaxel was reduced to 60 mg/m2) or XELOX (capecitabine the same dose with TX and oxaliplatin 130 mg/m2 on the 1st day) as first-line therapy. After progression, patients were crossover to the other group as second-line treatment.

Results

Total 134 MGC patients were randomized (69 in TX, 65 in XELOX). There was no significant difference between the PFS of the two groups (TX vs XELOX, 4.6 months vs 5.1 months, p=0.359), and the SFS (9.3 months vs 7.5 months, p=0.705), OS (13.1 months vs 9.6 months, p=0.261), and ORR (46.4% vs 46.2%) were also similar. Among patients with ascites, the TX group had significantly longer PFS and OS than the XELOX group. A total of 85 patients (48 in TX, 37 in XELOX) received second-line treatment, with overall survival of second-line chemotherapy (OS2) of 8.0 m and 5.3 m (p=0.046), respectively. Grade 3 to 4 treatment-related adverse events of first line treatment occurred more in TX group than that in XELOX group(60.6% vs 55.4%).

Conclusion

TX regimen is an alternative choice of first-line treatment for MGC patients. We still need to explore the large number of cohort to confirm this results.
A composite indicator of derived neutrophil–lymphocyte ratio and lactate dehydrogenase correlates with outcomes in pancreatic carcinoma patients treated with PD-1 inhibitors
Authors: Chen Shiyun , Guo Shiyuan , Gou Miaomiao , Pan Yuting , Fan Mengjiao , Zhang Nan , Tan Zhaoli , Dai Guanghai
Published: October 2022

Background

There are currently no established biomarkers that can predict whether advanced pancreatic carcinoma (PC) patients would benefit from immune checkpoint inhibitors (ICIs). Our study investigated whether the pretreatment composite biomarker of derived neutrophil–lymphocyte ratio (dNLR) and lactate dehydrogenase (LDH) can be used as a reliable prognostic factor for the survival of PC patients receiving PD-1 inhibitor therapy.

Methods

Patients with advanced PC treated with PD-1 inhibitors at a single center from September 2015 to September 2020 were included. The high levels of dNLR (≥3) and LDH (≥250 U/L) were considered to be risk factors. Based on these two risk factors, patients in this study were categorized into two risk groups: the good dNLR-LDH group, without risk factors, and the intermediate/poor dNLR-LDH group, with one to two risk factors. Overall survival (OS) and progression-free survival (PFS) served as this study’s primary and secondary endpoints. Cox regression models were used to identify independent prognostic factors for survival benefit.

Results

There were 98 patients in our study. The good group included 61 (62.2%) patients and the intermediate/poor group included 37 (37.8%). The overall patients with PC who received immunotherapy had a median OS of 12.1 months, and the good dNLR-LDH group had a significantly longer OS compared with the intermediate/poor dNLR-LDH group (44.2 vs. 6.4 months; p < 0.010); median PFS was 3.7 and 2.5 months (p = 0.010). The number of metastatic sites >2 and immunotherapy as third-line or later was associated with worse PFS, and the line of immunotherapy and the dNLR-LDH indicator were independent prognostic factors for OS, according to multivariate analysis.

Conclusion

The pretreatment composite biomarker of dNLR and LDH can be used as a prognostic biomarker in patients with advanced PC treated with PD-1 inhibitors.
Macrophages and glial cells: Innate immune drivers of inflammatory arthritic pain perception from peripheral joints to the central nervous system
Authors: Malange Kaue Franco , Navia-Pelaez Juliana M. , Dias Elayne Vieira , Lemes Julia Borges Paes , Choi Soo-Ho , Dos Santos Gilson Goncalves , Yaksh Tony L. , Corr Maripat
Published: October 2022

Millions of people suffer from arthritis worldwide, consistently struggling with daily activities due to debilitating pain evoked by this disease. Perhaps the most intensively investigated type of inflammatory arthritis is rheumatoid arthritis (RA), where, despite considerable advances in research and clinical management, gaps regarding the neuroimmune interactions that guide inflammation and chronic pain in this disease remain to be clarified. The pain and inflammation associated with arthritis are not isolated to the joints, and inflammatory mechanisms induced by different immune and glial cells in other tissues may affect the development of chronic pain that results from the disease. This review aims to provide an overview of the state-of-the-art research on the roles that innate immune, and glial cells play in the onset and maintenance of arthritis-associated pain, reviewing nociceptive pathways from the joint through the dorsal root ganglion, spinal circuits, and different structures in the brain. We will focus on the cellular mechanisms related to neuroinflammation and pain, and treatments targeting these mechanisms from the periphery and the CNS. A comprehensive understanding of the role these cells play in peripheral inflammation and initiation of pain and the central pathways in the spinal cord and brain will facilitate identifying new targets and pathways to aide in developing therapeutic strategies to treat joint pain associated with RA.
Unsolved problems in CDH follow-up
Authors: Valfré Laura , Conforti Andrea , Morini Francesco , Patel Neil , Bevilacqua Francesca , Cianci Maria Chiara , Bagolan Pietro , Braguglia Annabella
Published: October 2022

In patients affected by CDH, survival beyond the neonatal period continues to increase thanks to technological and pharmacological improvements. Conversely, patients, families and caregivers are more and more frequently facing “new” complex late comorbidities, including chronic pulmonary and cardiac dysfunctions, neurodevelopmental challenges, and specific nutritional requirements, that often require ongoing long-term medical or surgical care. Therefore, late morbidity is now a key focus in clinical care of CDH. The aims of this paper are to stress some of the most important “unsolved problems” for CDH patients at long-term follow-up.
A multifunctional drug consisting of tetracycline conjugated with odanacatib for efficient periodontitis therapy
Authors: Li Dengke , Zhang Wuyang , Ye Weiliang , Liu Yuan , Li Yuan , Wang Yiming , Shi Bingqing , Zheng Xueni , An Ying , Ma Zhen , Hu Kaijin , Zhou Hongzhi , Xue Yang
Published: October 2022

The treatment of periodontitis can be very challenging due to its complex etiologies. A new pharmacologic strategy entitled “host-modulation therapy,” has been introduced to improve periodontal treatment outcomes. Supposedly, a multifunctional drug with the potential for bacterial infection prevention, host-response modulation and bone healing promotion would be a promising option for periodontitis therapy, but related studies remain substantially lacking. In this study, we successfully conjugated tetracycline with odanacatib (a selective inhibitor of cathepsin K) to construct a multifunctional drug (TC-ODN). We discovered that TC-ODN could promote macrophages polarizing toward anti-inflammatory phenotype and promote osteogenesis of PDLSCs under inflammatory microenvironment. In vivo, TC-ODN could be absorbed and distributed specifically to the bone after systemic administration, and accumulation of TC-ODN increased bone mineral density in ovariectomized rats. Importantly, periodontal administration of TC-ODN could successfully promote bone healing in periodontitis rats with alveolar bone loss. The findings in our study uncovered the excellent biocompatibility and multifunction of TC-ODN, including bone-targeted accumulation, immunoregulation, anti-inflammatory activity and promotion of bone healing, which might contribute to the clinical treatment of periodontitis.
Pharmacological evaluation of enantiomerically separated positive allosteric modulators of cannabinoid 1 receptor, GAT591 and GAT593
Authors: Brandt Asher L. , Garai Sumanta , Zagzoog Ayat , Hurst Dow P. , Stevenson Lesley A. , Pertwee Roger G. , Imler Gregory H. , Reggio Patricia H. , Thakur Ganesh A. , Laprairie Robert B.
Published: October 2022

Positive allosteric modulation of the type 1 cannabinoid receptor (CB1R) has substantial potential to treat both neurological and immune disorders. To date, a few studies have evaluated the structure-activity relationship (SAR) for CB1R positive allosteric modulators (PAMs). In this study, we separated the enantiomers of the previously characterized two potent CB1R ago-PAMs GAT591 and GAT593 to determine their biochemical activity at CB1R. Separating the enantiomers showed that the R-enantiomers (GAT1665 and GAT1667) displayed mixed allosteric agonist-PAM activity at CB1R while the S-enantiomers (GAT1664 and GAT1666) showed moderate activity. Furthermore, we observed that the R and S-enantiomers had distinct binding sites on CB1R, which led to their distinct behavior both in vitro and in vivo. The R-enantiomers (GAT1665 and GAT1667) produced ago-PAM effects in vitro, and PAM effects in the in vivo behavioral triad, indicating that the in vivo activity of these ligands may occur via PAM rather than agonist-based mechanisms. Overall, this study provides mechanistic insight into enantiospecific interaction of 2-phenylindole class of CB1R allosteric modulators, which have shown therapeutic potential in the treatment of pain, epilepsy, glaucoma, and Huntington’s disease.
A transcriptional program associated with cell cycle regulation predominates in the anti-inflammatory effects of CX-5461 in macrophage
Authors: Wang Jie , Zheng Zhijian , Cui Xiaopei , Dai Chaochao , Li Jiaxin , Zhang Qunye , Cheng Mei , Jiang Fan
Published: October 2022

CX-5461, a novel selective RNA polymerase I inhibitor, shows potential anti-inflammatory and immunosuppressive activities. However, the molecular mechanisms underlying the inhibitory effects of CX-5461 on macrophage-mediated inflammation remain to be clarified. In the present study, we attempted to identify the systemic biological processes which were modulated by CX-5461 in inflammatory macrophages. Primary peritoneal macrophages were isolated from normal Sprague Dawley rats, and primed with lipopolysaccharide or interferon-γ. Genome-wide RNA sequencing was performed. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases were used for gene functional annotations. Enrichment analysis was conducted using the ClusterProfiler package of R software. We found that CX-5461 principally induced a molecular signature related to cell cycle inhibition in primed macrophages, featuring downregulation of genes encoding cell cycle mediators and concomitant upregulation of cell cycle inhibitors. At the same concentration, however, CX-5461 did not induce a systemic anti-inflammatory transcriptional program, although some inflammatory genes such as IL-1β and gp91phox NADPH oxidase were downregulated by CX-5461. Our data further highlighted a central role of p53 in orchestrating the molecular networks that were responsive to CX-5461 treatment. In conclusion, our study suggested that limiting cell proliferation predominated in the inhibitory effects of CX-5461 on macrophage-mediated inflammation.
Consistency of recommendations for pharmacotherapy of rheumatoid arthritis
Authors: Hu Yue , Han Yunze , Ma Yan , Fan Shumei , Wang Xue , Fu Xinyu , Hu Xiaopeng , Luo Xufei , Ma Yanfang , Xun Yangqin , Yang Nan , Wen Chengping , Cao Wei , Song Xuping , Chen Yaolong
Published: October 2022

Background: Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory arthropathy. Recommendations for RA, specifically on pharmacotherapy, are essential in clinical practice. However, the direction and strength of recommendations are controversial across current clinical practice guidelines (CPGs) of RA.

Objective: To systematically analyze the consistency of recommendations regarding pharmacotherapy of RA across CPGs.

Methods: 11 electronic databases and websites were comprehensively searched from inception to 14 March 2022, to identify CPGs for diagnosis, therapy, and management of RA. Unambiguous and discrete specifications of the population-intervention-comparison (PIC) framework were used to classify the recommendations. Based on the PIC framework, consistency analyses across CPGs on pharmacotherapy of RA were performed. Two researchers reached a consensus on coding the direction and strength of each recommendation.

Results: Finally, 26 CPGs were included in this study, and 14 of them, which included pharmacotherapy, were performed consistency analysis. 1) 64 recommendations from 14 CPGs were classified into 18 PICs. 2) Seven PICs (38%) were consistent in direction and strength, 10 PICs (56%) were consistent in direction but inconsistent in strength, and one PIC (6%) was inconsistent in direction (hydroxychloroquine, HCQ). 3) Sensitivity analysis tested the robustness, and the inconsistency remained high.

Conclusion: The direction was highly consistent among the recommendations of pharmacotherapy for RA, but the strength was highly inconsistent. Reasons for the inconsistency need to be further investigated, and consistent recommendations could guide the pharmacotherapy of RA in clinical practice.
Potential of nanoformulations in malaria treatment
Authors: Chaves Janaina Braga , Portugal Tavares de Moraes Bianca , Regina Ferrarini Stela , Noé da Fonseca Francisco , Silva Adriana Ribeiro , Gonçalves-de-Albuquerque Cassiano Felippe
Published: October 2022

Malaria is caused by the protozoan Plasmodium sp and affects millions of people worldwide. Its clinical form ranges from asymptomatic to potentially fatal and severe. Current treatments include single drugs such as chloroquine, lumefantrine, primaquine, or in combination with artemisinin or its derivatives. Resistance to antimalarial drugs has increased; therefore, there is an urgent need to diversify therapeutic approaches. The disease cycle is influenced by biological, social, and anthropological factors. This longevity and complexity contributes to the records of drug resistance, where further studies and proposals for new therapeutic formulations are needed for successful treatment of malaria. Nanotechnology is promising for drug development. Preclinical formulations with antimalarial agents have shown positive results, but only a few have progressed to clinical phase. Therefore, studies focusing on the development and evaluation of antimalarial formulations should be encouraged because of their enormous therapeutic potential.
Mean-field simulations of Es-254 + Ca-48 heavy-ion reactions
Authors: Stevenson Paul D.
Published: October 2022

Einstenium-254 (Z = 99, N = 155), can be prepared as a target for research into nuclear reaction studies. This work presents structure and reaction calculations of Es-254 and Ca-48 (Z = 20, N = 28), using the Skyrme-(Time-Dependent)-Energy-Density-Functional formalism. The reaction calculations show the initial parts of the heavy-ion reaction between the nuclei which, depending on the interaction parameters, can lead to capture to a compound nucleus of element 119. For collisions with the spherical 48Ca impinging on the tip of the prolate 254Es no fusion events are found. For collisions where the calcium approaches the belly of the einsteinium, capture occurs with the compound nucleus outlasting the lifetime of the calculation, indicating a possible fusion candidate. For a sample center-of-mass collision energy of 220 MeV, slightly non-central collisions, up to an impact parameter of 1 fm, also form long-lived compound nuclei.
All-polarization-maintaining fiber optical frequency comb for the dispersion measurement of a microcavity
Authors: Yanyan Zhang , Pan Zhang , Mingkun Li , Jiazheng Song , Faxi Chen , Libo Li , Xuelong Li , Yuanshan Liu
Published: October 2022

In this research, we demonstrate an optical frequency comb (OFC) based on a figure-9 laser and polarization-maintaining fibers to measure the dispersion of a microcavity. We adopt a multi-branch structure to obtain a broadband spectrum from 1,250 nm to 1,640 nm with 6-dB bandwidth. The single-mode power at each wavelength of the supercontinuum spectra is greater than 300 nJ, which assures the signal-to-noise ratio of the beat notes between the OFC and the diode laser. The frequency stability of the repetition rate is about 7.5 × 10–14 in an integration time of 1 s. This system allows us to extend the measurement bandwidth to 60 THz at the sub-megahertz resolution, which meets the requirements of the microcavity’s higher-order dispersion measurement.
Controllable single-photon routing between two waveguides by two giant two-level atoms
Authors: Zhang Y. Q. , Zhu Z. H. , Chen K. K. , Peng Z. H. , Yin W. J. , Yang Y. , Zhao Y. Q. , Lu Z. Y. , Chai Y. F. , Xiong Z. Z. , Tan L.
Published: October 2022

We investigate the single-photon quantum routing composed of two infinite waveguides coupled to two giant two-level atoms. The exact expressions of the single-photon transmission and reflection amplitudes are derived with the real-space approach. It is found that the single photon scattering behavior is strongly dependent on the phase difference between the two adjacent atom-waveguide coupling points, the frequency detuning, the coupling strength between the two giant atoms, and the interaction strengths between the giant atoms and the waveguides. Our studies show that an ideal single photon router with unit efficiency can be realised by designing the size of the giant atom, and the frequency detuning or adjusting the interaction strengths between the atoms and the waveguides. The results suggest the potential to effectively control the single-photon quantum routing based on the giant-atom setup.
Loss of Drosophila Clueless differentially affects the mitochondrial proteome compared to loss of Sod2 and Pink1
Authors: Sen Aditya , Cox Rachel T.
Published: October 2022

Mitochondria contain their own DNA, mitochondrial DNA, which encodes thirteen proteins. However, mitochondria require thousands of proteins encoded in the nucleus to carry out their many functions. Identifying the definitive mitochondrial proteome has been challenging as methods isolating mitochondrial proteins differ and different tissues and organisms may have specialized proteomes. Mitochondrial diseases arising from single gene mutations in nucleus encoded genes could affect the mitochondrial proteome, but deciphering which effects are due to loss of specific pathways or to accumulated general mitochondrial damage is difficult. To identify specific versus general effects, we have taken advantage of mutations in three Drosophila genes, clueless, Sod2, and Pink1, which are required for mitochondrial function through different pathways. We measured changes in each mutant’s mitochondrial proteome using quantitative tandem mass tag mass spectrometry. Our analysis identified protein classes that are unique to each mutant and those shared between them, suggesting that some changes in the mitochondrial proteome are due to general mitochondrial damage whereas others are gene specific. For example, clueless mutants had the greatest number of less and more abundant mitochondrial proteins whereas loss of all three genes increased stress and metabolism proteins. This study is the first to directly compare in vivo steady state levels of mitochondrial proteins by examining loss of three pathways critical for mitochondrial function. These data could be useful to understand disease etiology, and how mutations in genes critical for mitochondrial function cause specific mitochondrial proteomic changes as opposed to changes due to generalized mitochondrial damage.
An interactive game for rehabilitation based on real-time hand gesture recognition
Authors: Chen Jiang , Zhao Shuying , Meng Huaning , Cheng Xu , Tan Wenjun
Published: October 2022

Currently, cardiovascular and cerebrovascular diseases have become serious global health problems related to their high incidence and fatality rate. Some patients with cardiovascular cerebro-cardiovascular diseases even may face motor or cognitive dysfunction after surgery. In recent years, human–computer interactive systems with artificial intelligence have become an important part of human well-being because they enable novel forms of rehabilitation therapies. We propose an interactive game utilizing real-time skeleton-based hand gesture recognition, which aims to assist rehabilitation exercises by improving the hand-eye coordination of the patients during a game-like experience. For this purpose, we propose a lightweight residual graph convolutional architecture for hand gesture recognition. Furthermore, we designed the whole system using the proposed gesture recognition module and some third-party modules. Finally, some participants were invited to test our system and most of them showed an improvement in their passing rate of the game during the test process.
Unruptured ovarian ectopic pregnancy: Two case reports and literature review
Authors: Ren Fang , Liu Gang , Wang Tifang , Li Meijun , Guo Zhiqiang
Published: October 2022

In clinical practice, ovarian pregnancy is extremely rare and is always found to be ruptured. A definitive diagnosis for ruptured ovarian pregnancy is difficult to obtain. We present two cases of unruptured ovarian pregnancies detected during laparoscopy and review existing literature to better understand the clinical characteristics of ectopic pregnancies in this rare site. Intrauterine devices, assisted reproductive technology, and intrauterine operations are all high-risk factors in ovarian pregnancy. Moreover, menopause, abdominal pain, and vaginal bleeding are clinical manifestations. Ovarian pregnancy can be diagnosed using serum hCG, transvaginal ultrasound, and magnetic resonance imaging. Laparoscopy is the treatment of choice for ovarian pregnancy. It is recommended that the intact gestational sac be excised and the ovarian function be protected to the greatest extent possible during the operation. More definitive diagnosis of ovarian pregnancy must be reported in order to gain a better understanding of ovarian pregnancy.
Temperature dependence of dielectric properties of blood at 10 Hz–100 MHz
Authors: Wang Weice , Li Weichen , Liu Benyuan , Wang Lei , Li Kun , Wang Yu , Ji Zhenyu , Xu Canhua , Shi Xuetao
Published: October 2022

The temperature dependence of the dielectric properties of blood is important for studying the biological effects of electromagnetic fields, electromagnetic protection, disease diagnosis, and treatment. However, owing to the limitations of measurement methods, there are still some uncertainties regarding the temperature characteristics of the dielectric properties of blood at low and medium frequencies. In this study, we designed a composite impedance measurement box with high heat transfer efficiency that allowed for a four/two-electrode measurement method. Four-electrode measurements were carried out at 10 Hz-1 MHz to overcome the influence of electrode polarization, and two-electrode measurements were carried out at 100 Hz-100 MHz to avoid the influence of distribution parameters, and the data was integrated to achieve dielectric measurements at 10 Hz-100 MHz. At the same time, the temperature of fresh blood from rabbits was controlled at 17–39°C in combination with a temperature-controlled water sink. The results showed that the temperature coefficient for the real part of the resistivity of blood remained constant from 10 Hz to 100 kHz (−2.42%/°C) and then gradually decreased to −0.26%/°C. The temperature coefficient of the imaginary part was positive and bimodal from 6.31 kHz to 100 MHz, with peaks of 5.22%/°C and 4.14%/°C at 126 kHz and 39.8 MHz, respectively. Finally, a third-order function model was developed to describe the dielectric spectra at these temperatures, in which the resistivity parameter in each dispersion zone decreased linearly with temperature and each characteristic frequency increased linearly with temperature. The model could estimate the dielectric properties at any frequency and temperature in this range, and the maximum error was less than 1.39%, thus laying the foundation for subsequent studies.
Genome-wide association study reveals novel QTLs and candidate genes for seed vigor in rice
Authors: Dai Liping , Lu Xueli , Shen Lan , Guo Longbiao , Zhang Guangheng , Gao Zhenyu , Zhu Li , Hu Jiang , Dong Guojun , Ren Deyong , Zhang Qiang , Zeng Dali , Qian Qian , Li Qing
Published: October 2022

Highly seed vigor (SV) is essential for rice direct seeding (DS). Understanding the genetic mechanism of SV-related traits could contribute to increasing the efficiency of DS. However, only a few genes responsible for SV have been determined in rice, and the regulatory network of SV remains obscure. In this study, the seed germination rate (GR), seedling shoot length (SL), and shoot fresh weight (FW) related to SV traits were measured, and a genome-wide association study (GWAS) was conducted to detect high-quality loci responsible for SV using a panel of 346 diverse accessions. A total of 51 significant SNPs were identified and arranged into six quantitative trait locus (QTL) regions, including one (qGR1-1), two (qSL1-1, qSL1-2), and three (qFW1-1, qFW4-1, and qFW7-1) QTLs associated with GR, SL, and FW respectively, which were further validated using chromosome segment substitution lines (CSSLs). Integrating gene expression, gene annotation, and haplotype analysis, we found 21 strong candidate genes significantly associated with SV. In addition, the SV-related functions of LOC_Os01g11270 and LOC_Os01g55240 were further verified by corresponding CRISPR/Cas9 gene-edited mutants. Thus, these results provide clues for elucidating the genetic basis of SV control. The candidate genes or QTLs would be helpful for improving DS by molecular marker-assisted selection (MAS) breeding in rice.