bluuebunny/crossref_metadata_2025 huggingface dataset:
Development and Characterization of a Novel Non-Lytic Cancer Immunotherapy Using a Recombinant Arenavirus Vector Platform
Authors: Lauterbach Henning , Schmidt Sarah , Katchar Kia , Qing Xiaoping , Iacobucci Corinne , Hwang Andy , Schlienger Katia , Berka Ursula , Raguz Josipa , Ahmadi-Erber Sarah , Schippers Timo , Stemeseder Felix , Pinschewer Daniel D. , Matushansky Igor , Orlinger Klaus K.
Published: October 2021

Engineered viral vectors represent a promising strategy to trigger antigen-specific antitumor T cell responses. Arenaviruses have been widely studied because of their ability to elicit potent and protective T cell responses. Here, we provide an overview of a novel intravenously administered, replication-competent, non-lytic arenavirus-based vector technology that delivers tumor antigens to induce antigen-specific anti-cancer T cell responses. Preclinical studies in mice and cell culture experiments with human peripheral blood mononuclear cells demonstrate that arenavirus vectors preferentially infect antigen-presenting cells. This, in conjunction with a non-lytic functional activation of the infected antigen-presenting cells, leads to a robust antigen-specific CD8+ T cell response. T cell migration to, and infiltration of, the tumor microenvironment has been demonstrated in various preclinical tumor models with vectors encoding self- and non–self-antigens. The available data also suggest that arenavirus–based vector therapy can induce immunological memory protecting from tumor rechallenge. Based on promising preclinical data, a phase 1/2 clinical trial was initiated and is currently ongoing to test the activity and safety of arenavirus vectors, HB-201 and HB-202, created using lymphocytic choriomeningitis virus and Pichinde virus, respectively. Both vectors have been engineered to deliver non-oncogenic versions of the human papilloma virus 16 (HPV16) antigens E7 and E6 and will be injected intravenously with or without an initial intratumoral dose. This dose escalation/expansion study is being conducted in patients with recurrent or metastatic HPV16+ cancers. Promising preliminary data from this ongoing clinical study have been reported. Immunogenicity data from several patients demonstrate that a single injection of HB-201 or HB-202 monotherapy is highly immunogenic, as evidenced by an increase in inflammatory cytokines/chemokines and the expansion of antigen-specific CD8+ T cell responses. This response can be further enhanced by alternating injections of HB-202 and HB-201, which has resulted in frequencies of circulating HPV16 E7/E6-specific CD8+ T cells of up to 40% of the total CD8+ T cell compartment in peripheral blood in analyses to date. Treatment with intravenous administration also resulted in a disease control rate of 73% among 11 evaluable patients with head and neck cancer dosed every three weeks, including 2 patients with a partial response.
Current Advances and Challenges in Radiomics of Brain Tumors
Authors: Yi Zhenjie , Long Lifu , Zeng Yu , Liu Zhixiong
Published: October 2021

Imaging diagnosis is crucial for early detection and monitoring of brain tumors. Radiomics enable the extraction of a large mass of quantitative features from complex clinical imaging arrays, and then transform them into high-dimensional data which can subsequently be mined to find their relevance with the tumor’s histological features, which reflect underlying genetic mutations and malignancy, along with grade, progression, therapeutic effect, or even overall survival (OS). Compared to traditional brain imaging, radiomics provides quantitative information linked to meaningful biologic characteristics and application of deep learning which sheds light on the full automation of imaging diagnosis. Recent studies have shown that radiomics’ application is broad in identifying primary tumor, differential diagnosis, grading, evaluation of mutation status and aggression, prediction of treatment response and recurrence in pituitary tumors, gliomas, and brain metastases. In this descriptive review, besides establishing a general understanding among protocols, results, and clinical significance of these studies, we further discuss the current limitations along with future development of radiomics.
Protein Kinase CK1α Sustains B-Cell Receptor Signaling in Mantle Cell Lymphoma
Authors: Manni Sabrina , Fregnani Anna , Quotti Tubi Laura , Spinello Zaira , Carraro Marco , Scapinello Greta , Visentin Andrea , Barilà Gregorio , Pizzi Marco , Dei Tos Angelo Paolo , Vianello Fabrizio , Zambello Renato , Gurrieri Carmela , Semenzato Gianpietro , Trentin Livio , Piazza Francesco
Published: October 2021

Mantle Cell Lymphoma (MCL) is still an incurable B-cell malignancy characterized by poor prognosis and frequent relapses. B Cell Receptor (BCR) signaling inhibitors, in particular of the kinases BTK and PI3Kγ/δ, have demonstrated clinically meaningful anti-proliferative effects in B cell tumors. However, refractoriness to these drugs may develop, portending a dismal prognosis. Protein kinase CK1α is an emerging pro-growth enzyme in B cell malignancies. In multiple myeloma, this kinase sustains β-catenin and AKT-dependent survival and is involved in the activation of NF-κB in B cells. In this study, we analyzed the role of CK1α on MCL cell survival and proliferation, on the regulation of BCR-related BTK, NF-κB, PI3K/AKT signaling cascades and the effects of CK1α chemical inhibition or gene silencing in association with the BTK inhibitor Ibrutinib or the PI3Kγ/δ inhibitor Duvelisib. CK1α was found highly expressed in MCL cells as compared to normal B cells. The inactivation/loss of CK1α caused MCL cell apoptosis and proliferation arrest. CK1α sustained BCR signaling, in particular the NF-κB, AKT and BTK pathways by modulating the phosphorylation of Ser 652 on CARD11, Ser 536 p65 on NF-κB, Ser 473 on AKT, Tyr 223 on BTK, as well as the protein levels. We also provided evidence that CK1α-mediated regulation of CARD11 and BTK likely implicates a physical interaction. The combination of CK1α inhibition with Ibrutinib or Duvelisib synergistically increased cytotoxicity, leading to a further decrease of the activation of BCR signaling pathways. Therefore, CK1α sustains MCL growth through the regulation of BCR-linked survival signaling cascades and protects from Ibrutinib/Duvelisib-induced apoptosis. Thus, CK1α could be considered as a rational molecular target for the treatment of MCL, in association with novel agents.
The Value of Circulating Circular RNA in Cancer Diagnosis, Monitoring, Prognosis, and Guiding Treatment
Authors: Zhang Yunjing , Wang Ying , Su Xinwan , Wang Ping , Lin Weiqiang
Published: October 2021

Liquid biopsy includes non-invasive analysis of circulating tumor-derived substances. It is a novel, innovative cancer screening tool that overcomes the limitations of current invasive tissue examinations in precision oncology. Circular RNA (circRNA) is a recent, novel, and attractive liquid biomarker showing stability, abundance, and high specificity in various diseases, especially in human cancers. This review focused on the emerging potential of human circRNA in body fluids as the liquid biopsy biomarkers for cancers and the methods used to detect the circRNA expression and summarized the construction of circRNA biomarkers in body fluids for treating human cancers and their limitations before they become part of routine clinical medicine. Furthermore, the future opportunities and challenges of translating circRNAs in liquid biopsy into clinical practices were explored.
Exploring the Value of Radiomics Features Based on B-Mode and Contrast-Enhanced Ultrasound in Discriminating the Nature of Thyroid Nodules
Authors: Guo Shi Yan , Zhou Ping , Zhang Yan , Jiang Li Qing , Zhao Yong Feng
Published: October 2021

Background

With the improvement of ultrasound imaging resolution and the application of various new technologies, the detection rate of thyroid nodules has increased greatly in recent years. However, there are still challenges in accurately diagnosing the nature of thyroid nodules. This study aimed to evaluate the clinical application value of the radiomics features extracted from B-mode ultrasound (B-US) images combined with contrast-enhanced ultrasound (CEUS) images in the differentiation of benign and malignant thyroid nodules by comparing the diagnostic performance of four logistic models.

Methods

We retrospectively collected and ultimately included B-US images and CEUS images of 123 nodules from 123 patients, and then extracted the corresponding radiomics features from these images respectively. Meanwhile, a senior radiologist combined the thyroid imaging reporting and data system (TI-RADS) and the enhancement pattern of the ultrasonography to make a graded diagnosis of the malignancy of these nodules. Next, based on these radiomics features and grades, logistic regression was used to help build the models (B-US radiomics model, CEUS radiomics model, B-US+CEUS radiomics model, and TI-RADS+CEUS model). Finally, the study assessed the diagnostic performance of these radiomics features with a comparison of the area under the curve (AUC) of the receiver operating characteristic curve of four logistic models for predicting the benignity or malignancy of thyroid nodules.

Results

The AUC in the differential diagnosis of the nature of thyroid nodules was 0.791 for the B-US radiomics model, 0.766 for the CEUS radiomics model, 0.861 for the B-US+CEUS radiomics model, and 0.785 for the TI-RADS+CEUS model. Compared to the TI-RADS+CEUS model, there was no statistical significance observed in AUC between the B-US radiomics model, CEUS radiomics model, B-US+CEUS radiomics model, and TI-RADS+CEUS model (P>0.05). However, a significant difference was observed between the single B-US radiomics model or CEUS radiomics model and B-US+CEUS radiomics model (P<0.05).

Conclusion

In our study, the B-US radiomics model, CEUS radiomics model, and B-US+CEUS radiomics model demonstrated similar performance with the TI-RADS+CEUS model of senior radiologists in diagnosing the benignity or malignancy of thyroid nodules, while the B-US+CEUS radiomics model showed better diagnostic performance than single B-US radiomics model or CEUS radiomics model. It was proved that B-US radiomics features and CEUS radiomics features are of high clinical value as the combination of the two had better diagnostic performance.
Anti-Tumor Effects of Chinese Medicine Compounds by Regulating Immune Cells in Microenvironment
Authors: Chen Fengqian , Li Jingquan , Wang Hui , Ba Qian
Published: October 2021

As the main cause of death in the world, cancer is one of the major health threats for humans. In recent years, traditional Chinese medicine has gained great attention in oncology due to the features of multi-targets, multi-pathways, and slight side effects. Moreover, lots of traditional Chinese medicine can exert immunomodulatory effects in vivo. In the tumor microenvironment, tumor cells, immune cells as well as other stromal cells often coexist. With the development of cancer, tumor cells proliferate uncontrollably, metastasize aggressively, and modulate the proportion and status of immune cells to debilitate the antitumor immunity. Reversal of immunosuppressive tumor microenvironment plays an essential role in cancer prevention and therapy. Immunotherapy has become the most promising strategy for cancer therapy. Chinese medicine compounds can stimulate the activation and function of immune cells, such as promoting the maturation of dendritic cells and inducing the differentiation of myeloid-derived suppressor cells to dendritic cells and macrophages. In the present review, we summarize and discuss the effects of Chinese medicine compounds on immune cells in the tumor microenvironment, including innate immune cells (dendritic cells, natural killer cells, macrophages, and myeloid-derived suppressor cells) and adaptive immune cells (CD4+/CD8+ T lymphocytes and regulatory T cells), and the various immunomodulatory roles of Chinese medicine compounds in cancer therapy such as improving tumor-derived inflammation, enhancing the immunity after surgery or chemotherapy, blocking the immune checkpoints, et al., aiming to provide more thoughts for the anti-tumor mechanisms and applications of Chinese medicine compounds in terms of tumor immunity.
Second Malignant Neoplasms in Patients With Rhabdomyosarcoma
Authors: Zhen Hongnan , Liu Zhikai , Guan Hui , Ma Jiabin , Wang Wenhui , Shen Jing , Miao Zheng , Zhang Fuquan
Published: October 2021

Objective

Rhabdomyosarcoma (RMS) is a rare malignant tumor. The main treatment modality is comprehensive with chemotherapy, radiotherapy, and surgery. With the advancement in recent decades, patient survival has been prolonged, and long-term complications are attracting increasing attention among both physicians and patients. This study aimed to present the survival of patients with RMS and analyze the risk factors for the development of a second malignant neoplasm (SMN).

Methods

The Surveillance, Epidemiology, and End Results (SEER) Program 18 registry database from 1973 to 2015 of the National Cancer Institute of the United States was used for the survival analyses, and the SEER 9 for the SMN analysis.

Results

The 5-, 10-, and 20-year overall survival rates of the patients with RMS were 45%, 43%, and 33%, respectively. The risk of SMN was significantly higher in patients with RMS compared to the general population (SIR=1.95, 95% CI: 1.44 – 2.57, p < 0.001). The risk of developing SMN was increased in multiple locations, including the bones and joints (SIR = 35.25) soft tissues including the heart (SIR = 22.5), breasts (SIR = 2.10), male genital organs (SIR = 118.14), urinary system (SIR = 2.36), brain (SIR = 9.21), and all nervous system organs (SIR = 8.59). The multivariate analysis indicated that RMS in the limbs and earlier diagnosis time were independent risk factors for the development of SMN. Patients with head and neck (OR = 0.546, 95% CI: 0.313 – 0.952, p = 0.033) and trunk RMS (OR = 0.322, 95% CI: 0.184 – 0.564. p < 0.001) and a later diagnosis time were less likely to develop SMN (OR = 0.496, 95% CI: 0.421 – 0.585, p < 0.001).

Conclusion

This study describes the risk factors associated with the development of SMN in patients with RMS, which is helpful for the personalized screening of high-risk patients with RMS.
Artificial Intelligence Combined With Big Data to Predict Lymph Node Involvement in Prostate Cancer: A Population-Based Study
Authors: Wei Liwei , Huang Yongdi , Chen Zheng , Lei Hongyu , Qin Xiaoping , Cui Lihong , Zhuo Yumin
Published: October 2021

Background

A more accurate preoperative prediction of lymph node involvement (LNI) in prostate cancer (PCa) would improve clinical treatment and follow-up strategies of this disease. We developed a predictive model based on machine learning (ML) combined with big data to achieve this.

Methods

Clinicopathological characteristics of 2,884 PCa patients who underwent extended pelvic lymph node dissection (ePLND) were collected from the U.S. National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database from 2010 to 2015. Eight variables were included to establish an ML model. Model performance was evaluated by the receiver operating characteristic (ROC) curves and calibration plots for predictive accuracy. Decision curve analysis (DCA) and cutoff values were obtained to estimate its clinical utility.

Results

Three hundred and forty-four (11.9%) patients were identified with LNI. The five most important factors were the Gleason score, T stage of disease, percentage of positive cores, tumor size, and prostate-specific antigen levels with 158, 137, 128, 113, and 88 points, respectively. The XGBoost (XGB) model showed the best predictive performance and had the highest net benefit when compared with the other algorithms, achieving an area under the curve of 0.883. With a 5%~20% cutoff value, the XGB model performed best in reducing omissions and avoiding overtreatment of patients when dealing with LNI. This model also had a lower false-negative rate and a higher percentage of ePLND was avoided. In addition, DCA showed it has the highest net benefit across the whole range of threshold probabilities.

Conclusions

We established an ML model based on big data for predicting LNI in PCa, and it could lead to a reduction of approximately 50% of ePLND cases. In addition, only ≤3% of patients were misdiagnosed with a cutoff value ranging from 5% to 20%. This promising study warrants further validation by using a larger prospective dataset.
Efficacy and Toxicity of Three Induction Chemotherapy Regimens in Locoregionally Advanced Nasopharyngeal Carcinoma: Outcomes of 10-Year Follow-Up
Authors: Peng Hao , Chen Binbin , He Shuiqing , Tian Li , Huang Ying
Published: October 2021

Background/Objective

We aimed to compare the 10-year survival outcomes of induction docetaxel plus cisplatin and 5-fluorouracil (TPF), docetaxel plus cisplatin (TP), and cisplatin plus 5-fluorouracil (PF) regimens additional to concurrent chemoradiotherapy (CRT) in locoregionally advanced nasopharyngeal carcinoma (NPC).

Methods

Eligible patients with newly diagnosed stage III-IVA NPC were included. Propensity score matching (PSM) was used to balance prognostic covariates. Survival outcomes and toxicities between different groups were compared.

Results

A total of 855 patients between 2009 and 2012 were included, with 395 (46.2%), 258 (30.2%), and 202 (23.6%) receiving TPF plus CRT, TP plus CRT, and PF plus CRT regimens, respectively. After a median follow-up of 111.8 months, multivariate analysis both in the whole cohort and PSM selected 202 pairs showed that TPF plus CRT and TP plus CRT achieved significantly better 10-year overall survival (OS) than PF plus CRT. Sensitivity analysis after excluding patients with T3-4N0 disease demonstrated that TPF plus CRT still achieved significantly better OS than PF plus CRT (HR, 0.580; 95% CI, 0.395-0.852; P = 0.005), while the difference between TP plus CRT and PF plus CRT was marginally significant (HR, 0.712; 95% CI, 0.503-1.008; P = 0.056). With regard to toxicity profile, PF regimen achieved the lowest grade 3–5 toxicities (27.3%).

Conclusion

TPF plus CRT and TP plus CRT were better than PF plus CRT in improving the 10-year OS of patients with stage III-IVA NPC.
Dynamics of Adaptive Immune Cell and NK Cell Subsets in Patients With Ankylosing Spondylitis After IL-17A Inhibition by Secukinumab
Authors: Jiang Yutong , Yang Mingcan , Zhang Yanli , Huang Yefei , Wu Jialing , Xie Ya , Wei Qiujing , Liao Zetao , Gu Jieruo
Published: October 2021

Background: Anti-IL-17A therapy is generally effectively applied in patients with Ankylosing Spondylitis (AS) to achieve and maintain remission. However, the influence of anti-IL-17A on the composition of the immune system is not apparent. Our prospective study was to explore the changes in immune imbalance regarding T cell, B cell and natural killer (NK) cell subsets after secukinumab treatment in AS patients.

Methods: Immune cell distribution of 43 AS patients treated with secukinumab for 12 weeks and 47 healthy controls (HC) were evaluated. Flow cytometry using monoclonal antibodies against 25 surface markers was accomplished to explore the frequencies of lineage subsets. The differences between HC, AS pre-treatment, and post-treatment were compared using the paired Wilcoxon test, Mann-Whitney U test, and ANOVA.

Results: AS patients had altered immune cell distribution regarding T cell and B cell subsets. Apart from activated differentiation of CD4+ T cell, CD8+ T cell and B cell, higher levels of cytotoxic T (Tc) two cells and Tc17 cells were noted in AS patients. We confirmed that helper T (Th) one cell became decreased; however, Th17 cells and T follicular helper (Tfh) 17 cells went increased in AS. After 12 weeks of secukinumab therapy, CRP and ASDAS became significantly decreased, and meanwhile, the proportions of Th1 cells, Tfh17 cells and classic switched B cells were changed towards those of HC. A decreased CRP was positively correlated with a decrease in the frequency of naïve CD8+ T cells (p = 0.039) and B cells (p = 0.007) after secukinumab treatment. An elevated level of T cells at baseline was detected in patients who had a good response to secukinumab (p = 0.005).

Conclusion: Our study confirmed that AS patients had significant multiple immune cell dysregulation. Anti-IL-17A therapy (Secukinumab) could reverse partial immune cell imbalance.
Effects of Volume-Price Contracts on Pharmaceutical Prices: A Retrospective Comparative Study of Public Hospitals in Hubei of China
Authors: Li Zhuoxian , Liu Chaojie , Zuo Keyuan , Liu Junjie , Tang Yuqing
Published: October 2021

Background: Pharmaceutical expenditure has been increasing worldwide. Many countries have attempted to contain the increase through collective bargaining, including in China. In 2015, the Chinese government introduced a new policy to empower regional governments to reduce pharmaceutical prices through its existing tendering system which enables a lower price for products with higher procurement volumes. Xiangyang municipality in Hubei province took a lead in piloting this initiative.

Objectives: This study aimed to evaluate the effects of the volume-price contract initiative on pharmaceutical price procured by the public hospitals in Xiangyang.

Methods: A retrospective comparative design was adopted. The price of cardiovascular medicines (349 products under 164 International Nonproprietary Names) procured by the public hospitals in Xiangyang was compared with those procured in Yichang municipality in Hubei. A total of 15,921 procurement records over the period from January 2017 to December 2018 were examined (Xiangyang started the volume-price contract initiative in January 2018). Generalized linear regression models with a difference-in-differences approach which could reflect the differences between the two cities between January 2018 and December 2018 were established to test the effects of the volume-price contract initiative on pharmaceutical prices.

Results: On average, the procurement price for cardiovascular medicines adjusted by defined daily dosage in Xiangyang dropped by 41.51%, compared with a 0.22% decrease in Yichang. The difference-in-differences results showed that the volume-price contract initiative resulted in a 36.24% drop (p = 0.006) in the price (30.23% for the original brands, p = 0.008), in addition to the therapeutic competition effect (31.61% reduction in the price, p = 0.002). The top 100 domestic suppliers were highly responsive to the initiative (82.80% drop in the price, p = 0.001).

Conclusion: The volume-price contract initiative has the potential to bring down the price of pharmaceutical supplies. Higher responses from the domestic suppliers are evident.
Possible Interactions of Extracellular Loop IVP2-S6 With Voltage-Sensing Domain III in Cardiac Sodium Channel
Authors: Zaytseva Anastasia K. , Boitsov Aleksandr S. , Kostareva Anna A. , Zhorov Boris S.
Published: October 2021

Motion transmission from voltage sensors to inactivation gates is an important problem in the general physiology of ion channels. In a cryo-EM structure of channel hNav1.5, residues N1736 and R1739 in the extracellular loop IVP2-S6 approach glutamates E1225 and E1295, respectively, in the voltage-sensing domain III (VSD-III). ClinVar-reported variants E1230K, E1295K, and R1739W/Q and other variants in loops IVP2-S6, IIIS1-S2, and IIIS3-S4 are associated with cardiac arrhythmias, highlighting the interface between IVP2-S6 and VSD-III as a hot spot of disease mutations. Atomic mechanisms of the channel dysfunction caused by these mutations are unknown. Here, we generated mutants E1295R, R1739E, E1295R/R1739E, and N1736R, expressed them in HEK-293T cells, and explored biophysical properties. Mutation E1295R reduced steady-state fast inactivation and enhanced steady-state slow inactivation. In contrast, mutation R1739E slightly enhanced fast inactivation and attenuated slow inactivation. Characteristics of the double mutant E1295R/R1739E were rather similar to those of the wild-type channel. Mutation N1736R attenuated slow inactivation. Molecular modeling predicted salt bridging of R1739E with the outermost lysine in the activated voltage-sensing helix IIIS4. In contrast, the loss-of-function substitution E1295R repelled R1739, thus destabilizing the activated VSD-III in agreement with our data that E1295R caused a depolarizing shift of the G-V curve. In silico deactivation of VSD-III with constraint-maintained salt bridge E1295-R1739 resulted in the following changes: 1) contacts between IIIS4 and IVS5 were switched; 2) contacts of the linker-helix IIIS4-S5 with IVS5, IVS6, and fast inactivation tripeptide IFM were modified; 3) contacts of the IFM tripeptide with helices IVS5 and IVS6 were altered; 4) mobile loop IVP2-S6 shifted helix IVP2 that contributes to the slow inactivation gate and helix IVS6 that contributes to the fast inactivation gate. The likelihood of salt bridge E1295-R1739 in deactivated VSD-III is supported by Poisson–Boltzmann calculations and state-dependent energetics of loop IVP2-S6. Taken together, our results suggest that loop IVP2-S6 is involved in motion transmission from VSD-III to the inactivation gates.
Effect of Prophylactic Use of Intranasal Oil Formulations in the Hamster Model of COVID-19
Authors: Rizvi Zaigham Abbas , Tripathy Manas Ranjan , Sharma Nishant , Goswami Sandeep , Srikanth N , Sastry J. L. N. , Mani Shailendra , Surjit Milan , Awasthi Amit , Dikshit Madhu
Published: October 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection initiates with viral entry in the upper respiratory tract, leading to coronavirus disease 2019 (COVID-19). Severe COVID-19 is characterized by pulmonary pathologies associated with respiratory failure. Thus, therapeutics aimed at inhibiting the entry of the virus or its internalization in the upper respiratory tract are of interest. Herein, we report the prophylactic application of two intranasal formulations provided by the National Medicinal Plant Board (NMPB), Anu oil and til tailya, in the hamster model of SARS-CoV-2 infection. Prophylactic intra-nasal instillation of these oil formulations exhibited reduced viral load in lungs and resulted in reduced body weight loss and lung-pneumonitis. In line with reduced viral load, histopathological analysis revealed a reduction in lung pathology in the Anu oil group as compared to the control infected group. However, the til tailya group did not show a significant reduction in lung pathology. Furthermore, molecular analysis using mRNA expression profiling indicated reduced expression of pro-inflammatory cytokine genes, including Th1 and Th17 cytokines for both the intranasal formulations as a result of decreased viral load. Together, the prophylactic intranasal application of Anu oil seems to be useful in limiting both viral load and severity in SARS-CoV2 infection in the hamster model.
Dihydrotanshinone I Specifically Inhibits NLRP3 Inflammasome Activation and Protects Against Septic Shock In Vivo
Authors: Wei Ziying , Zhan Xiaoyan , Ding Kaixin , Xu Guang , Shi Wei , Ren Lutong , Fang Zhie , Liu Tingting , Hou Xiaorong , Zhao Jia , Li Hui , Li Jiayi , Li Zhiyong , Li Qiang , Lin Li , Yang Yan , Xiao Xiaohe , Bai Zhaofang , Cao Junling
Published: October 2021

The abnormal activation of the NLRP3 inflammasome is closely related to the occurrence and development of many inflammatory diseases. Targeting the NLRP3 inflammasome has been considered an efficient therapy to treat infections. We found that dihydrotanshinone I (DHT) specifically blocked the canonical and non-canonical activation of the NLRP3 inflammasome. Nevertheless, DHT had no relation with the activation of AIM2 or the NLRC4 inflammasome. Further study demonstrated that DHT had no influences on potassium efflux, calcium flux, or the production of mitochondrial ROS. We also discovered that DHT suppressed ASC oligomerization induced by NLRP3 agonists, suggesting that DHT inhibited the assembly of the NLRP3 inflammasome. Importantly, DHT possessed a significant therapeutic effect on NLRP3 inflammasome–mediated sepsis in mice. Therefore, our results aimed to clarify DHT as a specific small-molecule inhibitor for the NLRP3 inflammasome and suggested that DHT can be used as a potential drug against NLRP3-mediated diseases.
Attenuation of Circulating Trimethylamine N-Oxide Prevents the Progression of Cardiac and Renal Dysfunction in a Rat Model of Chronic Cardiorenal Syndrome
Authors: Zou Deling , Li Yanyu , Sun Guangping
Published: October 2021

Chronic heart failure (HF) frequently causes progressive decline in kidney function, known as cardiorenal syndrome-2 (CRS2). Current treatment options for CRS2 remain unacceptably limited. Trimethylamine-N-oxide (TMAO), a metabolite of gut microbiota, has recently been implicated in the pathogenesis of both HF and chronic kidney disease. Here we examined whether circulating TMAO is elevated in CRS2 and if so, whether attenuation of circulating TMAO would ameliorate the progression of CRS2. Sprague-Dawley rats underwent surgery for myocardial infarction (MI) or sham (week 0) followed by subtotal (5/6) nephrectomy (STNx) or sham at week 4 to induce CRS2 or control. At week 6, MI + STNx rats and control rats received vehicle or 1.0% 3,3-Dimethyl-1-butanol (DMB, a TMAO inhibitor) treatment for 8 weeks. Compared with control rats, MI + STNx rats exhibited elevated serum TMAO at week 6, which was increased further at week 14 but was attenuated by DMB treatment. MI + STNx rats showed cardiac dysfunction as assessed by echocardiography and renal dysfunction as evidenced by increased serum creatinine and urinary kidney injury molecule-1 and decreased creatinine clearance at week 6. The cardiac and renal dysfunction in MI + STNx rats was exacerbated at week 14 but was prevented by DMB treatment. Molecular and histological studies revealed myocyte hypertrophy and increases in interstitial myocardial fibrosis and gene expression of pro-hypertrophic and pro-fibrotic markers in both heart and kidney at week 14, which were accompanied by elevated gene expression of proinflammatory cytokines. The changes in molecular and histological parameters observed in MI + STNx rats were significantly reduced by DMB treatment. These findings suggest that rats with CRS2 have elevated circulating TMAO, which is associated with the exacerbation of cardiac and renal dysfunction. Attenuation of circulating TMAO can ameliorate cardiac and renal injury and prevents the progression of CRS2.
Traditional Uses, Chemistry, Pharmacology, Toxicology and Quality Control of Alhagi sparsifolia Shap.: A Review
Authors: Wei Feng , Yang Xinzhou , Pang Kejian , Tang Hui
Published: October 2021

Alhagi sparsifolia Shap. (Kokyantak) is a ethnic medicine used in the Uyghur traditional medicine system for the treatment of colds, rheumatic pains, diarrhea, stomach pains, headaches, and toothaches, in addition to being an important local source of nectar and high-quality forage grass, and playing a crucial role in improving the ecological environment. Currently, approximately 178 chemical constituents have been identified from A. sparsifolia, including flavonoids, alkaloids, phenolic acids, and 19 polysaccharides. Pharmacological studies have already confirmed that A. sparsifolia has antioxidant, anti-tumor, anti-neuroinflammatory effects, hepatoprotective effects, renoprotective effects and immune regulation. Toxicological tests and quality control studies reveal the safety and nontoxicity of A. sparsifolia. Therefore, this paper systematically summarizes the traditional uses, botany, phytochemistry, pharmacology, quality control and toxicology of A. sparsifolia, in order to provide a beneficial reference of its further research.
Contributions of UDP-Glucuronosyltransferases to Human Hepatic and Intestinal Metabolism of Ticagrelor and Inhibition of UGTs and Cytochrome P450 Enzymes by Ticagrelor and its Glucuronidated Metabolite
Authors: Liu Shuaibing , Hou Lei , Li Cai , Zhao Yibo , Yao Xia , Zhang Xiaojian , Tian Xin
Published: October 2021

Ticagrelor is the first reversibly binding, direct-acting, oral P2Y12 receptor inhibitor. The contribution of UDP-glucuronosyltransferases (UGTs) enzymes to the metabolism of ticagrelor to its glucuronide conjugation, ticagrelor-O-glucuronide, in human liver microsomes (HLM) and human intestinal microsomes (HIM), was well characterized in the current study. The inhibition potential of human major UGTs by ticagrelor and ticagrelor-O-glucuronide was explored. The inhibitory effects of ticagrelor-O-glucuronide on cytochrome P450s (CYPs) enzymes were investigated as well. Ticagrelor glucuronidation exhibits substrate inhibition kinetics in both HLM and HIM with apparent Km values of 5.65 and 2.52 μM, Vmax values of 8.03 and 0.90 pmol min−1·mg protein−1, Ksi values of 1,343.0 and 292.9 respectively. The in vitro intrinsic clearances (Vmax/Km) for ticagrelor glucuronidation by HLM and HIM were 1.42 and 0.36 μl min−1·mg protein−1, respectively. Study with recombinant human UGTs suggested that multiple UGT isoforms including UGT1A9, UGT1A7, UGT1A3, UGT1A4, UGT1A1, UGT2B7 and UGT1A8 are involved in the conversion of ticagrelor to ticagrelor-O-glucuronide with UGT1A9 showing highest catalytic activity. The results were further supported by the inhibition studies on ticagrelor glucuronidation with typical UGT inhibitors in pooled HLM and HIM. Little or no inhibition of UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9 and UGT2B7 by ticagrelor and ticagrelor-O-glucuronide was noted. Ticagrelor-O-glucuronide also exhibited limited inhibitory effects toward CYP2C8, CYP2D6 and CYP3A4. In contrast, ticagrelor-O-glucuronide weakly inhibited CYP2B6, CYP2C9 and CYP2C19 activity with apparent IC50 values of 45.0, 20.0 and 18.8 μM, respectively. The potential of ticagrelor-O-glucuronide to cause drug-drug interactions warrant further study.
Hypoxia-Induced Neuroinflammation in Alzheimer’s Disease: Potential Neuroprotective Effects of Centella asiatica
Authors: Hambali Aqilah , Kumar Jaya , Hashim Nur Fariesha Md , Maniam Sandra , Mehat Muhammad Zulfadli , Cheema Manraj Singh , Mustapha Muzaimi , Adenan Mohd Ilham , Stanslas Johnson , Hamid Hafizah Abdul
Published: October 2021

Alzheimer’s disease (AD) is a neurodegenerative disorder that is characterised by the presence of extracellular beta-amyloid fibrillary plaques and intraneuronal neurofibrillary tau tangles in the brain. Recurring failures of drug candidates targeting these pathways have prompted research in AD multifactorial pathogenesis, including the role of neuroinflammation. Triggered by various factors, such as hypoxia, neuroinflammation is strongly linked to AD susceptibility and/or progression to dementia. Chronic hypoxia induces neuroinflammation by activating microglia, the resident immune cells in the brain, along with an increased in reactive oxygen species and pro-inflammatory cytokines, features that are common to many degenerative central nervous system (CNS) disorders. Hence, interests are emerging on therapeutic agents and plant derivatives for AD that target the hypoxia-neuroinflammation pathway. Centella asiatica is one of the natural products reported to show neuroprotective effects in various models of CNS diseases. Here, we review the complex hypoxia-induced neuroinflammation in the pathogenesis of AD and the potential application of Centella asiatica as a therapeutic agent in AD or dementia.
Efficient Ventricular Parameter Estimation Using AI-Surrogate Models
Authors: Maso Talou Gonzalo D. , Babarenda Gamage Thiranja P. , Nash Martyn P.
Published: October 2021

The onset and progression of pathological heart conditions, such as cardiomyopathy or heart failure, affect its mechanical behaviour due to the remodelling of the myocardial tissues to preserve its functional response. Identification of the constitutive properties of heart tissues could provide useful biomarkers to diagnose and assess the progression of disease. We have previously demonstrated the utility of efficient AI-surrogate models to simulate passive cardiac mechanics. Here, we propose the use of this surrogate model for the identification of myocardial mechanical properties and intra-ventricular pressure by solving an inverse problem with two novel AI-based approaches. Our analysis concluded that: (i) both approaches were robust toward Gaussian noise when the ventricle data for multiple loading conditions were combined; and (ii) estimates of one and two parameters could be obtained in less than 9 and 18 s, respectively. The proposed technique yields a viable option for the translation of cardiac mechanics simulations and biophysical parameter identification methods into the clinic to improve the diagnosis and treatment of heart pathologies. In addition, the proposed estimation techniques are general and can be straightforwardly translated to other applications involving different anatomical structures.
Body Temperature Frequency Distributions: A Tool for Assessing Thermal Performance in Endotherms?
Authors: Levesque D.L. , Nowack J. , Boyles J.G.
Published: October 2021

There is increasing recognition that rather than being fully homeothermic, most endotherms display some degree of flexibility in body temperature. However, the degree to which this occurs varies widely from the relatively strict homeothermy in species, such as humans to the dramatic seasonal hibernation seen in Holarctic ground squirrels, to many points in between. To date, attempts to analyse this variability within the framework generated by the study of thermal performance curves have been lacking. We tested if frequency distribution histograms of continuous body temperature measurements could provide a useful analogue to a thermal performance curve in endotherms. We provide examples from mammals displaying a range of thermoregulatory phenotypes, break down continuous core body temperature traces into various components (active and rest phase modes, spreads and skew) and compare these components to hypothetical performance curves. We did not find analogous patterns to ectotherm thermal performance curves, in either full datasets or by breaking body temperature values into more biologically relevant components. Most species had either bimodal or right-skewed (or both) distributions for both active and rest phase body temperatures, indicating a greater capacity for mammals to tolerate body temperatures elevated above the optimal temperatures than commonly assumed. We suggest that while core body temperature distributions may prove useful in generating optimal body temperatures for thermal performance studies and in various ecological applications, they may not be a good means of assessing the shape and breath of thermal performance in endotherms. We also urge researchers to move beyond only using mean body temperatures and to embrace the full variability in both active and resting temperatures in endotherms.
An Explanation Based on Energy-Related Changes for Blue Mussel Mytilus edulis Coping With Seawater Acidification
Authors: Guo Ying , Zhou Bin , Sun Tianli , Zhang Yaya , Jiang Yongshun , Wang You
Published: October 2021

As ocean acidification (OA) is gradually increasing, concerns regarding its ecological impacts on marine organisms are growing. Our previous studies have shown that seawater acidification exerted adverse effects on physiological processes of the blue mussel Mytilus edulis, and the aim of the present study was to obtain energy-related evidence to verify and explain our previous findings. Thus, the same acidification system (pH: 7.7 or 7.1; acidification method: HCl addition or CO2 enrichment; experimental period: 21d) was set up, and the energy-related changes were assessed. The results showed that the energy charge (EC) and the gene expressions of cytochrome C oxidase (COX) reflecting the ATP synthesis rate increased significantly after acidification treatments. What’s more, the mussels exposed to acidification allocated more energy to gills and hemocytes. However, the total adenylate pool (TAP) and the final adenosine triphosphate (ATP) in M. edulis decreased significantly, especially in CO2 treatment group at pH 7.1. It was interesting to note that, TAP, ATP, and COXs gene expressions in CO2 treatment groups were all significantly lower than that in HCl treatment groups at the same pH, verifying that CO2-induced acidification exhibited more deleterious impacts on M. edulis, and ions besides H+ produced by CO2 dissolution were possible causes. In conclusion, energy-related changes in M. edulis responded actively to seawater acidification and varied with different acidification conditions, while the constraints they had at higher acidification levels suggest that M. edulis will have a limited tolerance to increasing OA in the future.
Conformational Change of Tetratricopeptide Repeats Region Triggers Activation of Phytochrome-Associated Protein Phosphatase 5
Authors: von Horsten Silke , Essen Lars-Oliver
Published: October 2021

Phytochrome activity is not only controlled by light but also by post-translational modifications, e. g. phosphorylation. One of the phosphatases responsible for plant phytochrome dephosphorylation and thereby increased activity is the phytochrome-associated protein phosphatase 5 (PAPP5). We show that PAPP5 recognizes phospho-site mimicking mutants of phytochrome B, when being activated by arachidonic acid (AA). Addition of AA to PAPP5 decreases the α-helical content as tracked by CD-spectroscopy. These changes correspond to conformational changes of the regulatory tetratricopeptide repeats (TPR) region as shown by mapping data from hydrogen deuterium exchange mass spectrometry onto a 3.0 Å crystal structure of PAPP5. Surprisingly, parts of the linker between the TPR and PP2A domains and of the so-called C-terminal inhibitory motif exhibit reduced deuterium uptake upon AA-binding. Molecular dynamics analyses of PAPP5 complexed to a phyB phosphopeptide show that this C-terminal motif remains associated with the TPR region in the substrate bound state, suggesting that this motif merely serves for restricting the orientations of the TPR region relative to the catalytic PP2A domain. Given the high similarity to mammalian PP5 these data from a plant ortholog show that the activation mode of these PPP-type protein phosphatases is highly conserved.
Cultivar Grain Yield in Durum Wheat-Grain Legume Intercrops Could Be Estimated From Sole Crop Yields and Interspecific Interaction Index
Authors: Kammoun Bochra , Journet Etienne-Pascal , Justes Eric , Bedoussac Laurent
Published: October 2021

Ensuring food security for a world population projected to reach over nine billion by 2050 while mitigating the environmental impacts and climate change represent the major agricultural challenges. Diversification of the cropping systems using notably cereal–legume mixtures is one key pathway for such agroecological intensification. Indeed, intercropping is recognised as a practice having the potential to increase and stabilise the yields in comparison with sole crops while limiting the use of inputs notably when species exploit resources in a complementary way. However, predicting intercropped species grain yield remains a challenge because the species respond to competition through complex genotype x cropping mode interactions. Here, we hypothesised that the grain yield achieved by a cultivar in low nitrogen input durum wheat–grain legume intercrops (ICs) could be estimated using a few simple variables. The present work is based on a 2-year field experiment carried out in southwestern France using two durum wheat (Triticum turgidum L.), four winter pea (Pisum sativum L.), and four winter faba bean (Vicia faba L.) genotypes with contrasting characteristics, notably in terms of height and precocity, to explore a wide range of durum wheat–grain legume phenotypes combinations to generate variability in terms of yield and species proportion. The major result is that the yield of durum wheat–grain legume IC component in low nitrogen input conditions could be correctly estimated from only three variables: (i) wheat cultivar full density sole crop (SC) yield, (ii) legume cultivar half density sole crop (SC½) yield, and (iii) an indicator of legume cultivar response to interspecific competition. The latter variable, the interspecific interaction index (IE), reveals cultivars' competitive abilities and tolerance to competition. However, to propose generic IC design and management procedures, further mechanistic understanding is required to better understand the links between tolerance to interspecific competition and cultivar phenotype characteristics. In particular, a special emphasis on the grain legume is needed as their response to interspecific competition appears less predictable than that of durum wheat. Cultivar choice is a key element to optimise the functional complementarity and subsequent IC advantages. This work proposes a simple tool to assist the design of specific breeding programs for cultivars ideotypes adapted to intercropping.
Integrated Transcriptomics and Metabolomics Analyses Provide Insights Into the Response of Chongyi Wild Mandarin to Candidatus Liberibacter Asiaticus Infection
Authors: Peng Ting , Kang Jing-Liang , Xiong Xin-Ting , Cheng Fang-Ting , Zhou Xiao-Juan , Dai Wen-Shan , Wang Min , Li Zhong-Yang , Su Hua-Nan , Zhong Ba-Lian
Published: October 2021

Candidatus Liberibacter asiaticus (CLas) is the causative agent of Huanglongbing (HLB), which has caused great economic losses to the citrus industry. The molecular mechanism of the host response to CLas in wild citrus germplasm has been reported less. Eighteen weeks after inoculation via grafting, all the CLas-inoculated Chongyi wild mandarin (Citrus reticulata) were positive and showed severe anatomical aberrations, suggesting its susceptibility to HLB. Transcriptomics and metabolomics analyses of leaves, barks, and roots from mock-inoculated (control) and CLas-inoculated seedlings were performed. Comparative transcriptomics identified 3,628, 3,770, and 1,716 differentially expressed genes (DEGs) between CLas-infected and healthy tissues in the leaves, barks, and roots, respectively. The CLas-infected tissues had higher transcripts per kilobase per million values and more genes that reached their maximal expression, suggesting that HLB might cause an overall increase in transcript accumulation. However, HLB-triggered transcriptional alteration showed tissue specificity. In the CLas-infected leaves, many DEGs encoding immune receptors were downregulated. In the CLas-infected barks, nearly all the DEGs involved in signaling and plant-pathogen interaction were upregulated. In the CLas-infected roots, DEGs encoding enzymes or transporters involved in carotenoid biosynthesis and nitrogen metabolism were downregulated. Metabolomics identified 71, 62, and 50 differentially accumulated metabolites (DAMs) in the CLas-infected leaves, barks and roots, respectively. By associating DEGs with DAMs, nitrogen metabolism was the only pathway shared by the three infected tissues and was depressed in the CLas-infected roots. In addition, 26 genes were determined as putative markers of CLas infection, and a hypothesized model for the HLB susceptibility mechanism in Chongyi was proposed. Our study may shed light on investigating the molecular mechanism of the host response to CLas infection in wild citrus germplasm.