bluuebunny/crossref_metadata_2025 huggingface dataset:
A Computed Tomography-Derived Radiomics Approach for Predicting Uncommon EGFR Mutation in Patients With NSCLC
Authors: Chen Wufei , Hua Yanqing , Mao Dingbiao , Wu Hao , Tan Mingyu , Ma Weiling , Huang Xuemei , Lu Jinjuan , Li Cheng , Li Ming
Published: December 2021

Purpose

This study aims to develop a CT-based radiomics approach for identifying the uncommon epidermal growth factor receptor (EGFR) mutation in patients with non-small cell lung cancer (NSCLC).

Methods

This study involved 223 NSCLC patients (107 with uncommon EGFR mutation-positive and 116 with uncommon EGFR mutation-negative). A total of 1,269 radiomics features were extracted from the non-contrast-enhanced CT images after image segmentation and preprocessing. Support vector machine algorithm was used for feature selection and model construction. Receiver operating characteristic curve analysis was applied to evaluate the performance of the radiomics signature, the clinicopathological model, and the integrated model. A nomogram was developed and evaluated by using the calibration curve and decision curve analysis.

Results

The radiomics signature demonstrated a good performance for predicting the uncommon EGFR mutation in the training cohort (area under the curve, AUC = 0.802; 95% confidence interval, CI: 0.736–0.858) and was verified in the validation cohort (AUC = 0.791, 95% CI: 0.642–0.899). The integrated model combined radiomics signature with clinicopathological independent predictors exhibited an incremental performance compared with the radiomics signature or the clinicopathological model. A nomogram based on the integrated model was developed and showed good calibration (Hosmer–Lemeshow test, P = 0.92 in the training cohort and 0.608 in the validation cohort) and discrimination capacity (AUC of 0.816 in the training cohort and 0.795 in the validation cohort).

Conclusion

Radiomics signature combined with the clinicopathological features can predict uncommon EGFR mutation in NSCLC patients.
Multi-Omics Analysis of Fatty Acid Metabolism in Thyroid Carcinoma
Authors: Lu Jinghui , Zhang Yankun , Sun Min , Ding Changyuan , Zhang Lei , Kong Youzi , Cai Meng , Miccoli Paolo , Ma Chunhong , Yue Xuetian
Published: December 2021

Objective

Papillary thyroid carcinoma (PTC) accounts for the majority of thyroid cancer and affects a large number of individuals. The pathogenesis of PTC has not been completely elucidated thus far. Metabolic reprogramming is a common feature in tumours. Our previous research revealed the reprogramming of lipid metabolism in PTC. Further studies on lipid metabolism reprogramming may help elucidate the pathogenesis of PTC.

Methods

Clinical samples of PTC and para-tumour tissue were analysed using lipidomic, proteomic, and metabolomic approaches. A multi-omics integrative strategy was adopted to identify the important pathways in PTC. The findings were further confirmed using western blotting, tissue microarray, bioinformatics, and cell migration assays.

Results

Multi-omics data and the results of integrated analysis revealed that the three steps of fatty acid metabolism (hydrolysis, transportation, and oxidation) were significantly enhanced in PTC. Especially, the expression levels of LPL, FATP2, and CPT1A, three key enzymes in the respective steps, were elevated in PTC. Moreover, LPL, FATP2 and CPT1A expression was associated with the TNM stage, lymph node metastasis of PTC. Moreover, high levels of FATP2 and CPT1A contributed to poor prognosis of PTC. In addition, ectopic overexpression of LPL, FATP2 and CPT1A can each promote the migration of thyroid cancer cells.

Conclusions

Our data suggested that enhanced fatty acid metabolism supplied additional energy and substrates for PTC progression. This may help elucidating the underlying mechanism of PTC pathogenesis and identifying the potential therapeutic targets for PTC.
Infiltrative Hepatocellular Carcinoma: Transcatheter Arterial Chemoembolization Versus Hepatic Arterial Infusion Chemotherapy
Authors: An Chao , Zuo Mengxuan , Li Wang , Chen Qifeng , Wu Peihong
Published: December 2021

Aims

To compare the effectiveness, safety, and survival outcomes in patients with infiltrative hepatocellular carcinoma (HCC) who underwent hepatic arterial infusion chemotherapy (HAIC) and transarterial chemoembolization (TACE).

Methods

A total of 160 patients with infiltrative HCCs who underwent initial TACE (n = 68) and HAIC (n = 92) treatment from January 2016 to March 2020. We applied the propensity score matching (PSM) to adjust for potential imbalances. The overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR) were compared between two groups. Multivariate analysis was evaluated through the forward stepwise Cox regression model and β coefficients was applied for the nomogram construction.

Results

The median follow-up duration for the study population was 20.8 months. After PSM, the median OS and PFS in the HAIC group were significantly higher than those in the TACE group (OS, 13.3 vs 10.8 months; p = 0.043; PFS, 7.8 vs 4.0 months; p = 0.035) and the ORR and DCR in the HAIC group were significantly higher than those in the TACE group (ORR, 34.8% vs 11.8%; p = 0.001; DCR, 54.3% vs 36.8%; p = 0.028). A nomogram model comprising albumin-bilirubin grade, treatment responses, sessions, and treatment modalities, showed good predictive accuracy and discrimination (training set, concordance index [C-index] of 0.789; validation set, C-index of 0.757), which outperformed other staging systems and conventional indices.

Conclusion

HAIC improve significantly survival compared to TACE in patients with infiltrative HCC. A prospective randomized trial is ongoing to confirm this finding.
The Dynamic Changes of AFP From Baseline to Recurrence as an Excellent Prognostic Factor of Hepatocellular Carcinoma After Locoregional Therapy: A 5-Year Prospective Cohort Study
Authors: Wang Qi , Liu Biyu , Qiao Wenying , Li Jianjun , Yuan Chunwang , Long Jiang , Hu Caixia , Zang Chaoran , Zheng Jiasheng , Zhang Yonghong
Published: December 2021

Background

Although many studies have confirmed the prognostic value of preoperative alpha-fetoprotein (AFP) in patients with hepatocellular carcinoma (HCC), the association between AFP at baseline (b-AFP), subsequent AFP at relapse (r-AFP), and AFP alteration and overall survival in HCC patients receiving locoregional therapy has rarely been systematically elucidated.

Patients and Methods

A total of 583 subjects with newly diagnosis of virus-related HCC who were admitted to Beijing You ‘an Hospital, Capital Medical University from January 1, 2012 to December 31, 2016 were prospectively enrolled. The influence of b-AFP, subsequent r-AFP, and AFP alteration on relapse and post-recurrence survival were analyzed.

Results

By the end of follow-up, a total of 431 (73.9%) patients relapsed and 200 (34.3%) died. Patients with positive b-AFP had a 24% increased risk of recurrence compared with those who were negative. Patients with positive r-AFP had a 68% increased risk of death after relapse compared with those who were negative. The cumulative recurrence-death survival (RDS) rates for 1, 3, 5 years in patients with negative r-AFP were 85.6% (184/215), 70.2%(151/215), and 67.4%(145/215), while the corresponding rates were 75.1% (154/205), 51.2% (105/205), and 48.8% (100/205) in those with positive AFP (P<0.001). 35 (21.6%) of the 162 patients with negative b-AFP turned positive at the time of recurrence, and of this subset, only 12 (34.3%) survived. Of the 255 patients with positive b-AFP, 86 (33.7%) turned negative at the time of relapse, and of this subset, only 30 (34.9%) died. The 1-, 3-, and 5-year cumulative RDS rates were also compared among groups stratified by AFP at baseline and relapse. The present study found that patients with positive AFP at baseline and relapse, as well as those who were negative turned positive, had the shortest RDS and OS.

Conclusions

Not only AFP at baseline but also subsequent AFP at relapse can be used to predict a post-recurrence survival, which can help evaluate mortality risk stratification of patients after relapse.
Case Report: Durable Response to Very Low Dose Tyrosine Kinase Inhibitors in Advanced Hepatocellular Carcinoma
Authors: Tang Tin-Yun , Daunov Katherine , Lee Richard T.
Published: December 2021

The oral tyrosine kinase inhibitors (TKI) sorafenib, regorafenib, and cabozantinib are approved for advanced hepatocellular carcinoma (aHCC) and improve survival. However, patients on these medications frequently require dose reductions or discontinuation due to multiple side effects leading to poor tolerability. Here we report three different aHCC patients with clinical responses outlasting those reported in their corresponding Phase 3 clinical trials on 1/8th the target dose for sorafenib, 1/4th the target dose for regorafenib and 1/6th the target dose for cabozantinib respectively. As these doses are below the minimal recommended doses on the FDA labels, this case series provides a preliminary demonstration that low dose TKI therapy can be effective and patients on TKIs should first assess for clinical response before empirically discontinuing TKI therapy on the basis of tolerating only a low dose.
FNDC3B and BPGM Are Involved in Human Papillomavirus-Mediated Carcinogenesis of Cervical Cancer
Authors: Zhang Luhan , Yu Hong , Deng Tian , Ling Li , Wen Juan , Lv Mingfen , Ou Rongying , Wang Qiaozhi , Xu Yunsheng
Published: December 2021

Human papillomavirus (HPV)-mediated cervical carcinogenesis is a multistep progressing from persistent infection, precancerous lesion to cervical cancer (CCa). Although molecular alterations driven by viral oncoproteins are necessary in cervical carcinogenesis, the key regulators behind the multistep process remain not well understood. It is pivotal to identify the key genes involved in the process for early diagnosis and treatment of this disease. Here we analyzed the mRNA expression profiles in cervical samples including normal, cervical intraepithelial neoplasia (CIN), and CCa. A co-expression network was constructed using weighted gene co-expression network analysis (WGCNA) to reveal the crucial modules in the dynamic process from HPV infection to CCa development. Furthermore, the differentially expressed genes (DEGs) that could distinguish all stages of progression of CCa were screened. The key genes involved in HPV-CCa were identified. It was found that the genes involved in DNA replication/repair and cell cycle were upregulated in CIN compared with normal control, and sustained in CCa, accompanied by substantial metabolic shifts. We found that upregulated fibronectin type III domain-containing 3B (FNDC3B) and downregulated bisphosphoglycerate mutase (BPGM) could differentiate all stages of CCa progression. In patients with CCa, a higher expression of FNDC3B or lower expression of BPGM was closely correlated with a shorter overall survival (OS) and disease-free survival (DFS). A receiver operating characteristic (ROC) analysis of CIN and CCa showed that FNDC3B had the highest sensitivity and specificity for predicting CCa development. Taken together, the current data showed that FNDC3B and BPGM were key genes involved in HPV-mediated transformation from normal epithelium to precancerous lesions and CCa.
Optimized Conformal Total Body Irradiation Among Recipients of TCRαβ/CD19-Depleted Grafts in Pediatric Patients With Hematologic Malignancies: Single-Center Experience
Authors: Kobyzeva Daria , Shelikhova Larisa , Loginova Anna , Kanestri Francheska , Tovmasyan Diana , Maschan Michael , Khismatullina Rimma , Ilushina Mariya , Baidildina Dina , Myakova Natalya , Nechesnyuk Alexey
Published: December 2021

Total body irradiation (TBI) in combination with chemotherapy is widely used as a conditioning regimen in pediatric and adult hematopoietic stem cell transplantation (HSCT). The combination of TBI with chemotherapy has demonstrated superior survival outcomes in patients with acute lymphoblastic and myeloid leukemia when compared with conditioning regimens based only on chemotherapy. The clinical application of intensity-modulated radiation therapy (IMRT)-based methods (volumetric modulated arc therapy (VMAT) and TomoTherapy) seems to be promising and has been actively used worldwide. The optimized conformal total body irradiation (OC-TBI) method described in this study provides selected dose reduction for organs at risk with respect to the most significant toxicity (lungs, kidneys, lenses). This study included 220 pediatric patients who received OC-TBI with subsequent chemotherapy and allogenic HSCT with TCRαβ/CD19 depletion. A group of 151 patients received OC-TBI using TomoTherapy, and 40 patients received OC-TBI using the Elekta Synergy™ linac with an Agility-MLC (Elekta, Crawley, UK) using volumetric modulated arc therapy (VMAT). Twenty-nine patients received OC-TBI with supplemental simultaneous boost to bone marrow—(SIB to BM) up to 15 Gy: 28 patients (pts)—TomoTherapy; one patient—VMAT. The follow-up duration ranged from 0.3 to 6.4 years (median follow-up, 2.8 years). Overall survival (OS) for all the patients was 63% (95% CI: 56–70), and event-free survival (EFS) was 58% (95% CI: 51–65). The cumulative incidence of transplant-related mortality (TRM) was 10.7% (95% CI: 2.2–16) for all patients. The incidence of early TRM (<100 days) was 5.0% (95% CI: 1.5–8.9), and that of late TRM (>100 days) was 5.7 (95% CI: 1.7–10.2). The main causes of death for all the patients were relapse and infection. The concept of OC-TBI using IMRT VMAT and helical treatment delivery on a TomoTherapy treatment unit provides maximum control of the dose distribution in extended targets with simultaneous dose reduction for organs at risk. This method demonstrated a low incidence of severe side effects after radiation therapy and predictable treatment effectiveness. Our initial experience demonstrates that OC-TBI appears to be a promising technique for the treatment of pediatric patients.
Evaluation of PD-L1 Expression Level in Patients With Non-Small Cell Lung Cancer by 18F-FDG PET/CT Radiomics and Clinicopathological Characteristics
Authors: Li Jihui , Ge Shushan , Sang Shibiao , Hu Chunhong , Deng Shengming
Published: December 2021

Purpose

In the present study, we aimed to evaluate the expression of programmed death-ligand 1 (PD-L1) in patients with non-small cell lung cancer (NSCLC) by radiomic features of 18F-FDG PET/CT and clinicopathological characteristics.

Methods

A total 255 NSCLC patients (training cohort: n = 170; validation cohort: n = 85) were retrospectively enrolled in the present study. A total of 80 radiomic features were extracted from pretreatment 18F-FDG PET/CT images. Clinicopathologic features were compared between the two cohorts. The least absolute shrinkage and selection operator (LASSO) regression was used to select the most useful prognostic features in the training cohort. Radiomics signature and clinicopathologic risk factors were incorporated to develop a prediction model by using multivariable logistic regression analysis. The receiver operating characteristic (ROC) curve was used to assess the prognostic factors.

Results

A total of 80 radiomic features were extracted in the training dataset. In the univariate analysis, the expression of PD-L1 in lung tumors was significantly correlated with the radiomic signature, histologic type, Ki-67, SUVmax, MTV, and TLG (p< 0.05, respectively). However, the expression of PD-L1 was not correlated with age, TNM stage, and history of smoking (p> 0.05). Moreover, the prediction model for PD-L1 expression level over 1% and 50% that combined the radiomic signature and clinicopathologic features resulted in an area under the curve (AUC) of 0.762 and 0.814, respectively.

Conclusions

A prediction model based on PET/CT images and clinicopathological characteristics provided a novel strategy for clinicians to screen the NSCLC patients who could benefit from the anti-PD-L1 immunotherapy.
Immune Checkpoint Inhibitors Combined With Chemotherapy Compared With Chemotherapy Alone for Triple-Negative Breast Cancer: A Systematic Review and Meta-Analysis
Authors: Ji Qiao , Ding Jingxian , Hao Meiqi , Luo Nachuan , Huang Jiabing , Zhang Wenxiong
Published: December 2021

Background

It is still controversial whether immune checkpoint inhibitors (ICIs) can improve the curative effect when added to original standard chemotherapy treatment for triple-negative breast cancer (TNBC). We compared their antitumor efficacy and adverse effects (AEs) to make a better clinical decision.

Methods

Seven databases were searched for eligible articles. Progression-free survival (PFS), overall survival (OS), and AEs were measured as the primary outcomes.

Results

Nine randomized controlled trials (RCTs) involving 4,501 patients were included. ICI+chemotherapy treatment achieved better PFS (hazard ratio [HR]: 0.78, [0.70–0.86], p < 0.00001), OS (HR: 0.86, [0.74–0.99], p = 0.04), and complete response (584/1,106 vs. 341/825, risk ratio [RR]: 1.38, [1.01–1.89], p = 0.04). With the prolongation of survival, the survival advantage of ICI+chemotherapy increased compared with chemotherapy. Subgroup analysis suggested that the addition of ICIs might not have a better effect in Asian patients, patients with locally advanced disease, or patients with brain metastases. In the toxicity analysis, more Grade 3–5 AEs and serious AEs were found in the ICI+chemotherapy group. For Grade 3–5 AEs, more cases of diarrhea, severe skin reactions, pneumonitis, hepatitis, and adrenal insufficiency were related to the ICI+chemotherapy group.

Conclusions

ICI+chemotherapy appears to be better than chemotherapy alone for TNBC treatment, with better OS and PFS. However, its high rates of serious AEs need to be taken seriously.

Systematic Review Registration

PROSPERO Registration: CRD42021276394.
Sex Differences in Migraine: A Twin Study
Authors: Fitzgerald Morgan C. , Saelzler Ursula G. , Panizzon Matthew S.
Published: December 2021

Migraine is a neurological disorder with a prominent sex difference such that two thirds of sufferers are female. The mechanisms behind the preponderance of migraine in women have yet to be elucidated. With data on 51,872 participants from the Swedish Twin Registry, we report results from two distinct analyses intended to clarify the degree to which genetic and environmental factors contribute to sex differences in migraine. First, we fit a sex-limitation model to determine if quantitative genetic differences (i.e., is migraine equally heritable across men and women) and/or qualitative genetic differences (i.e., are different genes involved in migraine across men and women) were present. Next, we used a multilevel logistic regression model to compare the prevalence of migraine in individuals from opposite-sex and same-sex twin pairs to determine whether differences in the prenatal hormone environment contribute to migraine risk. In the final analytic sample, women were found to have a significantly higher rate of migraine without aura relative to men (17.6% vs. 5.5%). The results from an ADE sex-limitation model indicate that migraine is equally heritable in men and women, with a broad sense heritability of 0.45, (95% CI = 0.40–0.50), while results from a reduced AE sex-limitation model provide subtle evidence for differences in the genes underlying migraine across men and women. The logistic regression analysis revealed a significant increase in migraine risk for females with a male co-twin relative to females with a female co-twin (OR = 1.51, 95% CI = 1.26–1.81). These results suggest that the prominent sex difference in migraine prevalence is not entirely accounted for by genetic factors, while demonstrating that masculinization of the prenatal environment may increase migraine risk for females. This effect points to a potential prenatal neuroendocrine factor in the development of migraine.
Using Ear Molding to Treat Congenital Auricular Deformities
Authors: Chen Yu , Wang Wei , Wang Yue , Mao Xiang
Published: December 2021

Objective: To explore the utility of ear molding in the treatment of congenital auricular deformations.

Study Design: A retrospective chart/photograph review of a consecutive series of infants treated with the EarWell System from 2017 to 2020 was performed. Data on type of auricular deformity, treatment side, and auricular length and width were collected weekly for all study participants.

Result: A total of 173 patients (274 ears) with congenital auricular anomalies were included. The treatment duration for lop ears and Stahl's ears was shorter than for other deformations. The mean treatment EarWell duration of participants who started ear molding within 14 days of birth was shorter than that of those who started treatment more than 14 days after birth with the same ear deformation. For participants with unilateral ear deformities, the length and width of both the affected and healthy ears increased over the course of treatment, equalizing after 3 weeks. For participants with bilateral ear deformities, the length and width of both ears increased rapidly over the first 3 weeks of treatment, and the length and width of both ears gradually equalized after treatment.

Conclusion: Ear molding is an important intervention for treating congenital auricular deformations, and can increase auricular length and width. Early identification and initiation of treatment is crucial in the management of congenital auricular deformation.
Orphan Medicine Incentives: How to Address the Unmet Needs of Rare Disease Patients by Optimizing the European Orphan Medicinal Product Landscape Guiding Principles and Policy Proposals by the European Expert Group for Orphan Drug Incentives (OD Expert Group)
Authors: Aartsma-Rus Annemieke , Dooms Marc , Le Cam Yann
Published: December 2021

Today policy makers face the challenge to devise a policy framework that improves orphan medicinal product (OMP) development by creating incentives to deliver treatments where there are none and to authorize innovative and transformative treatments where treatments already exist. The European Expert Group on Orphan Drug Incentives (hereafter, OD Expert Group) came together in 2020 to develop policy proposals to facilitate EU policy makers to meet this challenge. The group brings together representatives of the broad rare disease community, including researchers, academia, patient representatives, members of the investor community, rare disease companies and trade associations. The group’s work builds on the recognition that only an ambitious policy agenda developed in a multi-stakeholder setting can bring about the quantum leap needed to address unmet needs of rare disease patients today. Along the OMP development path, the OD Expert Group has identified four main needs that a policy revision should address: 1) Need to improve the R&D ecosystem for basic research and company take-up of development. 2) Need to improve the system of financial incentives and rewards. 3) Need to improve the flexibility, predictability and speed of the regulatory pathway. 4) Need to improve the coherence and predictability of demand and pricing for OMPs. This article presents the results of the OD Expert Group work as a set of guiding principles that the revision of the policy framework should follow and a set of 14 policy proposals that address the main needs of OMP development in Europe today.
Tetramethylpyrazine: A Review of Its Antitumor Potential and Mechanisms
Authors: Yang Shaojie , Wu Shuodong , Dai Wanlin , Pang Liwei , Xie Yaofeng , Ren Tengqi , Zhang Xiaolin , Bi Shiyuan , Zheng Yuting , Wang Jingnan , Sun Yang , Zheng Zhuyuan , Kong Jing
Published: December 2021

Cancer remains a major public health threat. The mitigation of the associated morbidity and mortality remains a major research focus. From a molecular biological perspective, cancer is defined as uncontrolled cell division and abnormal cell growth caused by various gene mutations. Therefore, there remains an urgent need to develop safe and effective antitumor drugs. The antitumor effect of plant extracts, which are characterized by relatively low toxicity and adverse effect, has attracted significant attention. For example, increasing attention has been paid to the antitumor effects of tetramethylpyrazine (TMP), the active component of the Chinese medicine Chuanqiong, which can affect tumor cell proliferation, apoptosis, invasion, metastasis, and angiogenesis, as well as reverse chemotherapeutic resistance in neoplasms, thereby triggering antitumor effects. Moreover, TMP can be used in combination with chemotherapeutic agents to enhance their effects and reduce the side effect associated with chemotherapy. Herein, we review the antitumor effects of TMP to provide a theoretical basis and foundation for the further exploration of its underlying antitumor mechanisms and promoting its clinical application.
The Preventive Effect of Decorin on Epidural Fibrosis and Epidural Adhesions After Laminectomy
Authors: Ding Qing , Wei Qi , Sheng Gaohong , Wang Shanxi , Jing Shaoze , Ma Tian , Zhang Ruizhuo , Wang Tianqi , Li Wenkai , Tang Xiangyu , Wu Hua , Liu Chaoxu
Published: December 2021

Laminectomy is commonly performed to treat degenerative spinal diseases by reducing compression on the spinal cord and nerve roots. The postoperative epidural fibrosis and epidural adhesions may result in failed back surgery syndrome, which is characterized by the symptoms of lower back pain or leg pain. There is currently no satisfactory treatment for this complication. The pathological processes of epidural fibrosis and epidural adhesions are relevant to the proliferation of fibroblasts, transdifferentiation of fibroblasts into myofibroblasts, and the excessive deposition of extracellular matrix (ECM) protein. According to reports, transforming growth factor-β1 (TGF-β1) played a vital role in the development of fibrosis by promoting aforementioned processes. Decorin, an endogenous proteoglycan and natural inhibitor of TGF-β1, has exhibited prominent anti-fibrosis activity in various scar formation and fibrosis models of many organs. However, the preventive effect of decorin on epidural fibrosis and epidural adhesions requires further investigation. Here, we investigated the therapeutic effects and potential mechanisms of decorin on epidural fibrosis and epidural adhesions. Our results indicated that decorin could significantly suppress the TGF-β1-induced proliferation, transdifferentiation, and extracellular matrix production in primary fibroblasts. Furthermore, Smad2/3 signaling pathway had been demonstrated to be involved in the preventive effect of decorin. Moreover, administration of decorin in vivo could notably inhibit epidural fibrosis and epidural adhesions after laminectomy. To date, there is no approved therapy to target TGF-β1 for the treatment of epidural fibrosis and epidural adhesions after laminectomy. Our research proved the anti-fibrosis effect of decorin, which may provide an effective and promising treatment for epidural fibrosis and epidural adhesions.
Low-Dose Fluvoxamine Modulates Endocytic Trafficking of SARS-CoV-2 Spike Protein: A Potential Mechanism for Anti-COVID-19 Protection by Antidepressants
Authors: Glebov Oleg O.
Published: December 2021

Commonly prescribed antidepressants may be associated with protection against severe COVID-19. The mechanism of their action in this context, however, remains unknown. Here, I investigated the effect of an antidepressant drug fluvoxamine on membrane trafficking of the SARS-CoV-2 spike protein and its cell host receptor ACE2 in HEK293T cells. A sub-therapeutic concentration (80 nM) of fluvoxamine rapidly upregulated fluid-phase endocytosis, resulting in enhanced accumulation of the spike-ACE2 complex in enlarged early endosomes. Diversion of endosomal trafficking provides a simple cell biological mechanism consistent with the protective effect of antidepressants against COVID-19, highlighting their therapeutic and prophylactic potential.
Immune Characteristics of IgA Nephropathy With Minimal Change Disease
Authors: Li Huixian , Lu Wanhong , Li Haiyun , Liu Xiaoling , Zhang Xue , Xie Liyi , Lan Ping , Yu Xiaoyang , Dai Yinjuan , Xie Xinfang , Lv Jicheng
Published: December 2021

Background: IgA nephropathy (IgAN) has a high degree of heterogeneity in clinical and pathological features. Among all subsets of IgAN, the pathogenesis of IgAN with minimal change disease (MCD-IgAN) remained controversial.

Methods: We analyzed the clinical and pathological characteristics of MCD-IgAN patients in a retrospective cohort. Patients diagnosed with IgAN, excluding MCD-IgAN, were randomly selected as controls. Levels of plasma galactose-deficient IgA1 (GdIgA1), IgG autoantibodies against GdIgA1, GdIgA1 deposition in the glomerulus, and inflammatory reactivity of circulating poly-IgA1 complexes to cultured mesangial cells were evaluated.

Results: Patients with MCD-IgAN had significantly higher levels of proteinuria and estimated glomerular filtration rate (eGFR), lower levels of albumin and urine blood cells, and milder histological lesions by a light microscope compared to IgAN patients, which bears a resemblance to MCD. Lower levels of GdIgA1 (3.41 ± 1.68 vs. 4.92 ± 2.30 μg/ml, p = 0.009) and IgG antiglycan autoantibodies (23.25 ± 22.59 vs. 76.58 ± 71.22 IU/ml, p < 0.001) were found in MCD-IgAN patients than those in IgAN controls. Meanwhile, weaker fluorescence intensities of both IgA and GdIgA1 were observed in the glomerulus of MCD-IgAN patients compared to those in IgAN patients. Furthermore, poly-IgA1 complexes from MCD-IgAN patients induced weaker inflammatory effects on cultured mesangial cells than those from IgAN patients in vitro.

Conclusion: The results demonstrated that MCD-IgAN cases represent a dual glomerulopathy, namely, mild IgAN with superimposed MCD, which furthermore provides substantial evidence for the corticosteroids therapy in MCD-IgAN patients as the guidelines recommended.
The Linkage Phase of the Polymorphism KCNH2-K897T Influences the Electrophysiological Phenotype in hiPSC Models of LQT2
Authors: van den Brink Lettine , Brandão Karina O. , Yiangou Loukia , Blanch-Asensio Albert , Mol Mervyn P. H. , Mummery Christine L. , Verkerk Arie O. , Davis Richard P.
Published: December 2021

While rare mutations in ion channel genes are primarily responsible for inherited cardiac arrhythmias, common genetic variants are also an important contributor to the clinical heterogeneity observed among mutation carriers. The common single nucleotide polymorphism (SNP) KCNH2-K897T is associated with QT interval duration, but its influence on the disease phenotype in patients with long QT syndrome type 2 (LQT2) remains unclear. Human induced pluripotent stem cells (hiPSCs), coupled with advances in gene editing technologies, are proving an invaluable tool for modeling cardiac genetic diseases and identifying variants responsible for variability in disease expressivity. In this study, we have used isogenic hiPSC-derived cardiomyocytes (hiPSC-CMs) to establish the functional consequences of having the KCNH2-K897T SNP in cis- or trans-orientation with LQT2-causing missense variants either within the pore-loop domain (KCNH2A561T/WT) or tail region (KCNH2N996I/WT) of the potassium ion channel, human ether-a-go-go-related gene (hERG). When KCNH2-K897T was on the same allele (cis) as the primary mutation, the hERG channel in hiPSC-CMs exhibited faster activation and deactivation kinetics compared to their trans-oriented counterparts. Consistent with this, hiPSC-CMs with KCNH2-K897T in cis orientation had longer action and field potential durations. Furthermore, there was an increased occurrence of arrhythmic events upon pharmacological blocking of hERG. Collectively, these results indicate that the common polymorphism KCNH2-K897T differs in its influence on LQT2-causing KCNH2 mutations depending on whether it is present in cis or trans. This study corroborates hiPSC-CMs as a powerful platform to investigate the modifying effects of common genetic variants on inherited cardiac arrhythmias and aids in unraveling their contribution to the variable expressivity of these diseases.
Influence of Menstrual Cycle or Hormonal Contraceptive Phase on Physiological Variables Monitored During Treadmill Testing
Authors: Taipale-Mikkonen Ritva S. , Raitanen Anna , Hackney Anthony C. , Solli Guro Strøm , Valtonen Maarit , Peltonen Heikki , McGawley Kerry , Kyröläinen Heikki , Ihalainen Johanna K.
Published: December 2021

Purpose: To examine the influence of menstrual cycle (MC) and hormonal contraceptive (HC) cycle phases on physiological variables monitored during incremental treadmill testing in physically active women (eumenorrheic, EUM = 16 and monophasic HC-users, CHC = 12).

Methods: Four running tests to exhaustion were performed at bleeding, mid follicular (mid FOL)/active 1, ovulation/active 2, and mid luteal (mid LUT)/inactive. HC and MC phases were confirmed from serum hormones. Heart rate (HR), blood lactate (Bla), and V˙O2 were monitored, while aerobic (AerT) and anaerobic (AnaT) thresholds were determined. V˙O2peak, maximal running speed (RUNpeak), and total running time (RUNtotal) were recorded.

Results: No significant changes were observed in V˙O2 or Bla at AerT or AnaT across phases in either group. At maximal effort, absolute and relative V˙O2peak, RUNpeak, and RUNtotal remained stable across phases in both groups. No significant fluctuations in HRmax were observed across phases, but HR at both AerT and AnaT tended to be lower in EUM than in CHC across phases.

Conclusion: Hormonal fluctuations over the MC and HC do not systematically influence physiological variables monitored during incremental treadmill testing. Between group differences in HR at AerT and AnaT underline why HR-based training should be prescribed individually, while recording of MC or HC use when testing should be encouraged as phase may explain minor, but possibly meaningful, changes in, e.g., Bla concentrations or differences in HR response.
Perfusion of Brain Preautonomic Areas in Hypertension: Compensatory Absence of Capillary Rarefaction and Protective Effects of Exercise Training
Authors: Jordão Maria Tereza , Ceroni Alexandre , Michelini Lisete C.
Published: December 2021

Remodeling of capillary rarefaction and deleterious arteries are characteristic hallmarks of hypertension that are partially corrected by exercise training. In addition, experimental evidence showed capillary rarefaction within the brain cortex and reduced cerebral blood flow. There is no information on hypertension- and exercise-induced effects on capillary profile and function within preautonomic nuclei. We sought now to evaluate the effects of hypertension and exercise training (T) on the capillary network within hypothalamic paraventricular (PVN) and solitary tract (NTS) nuclei, and on the remodeling of brain arteries. Age-matched spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY), submitted to moderate T or kept sedentary (S) for three months, were chronically cannulated for hemodynamic recordings at rest. Rats were anesthetized for i.v. administration of fluorescein isothiocyanate (FITC)-dextran (capillary volume/density measurements) or 4% paraformaldehyde perfusion (basilar, middle, and posterior arteries' morphometry) followed by brain harvesting and processing. Other groups of conscious rats had carotid blood flow (CBF, ultrasound flowmeter) acquired simultaneously with hemodynamic recordings at rest and exercise. SHR-S exhibited elevated pressure and heart rate, reduced CBF, increased wall/lumen ratio of arteries, but no capillary rarefaction within the PVN and NTS. T improved performance gain and caused resting bradycardia in both groups; reduction of pressure and sympathetic vasomotor activity and normalization of the wall/lumen ratio were only observed in SHR-T. T groups responded with marked PVN and NTS capillary angiogenesis and augmented CBF during exercise; to avoid overperfusion at rest, reduced basal CBF was observed only in WKY-T. Data indicated that the absence of SHR-S capillary rarefaction and the intense SHR-T angiogenesis within autonomic areas associated with correction of deleterious arteries' remodeling are essential adjustments to hypertension and exercise training, respectively. These adaptive responses maintain adequate baseline perfusion in SHR-S and SHR-T preautonomic nuclei, augmenting it in exercised rats when a well-coordinated autonomic control is required.
Mechanical, Cardiorespiratory, and Muscular Oxygenation Responses to Sprint Interval Exercises Under Different Hypoxic Conditions in Healthy Moderately Trained Men
Authors: Solsona Robert , Berthelot Hugues , Borrani Fabio , Sanchez Anthony M. J.
Published: December 2021

Objective: The aim of this study was to determine the effects of sprint interval exercises (SIT) conducted under different conditions (hypoxia and blood flow restriction [BFR]) on mechanical, cardiorespiratory, and muscular O2 extraction responses.

Methods: For this purpose, 13 healthy moderately trained men completed five bouts of 30 s all-out exercises interspaced by 4 min resting periods with lower limb bilateral BFR at 60% of the femoral artery occlusive pressure (BFR60) during the first 2 min of recovery, with gravity-induced BFR (pedaling in supine position; G-BFR), in a hypoxic chamber (FiO2≈13%; HYP) or without additional stress (NOR). Peak and average power, time to achieve peak power, rating of perceived exertion (RPE), and a fatigue index (FI) were analyzed. Gas exchanges and muscular oxygenation were measured by metabolic cart and NIRS, respectively. Heart rate (HR) and peripheral oxygen saturation (SpO2) were continuously recorded.

Results: Regarding mechanical responses, peak and average power decreased after each sprint (p < 0.001) excepting between sprints four and five. Time to reach peak power increased between the three first sprints and sprint number five (p < 0.001). RPE increased throughout the exercises (p < 0.001). Of note, peak and average power, time to achieve peak power and RPE were lower in G-BFR (p < 0.001). Results also showed that SpO2 decreased in the last sprints for all the conditions and was lower for HYP (p < 0.001). In addition, Δ[O2Hb] increased in the last two sprints (p < 0.001). Concerning cardiorespiratory parameters, BFR60 application induced a decrease in gas exchange rates, which increased after its release compared to the other conditions (p < 0.001). Moreover, muscle blood concentration was higher for BFR60 (p < 0.001). Importantly, average and peak oxygen consumption and muscular oxyhemoglobin availability during sprints decreased for HYP (p < 0.001). Finally, the tissue saturation index was lower in G-BFR.

Conclusions: Thus, SIT associated with G-BFR displayed lower mechanical, cardiorespiratory responses, and skeletal muscle oxygenation than the other conditions. Exercise with BFR60 promotes higher blood accumulation within working muscles, suggesting that BFR60 may additionally affect cellular stress. In addition, HYP and G-BFR induced local hypoxia with higher levels for G-BFR when considering both exercise bouts and recovery periods.
The CXCL1-CXCR2 Axis Mediates Tubular Injury in Diabetic Nephropathy Through the Regulation of the Inflammatory Response
Authors: Tang Hanfen , Yang Ming , Liu Yinghong , Liu Hong , Sun Lin , Song Panai
Published: December 2021

Diabetic nephropathy (DN) is one of the most severe complications of diabetes. Inflammation mediated by inflammatory factors is thought to accelerate the progression of renal damage in DN. However, which inflammatory factors mediate the inflammatory response in DN remains unclear. In this study, we determined that the CXCL1-mediated inflammatory response may play an essential role in DN progression through bioassays. Subsequently, we observed that the expression of CXCL1 and its receptor (CXCR2) was significantly increased in the kidneys of mice with HFD + STZ induced diabetes and DN patients. In addition, inhibition of the CXCL1/CXCR2 axis by repertaxin alleviates renal inflammation and pathological damage in the kidneys of db/db mice. Finally, we noted that the CXCL1/CXCR2 axis might lead to inflammatory damage through phosphorylated NF-κB and further activate the NLRP3 inflammasome. Our results revealed the role of the CXCL1/CXCR2 axis in DN progression for the first time, which may be a novel therapeutic target for DN.
A Redox-Sensitive Cysteine Is Required for PIN1At Function
Authors: Selles Benjamin , Dhalleine Tiphaine , Boutilliat Alexis , Rouhier Nicolas , Couturier Jérémy
Published: December 2021

Parvulins are ubiquitous peptidyl-prolyl isomerases (PPIases) required for protein folding and regulation. Among parvulin members, Arabidopsis PIN1At, human PIN1, and yeast ESS1 share a conserved cysteine residue but differ by the presence of an N-terminal WW domain, absent in PIN1At. In this study, we have explored whether the cysteine residue of Arabidopsis PIN1At is involved in catalysis and subject to oxidative modifications. From the functional complementation of yeast ess1 mutant, we concluded that the cysteine at position 69 is mandatory for PIN1At function in vivo, unless being replaced by an Asp which is found in a few parvulin members. This result correlates with a decrease of the in vitro PPIase activity of non-functional PIN1At cysteinic variants. A decrease of PIN1At activity was observed upon H2O2 treatment. The in vitro oxidation of cysteine 69, which has an acidic pKa value of 4.9, leads to the formation of covalent dimers that are reduced by thioredoxins, or to sulfinic or sulfonic acid forms at higher H2O2 excess. These investigations highlight the importance of the sole cysteine residue of PIN1At for activity. The reversible formation of an intermolecular disulfide bond might constitute a protective or regulatory mechanism under oxidizing conditions.
Comparative Analysis of NADPH-Cytochrome P450 Reductases From Legumes for Heterologous Production of Triterpenoids in Transgenic Saccharomyces cerevisiae
Authors: Istiandari Pramesti , Yasumoto Shuhei , Srisawat Pisanee , Tamura Keita , Chikugo Ayaka , Suzuki Hideyuki , Seki Hikaru , Fukushima Ery Odette , Muranaka Toshiya
Published: December 2021

Triterpenoids are plant specialized metabolites with various pharmacological activities. They are widely distributed in higher plants, such as legumes. Because of their low accumulation in plants, there is a need for improving triterpenoid production. Cytochrome P450 monooxygenases (CYPs) play critical roles in the structural diversification of triterpenoids. To perform site-specific oxidations, CYPs require the electrons that are transferred by NADPH-cytochrome P450 reductase (CPR). Plants possess two main CPR classes, class I and class II. CPR classes I and II have been reported to be responsible for primary and specialized (secondary) metabolism, respectively. In this study, we first analyzed the CPR expression level of three legumes species,Medicago truncatula,Lotus japonicus, andGlycyrrhiza uralensis, showing that the expression level of CPR class I was lower and more stable, while that of CPR class II was higher in almost all the samples. We then co-expressed different combinations of CYP716As and CYP72As with different CPR classes from these three legumes in transgenic yeast. We found that CYP716As worked better with CPR-I from the same species, while CYP72As worked better with any CPR-IIs. Using engineered yeast strains, CYP88D6 paired with class II GuCPR produced the highest level of 11-oxo-β-amyrin, the important precursor of high-value metabolites glycyrrhizin. This study provides insight into co-expressing genes from legumes for heterologous production of triterpenoids in yeast.
Bundling up the Role of the Actin Cytoskeleton in Primary Root Growth
Authors: García-González Judith , van Gelderen Kasper
Published: December 2021

Primary root growth is required by the plant to anchor in the soil and reach out for nutrients and water, while dealing with obstacles. Efficient root elongation and bending depends upon the coordinated action of environmental sensing, signal transduction, and growth responses. The actin cytoskeleton is a highly plastic network that constitutes a point of integration for environmental stimuli and hormonal pathways. In this review, we present a detailed compilation highlighting the importance of the actin cytoskeleton during primary root growth and we describe how actin-binding proteins, plant hormones, and actin-disrupting drugs affect root growth and root actin. We also discuss the feedback loop between actin and root responses to light and gravity. Actin affects cell division and elongation through the control of its own organization. We remark upon the importance of longitudinally oriented actin bundles as a hallmark of cell elongation as well as the role of the actin cytoskeleton in protein trafficking and vacuolar reshaping during this process. The actin network is shaped by a plethora of actin-binding proteins; however, there is still a large gap in connecting the molecular function of these proteins with their developmental effects. Here, we summarize their function and known effects on primary root growth with a focus on their high level of specialization. Light and gravity are key factors that help us understand root growth directionality. The response of the root to gravity relies on hormonal, particularly auxin, homeostasis, and the actin cytoskeleton. Actin is necessary for the perception of the gravity stimulus via the repositioning of sedimenting statoliths, but it is also involved in mediating the growth response via the trafficking of auxin transporters and cell elongation. Furthermore, auxin and auxin analogs can affect the composition of the actin network, indicating a potential feedback loop. Light, in its turn, affects actin organization and hence, root growth, although its precise role remains largely unknown. Recently, fundamental studies with the latest techniques have given us more in-depth knowledge of the role and organization of actin in the coordination of root growth; however, there remains a lot to discover, especially in how actin organization helps cell shaping, and therefore root growth.
Restoration of Degraded Grassland Significantly Improves Water Storage in Alpine Grasslands in the Qinghai-Tibet Plateau
Authors: Guo Xiaowei , Zhou Huakun , Dai Licong , Li Jing , Zhang Fawei , Li Yikang , Lin Li , Li Qian , Qian Dawen , Fan Bo , Lan Yuting , Si Mengke , Li Bencuo , Cao Guangmin , Du Yangong , Wang Bin
Published: December 2021

Alpine grassland has very important water conservation function. Grassland degradation seriously affects the water conservation function; moreover, there is little understanding of the change of water state during grassland restoration. Our study aims to bridge this gap and improve our understanding of changes in soil moisture during the restoration process. In this study, the water storage, vegetation, and meteorology of a non-degradation grassland (grazing intensity of 7.5 sheep/ha) and a severely degraded grassland (grazing intensity of 12–18 sheep/ha) were monitored in the Qinghai-Tibet Plateau for seven consecutive years. We used correlation, stepwise regression, and the boosted regression trees (BRT) model analyses, five environmental factors were considered to be the most important factors affecting water storage. The severely degraded grassland recovered by light grazing treatment for 7 years, with increases in biomass, litter, and vegetation cover, and a soil-water storage capacity 41.9% higher in 2018 compared to that in 2012. This increase in soil-water storage was primarily due to the increase in surface soil moisture content. The key factors that influenced water storage were listed in a decreasing order: air temperature, litter, soil heat flux, precipitation, and wind speed. Their percentage contributions to soil-water storage were 50.52, 24.02, 10.86, 7.82, and 6.77%, respectively. Current and future climate change threatens soil-water conservation in alpine grasslands; however, grassland restoration is an effective solution to improve the soil-water retention capacity in degraded grassland soils.