bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Maltodextrin and Soy Protein Isolate on the Physicochemical and Flow Properties of Button Mushroom Powder
Authors: Shams Rafeeya , Singh Jagmohan , Dash Kshirod K. , Dar Aamir Hussain , Nayik Gulzar Ahmad , Ansari Mohammad Javed , Hemeg Hassan A. , Ahmed Abdelhakam Esmaeil Mohamed , Shaikh Ayaz Mukarram , Kovács Béla
Published: June 2022

In this investigation, the effect of different drying techniques, such as freeze-drying and cabinet drying, with two different carrier agents, such as maltodextrin (MD) and soy protein isolate (SPI), at different levels (10, 15, and 20%) on button mushrooms has been revealed. The results showed that the button mushroom powders (BMPs) formulated with SPI as a carrier agent had significantly higher powder yield, hygroscopicity, L*, a*, and b* values, whereas BMP formulated with MD had significantly higher water activity, solubility index, tapped density, bulk density, and flowability. The highest retention of bioactive compounds was reported in freeze-dried mushroom powder compared to cabinet dried powder using SPI as a carrier agent. Fourier transform infrared (FTIR) analysis confirmed that certain additional peaks were produced in the mushroom button powder-containing SPI (1,035–3,271 cm−1) and MD (930–3,220 cm−1). Thus, the results revealed that SPI showed promising results for formulating the BMP using the freeze-drying technique.
Characteristics, Prognosis, and Competing Risk Nomograms of Cutaneous Malignant Melanoma: Evidence for Pigmentary Disorders
Authors: Li Zichao , Li Xinrui , Yi Xiaowei , Li Tian , Huang Xingning , Ren Xiaoya , Ma Tianyuan , Li Kun , Guo Hanfeng , Chen Shengxiu , Ma Yao , Shang Lei , Song Baoqiang , Hu Dahai
Published: June 2022

Purpose

Cutaneous malignant melanoma (CMM) always presents as a complex disease process with poor prognosis. The objective of the present study was to explore the influence of solitary or multiple cancers on the prognosis of patients with CMM to better understand the landscape of CMM.

Methods

We reviewed the records of CMM patients between 2004 and 2015 from the Surveillance, Epidemiology, and End Results Program. The cumulative incidence function was used to represent the probabilities of death. A novel causal inference method was leveraged to explore the risk difference to death between different types of CMM, and nomograms were built based on competing risk models.

Results

The analysis cohort contained 165,043 patients with CMM as the first primary malignancy. Patients with recurrent CMM and multiple primary tumors had similar overall survival status (p = 0.064), while their demographics and cause-specific death demonstrated different characteristics than those of patients with solitary CMM (p < 0.001), whose mean survival times are 75.4 and 77.3 months and 66.2 months, respectively. Causal inference was further applied to unveil the risk difference of solitary and multiple tumors in subgroups, which was significantly different from the total population (p < 0.05), and vulnerable groups with high risk of death were identified. The established competing risk nomograms had a concordance index >0.6 on predicting the probabilities of death of CMM or other cancers individually across types of CMM.

Conclusion

Patients with different types of CMM had different prognostic characteristics and different risk of cause-specific death. The results of this study are of great significance in identifying the high risk of cause-specific death, enabling targeted intervention in the early period at both the population and individual levels.
Preoperative and Noninvasive Prediction of Gliomas Histopathological Grades and IDH Molecular Types Using Multiple MRI Characteristics
Authors: Du Ningfang , Zhou Xiaotao , Mao Renling , Shu Weiquan , Xiao Li , Ye Yao , Xu Xinxin , Shen Yilang , Lin Guangwu , Fang Xuhao , Li Shihong
Published: June 2022

Background and Purpose

Gliomas are one of the most common tumors in the central nervous system. This study aimed to explore the correlation between MRI morphological characteristics, apparent diffusion coefficient (ADC) parameters and pathological grades, as well as IDH gene phenotypes of gliomas.

Methods

Preoperative MRI data from 166 glioma patients with pathological confirmation were retrospectively analyzed to compare the differences of MRI characteristics and ADC parameters between the low-grade and high-grade gliomas (LGGs vs. HGGs), IDH mutant and wild-type gliomas (IDHmut vs. IDHwt). Multivariate models were constructed to predict the pathological grades and IDH gene phenotypes of gliomas and the performance was assessed by the receiver operating characteristic (ROC) analysis.

Results

Two multivariable logistic regression models were developed by incorporating age, ADC parameters, and MRI morphological characteristics to predict pathological grades, and IDH gene phenotypes of gliomas, respectively. The Noninvasive Grading Model classified tumor grades with areas under the ROC curve (AUROC) of 0.934 (95% CI=0.895-0.973), sensitivity of 91.2%, and specificity of 78.6%. The Noninvasive IDH Genotyping Model differentiated IDH types with an AUROC of 0.857 (95% CI=0.787-0.926), sensitivity of 88.2%, and specificity of 63.8%.

Conclusion

MRI features were correlated with glioma grades and IDH mutation status. Multivariable logistic regression models combined with MRI morphological characteristics and ADC parameters may provide a noninvasive and preoperative approach to predict glioma grades and IDH mutation status.
The Interaction Between Epigenetic Changes, EMT, and Exosomes in Predicting Metastasis of Colorectal Cancers (CRC)
Authors: Yang Meiqi , Sun Mingjun , Zhang Huijing
Published: June 2022

Worldwide, colorectal cancer (CRC) ranks as the third most common malignancy, and the second most deadly with nearly one million attributable deaths in 2020. Metastatic disease is present in nearly 25% of newly diagnosed CRC, and despite advances in chemotherapy, less than 20% will remain alive at 5 years. Epigenetic change plays a key role in the epithelial-to-mesenchymal transition (EMT), which is a crucial phenotype for metastasis and mainly includes DNA methylation, non-coding RNAs (ncRNAs), and N6-methyladenosine (m6A) RNA, seemingly valuable biomarkers in CRCs. For ncRNAs, there exists a “molecular sponge effect” between long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and microRNAs (miRNAs). The detection of exosomes is a novel method in CRC monitoring, especially for predicting metastasis. There is a close relationship between exosomes and EMT in CRCs. This review summarizes the close relationship between epigenetic changes and EMT in CRCs and emphasizes the crucial function of exosomes in regulating the EMT process.
Patient-Derived Organoid Serves as a Platform for Personalized Chemotherapy in Advanced Colorectal Cancer Patients
Authors: Geevimaan Khamushavalli , Guo Jing-You , Shen Chia-Ning , Jiang Jeng-Kai , Fann Cathy S. J. , Hwang Ming-Jing , Shui Jr-Wen , Lin Hsiu-Ting , Wang Mei-Jung , Shih Hsuan-Cheng , Li Anna Fen-Yau , Chang Shih-Ching , Yang Shung-Haur , Chen Jeou-Yuan
Published: June 2022

Background

Addition of oxaliplatin to adjuvant 5-FU has significantly improved the disease-free survival and served as the first line adjuvant chemotherapy in advanced colorectal cancer (CRC) patients. However, a fraction of patients remains refractory to oxaliplatin-based treatment. It is urgent to establish a preclinical platform to predict the responsiveness toward oxaliplatin in CRC patients as well as to improve the efficacy in the resistant patients.

Methods

A living biobank of organoid lines were established from advanced CRC patients. Oxaliplatin sensitivity was assessed in patient-derived tumor organoids (PDOs) in vitro and in PDO-xenografted tumors in mice. Based on in vitro oxaliplatin IC50 values, PDOs were classified into either oxaliplatin-resistant (OR) or oxaliplatin-sensitive (OS) PDOs. The outcomes of patients undergone oxaliplatin-based treatment was followed. RNA-sequencing and bioinformatics tools were performed for molecular profiling of OR and OS PDOs. Oxaliplatin response signatures were submitted to Connectivity Map algorithm to identify perturbagens that may antagonize oxaliplatin resistance.

Results

Oxaliplatin sensitivity in PDOs was shown to correlate to oxaliplatin-mediated inhibition on PDO xenograft tumors in mice, and parallelled clinical outcomes of CRC patients who received FOLFOX treatment. Molecular profiling of transcriptomes revealed oxaliplatin-resistant and -sensitive PDOs as two separate entities, each being characterized with distinct hallmarks and gene sets. Using Leave-One-Out Cross Validation algorithm and Logistic Regression model, 18 gene signatures were identified as predictive biomarkers for oxaliplatin response. Candidate drugs identified by oxaliplatin response signature-based strategies, including inhibitors targeting c-ABL and Notch pathway, DNA/RNA synthesis inhibitors, and HDAC inhibitors, were demonstrated to potently and effectively increase oxaliplatin sensitivity in the resistant PDOs.

Conclusions

PDOs are useful in informing decision-making on oxaliplatin-based chemotherapy and in designing personalized chemotherapy in CRC patients.
Distinguishing Tumor Admixed in a Radiation Necrosis (RN) Background: 1H and 2H MR With a Novel Mouse Brain-Tumor/RN Model
Authors: Ge Xia , Song Kyu-Ho , Engelbach John A. , Yuan Liya , Gao Feng , Dahiya Sonika , Rich Keith M. , Ackerman Joseph J. H. , Garbow Joel R.
Published: June 2022

Purpose

Distinguishing radiation necrosis (RN) from recurrent tumor remains a vexing clinical problem with important health-care consequences for neuro-oncology patients. Here, mouse models of pure tumor, pure RN, and admixed RN/tumor are employed to evaluate hydrogen (1H) and deuterium (2H) magnetic resonance methods for distinguishing RN vs. tumor. Furthermore, proof-of-principle, range-finding deuterium (2H) metabolic magnetic resonance is employed to assess glycolytic signatures distinguishing RN vs. tumor.

Materials and Methods

A pipeline of common quantitative 1H MRI contrasts, including an improved magnetization transfer ratio (MTR) sequence, and 2H magnetic resonance spectroscopy (MRS) following administration of 2H-labeled glucose, was applied to C57BL/6 mouse models of the following: (i) late time-to-onset RN, occurring 4–5 weeks post focal 50-Gy (50% isodose) Gamma Knife irradiation to the left cerebral hemisphere, (ii) glioblastoma, growing ~18–24 days post implantation of 50,000 mouse GL261 tumor cells into the left cerebral hemisphere, and (iii) mixed model, with GL261 tumor growing within a region of radiation necrosis (1H MRI only). Control C57BL/6 mice were also examined by 2H metabolic magnetic resonance.

Results

Differences in quantitative 1H MRI parametric values of R1, R2, ADC, and MTR comparing pure tumor vs. pure RN were all highly statistically significant. Differences in these parameter values and DCEAUC for tumor vs. RN in the mixed model (tumor growing in an RN background) are also all significant, demonstrating that these contrasts—in particular, MTR—can effectively distinguish tumor vs. RN. Additionally, quantitative 2H MRS showed a highly statistically significant dominance of aerobic glycolysis (glucose ➔ lactate; fermentation, Warburg effect) in the tumor vs. oxidative respiration (glucose ➔ TCA cycle) in the RN and control brain.

Conclusions

These findings, employing a pipeline of quantitative 1H MRI contrasts and 2H MRS following administration of 2H-labeled glucose, suggest a pathway for substantially improving the discrimination of tumor vs. RN in the clinic.
A Novel Model Combining Tumor Length, Tumor Thickness, TNM_Stage, Nutritional Index, and Inflammatory Index Might Be Superior to the 8th TNM Staging Criteria in Predicting the Prognosis of Esophageal Squamous Cell Carcinoma Patients Treated With Definitive Chemoradiotherapy
Authors: Chen Xiaohui , Yu Yilin , Wu Haishan , Qiu Jianjian , Ke Dongmei , Wu Yahua , Lin Mingqiang , Liu Tianxiu , Zheng Qunhao , Zheng Hongying , Yang Jun , Wang Zhiping , Li Hui , Liu Lingyun , Yao Qiwei , Li Jiancheng , Cheng Wenfang
Published: June 2022

Background

We aimed to determine whether the tumor length and tumor thickness should be used as prognostic factors for esophageal squamous cell carcinoma (ESCC) patients treated with definitive chemoradiotherapy (dCRT).

Methods

A retrospective analysis consists of 902 non-operative ESCC patients received dCRT. The nomogram was used to predict the survival. Besides, Restricted Cubic Splines (RCS) was used to examine the relationship between prognostic factors and survival outcomes. Finally, the prognostic index (PI) scores were constructed according to the tumor length and tumor thickness, and the patients were divided into the low-, medium-, and high-risk groups.

Results

The median follow-up of overall survival (OS) and progression-free survival (PFS) were 23.0 months and 17.5 months. Multivariate Cox regression analysis showed that tumor length and tumor thickness were independent prognostic factors associated with survival. Our novel nomograms for OS and PFS were superior to the TNM classification (p < 0.001). Besides, RCS analysis demonstrated that the death hazard of tumor length and tumor thickness sharply increased at 7.7 cm and 1.6 cm (p < 0.001). Finally, there were significant differences for ESCC patients with clinical TNM stage group of the OS and PFS in different risk groups. The higher risk group was significantly associated with shorter OS and PFS in ESCC patients (both p < 0.001 for all).

Conclusion

The study results suggest that the novel models integrating tumor length and tumor thickness may provide a simple and widely available method for evaluating the prognosis of non-operative ESCC patients. The tumor length and tumor thickness should be considered as prognostic factors for ESCC.
Medicinal Formula Huazhi-Rougan Attenuates Non-Alcoholic Steatohepatitis Through Enhancing Fecal Bile Acid Excretion in Mice
Authors: Li Chunlin , Yu Siyu , Li Xiaoxiao , Cao Ying , Li Meng , Ji Guang , Zhang Li
Published: June 2022

Huazhi-Rougan (HZRG) formula is a Traditional Chinese medicine prescription, and has been widely used to treat non-alcoholic fatty liver disease (NAFLD) and its progressive form non-alcoholic steatohepatitis (NASH). However, the anti-NASH effects and the underlying mechanisms of HZRG have not yet been characterized. Here we showed that 4-week HZRG treatment alleviated methionine-choline-deficiency (MCD) diet-induced NASH in C57BL/6J mice, as evidenced by the improvement of hepatic steatosis and inflammation, as well as the decrease of serum levels of alanine and aspartate transaminases. Fecal 16S rDNA sequencing indicated that HZRG reduced the enrichment of pathogenic bacteria and increased the abundance of bacteria gena that are involved in bile acid (BA) conversation. The alteration of fecal and serum BA profile suggested that HZRG enhanced fecal BA excretion, and reduced the reabsorption of toxic secondary BA species (LCA, DCA, HCA). We further analyzed the BA receptors and transporters, and found that HZRG inhibited the expression of ileal bile acid transporter, and organic solute transporter subunit β, and increased the expression of intestinal tight junction proteins (ZO-1, Occludin, Claudin-2). The modulation of gut dysbiosis and BA profile, as well as the improvement of the intestinal environment, may contribute to the decrease of the p-65 subunit of NF-κB phosphorylation, liver F4/80 positive macrophages, inflammatory cytokine IL-1β and TNF-α expression. In conclusion, HZRG treatment enhances fecal BA excretion via inhibiting BA transporters, modulates BA profiles, gut dysbiosis as well as the intestinal environment, thus contributing to the beneficial effect of HZRG on NASH mice.
Traditional Chinese Medicine as a Promising Strategy for the Treatment of Alzheimer’s Disease Complicated With Osteoporosis
Authors: Xu Weifan , Jiang Yiping , Wang Nani , Bai Huanhuan , Xu Shengyan , Xia Tianshuang , Xin Hailiang
Published: June 2022

Alzheimer’s disease (AD) and osteoporosis (OP) are progressive degenerative diseases caused by multiple factors, placing a huge burden on the world. Much evidence indicates that OP is a common complication in AD patients. In addition, there is also evidence to show that patients with OP have a higher risk of AD than those without OP. This suggests that the association between the two diseases may be due to a pathophysiological link rather than one disease causing the other. Several in vitro and in vivo studies have also proved their common pathogenesis. Based on the theory of traditional Chinese medicine, some classic and specific natural Chinese medicines are widely used to effectively treat AD and OP. Current evidence also shows that these treatments can ameliorate both brain damage and bone metabolism disorder and further alleviate AD complicated with OP. These valuable therapies might provide effective and safe alternatives to major pharmacological strategies.
The XPO1 Inhibitor KPT-8602 Ameliorates Parkinson’s Disease by Inhibiting the NF-κB/NLRP3 Pathway
Authors: Liu Shuhan , Wang Shengxiang , Gu Runze , Che Na , Wang Jing , Cheng Jinbo , Yuan Zengqiang , Cheng Yong , Liao Yajin
Published: June 2022

Exportin 1 (XPO1) is an important transport receptor that mediates the nuclear export of various proteins and RNA. KPT-8602 is a second-generation inhibitor of XPO1, demonstrating the lowest level of side effects, and is currently in clinical trials for the treatment of cancers. Previous studies suggest that several first-generation inhibitors of XPO1 demonstrate anti-inflammation activities, indicating the application of this drug in inflammation-related diseases. In this study, our results suggested the potent anti-inflammatory effect of KPT-8602 in vitro and in vivo. KPT-8602 inhibited the activation of the NF-κB pathway by blocking the phosphorylation and degradation of IκBα, and the priming of NLRP3. Importantly, the administration of KPT-8602 attenuated both lipopolysaccharide (LPS)-induced peripheral inflammation and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neuroinflammation in vivo. In addition, the tissue damage was also ameliorated by KPT-8602, indicating that KPT-8602 could be used as a novel potential therapeutic agent for the treatment of inflammasome-related diseases such as Parkinson’s disease, through the regulation of the NF-κB signaling pathway and the NLRP3 inflammasome.
Influence of Nanobubble Size Distribution on Ultrasound-Mediated Plasmid DNA and Messenger RNA Gene Delivery
Authors: Kida Hiroshi , Feril Loreto B. , Irie Yutaka , Endo Hitomi , Itaka Keiji , Tachibana Katsuro
Published: June 2022

The use of nanobubbles (NBs) for ultrasound-mediated gene therapy has recently attracted much attention. However, few studies have evaluated the effect of different NB size distribution to the efficiency of gene delivery into cells. In this study, various size of albumin stabilized sub-micron bubbles were examined in anin vitroultrasound (1 MHz) irradiation setup in the aim to compare and optimize gene transfer efficiency. Results with pDNA showed that gene transfer efficiency in the presence of NB size of 254.7 ± 3.8 nm was 2.5 fold greater than those with 187.3 ± 4.8 nm. Similarly, carrier-free mRNA transfer efficiency increased in the same conditions. It is suggested that NB size greater than 200 nm contributed more to the delivery of genes into the cytoplasm with ultrasound. Although further experiments are needed to understand the underlying mechanism for this phenomenon, the present results offer valuable information in optimizing of NB for future ultrasound-mediate gene therapy.
Recombinant EGFL7 Mitigated Pressure Overload-Induced Cardiac Remodeling by Blocking PI3Kγ/AKT/NFκB Signaling in Macrophages
Authors: Li Lei , Zhao Ying , Hu Ying , Wang Xiaohui , Jin Qun , Zhao Ying
Published: June 2022

Inflammation and endothelial dysfunction play an essential role in heart failure (HF). Epidermal growth factor-like protein 7 (EGFL7) is upregulated during pathological hypoxia and exerts a protective role. However, it is unclear whether there is a link between abnormal EGFL7 expression and inflammation in overload stress-induced heart failure. Our results showed that EGFL7 transiently increased during the early 4 weeks of TAC and in hypertensive patients without heart failure. However, it decreased to the basal line in the heart tissue 8 weeks post-transverse aortic constriction (TAC) or hypertensive patients with heart failure. Knockdown of EGFL7 with siRNA in vivo accelerated cardiac dysfunction, fibrosis, and macrophage infiltration 4 weeks after TAC. Deletion of macrophages in siRNA-EGFL7-TAC mice rescued that pathological phenotype. In vitro research revealed the mechanism. PI3Kγ/AKT/NFκB signaling in macrophages was activated by the supernatant from endothelial cells stimulated by siRNA-EGFL7+phenylephrine. More macrophages adhered to endothelial cells, but pretreatment of macrophages with PI3Kγ inhibitors decreased the adhesion of macrophages to endothelial cells. Ultimately, treatment with recombinant rmEGFL7 rescued cardiac dysfunction and macrophage infiltration in siRNA-EGFL7-TAC mice. In conclusion, EGFL7 is a potential inhibitor of macrophage adhesion to mouse aortic endothelial cells. The downregulation of EGFL7 combined with increased macrophage infiltration further promoted cardiac dysfunction under pressure overload stress. Mechanistically, EGFL7 reduced endothelial cell adhesion molecule expression and inhibited the PI3Kγ/AKT/NFκB signaling pathway in macrophages.
First Year Real Life Experience With Intravitreal Brolucizumab for Treatment of Refractory Neovascular Age-Related Macular Degeneration
Authors: Abdin Alaa Din , Aljundi Wissam , El Jawhari Khalil , Suffo Shady , Weinstein Isabel , Seitz Berthold
Published: June 2022

Purpose: To assess the morphological and functional outcomes within the first year of treatment with intravitreal brolucizumab for refractory neovascular age-related macular degeneration (nAMD).

Methods: This retrospective study included 21 eyes from 19 patients with refractory nAMD followed for 12 months. All patients were switched to brolucizumab after treatment with at least two other anti-vascular endothelial growth factors (VEGF). All eyes received 3x brolucizumab 6 mg/0.05 ml intravitreal injections (IVI) monthly as an upload phase. Then eyes received an IVI every 8 weeks with interval adjustment to every 12 weeks if disease activity was not present. Main outcome measures: best corrected visual acuity (BCVA), central macular thickness (CMT) and retinal fluid distribution. In addition, we reported the adverse event rate.

Results: The number of previous anti-VEGF IVIs/eye was 36 ± 22 before switching to brolucizumab. BCVA (ETDRS) was 51 ± 16 before treatment and 50 ± 19 at week 52 (p = 0.6). CMT was 374 ± 158 μm before treatment and 298 ± 92 μm at week 52 (p = 0.01). The number of IVIs/eye decreased from 9.6 ± 1.9 IVIs in the last year before switching to 6.4 ± 0.9 IVIs in the first year after switching to brolucizumab (p < 0.001). The rate of eyes with subretinal fluid and pigment epithelial detachment decreased at week 52. Finally, two cases of intraocular inflammation were observed as adverse events.

Conclusion: In the first year of treatment, intravitreal brolucizumab was able to stabilize visual acuity with significantly less IVIs in patients with refractory nAMD. It also improved anatomic outcomes in these patients, particularly reducing subretinal fluid and pigment epithelial detachment and subsequently central macular thickness. However, two cases of intraocular inflammation were observed as adverse events.
Revisiting Preclinical Observations of Several Histamine H3 Receptor Antagonists/Inverse Agonists in Cognitive Impairment, Anxiety, Depression, and Sleep–Wake Cycle Disorder
Authors: Alhusaini Mera , Eissa Nermin , Saad Ali K. , Beiram Rami , Sadek Bassem
Published: June 2022

A relationship appears to exist between dysfunction of brain histamine (HA) and various neuropsychiatric brain disorders. The possible involvement of brain HA in neuropathology has gained attention recently, and its role in many (patho)physiological brain functions including memory, cognition, and sleep–wake cycle paved the way for further research on the etiology of several brain disorders. Histamine H3 receptor (H3R) evidenced in the brains of rodents and humans remains of special interest, given its unique position as a pre- and postsynaptic receptor, controlling the synthesis and release of HA as well as different other neurotransmitters in different brain regions, respectively. Despite several disappointing outcomes for several H3R antagonists/inverse agonists in clinical studies addressing their effectiveness in Alzheimer’s disease (AD), Parkinson’s disease (PD), and schizophrenia (SCH), numerous H3R antagonists/inverse agonists showed great potentials in modulating memory and cognition, mood, and sleep–wake cycle, thus suggesting its potential role in neurocognitive and neurodegenerative diseases such as AD, PD, SCH, narcolepsy, and major depression in preclinical rodent models. In this review, we present preclinical applications of selected H3R antagonists/inverse agonists and their pharmacological effects on cognitive impairment, anxiety, depression, and sleep–wake cycle disorders. Collectively, the current review highlights the behavioral impact of developments of H3R antagonists/inverse agonists, aiming to further encourage researchers in the preclinical drug development field to profile the potential therapeutic role of novel antagonists/inverse agonists targeting histamine H3Rs.
A Bibliometric Analysis of Triptolide and the Recent Advances in Treating Non–Small Cell Lung Cancer
Authors: Yang Quancheng , Zhai Xuejia , Lv Yi
Published: June 2022

In recent decades, natural products derived from plants and their derivatives have attracted great interest in the field of disease treatment. Triptolide is a tricyclic diterpene extracted from Tripterygium wilfordii, a traditional Chinese medicine, which has shown excellent therapeutic potential in the fields of immune inflammation and cancer treatment. In this study, 1,106 Web-of-Science-indexed manuscripts and 1,160 Chinese-National-Knowledge-Infrastructure-indexed manuscripts regarding triptolide published between 2011 and 2021 were analyzed, mapping the co-occurrence networks of keywords and clusters using CiteSpace software. The research frontier and development trend were determined by keyword frequency and cluster analysis, which can be used to predict the future research development of triptolide. Non–small cell lung cancer (NSCLC) is most common in lung cancer patients, accounting for about 80% of all lung cancer patients. New evidence suggests that triptolide effectively inhibits the development and metastasis of NSCLC by the induction of apoptosis, reversion of EMT, and regulation of gene expression. Specifically, it acts on NF-κB, MAPKs, P53, Wnt/β-catenin, and microRNAs (miRNAs), signaling pathways and molecular mechanisms. Consequently, this article reviews the research progress of the anti-NSCLC effect of triptolide. In addition, attenuated studies on triptolide and the potential of tumor immunotherapy are also discussed.
Cost-Effectiveness of Pembrolizumab Plus Chemotherapy as First-Line Therapy for Advanced Oesophageal Cancer
Authors: Wu Meiyu , Qin Shuxia , Wang Liting , Tan Chongqing , Peng Ye , Zeng Xiaohui , Luo Xia , Yi Lidan , Wan Xiaomin
Published: June 2022

Objective: Pembrolizumab plus chemotherapy is recommended as the first-line treatment for advanced oesophageal cancer. The objective of this study is to evaluate the cost-effectiveness of pembrolizumab plus chemotherapy as first-line therapy for advanced oesophageal cancer from the healthcare system perspective in China.

Methods: Based on the KEYNOTE-590 trial, a Markov model was constructed to estimate the cost and effectiveness of pembrolizumab plus chemotherapy and placebo plus chemotherapy, respectively. Total costs, life years (LYs), quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated. One-way, probabilistic sensitivity analyses (PSA), and subgroup analyses were adapted to test the model robustness.

Result: Compared with the placebo group, pembrolizumab group obtained an additional 1.05 QALY, but the cost was also increased by $121,478.76. The ICER was $115,391.84 per QALY gained, which was higher than the willingness-to-pay (WTP) of $31,304.31. The results of One-way sensitivity analyses showed that the ICER was sensitive to the hazard ratio of PFS and per cycle cost of pembrolizumab. At a WTP threshold of $31,304.31, the probability of pembrolizumab plus chemotherapy being cost-effective was 0%.

Conclusion: From the perspective of China healthcare system, pembrolizumab plus chemotherapy as first-line treatment is not cost-effective for patients with advanced oesophageal cancer compared with placebo plus chemotherapy.
Kaempferol Inhibits Hepatic Stellate Cell Activation by Regulating miR-26b-5p/Jag1 Axis and Notch Pathway
Authors: Zhou Guangyao , Li Chunxue , Zhang Rongrong , Zhan Yating , Lin Lifan , Lang Zhichao , Tao Qiqi , Zheng Jianjian
Published: June 2022

Kaempferol, a natural flavonoid molecule, has demonstrated anti-inflammatory, antimicrobial and antioxidant activities. Recent studies have shown the beneficial effects of kaempferol on liver fibrosis. Notch pathway has been reported to be involved in the aberrant activation of hepatic stellate cells (HSCs). However, whether Notch pathway plays a key role in the anti-fibrotic effects of kaempferol is largely unknown. In this study, kaempferol significantly suppressed liver fibrosis in CCl4 mice, with reduced collagen deposition as well as restored liver function. In vitro, kaempferol enhanced the suppression of HSC activation, with a decrease in α-SMA as well as collagen level. It was found that Notch pathway played an important role in kaempferol-reduced the activation of HSCs. Jag1, a ligand of Notch pathway, was obviously inhibited by kaempferol. Overexpression of Jag1 effectively abolished kaempferol-induced HSC inactivation. Furthermore, Jag1 was demonstrated as a target of microRNA-26b-5p (miR-26b-5p). Interestingly, miR-26b-5p inhibitor prevented HSC activation inhibition caused by kaempferol. Further studies indicated that kaempferol inhibited Notch pathway via miR-26b-5p and Jag1, leading to HSC inactivation. Collectively, we demonstrate that kaempferol could inhibit HSC activation, at least in part, via miR-26b-5p-mediated Jag1 axis and Notch pathway. Kaempferol may serve as a promising drug in the application of treating liver fibrosis.
In vitro Activity of Repurposed Nitroxoline Against Clinically Isolated Mycobacteria Including Multidrug-Resistant Mycobacterium tuberculosis
Authors: Hoffmann Ada Marie , Wolke Martina , Rybniker Jan , Plum Georg , Fuchs Frieder
Published: June 2022

Antimicrobial treatment options for mycobacterial infections are limited due to intrinsic resistance and the emergence of acquired resistance in Mycobacterium tuberculosis. Isolates resisting first- and second line drugs are raising concerns about untreatable infections and make the development of new therapeutic strategies more pressing. Nitroxoline is an old oral antimicrobial that is currently repurposed for the treatment of urinary tract infection (UTI). In this study, we report the in vitro activity of nitroxoline against 18 clinical isolates of M. tuberculosis complex (MTBC) (M. tuberculosis N = 16, M. bovis BCG N = 1, M. bovis sp. bovis N = 1). Since nitroxoline achieves high concentrations in the urinary tract, we included all MTBC-isolates from urinary samples sent to our laboratory between 2008 and 2021 (University Hospital of Cologne, Germany). Isolates from other sources (N = 7/18) were added for higher sample size and for inclusion of drug-resistant M. tuberculosis isolates (N = 4/18). Based on our clinical routine the fluorescence-based liquid media system BACTEC MGIT 960 was used for susceptibility testing of nitroxoline and mainstay antitubercular drugs. Nitroxoline yielded a MIC90 of 4 mg/L for MTBC. In all M. tuberculosis isolates nitroxoline MICs were at least two twofold dilutions below the current EUCAST susceptibility breakpoint of ≤16 mg/L (limited to E. coli and uncomplicated UTI). In vitro activity of nitroxoline can be considered excellent, even in multidrug-resistant isolates. Future studies with in vivo models should evaluate a potential role of nitroxoline in the treatment of tuberculosis in the era of drug resistance.
Roles of Exosome Genomic DNA in Colorectal Cancer
Authors: Li Xiaoshuai , Wang Qiushi , Wang Rui
Published: June 2022

Exosomes are extracellular vesicles that mediate cell-to-cell communication. Bioactive substances such as DNA, RNA, lipids, and proteins are present in it, and they play an essential role in the pathogenesis of colorectal cancer (CRC). The role of RNA and protein in exosomes has been extensively studied. Exosome DNA has recently attracted the attention of a great deal of scientists. According to studies, exosome DNA mainly contains genomic DNA (gDNA) and mitochondrial DNA (mtDNA), of which exosome gDNA is widely used in liquid biopsy of CRC. It includes a variety of clinically relevant tumor-specific mutation genes. In addition to liquid biopsy, researchers find that exosome gDNA regulates immune and metabolic functions in CRC, making it an important research object. However, the primary research on exosome gDNA is still limited. Here, we describe the occurrence and composition of exosomes. Summarize the essential characteristics and mode of action of exosome gDNA. Remarkably, this paper constitutes a comprehensive summary on the role of exosome gDNA on CRC with the intent of providing a theoretical basis and reference for early diagnosis and clinical treatment of cancer.
Hydrodynamic Coupling of Inverted Flags in Side-by-Side, Left Triangular and Right Triangular Configurations in a Uniform Flow
Authors: Zou Kaimin , Peng Ze-Rui , Chen Bo , Dai Huliang , Xiong Yongliang , Wang Lin
Published: June 2022

The hydrodynamic coupling of inverted flexible flags in side-by-side, left triangular and right triangular configurations in a uniform flow is investigated numerically. Various arrangements can be characterized by the lateral and longitudinal gaps, i.e., H and G, respectively. For the side-by-side configurations, three typical modes are identified in flapping region, i.e., in-phase quasi out-of-phase (QOP) and out-of-phase (OP) modes, corresponding to 2P, irregular and 4(P + S) wake patterns, respectively. Further analysis on the mean drag coefficient (Cd̄) and bending energy (Eb̄) indicates that the side-by-side flags can not harvest more bending energy from surrounding flows than the isolated one, except for a narrow range of H ∈ (1.8, 2.5). Moreover, an additional inverted flag is placed in front or rear of the side-by-side flags to explore possible favorable arrangements for bending energy enhancement. Three typical modes have been identified in the H − G planes for both left and right triangular configurations, i.e., the regular-coupled (RC), irregular-coupled (IC) and decoupled (DC) modes, respectively. For left triangular configurations, the overall system may experience significant performance enhancement in some favorable configurations, corresponding to harvest enhancement region (HER) in the G − H plane; For the case in HER, especially, the Eb̄ of the rear flag may increase by up to 30% than isolated flag. While for right triangular configurations, no HER is observed. The unsteady flow characteristics are further explored to reveal the mechanism of hydrodynamic coupling in system. The present study may shed some light on understanding the dynamics of this multi-flag system.
OPN5 Regulating Mechanism of Follicle Development Through the TSH-DIO2/DIO3 Pathway in Mountain Ducks Under Different Photoperiods
Authors: Liufu Sui , Pan Jianqiu , Sun Junfeng , Shen Xu , Jiang Danli , Ouyang Hongjia , Xu Danning , Tian Yunbo , Huang Yunmao
Published: June 2022

Abstract: Photoperiod is an important environmental factor that influence seasonal reproduction behavior in bird. Birds translates photoperiodic information into neuroendocrine signals through deep brain photoreceptors (DBPs). OPN5 has been considered as candidate DBPs involving in regulation of seasonal reproduction in birds. However, little is known about the effect of OPN5 in non-seasonal breeding birds. Thus, we pondered on whether OPN5 regulating follicular development through TSH-DIO2/DIO3 system responds to different photoperiods in non-seasonal laying ducks. As an ideal non-seasonal breeding bird, a total of 120 mountain ducks were randomly divided into three groups and treated respectively to a different photoperiod: group S (8 L:16D), group C (17 L:7D), and group L (24 L:0D). The ducks were caged in a fully enclosed shelter with the same feeding conditions for each group, free water and limited feeding (150 g per duck each day). Samples were collected from each group at d 0, d 5, d 8, d 20, and d 35 (n = 8). The ducks in 24 h photoperiod had the highest laying rate and the lowest feed-to-egg ratio, while the ducks in 8 h photoperiod had the lowest laying rate and the highest feed-to-egg ratio. Long-day photoperiod for 24 h significantly increased the ovarian index and GnRH, LH, E2, and P4 levels in serum; short-day photoperiod for 8 h increased testosterone levels in serum. Compared with 8 h photoperiod, long-day photoperiod significantly or highly significantly increased the mRNA level and protein expression of OPN5 in the hypothalamus of long-day photoperiod on d 35 (p < 0.05). The gene or protein expression patterns of GnRH, TRH, TSHβ, DIO2, THRβ, VIP, and PRL were positively correlated with OPN5, whereas the gene expression patterns of GnIH and DI O 3 were negatively correlated with OPN5. The results revealed that OPN5 mediated the effect of light on follicular development through the TSH-DIO2/DIO3 pathway, the expression of OPN5 increased with light duration and improved the efficiency of the HPG axis to promote follicular development in mountain ducks.
Dietary Supplementation With Hydroxyproline Enhances Growth Performance, Collagen Synthesis and Muscle Quality of Carassius auratus Triploid
Authors: Cao Shenping , Xiao Yangbo , Huang Rong , Zhao Dafang , Xu Wenqian , Li Shitao , Tang Jianzhou , Qu Fufa , Jin Junyan , Xie Shouqi , Liu Zhen
Published: June 2022

An eight-week experiment was undertaken to examine the effect of dietary hydroxyproline (Hyp) supplementation on growth performance, collagen synthesis, muscle quality of an improved triploid crucian carp (Carassius auratus Triploid) (ITCC). Six isonitrogenous (340 g/kg diet), isolipidic (60 g/kg diet) and isocaloric (17.80 MJ/kg diet) diets were formulated containing a certain amount of Hyp: 0.09% (the control group), 0.39, 0.76, 1.14, 1.53 and 1.90%. Each diet was randomly assigned to three tanks and each group was fed two times daily until apparent satiation. The results showed that growth performance and feed utilization of ITCC were significantly improved with the dietary Hyp level was increased from 0.09 to 0.76%. Crude protein, threonine and arginine content in the dorsal muscle in 0.76% hydroxyproline group were significantly higher than those in basic diet group (p < 0.05). The muscle textural characteristics increased remarkably with the amount of Hyp in the diet rising from 0.09 to 1.53% (p < 0.05). Meanwhile, the contents of type I collagen (Col I) and Pyridinium crosslink (PYD) in the muscle of fish were significantly increased by dietary Hyp (p < 0.05). The muscle fiber diameter and density of the fish were significantly increased when fed with 0.76% Hyp (p < 0.05). Furthermore, dietary supplementation with an appropriate concentration of Hyp substantially increased the expression of genes involved in collagen synthesis (col1a1, col1a2, p4hα1, p4hβ, smad4, smad5, smad9, and tgf-β) and muscle growth (igf-1, tor, myod, myf5, and myhc) (p < 0.05). In conclusion, dietary supplementation of Hyp can enhance fish growth performance, collagen production, muscle textural characteristics and muscle growth of ITCC. According to the SGR broken-line analysis, the recommended supplementation level of Hyp was 0.74% in the diet for ITCC, corresponding to 2.2% of dietary protein.
Pervasive Phylogenomic Incongruence Underlies Evolutionary Relationships in Eyebrights (Euphrasia, Orobanchaceae)
Authors: Garrett Phen , Becher Hannes , Gussarova Galina , dePamphilis Claude W. , Ness Rob W. , Gopalakrishnan Shyam , Twyford Alex D.
Published: June 2022

Disentangling the phylogenetic relationships of taxonomically complex plant groups is often mired by challenges associated with recent speciation, hybridization, complex mating systems, and polyploidy. Here, we perform a phylogenomic analysis of eyebrights (Euphrasia), a group renowned for taxonomic complexity, with the aim of documenting the extent of phylogenetic discordance at both deep and at shallow phylogenetic scales. We generate whole-genome sequencing data and integrate this with prior genomic data to perform a comprehensive analysis of nuclear genomic, nuclear ribosomal (nrDNA), and complete plastid genomes from 57 individuals representing 36 Euphrasia species. The species tree analysis of 3,454 conserved nuclear scaffolds (46 Mb) reveals that at shallow phylogenetic scales postglacial colonization of North Western Europe occurred in multiple waves from discrete source populations, with most species not being monophyletic, and instead combining genomic variants from across clades. At a deeper phylogenetic scale, the Euphrasia phylogeny is structured by geography and ploidy, and partially by taxonomy. Comparative analyses show Southern Hemisphere tetraploids include a distinct subgenome indicative of independent polyploidy events from Northern Hemisphere taxa. In contrast to the nuclear genome analyses, the plastid genome phylogeny reveals limited geographic structure, while the nrDNA phylogeny is informative of some geographic and taxonomic affinities but more thorough phylogenetic inference is impeded by the retention of ancestral polymorphisms in the polyploids. Overall our results reveal extensive phylogenetic discordance at both deeper and shallower nodes, with broad-scale geographic structure of genomic variation but a lack of definitive taxonomic signal. This suggests that Euphrasia species either have polytopic origins or are maintained by narrow genomic regions in the face of extensive homogenizing gene flow. Moreover, these results suggest genome skimming will not be an effective extended barcode to identify species in groups such as Euphrasia, or many other postglacial species groups.
PhcA and PhcR Regulate Ralsolamycin Biosynthesis Oppositely in Ralstonia solanacearum
Authors: Li Peng , Cao Xiulan , Zhang Liwen , Lv Mingfa , Zhang Lian-Hui
Published: June 2022

Ralsolamycin, one of secondary metabolites in Ralstonia solanacearum, is known to be involved in crosstalk between R. solanacearum and fungi. Ralsolamycin formation is catalyzed by two-hybrid synthetases of RmyA (non-ribosomal peptide synthetase) and RmyB (polyketide synthase). A methyltransferase PhcB catalyzes formation of 3-OH MAME or 3-OH PAME, signals for the quorum sensing (QS) in R. solanacearum, while PhcB positively modulates ralsolamycin biosynthesis. A two-component system of PhcS and PhcR can response these QS signals and activate phcA expression. Here, we experimentally demonstrated that deletion of phcA (ΔphcA) substantially impaired the ralsolamycin production and expression of rmyA and rmyB in R. solanacearum strain EP1, and failed to induce chlamydospore formation of plant fungal pathogen Fusarium oxysporum f. cubense (stran FOC4). However, deletion of phcR significantly increased ralsolamycin production and expression of rmyA and rmyB, and phcR mutants exhibited enhanced ability to induce chlamydospore formation of FOC4. Results of the electrophoretic mobility shift assay suggested that both PhcA and PhcR bind to promoter of rmy operon. Taken together, these results demonstrated that both PhcA and PhcR bind to promoter of rmy operon, but regulate ralsolamycin biosynthesis in an opposite way. It could extend our knowledge on the sophisticated regulatory networks of ralsolamycin biosynthesis in R. solanacearum.
Molecular Mechanisms of Plant Trichome Development
Authors: Han Guoliang , Li Yuxia , Yang Zongran , Wang Chengfeng , Zhang Yuanyuan , Wang Baoshan
Published: June 2022

Plant trichomes, protrusions formed from specialized aboveground epidermal cells, provide protection against various biotic and abiotic stresses. Trichomes can be unicellular, bicellular or multicellular, with multiple branches or no branches at all. Unicellular trichomes are generally not secretory, whereas multicellular trichomes include both secretory and non-secretory hairs. The secretory trichomes release secondary metabolites such as artemisinin, which is valuable as an antimalarial agent. Cotton trichomes, also known as cotton fibers, are an important natural product for the textile industry. In recent years, much progress has been made in unraveling the molecular mechanisms of trichome formation in Arabidopsis thaliana, Gossypium hirsutum, Oryza sativa, Cucumis sativus, Solanum lycopersicum, Nicotiana tabacum, and Artemisia annua. Here, we review current knowledge of the molecular mechanisms underlying fate determination and initiation, elongation, and maturation of unicellular, bicellular and multicellular trichomes in several representative plants. We emphasize the regulatory roles of plant hormones, transcription factors, the cell cycle and epigenetic modifications in different stages of trichome development. Finally, we identify the obstacles and key points for future research on plant trichome development, and speculated the development relationship between the salt glands of halophytes and the trichomes of non-halophytes, which provides a reference for future studying the development of plant epidermal cells.
“They Now Know That They Are Children of War”: Forcibly Abducted Mothers and Fathers Balancing Disclosure and Silencing to Their Children Born of War in Northern Uganda
Authors: De Nutte Leen , De Haene Lucia , Derluyn Ilse
Published: June 2022

In recent years, scholars have emphasized the need for a relational understanding of the impact of collective violence pointing to the myriad interconnections between individual and communal experiences and consequences. These interconnections are particularly strong in the (re)integration of formerly abducted children and youth, and their children born of war, since various social, relational and cultural processes play a key role in their wellbeing and healing. One example is the way in which trauma communication is shaped by culture and context, and intersects at the level of the individual and the collective. In this paper, we will explore how forcibly abducted mothers and fathers in post-conflict Northern Uganda perceive the trauma communication about the context in which their children born in forced captivity were conceived. Case study research was used to understand the dynamic trajectories of this trauma communication, placing parents' experiences within broader life histories, and the social and relational context. Repeated interviews were performed with six mothers and four fathers who became parents in forced captivity with the Lord's Resistance Army (LRA). Central in the participants' stories is their agency in the careful, individual choice “to be silent” or “not to be silent” toward their children, family and community members. However, these choices are shaped—and often restricted—by the relational and cultural context. A dynamic interplay of several factors, such as the age of the child, the emotional impact of disclosure, a lack of resources and support in the upbringing of children, identity and belonging, and perceived or potential future stigmatization are explored in this paper. Trauma communication can be seen as a socially negotiated choice, interacting in a complex dialectic relationship between silencing, disclosing, forgetting and remembering. As such, the study revealed important insights into post-conflict healing and reintegration in the day-to-day lives of formerly abducted children and youth, and their children born of war, on an individual and collective level.