bluuebunny/crossref_metadata_2025 huggingface dataset:
PaDef (Persea americana var. drymifolia), a Plant Antimicrobial Peptide, Triggers Apoptosis, and Induces Global Epigenetic Modifications on Histone 3 in an Acute Lymphoid Leukemia Cell Line
Authors: Jiménez-Alcántar Paola , López-Gómez Rodolfo , López-Meza Joel E. , Ochoa-Zarzosa Alejandra
Published: January 2022

In recent years, it has been recognized that epigenetic alterations play an important role in the development and maintenance of cancer, including leukemias. Furthermore, it is known that these alterations are involved in the emergence of resistance to conventional chemotherapeutics. Consequently, molecules with an anticancer activity whose activity is ruled by epigenetic modifications are attractive to search for new therapies against cancer. The plant antimicrobial peptides have been widely evaluated as molecules with anticancer activity; however, the analysis of the epigenetic regulation induced by these molecules associated with this activity is scarce and still is an unexplored field. In this work, we show that the PaDef defensin, a plant antimicrobial peptide from Mexican avocado fruit (Persea americana var. drymifolia) is cytotoxic for Jurkat cell line from acute lymphoid leukemia cells, through an apoptotic process. PaDef inhibited cell viability in a concentration-dependent manner, with an IC50 = 47.3 μM. Treatment of Jurkat cells with PaDef (IC50) induced cell death by apoptosis dependent on caspases 8 and 9; besides, it was related to an increase in the production of reactive oxygen species and the loss of mitochondrial membrane potential. Interestingly, the inhibition of caspase activation by inhibitors of caspases 8 and 9 does not revert the reduction in viability, suggesting that other mechanisms, in addition to caspase activity, could be participating in the PaDef cytotoxic effect. Also, the modifications in the histone 3 tails induced by PaDef in Jurkat cells were evaluated, specifically acetylation and methylation. PaDef increased global histone 3 acetylation and lysine 9 specific marks (2-fold and up to 4-fold, respectively). These effects correlated with the reduction of the Histone Deacetylase activity (HDAC, ∼50%). Based on methylation marks, PaDef treatment increased lysine 9 di- and tri-methylation tags (2-fold in both cases). The epigenetic modulation induced by PaDef on Jurkat cells could be related to the chromatin compaction-decompaction promoting gene expression or repression; however, further studies are necessary to correlate these marks with the transcription of specific genes. Therefore, the study of new molecules that may have anticancer activity through epigenetic modulation is interesting.
Infection in the Developing Brain: The Role of Unique Systemic Immune Vulnerabilities
Authors: Singh Gabriela , Tucker Elizabeth W. , Rohlwink Ursula K.
Published: January 2022

Central nervous system (CNS) infections remain a major burden of pediatric disease associated with significant long-term morbidity due to injury to the developing brain. Children are susceptible to various etiologies of CNS infection partly because of vulnerabilities in their peripheral immune system. Young children are known to have reduced numbers and functionality of innate and adaptive immune cells, poorer production of immune mediators, impaired responses to inflammatory stimuli and depressed antibody activity in comparison to adults. This has implications not only for their response to pathogen invasion, but also for the development of appropriate vaccines and vaccination strategies. Further, pediatric immune characteristics evolve across the span of childhood into adolescence as their broader physiological and hormonal landscape develop. In addition to intrinsic vulnerabilities, children are subject to external factors that impact their susceptibility to infections, including maternal immunity and exposure, and nutrition. In this review we summarize the current evidence for immune characteristics across childhood that render children at risk for CNS infection and introduce the link with the CNS through the modulatory role that the brain has on the immune response. This manuscript lays the foundation from which we explore the specifics of infection and inflammation within the CNS and the consequences to the maturing brain in part two of this review series.
Comparison of Minimally Invasive Versus Abdominal Radical Hysterectomy for Early-Stage Cervical Cancer: An Updated Meta-Analysis
Authors: Zhang Mengting , Dai Wei , Si Yuexiu , Shi Yetan , Li Xiangyuan , Jiang Ke , Shen Jingyi , Ying Liying
Published: January 2022

Background

Although minimally invasive surgery (MIS) was commonly used to treat patients with early-stage cervical cancer, its efficacy remained controversial.

Methods

We systematically searched PubMed, Web of Science, and Cochrane Library databases until March 2021 to compare the prognosis of early-stage cervical cancer patients who underwent MIS (laparoscopic or robot-assisted radical hysterectomy) or ARH. The primary outcomes included rates of 3- and 5-year disease-free survival (DFS) and overall survival (OS). The study protocol was registered in PROSPERO: CRD42021258116.

Results

This meta-analysis included 48 studies involving 23346 patients (11220, MIS group; 12126, ARH group). The MIS group had a poorer medium-term (3-year) DFS (HR=1.08, 95% CI: 1.01-1.16, p=0.031) than the ARH group, without significant difference in medium-term OS as well as long-term (5-year) DFS and OS. Subgroup analysis of 3-year prognosis revealed that although patients in Western countries who underwent MIS had shorter DFS than those who underwent ARH (HR=1.10, p=0.024), no difference was observed in DFS among those in Asian countries. Moreover, MIS was linked to poorer 3-year DFS in patients with stage I cervical cancer (HR=1.07, p=0.020). Notably, subgroup analysis of 5-year prognosis revealed that patients with tumor size ≥2 cm undergoing MIS exhibited a shorter DFS than those who underwent ARH (HR=1.65, p=0.041).

Conclusion

Patients with early-stage cervical cancer undergoing MIS may have a poorer prognosis than those undergoing ARH. Therefore, applying MIS in early-stage cervical cancer patients should be conducted with caution.

Systematic Review Registration

The study protocol was registered in PROSPERO: CRD42021258116.
Deep Learning–Based Classification of Epithelial–Mesenchymal Transition for Predicting Response to Therapy in Clear Cell Renal Cell Carcinoma
Authors: Chen Qiwei , Kuai Yue , Wang Shujing , Zhu Xinqing , Wang Hongyu , Liu Wenlong , Cheng Liang , Yang Deyong
Published: January 2022

Epithelial–mesenchymal transition (EMT) profoundly impacts prognosis and immunotherapy of clear cell renal cell carcinoma (ccRCC). However, not every patient is tested for EMT status because this requires additional genetic studies. In this study, we developed an EMT gene signature to classify the H&E-stained slides from The Cancer Genome Atlas (TCGA) into epithelial and mesenchymal subtypes, then we trained a deep convolutional neural network to classify ccRCC which according to our EMT subtypes accurately and automatically and to further predict genomic data and prognosis. The clinical significance and multiomics analysis of the EMT signature was investigated. Patient cohorts from TCGA (n = 252) and whole slide images were used for training, testing, and validation using an algorithm to predict the EMT subtype. Our approach can robustly distinguish features predictive of the EMT subtype in H&E slides. Visualization techniques also detected EMT-associated histopathological features. Moreover, EMT subtypes were characterized by distinctive genomes, metabolic states, and immune components. Deep learning convolutional neural networks could be an extremely useful tool for predicting the EMT molecular classification of ccRCC tissue. The underlying multiomics information can be crucial in applying the appropriate and tailored targeted therapy to the patient.
Modulated TRPC1 Expression Predicts Sensitivity of Breast Cancer to Doxorubicin and Magnetic Field Therapy: Segue Towards a Precision Medicine Approach
Authors: Tai Yee Kit , Chan Karen Ka Wing , Fong Charlene Hui Hua , Ramanan Sharanya , Yap Jasmine Lye Yee , Yin Jocelyn Naixin , Yip Yun Sheng , Tan Wei Ren , Koh Angele Pei Fern , Tan Nguan Soon , Chan Ching Wan , Huang Ruby Yun Ju , Li Jing Ze , Fröhlich Jürg , Franco-Obregón Alfredo
Published: January 2022

Chemotherapy is the mainstream treatment modality for invasive breast cancer. Unfortunately, chemotherapy-associated adverse events can result in early termination of treatment. Paradoxical effects of chemotherapy are also sometimes observed, whereby prolonged exposure to high doses of chemotherapeutic agents results in malignant states resistant to chemotherapy. In this study, potential synergism between doxorubicin (DOX) and pulsed electromagnetic field (PEMF) therapy was investigated in: 1) MCF-7 and MDA-MB-231 cellsin vitro; 2) MCF-7 tumors implanted onto a chicken chorioallantoic membrane (CAM) and; 3) human patient-derived and MCF-7 and MDA-MB-231 breast cancer xenografts implanted into NOD-SCID gamma (NSG) mice.In vivo, synergism was observed in patient-derived and breast cancer cell line xenograft mouse models, wherein PEMF exposure and DOX administration individually reduced tumor size and increased apoptosis and could be augmented by combined treatments. In the CAM xenograft model, DOX and PEMF exposure also synergistically reduced tumor size as well as reduced Transient Receptor Potential Canonical 1 (TRPC1) channel expression.In vitro, PEMF exposure alone impaired the survival of MCF-7 and MDA-MB-231 cells, but not that of non-malignant MCF10A breast cells; the selective vulnerability of breast cancer cells to PEMF exposure was corroborated in human tumor biopsy samples. Stable overexpression of TRPC1 enhanced the vulnerability of MCF-7 cells to both DOX and PEMF exposure and promoted proliferation, whereas TRPC1 genetic silencing reduced sensitivity to both DOX and PEMF treatments and mitigated proliferation. Chronic exposure to DOX depressed TRPC1 expression, proliferation, and responses to both PEMF exposure and DOX in a manner that was reversible upon removal of DOX. TRPC1 channel overexpression and silencing positively correlated with markers of epithelial-mesenchymal transition (EMT), includingSLUG,SNAIL,VIMENTIN, andE-CADHERIN, indicating increased and decreased EMT, respectively. Finally, PEMF exposure was shown to attenuate the invasiveness of MCF-7 cells in correlation with TRPC1 expression. We thus demonstrate that the expression levels of TRPC1 consistently predicted breast cancer sensitivity to DOX and PEMF interventions and positively correlated to EMT status, providing an initial rationale for the use of PEMF-based therapies as an adjuvant to DOX chemotherapy for the treatment of breast cancers characterized by elevated TRPC1 expression levels.
One Cycle of Concurrent Chemotherapy vs. Two Cycles of Concurrent Chemotherapy With Radiation Therapy in Patients With Limited-Stage Small Cell Lung Cancer
Authors: Yu Hao , Zhang Jiaqi , Zhang Zhen , Wang Youyou , Xu Guangying , Xu Liming , Liu Ningbo , Zhao Lujun , Wang Ping
Published: January 2022

Background

The optimal number of concurrent chemotherapy cycles during thoracic radiotherapy (RT) in patients with limited stage-small cell lung cancer (LS-SCLC) is not well defined. The purpose of this study was to evaluate the impact of the number of concurrent chemotherapy cycles on prognosis of LS-SCLC.

Material and Methods

Patients with LS-SCLC treated with concurrent chemo-radiotherapy from May 2008 to December 2020 in our hospital were retrospectively analyzed. The prescribed radiation dose was 60Gy administrated with conventional RT in 30 fractions within 6 weeks. The prognostic role of cycle number of chemotherapy administrated concurrently with RT were analyzed. All patients were followed up at one month after the treatment, then once every three months until two years after the treatment, and every six months thereafter. Propensity score matching (PSM) was performed to reduce confounding factors. The primary endpoint was overall survival (OS). Survival analysis was performed with Kaplan-Meier and multivariate analysis was performed with Cox regression model.

Results

Among the 370 patients who received radical radiotherapy, 206 patients received concurrent chemo-radiotherapy and were included for the analysis. Multivariate analysis showed that stage and PCI were independent prognostic factors for OS. The median OS in patients who received one cycle and two cycles of chemotherapy concurrently with RT were 32.9 months and 31.6 months, respectively (P = 0.241). And the median PFS were 20.6 months and 18.4 months, respectively (P = 0.764). After PSM, no statistical differences in OS and PFS were observed between patients who received one cycle and those who received two cycles of concurrent chemotherapy.

Conclusion

Two cycles of concurrent chemotherapy during RT were not necessarily superior compared to one cycle in LS-SCLC. The optimal cycle number of concurrent chemotherapy during RT needs to be further studied.
Multi-Institutional Validation of Two-Streamed Deep Learning Method for Automated Delineation of Esophageal Gross Tumor Volume Using Planning CT and FDG-PET/CT
Authors: Ye Xianghua , Guo Dazhou , Tseng Chen-Kan , Ge Jia , Hung Tsung-Min , Pai Ping-Ching , Ren Yanping , Zheng Lu , Zhu Xinli , Peng Ling , Chen Ying , Chen Xiaohua , Chou Chen-Yu , Chen Danni , Yu Jiaze , Chen Yuzhen , Jiao Feiran , Xin Yi , Huang Lingyun , Xie Guotong , Xiao Jing , Lu Le , Yan Senxiang , Jin Dakai , Ho Tsung-Ying
Published: January 2022

Background

The current clinical workflow for esophageal gross tumor volume (GTV) contouring relies on manual delineation with high labor costs and inter-user variability.

Purpose

To validate the clinical applicability of a deep learning multimodality esophageal GTV contouring model, developed at one institution whereas tested at multiple institutions.

Materials and Methods

We collected 606 patients with esophageal cancer retrospectively from four institutions. Among them, 252 patients from institution 1 contained both a treatment planning CT (pCT) and a pair of diagnostic FDG-PET/CT; 354 patients from three other institutions had only pCT scans under different staging protocols or lacking PET scanners. A two-streamed deep learning model for GTV segmentation was developed using pCT and PET/CT scans of a subset (148 patients) from institution 1. This built model had the flexibility of segmenting GTVs via only pCT or pCT+PET/CT combined when available. For independent evaluation, the remaining 104 patients from institution 1 behaved as an unseen internal testing, and 354 patients from the other three institutions were used for external testing. Degrees of manual revision were further evaluated by human experts to assess the contour-editing effort. Furthermore, the deep model’s performance was compared against four radiation oncologists in a multi-user study using 20 randomly chosen external patients. Contouring accuracy and time were recorded for the pre- and post-deep learning-assisted delineation process.
Racial/Ethnic Disparities on the Risk of Second Malignant Neoplasm Among Hodgkin Lymphoma Survivors
Authors: Xiao Han , He Jianghua , Liang Simin , Cai Duo , Zhou Qiao , Liu Lanxiang , Yan Xinyu , Chi Jianxiang , Xiao Qing , Wang Li
Published: January 2022

Background

Hodgkin lymphoma survivors are at risk for second malignant neoplasm (SMN). How race/ethnicity affects the risk remains unclear.

Methods

This retrospective cohort study included 22,415 patients diagnosed with primary Hodgkin lymphoma from January 1992 to December 2015 in 13 Surveillance, Epidemiology, and End Results-based registries and divided patients into four groups: non-Hispanic whites, non-Hispanic blacks, Hispanics, and Asian/others. Taking non-Hispanic whites as a reference, both the proportional subdistribution hazard (PSH) and the cause-specific hazard (CSH) methods were used to calculate the SMN hazard ratio for other racial/ethnic groups with and without considering the competing mortality risk.

Results

1,778 patients developed SMN with a median follow-up of 11.63 years. In the adjusted PSH model, Hispanic, Asian/others, and non-Hispanic black patients had 26% (PSH, 0.74; 95% CI, 0.63–0.87), 20% (PSH, 0.80; 95% CI, 0.64–1.01), and 12% (PSH, 0.88; 95% CI, 0.75–1.03) decreased overall SMN hazard, respectively. Moreover, the PSH method revealed the racial/ethnic difference in the SMN risk in the skin, the respiratory system, and the endocrine system. These hazards were slightly higher and different with the use of the CSH approach. In addition to the aforementioned overall SMN and subtypes, adjusted CSH analysis also revealed the racial/ethnic disparities in the risk of subsequent female breast cancer, digestive cancer, and non-Hodgkin lymphoma.

Conclusions

The subtype and SMN risk among Hodgkin lymphoma survivors varied by race/ethnicity. The use of CSH and PSH provides a dynamic view of racial/ethnic effects on SMN risk in Hodgkin lymphoma survivors.
Pan-Cancer Analyses Reveal Oncogenic Role and Prognostic Value of F-Box Only Protein 22
Authors: Chen Sen , Ma Shuangxin , Yan Jiaoyan , Wang Haiqing , Ding Bojiao , Guo Zihu , Ma Yaohua , Chen Xuetong , Wang Yonghua
Published: January 2022

The F-box protein 22 (FBXO22), an F-box E3 ligase, has been identified to be critically involved in carcinogenesis. However, a systematic assessment of the role of FBXO22 across human cancers is lacking. Here, we performed a pan-cancer analysis to explore the role of FBXO22 in 33 cancer types using multiomic data from The Cancer Genome Atlas (TCGA). First, we found that high FBXO22 expression in multiple cancers was closely associated with poor overall survival and relapse-free survival. Next, we identified ten proteins that interact with FBXO22 and 13 of its target substrates using the STRING database and a literature search to explore the regulatory role of FBXO22 in tumorigenesis. Genes encoding these proteins were found to be significantly enriched in cell cycle negative regulation and ubiquitination pathways. This was confirmed in nonsmall cell lung cancer A549 cells, where FBXO22 overexpression enhanced cyclin-dependent kinase 4 (CDK4) protein levels and promoted cell proliferation. Similarly, overexpression or interference of FBXO22 changed the protein level of one of its substrates, PTEN. Additionally, we found that FBXO22 mutations were accompanied by altered substrate expression, especially in uterine corpus endometrial carcinoma and lung adenocarcinoma; endometrial carcinoma patients with FBXO22 genetic alterations also had better overall and relapse-free survival. Notably, FBXO22 methylation levels were also decreased in most tumors, and hypomethylation of FBXO22 was associated with poor overall survival, relapse-free interval, and progression-free interval in pancreatic adenocarcinoma. Finally, we analyzed the correlation between the abundance of tumor infiltrating lymphocytes (TILs) and FBXO22 expression, copy number variation, and methylation. Multiple algorithms revealed that high FBXO22 expression was associated with lower TIL levels, especially in lung adenocarcinoma, lung squamous cell carcinoma, and sarcoma. Taken together, our findings demonstrate that FBXO22 degrades tumor suppressor genes by ubiquitination and inhibits the cell cycle to promote nonsmall cell lung cancer progression. Our study also provides a relatively comprehensive understanding of the oncogenic role of FBXO22 in different tumors.
Efficacy and Safety of Thalidomide As a Pre-Medication of Chemotherapy-Induced Nausea and Vomiting (CINV) Following Highly Emetogenic Chemotherapy (HEC): A Systematic Review and Meta-Analysis
Authors: Xie Jiyi , Zhang Cong , Li Shijun , Dai Rong , Sullivan Mitchell A. , Deng Bin , Xu Qiling , Wang Jinglin , Shi Chen , Zhang Yu
Published: January 2022

Background

In China, thalidomide (THD) has been used to prevent chemotherapy-induced nausea and vomiting (CINV) following highly emetogenic chemotherapy (HEC); however, there is limited evidence on the efficacy and safety of THD in this setting. The aim of this study was to evaluate the efficacy, safety, and impact on quality of life (QoL) of THD on CINV following HEC.

Methods

Electronic databases were systematically searched for all randomized controlled trials (RCTs) in HEC using THD. The primary outcomes were complete response (CR) and no nausea, Secondary outcomes were the incidence of adverse events and QoL related indicators. We calculated risk ratios (RRs) and 95% confidence intervals (CIs) using a fixed-effects model. In the case of heterogeneity (I2≥50%), a random-effects model was performed.

Results

A total of 3168 patients were included from 34 RCTs. In terms of CR rate, THD plus 5-HT3 receptor antagonist (5-HT3RA) with or without dexamethasone (DEX) was significantly higher than 5-HT3RA with or without DEX in the acute phase (74.4% vs 67.4%; RR 1.10), delayed phase (70.6% vs 50.4%; RR 1.53), and overall phase (68.4% vs 53.4%; RR 1.28). In terms of no nausea rate, the THD group was also significantly higher than the control group in the acute phase (61.7% vs 55.5%; RR 1.12), delayed phase (50.5% vs 30.0%; RR 1.69), and overall phase (44.6% vs 29.9%; RR 1.50). There was no statistical difference in the incidence of fatigue, headache, diarrhea, rash, hepatorenal damage, and myelosuppression between those with and without THD. The incidence of increase in KPS scores, weight gain, appetite improvement, and sleep quality improvement were significantly higher with the addition of THD.

Conclusions

THD may be effective and safe for the prevention of CINV patients treated with HEC and may improve QoL.
Interventional Optical Imaging-Monitored Synergistic Effect of Radio-Frequency Hyperthermia and Oncolytic Immunotherapy
Authors: Zheng Hui , Zhang Feng , Monsky Wayne , Ji Hongxiu , Yang Weizhu , Yang Xiaoming
Published: January 2022

Purpose

To develop a new interventional oncology technique using indocyanine green (ICG)-based interventional optical imaging (OI) to monitor the synergistic effect of radiofrequency hyperthermia (RFH)-enhanced oncolytic immunotherapy.

Materials and Methods

This study included (1) optimization of ICG dose and detection time-window for intracellular uptake by VX2 tumor cells; (2) in-vitro confirmation of capability of using ICG-based OI to assess efficacy of RFH-enhanced oncolytic therapy (LTX-401) for VX2 cells; and (3) in-vivo validation of the interventional OI-monitored, intratumoral RFH-enhanced oncolytic immunotherapy using rabbit models with orthotopic liver VX2 tumors. Both in-vitro and in-vivo experiments were divided into four study groups (n=6/group) with different treatments: (1) combination therapy of RFH+LTX-401; (2) RFH alone at 42°C for 30 min; (3) oncolytic therapy with LTX-401; and (4) control with saline. For in-vivo validation, orthotopic hepatic VX2 tumors were treated using a new multi-functional perfusion-thermal radiofrequency ablation electrode, which enabled simultaneous delivery of both LTX-401 and RFH within the tumor and at the tumor margins.

Results

In in-vitro experiments, taking up of ICG by VX2 cells was linearly increased from 0 μg/mL to 100 μg/mL, while ICG-signal intensity (SI) reached the peak at 24 hours. MTS assay and apoptosis analysis demonstrated the lowest cell viability and highest apoptosis in combination therapy, compared to three monotherapies (P<0.005). In in-vivo experiments, ultrasound imaging detected the smallest relative tumor volume for the combination therapy, compared to other monotherapies (P<0.005). In both in-vitro and in-vivo experiments, ICG-based interventional optical imaging detected a significantly decreased SI in combination therapy (P<0.005), which was confirmed by the “gold standard” optical/X-ray imaging (P<0.05). Pathologic/laboratory examinations further confirmed the significantly decreased cell proliferation with Ki-67 staining, significantly increased apoptotic index with TUNEL assay, and significantly increased quantities of CD8 and CD80 positive cells with immunostaining in the combination therapy group, compared to other three control groups (P<0.005).

Conclusions

We present a new interventional oncology technique, interventional optical imaging-monitored RFH-enhanced oncolytic immunotherapy, which may open new avenues to effectively manage those patients with larger, irregular and unresectable malignancies, not only in liver but also the possibility in other organs.
TRUS-Guided Target Biopsy for a PI-RADS 3–5 Index Lesion to Reduce Gleason Score Underestimation: A Propensity Score Matching Analysis
Authors: Chung Jae Hoon , Park Byung Kwan , Song Wan , Kang Minyong , Sung Hyun Hwan , Jeon Hwang Gyun , Jeong Byong Chang , Seo Seong Il , Jeon Seong Soo , Lee Hyun Moo
Published: January 2022

Background

Magnetic resonance imaging (MRI) and transrectal ultrasound (TRUS)-guided cognitive or image fusion biopsy is performed to target a prostate imaging reporting and data system (PI-RADS) 3–5 lesion. Biopsy Gleason score (GS) is frequently underestimated compared to prostatectomy GS. However, it is still unclear about how many cores on target are necessary to reduce undergrading and if additional cores around the target may improve grade prediction on surgical specimen.

Purpose

To determine the number of target cores and targeting strategy to reduce GS underestimation.

Materials and Methods

Between May 2017 and April 2020, a total of 385 patients undergoing target cognitive or image fusion biopsy of PI-RADS 3–5 index lesions and radical prostatectomies (RP) were 2:1 matched with propensity score using multiple variables and divided into the 1–4 core (n = 242) and 5–6 core (n = 143) groups, which were obtained with multiple logistic regression with restricted cubic spline curve. Target cores of 1–3 and 4–6 were sampled from central and peripheral areas, respectively. Pathologic outcomes and target cores were retrospectively assessed to analyze the GS difference or changes between biopsy and RP with Wilcoxon signed-rank test.

Results

The median of target cores was 3 and 6 in the 1–4 core and 5–6 core groups, respectively (p < 0.001). Restricted cubic spline curve showed that GS upgrade was significantly reduced from the 5th core and there was no difference between 5th and 6th cores. Among the matched patients, 35.4% (136/385; 95% confidence interval, 0.305–0.403) had a GS upgrade after RP. The GS upgrades in the 1–4 core and 5–6 core groups were observed in 40.6% (98/242, 0.343–0.470) and 26.6% (38/143, 0.195–0.346), respectively (p = 0.023). Although there was no statistical difference between the matched groups in terms of RP GS (p = 0.092), the 5–6 core group had significantly higher biopsy GS (p = 0.006) and lower GS change from biopsy to RP (p = 0.027).

Conclusion

Five or more target cores sampling from both periphery and center of an index tumor contribute to reduce GS upgrade.
Comprehensive Analysis of N6-Methylandenosine-Related Long Non-Coding RNAs Signature in Prognosis and Tumor Microenvironment of Bladder Cancer
Authors: Chen Kang , Zhu Shaoming , Yu Weimin , Xia Yuqi , Xing Ji , Geng Jie , Cheng Fan
Published: January 2022

To investigate the role of N6-methyladenosine (m6A)- related long non-coding RNAs (lncRNAs) in bladder cancer (BC). 50 m6A-related lncRNAs were screened out and were correlated with prognosis from BC samples in The Cancer Genome Atlas (TCGA). The lncRNAs were subdivided into cluster 1 and cluster 2 with consensus cluster analysis, and it was found that lncRNAs in cluster 2 were associated with poor prognosis and increased PD-L1 expression. Gene set enrichment analysis (GSEA) revealed tumor-related pathways in cluster 2. Through least absolute shrinkage and selection operator (LASSO) Cox regression analysis, univariate and multivariate Cox regression, and ROC analyses, 14 prognostic lncRNAs were selected and used to construct the m6A-related lncRNA prognostic signature (m6A-LPS), furthermore, that m6A-LPS was as a valuable independent prognostic factor. Interestingly, the m6A-LPS risk score was positively correlated with the immune score, PD-L1 expression, and the infiltration of immune cell subtypes in BC. SNHG16, a member of the high-risk group based on m6A-LPS, was highly expressed in BC tissues and cell lines and interfered with siRNA resulted in suppressed proliferation, migration, and invasion in vitro. Our study illustrates the role of m6A-related lncRNAs in BC. The m6A-LPS may be an important regulatory target of the tumor microenvironment (TME) in BC.
Dimethyl Fumarate Combined With Vemurafenib Enhances Anti-Melanoma Efficacy via Inhibiting the Hippo/YAP, NRF2-ARE, and AKT/mTOR/ERK Pathways in A375 Melanoma Cells
Authors: Li Hongxia , Wang Yaping , Su Rina , Jia Yuchen , Lai Xiong , Su Huimin , Fan Yaochun , Wang Yuewu , Xing Wanjin , Qin Jianzhong
Published: January 2022

Melanoma is a deadly form of skin cancer with high rates of resistance to traditional chemotherapy and radiotherapy. BRAF inhibitors (BRAFi) can achieve initial efficacy when used to treat melanoma patients, but drug resistance and relapse are common, emphasizing the need for new therapeutic strategies. Herein, we reported that combination of dimethyl fumarate (DMF) and vemurafenib (Vem) inhibited melanoma cell proliferation more significantly and induced more cell death than single agent did both in vitro and in vivo. DMF/Vem treatment induced cell death through inhibiting the expression and transcriptional activity of NRF2 thereby resulting in more reactive oxygen species (ROS) and via inhibiting the expression of YAP, a key downstream effector of Hippo pathway. DMF/Vem treatment also reduced phosphorylation of AKT, 4EBP1, P70S6K and ERK in AKT/mTOR/ERK signaling pathways. RNA-seq analysis revealed that DMF/Vem treatment specifically suppressed 4561 genes which belong to dozens of cell signaling pathways. These results indicated that DMF/Vem treatment manifested an enhanced antitumor efficacy through inhibiting multiple cell signaling pathways, and thus would be a novel promising therapeutic approach targeted for melanoma.
Phase II Study of Gemcitabine, Peg-Asparaginase, Dexamethasone and Methotrexate Regimen for Newly Diagnosed Extranodal Natural Killer/T-Cell Lymphoma, Nasal Type: Final Analysis With Long-Term Follow-Up and Rational Research for the Combination
Authors: Wang Yu , Wang Cai-Qin , Sun Peng , Liu Pan-Pan , Yang Hang , Wang Han-Yu , Rao Hui-Lan , Li Su , Jiang Wen-Qi , Huang Jia-Jia , Li Zhi-Ming
Published: January 2022

Patients with extranodal natural killer/T-cell lymphoma (ENKTL), nasal type are benefit from peg-asparaginase, gemcitabine, and methotrexate. Therefore, we conducted a prospective phase II trial using a combination of these drugs as GAD-M regimen in naïve ENKTL patients, simultaneously, explored the combinational mechanism. The GAD-M regimen was administered for 6 cycles sandwiched by radiotherapy for stage I/II and 6 cycles for stage III/IV patients. After 6 cycles, the overall response rate of 36 patients was 91.6%, and the complete remission rate increased to 83.3%. The 3-year progression-free survival (PFS) and overall survival (OS) rates were 74.8% and 77.8%, respectively. The 5-year PFS and OS were 68.3% and 77.8%. No patient suffered from the central nervous system (CNS) relapse. Most patients experienced recoverable liver dysfunction and anemia in this study. The plasma MTX concentration ratio at 12 to 24 hr during the first cycle could be an early predictor of outcomes in ENKTL (PFS, P=0.005; OS, P=0.002). Additionally, we found that high dose MTX (HD-MTX) and gemcitabine had the synergistic effect of ENKTL cell in vitro. Mechanistically, we demonstrated that the combination could lead to obviously apoptosis in ENKTL cell with extremely release of reactive oxygen spices (ROS), which mediated by endoplasmic reticulum stress. In conclusion, the GAD-M regimen could be a new choice to newly diagnosed ENKTL, especially for stage I/II patients. Furthermore, our results showed the synergy effect of HD-MTX with gemcitabine in ENKTL.

Clinical Trial Registration

This trial was registered at www.clinicaltrials.gov as #NCT01991158.
Cytology–Based Specimen Triage for Epidermal Growth Factor Receptor Mutation Testing of Malignant Pleural Effusions in Non–Small Cell Lung Cancer
Authors: Chiang Chi-Lu , Shen Chia-I , Huang Hsu-Ching , Chang Han-Jhih , Huang Yu-Ting , Chiu Chao-Hua
Published: January 2022

Introduction

Malignant pleural effusions are common in non–small cell lung cancer (NSCLC). Molecular testing is among the most critical steps in the management of patients with advanced NSCLC. However, the optimal approach for epidermal growth factor receptor (EGFR) mutation testing in such effusion samples remains unclear.

Methods

We prospectively collected effusion samples from patients with EGFR–mutant NSCLC. Following sample centrifugation, genomic DNA and cell–free DNA were respectively extracted from the sediment and supernatants. EGFR mutation was detected through a real–time PCR assay.

Results

A total of 108 effusions from 78 patients were examined, with 12 and 96 obtained before and after EGFR tyrosine kinase inhibitor treatment, respectively. Carcinoma cells or atypical cells were identified in 73 effusions (67.6%). EGFR mutations were detected in 86 (79.6%) sediment and 84 (77.8%) supernatant samples. Among the effusions with positive cytological findings, the EGFR mutation detection rates were 95.9% (70/73) and 86.3% (63/73) in the sediment and supernatants, respectively. Among the effusions with negative cytological findings, the corresponding detection rates were 45.7% (16/35) and 60% (21/35), respectively. Current clinical practice is to arrange EGFR mutation testing only for sediment from cytologically positive effusions. Through the proposed cytology–based specimen triage, wherein sediment and supernatants with positive and negative cytological findings, respectively, are tested, the detection rate was increased from 64.8% (70/108) to 84.3% (91/108). At half of the cost, this strategy provided a detection rate only slightly lower than the rate in a combined test of all the sediment and supernatants (87.0%, 94/108).

Conclusions

The separate extraction of DNA from sediment and supernatants obtained from centrifuged effusion samples can improve the overall EGFR mutation detection rate. The present cytology–based specimen triage is an efficient strategy for EGFR mutation testing in patients with EGFR–mutant NSCLC.
Effectiveness of Interventions to Reduce Potentially Inappropriate Medication in Older Patients: A Systematic Review
Authors: Rodrigues Daniela A. , Plácido Ana I. , Mateos-Campos Ramona , Figueiras Adolfo , Herdeiro Maria Teresa , Roque Fátima
Published: January 2022

Background: Age-related multiple comorbidities cause older adults to be prone to the use of potentially inappropriate medicines (PIM) resulting in an increased risk of adverse events. Several strategies have emerged to support PIM prescription, and a huge number of interventions to reduce PIM have been proposed. This work aims to analyze the effectiveness of PIM interventions directed to older adults.

Methods: A systematic review was performed searching the literature in the MEDLINE PubMed, EMBASE, and Cochrane scientific databases for interventional studies that assessed the PIM interventions in older adults (≥65 years).

Results: Forty-seven articles were included, involving 52 to 124,802 patients. Various types of interventions were analyzed such as medication review, educational strategies, clinical decision support system, and organizational and multifaceted approaches. In the hospital, the most successful intervention was medication review (75.0%), while in primary care, the analysis of all included studies revealed that educational strategies were the most effective. However, the analysis of interventions that have greater evidence by its design was inconclusive.

Conclusion: The results obtained in this work suggested that PIM-setting-directed interventions should be developed to promote the wellbeing of the patients through PIM reduction. Although the data obtained suggested that medication review was the most assertive strategy to decrease the number of PIM in the hospital setting, more studies are necessary.

Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021233484], identifier [PROSPERO 2021 CRD42021233484].
Confirmation of inhibitingTLR4/MyD88/NF-κB Signalling Pathway by Duhuo Jisheng Decoction on Osteoarthritis: A Network Pharmacology Approach-Integrated Experimental Study
Authors: Liu Linglong , Xu Limei , Wang Shengjie , Wang Lili , Wang Xiaoning , Xu Huifeng , Li Xihai , Ye Hongzhi
Published: January 2022

This study was conducted to identify whether the TLR4/MyD88/NF-κB signalling pathway plays a vital role in osteoarthritis (OA) treatment with Duhuo Jisheng Decoction (DHJSD) on the basis of a network pharmacology approach (NPA)-integrated experiment. Two experiments were conducted as follow: NPA for DHJSD using six OA-related gene series and the key pathway was screened out using NPA. NPA identified a vital role for the TLR4/MyD88/NF-κB signalling pathway in OA treatment with DHJSD, the conventional western blot analysis and qPCR confirmed it. Furthermore, changes of miR-146a-5p and miR-34a-5p in the cellular models were recovered by DHJSD administration, which synergistically contributed to OA therapy. The toll-like receptor signalling pathway and the NF-κB signalling pathway were meaningfully enriched by the miRNA-regulated gene pathways. This study identified and confirmed the TLR4/MyD88/NF-κB signalling pathway is an essential inflammatory signalling pathway in the DHJSD underlying OA treatment. The results provide a basis for further evaluation of the regulatory mechanism of the drug’s efficacy in treating OA.
Nephrotoxicity of Calcineurin Inhibitors in Kidney Epithelial Cells is Independent of NFAT Signaling
Authors: Karolin Andrea , Escher Geneviève , Rudloff Stefan , Sidler Daniel
Published: January 2022

Background: Calcineurin inhibitors (CNIs) such as cyclosporine A and tacrolimus are commonly used after renal transplantation to suppress the immune system. In lymphoid cells, cyclosporine A acts via the calcineurin/nuclear factor of activated T-cell (NFAT) axis. In non-lymphoid cells, such as kidney epithelial cells, cyclosporine A induces calcineurin inhibitor toxicity. It is unknown via which off-targets cyclosporine A induces calcineurin inhibitor toxicity in kidney epithelial cells.

Methods: To measure a compound’s potential to induce nephrotoxicity, the expression of the surrogate marker Fn14 was measured by flow cytometry. Compounds were tested for their potential to induce Fn14 either chemically or plasmid-mediated. Mice were injected with various compounds, and changes in nephrotoxic gene expression levels of the kidney epithelial cells were then analyzed.

Results: Fn14 is specifically upregulated due to calcineurin inhibitor toxicity inducing agents. Inhibition of the NFAT axis showed no increase of the Fn14 expression on the surface of kidney cells. However, inhibition of p38 MAPK, phosphoinositide-3-kinase (PI3K)/Akt, protein kinase C (PKC), and inhibitor of nuclear factor-κB (IκB) kinase (IKK) showed clear induction of Fn14 and increased expressions of nephrotoxic, inflammatory, and fibrotic genes in vitro and in vivo.

Conclusions: These findings show that cyclosporine A acts independently of NFAT on kidney epithelial cells. Moreover, inhibition of serine/threonine protein kinases mimics cyclosporine A’s activity on kidney epithelial cells. This mimicking effect indicates that these protein kinases are off-targets of cyclosporine A and damage structural renal cells when inhibited and therefore contributes likely to the development and progression of calcineurin inhibitor toxicity.
Limonoids From the Genus Melia (Meliaceae): Phytochemistry, Synthesis, Bioactivities, Pharmacokinetics, and Toxicology
Authors: Fan Wenxiang , Fan Linhong , Wang Zhengtao , Yang Li
Published: January 2022

Limonoids, as the vital bioactive chemical compounds in genus Melia plants, have attracted significant attention owing to their exclusive structural characteristics and remarkable biological activity. These compounds can be usually classified into two categories, including the ring-intact group and the ring-C-seco group. Benefiting from the development of separation and analysis technology, more than 200 limonoids have been isolated and identified from this genus. There is growing evidence that limonoids from genus Melia possess diverse pharmacological activities, especially anti-cancer effects, insecticidal activities, and anti-botulism effects. Toosendanin, one of the paramount limonoids, was considered as the pivotal bioactive marker in two medicinal herbs, including Melia toosendan Sieb. et Zucc and Melia azedarach L. In particular, limonoids are found to exhibit non-negligible toxic effects, a finding which needs further research. Besides this, the lack of clinical research data seriously hinders its further development and utilization, and necessary clinical trials should be taken into consideration. In this review, we systematically summarized the phytochemical compounds and their synthesis methods, pharmacological activities, and the structure–activity relationship, pharmacokinetics, and toxicology of genus Melia-derived limonoids. We believe that this up-to-date review could provide scientific evidence for the application of limonoids as agents beneficial to health in future clinical practice.
Genetic Factors Associated With Tardive Dyskinesia: From Pre-clinical Models to Clinical Studies
Authors: Tsermpini Evangelia Eirini , Redenšek Sara , Dolžan Vita
Published: January 2022

Tardive dyskinesia is a severe motor adverse event of antipsychotic medication, characterized by involuntary athetoid movements of the trunk, limbs, and/or orofacial areas. It affects two to ten patients under long-term administration of antipsychotics that do not subside for years even after the drug is stopped. Dopamine, serotonin, cannabinoid receptors, oxidative stress, plasticity factors, signaling cascades, as well as CYP isoenzymes and transporters have been associated with tardive dyskinesia (TD) occurrence in terms of genetic variability and metabolic capacity. Besides the factors related to the drug and the dose and patients’ clinical characteristics, a very crucial variable of TD development is individual susceptibility and genetic predisposition. This review summarizes the studies in experimental animal models and clinical studies focusing on the impact of genetic variations on TD occurrence. We identified eight genes emerging from preclinical findings that also reached statistical significance in at least one clinical study. The results of clinical studies are often conflicting and non-conclusive enough to support implementation in clinical practice.
Genistein: A Review on its Anti-Inflammatory Properties
Authors: Goh Yu Xian , Jalil Juriyati , Lam Kok Wai , Husain Khairana , Premakumar Chandini Menon
Published: January 2022

Nowadays, non-resolving inflammation is becoming a major trigger in various diseases as it plays a significant role in the pathogenesis of atherosclerosis, asthma, cancer, obesity, inflammatory bowel disease, chronic obstructive pulmonary disease, neurodegenerative disease, multiple sclerosis, and rheumatoid arthritis. However, prolonged use of anti-inflammatory drugs is usually accompanied with undesirable effects and hence more patients tend to seek for natural compounds as alternative medicine. Considering the fact above, there is an urgency to discover and develop potential novel, safe and efficacious natural compounds as drug candidates for future anti-inflammatory therapy. Genistein belongs to the flavonoid family, in the subgroup of isoflavones. It is a phytoestrogen that is mainly derived from legumes. It is a naturally occurring chemical constituent with a similar chemical structure to mammalian estrogens. It is claimed to exert many beneficial effects on health, such as protection against osteoporosis, reduction in the risk of cardiovascular disease, alleviation of postmenopausal symptoms and anticancer properties. In the past, numerous in vitro and in vivo studies have been conducted to investigate the anti-inflammatory potential of genistein. Henceforth, this review aims to summarize the anti-inflammatory properties of genistein linking with the signaling pathways and mediators that are involved in the inflammatory response as well as its toxicity profile. The current outcomes are analysed to highlight the prospect as a lead compound for drug discovery. Data was collected using PubMed, ScienceDirect, SpringerLink and Scopus databases. Results showed that genistein possessed strong anti-inflammatory activities through inhibition of various signaling pathways such as nuclear factor kappa-B (NF-κB), prostaglandins (PGs), inducible nitric oxide synthase (iNOS), proinflammatory cytokines and reactive oxygen species (ROS). A comprehensive assessment of the mechanism of action in anti-inflammatory effects of genistein is included. However, evidence for the pharmacological effects is still lacking. Further studies using various animal models to assess pharmacological effects such as toxicity, pharmacokinetics, pharmacodynamics, and bioavailability studies are required before clinical studies can be conducted. This review will highlight the potential use of genistein as a lead compound for future drug development as an anti-inflammatory agent.
Pharmacokinetics, Pharmacodynamics, Safety and Immunogenicity of CMAB807, a New Denosumab Biosimilar, in Healthy Chinese Subjects
Authors: Chen Hanjing , Chen Weili , Yuan Fei , Guo Qingcheng , Zhang Xunmin , Wang Chenguang , Li Xuening
Published: January 2022

Objective: Pharmacokinetics (PK), pharmacodynamics (PD), safety and immunogenicity studies were conducted to evaluate the bioequivalence of CMAB807, a biosimilar to denosumab (Prolia®), which is the only approved RANKL inhibitor for the treatment of osteoporosis.

Methods: In this randomized, double-blind, single-dose phase I study, 132 healthy Chinese male subjects received a subcutaneous injection of 60 mg of CMAB807 or denosumab at a 1:1 ratio. The PK, PD, safety and immunogenicity results were assessed prior to and up to 126 days after administration.

Results: The PK profiles of CMAB807 and denosumab were similar. The geometric mean ratios of the maximum concentration (Cmax), AUC0-t and AUCo-∞ were 102.41, 104.15 and 103.89%, respectively, and the 90% confidence interval was observed to be within 80.00–125.00%, which indicated the bioequivalence of CMAB807 and denosumab. The PD profiles of the two groups were also comparable. The production of the C-terminal cross-linking telopeptide of type I collagen (CTX1) was inhibited by up to 85% for 10 days, and this inhibition was sustained for up to 126 days in both the CMAB807 and denosumab groups. No subjects in the CMAB807 group, three subjects in the denosumab group before administration, and two subjects in the denosumab group after administration were positive for anti-drug antibody (ADA). Adverse events (AEs) were observed in 98.5% of subjects in both groups. The most common AE recorded was increased parathyroid hormone (PTH) levels, with incidences of 92.4 and 95.5% in the CMAB807 and denosumab groups, respectively. No clinically meaningful differences were observed in safety and immunogenicity between CMAB807 and denosumab.

Conclusion: CMAB807 represents a new potential treatment option for patients with osteoporosis.

Clinical Trial Registration:https://clinicaltrials.gov (Registration No. NCT03925051), http://www.chinadrugtrial/org.cn/index.html (Registration No. CTR20190800).