bluuebunny/crossref_metadata_2025 huggingface dataset:
nab-Paclitaxel/Carboplatin in Vulnerable Populations With Advanced Non-Small Cell Lung Cancer: Pooled Analysis
Authors: Langer Corey J. , Gajra Ajeet , Gridelli Cesare , Konduri Kartik , Morgensztern Daniel , Spigel David , Talbot Denis , Thomas Michael , Weiss Jared , Pilot Richard , Bhore Rafia , Wolfsteiner Marianne , Ong Teng Jin , Socinski Mark
Published: January 2021

Introduction

Despite improvements in the treatment of advanced non-small cell lung cancer (NSCLC), certain patient populations remain underrepresented in clinical trials. Many patients have benefited from platinum doublets, including nab-paclitaxel–based regimens, but there are patients with comorbidities who particularly require careful balancing of efficacy and safety. Clinical trial data are limited for patients who are elderly or have renal impairment, diabetes, or impaired performance status.

Methods

To better understand outcomes in these patient populations, we performed a pooled analysis using data from the ABOUND clinical trial program (ABOUND.SQM, ABOUND.PS2, ABOUND.70+) and the key phase III trial of nab-paclitaxel/carboplatin in advanced NSCLC. The populations included in this pooled analysis consisted of elderly patients (≥ 70 years) and patients with renal impairment (eGFR < 60 ml/min/1.73 m2), diabetes, or poor performance status (ECOG PS 2).

Results

Median progression-free survival (PFS) ranged from 4.1 months in patients with ECOG PS 2 (95% CI, 2.04–5.09 months) to 7.7 months in patients with diabetes (95% CI, 5.88–10.12 months). PFS for elderly patients and patients with renal impairment was 6.9 months each (95% CI, 6.01–7.98 months and 4.47–9.79 months, respectively). Median overall survival (OS) was 18.2 months (95% CI, 10.94–28.22 months), 17.4 months (95% CI, 14.59–20.14 months), and 16.1 months (95% CI, 14.09–18.50 months) in patients with renal impairment, patients with diabetes, and elderly patients, respectively. Patients with ECOG PS 2 exhibited the shortest median OS: 5.6 months (95% CI, 3.98–11.37 months). Overall response rates were 56.9%, 54.6%, 45.9%, and 29.4% in patients with diabetes, elderly patients, patients with renal impairment, and patients with ECOG PS 2, respectively. Most treatment-related adverse events were hematologic. The most common grade 3/4 hematologic adverse events in patients with renal impairment, elderly patients, patients with diabetes, and patients with poor performance status included neutropenia, anemia, and thrombocytopenia.

Conclusions

Although survival data in patients with ECOG PS 2 were notably inferior to the other cohorts, our findings are consistent with those previously reported in the population-specific studies of the ABOUND trials and lend additional support for the use of nab-paclitaxel–based regimens in historically understudied and vulnerable populations.
A Simulated Dosimetric Study of Contribution to Radiotherapy Accuracy by Fractional Image Guidance Protocol of Halcyon System
Authors: Wang Haiyang , Huang Yuliang , Hu Qiaoqiao , Li Chenguang , Liu Hongjia , Wang Xuejuan , Li Weibo , Ma Wenjun , Pu Yichen , Du Yixiao , Wu Hao , Zhang Yibao
Published: January 2021

Purpose

Frequency of conventional kV-image guidance is sometimes sacrificed to reduce concomitant risk, leaving deviations of unguided fractions unknown. MV-imaging and treatment dose can be collectively optimized on Halcyon, where fractional MVCBCT provides complete anatomic records for course-wide dose reconstruction. By retrospective dose accumulation, this work simulated the impact of imaging frequency on patient treatment dose on the platform of Halcyon.

Methods

Four hundred and sixteen MVCBCT image sets from 16 patients of various tumor sites treated with radiotherapy on Halcyon were retrospectively selected. After applying the image-guided couch shifts of the clinical records, deformable image registration was performed using Velocity software, to deform the planning CTs to the corresponding MVCBCTs, generating pseudo CTs representing the actual anatomies on the treatment day. Fractional treatment dose was reconstructed on pseudo CTs for accumulation, representing the actual patient dose (Ddaily). To simulate weekly image guidance, fractional dose was reconstructed and accumulated by incorporating 1 CBCT-guided corrections and 4 laser-guided setups of each week (Dweekly). Limited by partially imaged volumes and different organs-at-risk of various sites, only target dose-volume parameters were evaluated across all patients.

Results

GTV_D98%, CTV_D98%, PTV_D90%, PTV_D95%, PGTV_D90%, and PGTV_D95% were evaluated, where Dx% means the minimal dose received by x% volume. Pairwise comparisons were made between plan dose and Ddaily, Ddaily and Dweekly respectively. PGTV_D95% of accumulated Dweekly were significantly lower than those of accumulated Ddaily by up to 32.90% of prescription dose, suggesting that weekly-guidance may result in unacceptable under dose to the target. The broad distribution of fractional differences between Ddaily and Dweekly suggested unreliable patient positioning based on aligning surface markers to laser beams, as a popular approach broadly used on conventional Linac systems. Slight target under-dose was observed on daily reconstructed results compared with planned dose, which provided quantitative data to guide clinical decisions such as the necessity of adaptive radiotherapy.

Conclusion

Fractional image guided radiotherapy on Halcyon provides more reliable treatment accuracy than using sacrificed imaging frequency, which also provides complete anatomic records for deformable dose reconstruction supporting more informed clinical decisions.
The Mitochondrial Chaperone TRAP1 as a Candidate Target of Oncotherapy
Authors: Xie Shulan , Wang Xuanwei , Gan Shuyuan , Tang Xiaodong , Kang Xianhui , Zhu Shengmei
Published: January 2021

Tumor necrosis factor receptor-associated protein 1 (TRAP1), a member of the heat shock protein 90 (Hsp90) chaperone family, protects cells against oxidative stress and maintains mitochondrial integrity. To date, numerous studies have focused on understanding the relationship between aberrant TRAP1 expression and tumorigenesis. Mitochondrial TRAP1 is a key regulatory factor involved in metabolic reprogramming in tumor cells that favors the metabolic switch of tumor cells toward the Warburg phenotype. In addition, TRAP1 is involved in dual regulation of the mitochondrial apoptotic pathway and exerts an antiapoptotic effect on tumor cells. Furthermore, TRAP1 is involved in many cellular pathways by disrupting the cell cycle, increasing cell motility, and promoting tumor cell invasion and metastasis. Thus, TRAP1 is a very important therapeutic target, and treatment with TRAP1 inhibitors combined with chemotherapeutic agents may become a new therapeutic strategy for cancer. This review discusses the molecular mechanisms by which TRAP1 regulates tumor progression, considers its role in apoptosis, and summarizes recent advances in the development of selective, targeted TRAP1 and Hsp90 inhibitors.
Correlation of HPV16 Gene Status and Gene Expression With Antibody Seropositivity and TIL Status in OPSCC
Authors: von Witzleben Adrian , Currall Eve , Wood Oliver , Chudley Lindsey , Akinyegun Oluyemisi , Thomas Jaya , Bendjama Kaïdre , Thomas Gareth J. , Friedmann Peter S. , King Emma V. , Laban Simon , Ottensmeier Christian H.
Published: January 2021

Introduction

Human papillomavirus 16 (HPV16) is the main cause of oropharyngeal squamous cell carcinoma (OPSCC). To date, the links between HPV16 gene expression and adaptive immune responses have not been investigated. We evaluated the correlation of HPV16 DNA, RNA transcripts and features of adaptive immune response by evaluating antibody isotypes against E2, E7 antigens and density of tumor-infiltrating lymphocytes (TIL).

Material and Methods

FFPE-tissue from 27/77 p16-positive OPSCC patients was available. DNA and RNA were extracted and quantified using qPCR for all HPV16 genes. The TIL status was assessed. Immune responses against E2 and E7 were quantified by ELISA (IgG, IgA, and IgM; 77 serum samples pre-treatment, 36 matched post-treatment).

Results

Amounts of HPV16 genes were highly correlated at DNA and RNA levels. RNA co-expression of all genes was detected in 37% (7/19). E7 qPCR results were correlated with higher anti-E7 antibody (IgG, IgA) level in the blood. Patients with high anti-E2 IgG antibody (>median) had better overall survival (p=0.0311); anti-E2 and anti-E7 IgA levels had no detectable effect. During the first 6 months after treatment, IgA but not IgG increased significantly, and >6 months both antibody classes declined over time. Patients with immune cell-rich tumors had higher levels of circulating antibodies against HPV antigens.

Conclusion

We describe an HPV16 qPCR assay to quantify genomic and transcriptomic expression and correlate this with serum antibody levels against HPV16 oncoproteins. Understanding DNA/RNA expression, relationship to the antibody response in patients regarding treatment and outcome offers an attractive tool to improve patient care.
Case Report: Afatinib Treatment in a Patient With NSCLC Harboring a Rare EGFR Exon 20 Mutation
Authors: Zöchbauer-Müller Sabine , Kaserer Bettina , Prosch Helmut , Cseh Agnieszka , Solca Flavio , Bauer Markus Johann , Müllauer Leonhard
Published: January 2021

Unlike most other primary epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC), exon 20 insertions, comprising approximately 4% to 10% of all EGFR mutations, are generally considered to be resistant to EGFR tyrosine kinase inhibitors (TKIs). However, EGFR exon 20 insertions are structurally and pharmacologically heterogeneous, with variability in their position and size having implications for response to different EGFR TKIs. The second-generation ErbB family blocker, afatinib, is approved for the first-line treatment of EGFR mutation-positive NSCLC and has been shown to have a broad inhibitory profile against common and uncommon EGFR mutations. Here, we describe a patient with bilateral multifocal lung adenocarcinoma harboring a very rare EGFR exon 20 insertion (c.2317_2319dup3; p.H773dup), who has been receiving treatment with afatinib for 4.5 years. To our knowledge, this is the first report describing long-term benefit for a patient treated with afatinib with this rare exon 20 insertion. We are aware of two further cases with this rare EGFR mutation. One patient, also reported here, has early-stage lung adenocarcinoma and has not yet received systemic therapy for NSCLC. The other patient received afatinib in the context of a global compassionate use program and had progressive disease. Our findings may be of clinical relevance for patients carrying tumors with this rare mutation as epidemiological evidence suggests that p.H773dup may function as a driver mutation in NSCLC. Together with previous preclinical and clinical evidence for the activity of afatinib against certain EGFR exon 20 insertions, these findings warrant further investigation.
Identification of Three Autophagy-Related Long Non-Coding RNAs as a Novel Head and Neck Squamous Cell Carcinoma Prognostic Signature
Authors: Guo Ya , Yang Peng Tao , Wang Zhong Wei , Xu Kun , Kou Wei Hua , Luo Heng
Published: January 2021

Head and neck squamous cell carcinoma (HNSCC) has a poor prognosis. Considerable evidence indicates that autophagy and non-coding RNA play essential roles in the biological processes involved in cancers, but associations between autophagy-related long non-coding RNAs (lncRNAs) and HNSCC remain unclear. In the present study, HNSCC RNA sequences and autophagy-related gene data were extracted from The Cancer Genome Atlas database and the Human Autophagy Database. A total of 1,153 autophagy-related lncRNAs were selected via calculating Pearson’s correlation coefficient. Three prognosis-related autophagy lncRNAs were identified via univariate Cox regression, least absolute shrinkage and selection operator analysis, and multivariate Cox regression analysis. We also constructed a prognostic model based on these autophagy-related lncRNAs and evaluated its ability to accurately and independently predict the prognosis of HNSCC patients. The area under the curve (AUC) was 0.864 (3-year) and 0.836 (5-year), and our model can independently predict the prognosis of HNSCC. The prognostic value of the three autophagy lncRNAs was confirmed via analysis of samples from five databases. To further identify the functions of the three lncRNAs, a co-expression network was constructed and pathway analysis was performed. In that analysis the lncRNAs were correlated with 189 related genes and 20 autophagy-related genes, and these lncRNAs mainly involved homologous recombination, the Fanconi anemia pathway, the autophagy-related pathway, and immune-related pathways. In addition, we validated the expression levels of three lncRNAs and autophagy markers (ATG12, BECN1, and MAP1LC3B) based on TIMER, Oncomine, and HPA database analysis. Our results indicated that TTTY15 was increased in HPV positive and HPV negative HNSCC patients, and three autophagy markers were up-regulated in all HNSCCC patients. Lastly, association between three lncRNAs and autophagy markers was performed, and our results showed that TTTY15 and MIF-AS1 were associated with autophagy markers. Collectively, these results suggested that three autophagy-related lncRNAs have prognostic value in HNSCC patients.
Everolimus in Invasive Malignant Renal Epithelioid Angiomyolipoma
Authors: Guo Gang , Gu Liangyou , Zhang Xu
Published: January 2021

Background

To evaluate the efficacy and safety of everolimus, a mTOR inhibitor, on invasive malignant renal epithelioid angiomyolipoma (EAML).

Materials and Methods

From Oct 2014 to May 2019, we collected data from seven patients with a definite (clinical and pathological) diagnosis of EAML received everolimus in our hospital. Targeted sequence capture array technique with next-generation of high throughput sequencing (NGS) were performed to detect mutations of TSC1/2 genes. All patients had received surgery and everolimus. The clinical efficacy and safety of the therapy were evaluated.

Results

Mutations of TSC1 and TSC2 were detected in two and three patients though targeted sequence capture array technique with NGS, respectively. Among seven patients, three had missense mutations, one had nonsense mutation, and one had the large fragment deletion mutation. Five patients accompanied with tuberous sclerosis complex (TSC) were identified. All patients were administered 10mg everolimus once daily, the treatment duration lasted for 3 to 28 months. The objective response was assessed 3 months later, five partial response, two stable disease (SD), the mean greatest tumor diameter of all patients decreased from 9.6 to 5.2cm. Six patients stayed SD and one patient died during follow up. Patients accompanying with TSC had better responses to everolimus compared with non-TSC.

Conclusion

The mTOR inhibitor can be an effective treatment for patients with invasive malignant renal EAML. Patients with TSC may benefit more from the therapy.
Inflammation-Driven Breast Tumor Cell Plasticity: Stemness/EMT, Therapy Resistance and Dormancy
Authors: Baram Tamir , Rubinstein-Achiasaf Linor , Ben-Yaakov Hagar , Ben-Baruch Adit
Published: January 2021

Cellular heterogeneity poses an immense therapeutic challenge in cancer due to a constant change in tumor cell characteristics, endowing cancer cells with the ability to dynamically shift between states. Intra-tumor heterogeneity is largely driven by cancer cell plasticity, demonstrated by the ability of malignant cells to acquire stemness and epithelial-to-mesenchymal transition (EMT) properties, to develop therapy resistance and to escape dormancy. These different aspects of cancer cell remodeling are driven by intrinsic as well as by extrinsic signals, the latter being dominated by factors of the tumor microenvironment. As part of the tumor milieu, chronic inflammation is generally regarded as a most influential player that supports tumor development and progression. In this review article, we put together recent findings on the roles of inflammatory elements in driving forward key processes of tumor cell plasticity. Using breast cancer as a representative research system, we demonstrate the critical roles played by inflammation-associated myeloid cells (mainly macrophages), pro-inflammatory cytokines [such as tumor necrosis factor α (TNFα) and interleukin 6 (IL-6)] and inflammatory chemokines [primarily CXCL8 (interleukin 8, IL-8) and CXCL1 (GROα)] in promoting tumor cell remodeling. These inflammatory components form a common thread that is involved in regulation of the three plasticity levels: stemness/EMT, therapy resistance, and dormancy. In view of the fact that inflammatory elements are a common denominator shared by different aspects of tumor cell plasticity, it is possible that their targeting may have a critical clinical benefit for cancer patients.
TBX1 Functions as a Tumor Activator in Prostate Cancer by Promoting Ribosome RNA Gene Transcription
Authors: Cui Jie , Zhang Yamin , Ren Xiaoyue , Jin Lei , Zhang Hongyi
Published: January 2021

TBX1 belongs to an evolutionarily conserved family of transcription factors involved in organ development. TBX1 has been reported to have a hypermethylated cytosine guanine dinucleotide island around its second exon, which was related to prostate cancer (PCa) progression. However, the role and exact mechanism of TBX1 in PCa remains unknown. Using human prostate samples, online data mining and multiple in vitro and in vivo models, we examined the biological role and underlying mechanisms of TBX1 in PCa. TBX1 was highly expressed in PCa tissues, and high TBX1 expression was positively associated with Gleason score, pathological tumor stage, pathological lymph node stage, extraprostatic extension and disease/progression-free survival. In vitro and in vivo data demonstrated that TBX1 silencing inhibits PCa cell proliferation and colony formation and increases the cell population at the G0/G1 phase. The exogenous expression of TBX1 rescued these phenotypes. Mechanistically, TBX1 silencing suppressed the expression of 45S ribosomal RNA (rRNA), which was rescued by the exogenous expression of TBX1. TBX1 silencing inhibited the monomethylation of histone 3 lysine 4 (H3K4me1) binding with the non-coding intergenic spacer (IGS) regions of ribosomal DNA (rDNA) and the recruitment of upstream binding factor to the promoter and IGS regions of rDNA. The drug-induced enhancement of H3K4me1 counteracted the effect of TBX1 silencing. These findings indicate that TBX1 exerts its tumor activator function in PCa cells via epigenetic control, thereby promoting rRNA gene transcription. Thus, TBX1 may represent a prognostic biomarker and therapeutic target for PCa patients.
Low Pretreatment Albumin-to-Globulin Ratio Predicts Poor Prognosis in Gastric Cancer: Insight From a Meta-Analysis
Authors: Wei Chengzhi , Yu Zhu , Wang Gonghe , Zhou Yiming , Tian Lei
Published: January 2021

Background

In recent five years, reports regarding albumin-to-globulin ratio (AGR) and the survival of gastric cancer (GC) have emerged rapidly, yet their association remains controversial. This meta-analysis was aimed to provide an insight into the prognostic significance of pretreatment AGR in GC.

Methods

PubMed, Embase, Cochrane library, Web of Science, WanFang, China National Knowledge Infrastructure (CNKI) and VIP databases were searched for relevant studies, from inception to September 30, 2020. Individual hazard ratios (HRs) with their 95% confidence intervals (CIs) were combined by Stata 12.0 software to evaluate the association between pretreatment AGR and overall survival (OS) and disease-free survival/progression-free survival (DFS/PFS).

Results

A total of 8,305 patients with GC from 12 studies were included for further analysis. Pooled analyses indicated that low AGR was closely associated with worse OS (HR = 1.531, 95% CI: 1.300–1.803, P < 0.001) and worse DFS/PFS (HR = 2.008, 95% CI: 1.162–3.470, P = 0.012) in GC patients. Moreover, subgroup analyses demonstrated that the association between low AGR and worse OS remained constant despite variations in country, tumor stage, cut-off value, cut-off selection and treatment method.

Conclusion

AGR could act as an efficient prognostic indicator for GC, and that low pretreatment AGR predicts poor prognosis in GC.
Upregulation of Long Non-Coding RNA GCC2-AS1 Facilitates Malignant Phenotypes and Correlated With Unfavorable Prognosis for Lung Adenocarcinoma
Authors: Yu Fengqiang , Liang Mingqiang , Wu Weidong , Huang Yu , Zheng Jiantao , Zheng Bin , Chen Chun
Published: January 2021

Background

The role played by long noncoding RNA GCC2-AS1 in primary malignant tumors remains poorly understood. This study aimed to determine the expression levels and evaluate the clinical significance and biological effects of GCC2-AS1 in lung adenocarcinoma (LUAD).

Methods

We used data obtained from tissue samples and the TCGA database to determine the levels of GCC2-AS1 expression LUAD patients, and the prognostic value of those levels. Functional experiments were performed to investigate the effect of GCC2-AS1 on LUAD cells. Genes that were differentially expressed in GCC2-AS1-low and -high groups were analyzed by an enrichment analysis. Additionally, a nomogram model was created and subgroup analyses were performed to further determine the prognostic value of GCC2-AS1 in LUAD.

Results

GCC2-AS1 expression was significantly upregulated in lung adenocarcinoma tissues as compared with normal tissues. Depletion of GCC2-AS1 inhibited the proliferation and invasion of LUAD cells in vitro. An elevated level of GCC2-AS1 was strongly correlated with shorter overall survival time and was identified as an independent prognostic marker for LUAD patients. Enrichment analyses conducted using GO, KEGG, and GSEA databases were performed to identify biological pathways that might involve GCC2-AS1. Several subgroups were found to have a significant prognostic value for patients in the GCC2-AS1-low and -high groups.

Conclusions

Our findings suggest that GCC2-AS1 can serve as a diagnostic and prognostic biomarker for LUAD patients.
Minimally Invasive Management of Bladder Stones in Children
Authors: Esposito Ciro , Autorino Giuseppe , Masieri Lorenzo , Castagnetti Marco , Del Conte Fulvia , Coppola Vincenzo , Cerulo Mariapina , Crocetto Felice , Escolino Maria
Published: January 2021

Background: Bladder stones (BS) are rare in children. Minimally invasive surgery (MIS) seems to be nowadays the procedure of choice to treat pediatric patients with BS. This study aimed to analyze retrospectively our experience with percutaneous cystolithotomy, endourological treatment with Holmium laser and robotic cystolithotomy in children with BS.

Methods: We retrospectively analyzed the data of 13 children (eight boys and five girls) with BS who were treated at our centers between July 2013 and July 2020. The patients received three different MIS procedures for stones removal: five underwent robotic cystolithotomy, five underwent endourological treatment and three received percutaneous cystolithotomy (PCCL). We preferentially adopted endourological approach for stones <10 mm, percutaneous approach between 2014 and 2016 and robotic approach since 2016 for larger stones.

Results: Mean patients' age at the time of diagnosis was 13 years (range 5–18). Ten/13 patients (76.9%) had primary BS and 3/13 patients (23.1%) had secondary BS. Mean stone size was 18.8 mm (range 7–50). In all cases the stones were removed successfully. One Clavien II post-operative complication occurred following PCCL (33.3%). All the procedures were completed without conversions. Operative time ranged between 40 and 90 min (mean 66) with no significant difference between the three methods (p = 0.8). Indwelling bladder catheter duration was significantly longer after PCCL (mean 72 h) compared with robotic and endourological approaches (mean 15.6 h) (p = 0.001). Hospitalization was significantly longer after PCCL (mean 7.6 days) compared with the other two approaches (mean 4.7 days) (p = 0.001). The endourological approach was the most cost-effective method compared with the other two approaches (p = 0.001).

Conclusions: Minimally invasive management of bladder stones in children was safe and effective. Endourological management was the most cost-effective method, allowing a shorter hospital stay compared with the other procedures but it was mainly indicated for smaller stones with a diameter < 10 mm. Based upon our preliminary results, robotic surgery seemed to be a feasible treatment option for BS larger than 15–20 mm. It allowed to remove the big stones without crushing them with a safe and easy closure of the bladder wall thanks to the easy suturing provided by the Robot technology.
2-NPPA Mitigates Osteoclastogenesis via Reducing TRAF6-Mediated c-fos Expression
Authors: Chen Zhihao , Ding Mina , Cho Eunjin , Seong Jihyoun , Lee Sunwoo , Lee Tae-Hoon
Published: January 2021

Excessive bone resorption leads to bone destruction in pathological bone diseases. Osteoporosis, which occurs when osteoclast-mediated bone resorption exceeds osteoblast-mediated bone synthesis, is regarded a global health challenge. Therefore, it is of great importance to identify agents that can regulate the activity of osteoclasts and prevent bone diseases mediated mainly by bone loss. We screened compounds for this purpose and found that 2-(2-chlorophenoxy)-N-[2-(4-propionyl-1piperazinyl) phenyl] acetamide (2-NPPA) exhibited a strong inhibitory effect on osteoclastogenesis. 2-NPPA suppressed the mRNA and protein expression of several osteoclast-specific markers and blocked the formation of mature osteoclasts, reducing the F-actin ring formation and bone resorption activity. In a cell signaling point of view, 2-NPPA exhibited a significant inhibitory effect on the phosphorylation of nuclear factor kappa-B (NF-κB) and c-fos expression in vitro and prevented ovariectomy-induced bone loss in vivo. These findings highlighted the potential of 2-NPPA as a drug for the treatment of bone loss-mediated disorders.
Unraveling the Contribution of Fluid Therapy to the Development of Augmented Renal Clearance in a Piglet Model
Authors: Dhondt Laura , Croubels Siska , De Paepe Peter , Goethals Klara , De Cock Pieter , Devreese Mathias
Published: January 2021

Augmented renal clearance (ARC) observed in the critically ill pediatric population has received an increased attention over the last years due to its major impact on the disposition and pharmacokinetics of mainly renally excreted drugs. Apart from an important inflammatory trigger, fluid administration has been suggested to contribute to the development of ARC. Therefore, the primary objective of this study was to evaluate the effect of continuous intravenous fluid administration on renal function using a conventional piglet animal model and to quantify the impact of fluid administration on the pharmacokinetics of renally excreted drugs. At baseline, twenty-four piglets (12 treatment/12 control; 7 weeks old, all ♂) received the marker drugs iohexol (64.7 mg/kg body weight (BW)) and para-aminohippuric acid (10 mg/kg BW) to quantify glomerular filtration rate and effective renal plasma flow, respectively. In addition, the hydrophilic antibiotic amikacin (7.5 mg/kg BW) was administered. Following this baseline measurement, the treatment group received fluid therapy as a constant rate infusion of 0.9% saline at 6 mL/kg/h over 36 h. After 24 h of fluid administration, the marker drugs and amikacin were administered again. When comparing both groups, a significant effect of fluid administration on the total body clearances of iohexol (p= 0.032) and amikacin (p= 0.0014) was observed. Clearances of iohexol and amikacin increased with on average 15 and 14%, although large interindividual variability was observed. This led to decreased systemic exposure to amikacin, which was manifested as decrease in area under the plasma concentration-time curve from time 0 h to infinity from 34,807 to 30,804 ng.h/mL. These results suggest that fluid therapy is a key factor involved in the development of ARC and should be taken into account when administering mainly renally excreted drugs. However, further research is necessary to confirm these results in children.
Corydalis Saxicola Bunting Total Alkaloids Attenuate Walker 256-Induced Bone Pain and Osteoclastogenesis by Suppressing RANKL-Induced NF-κB and c-Fos/NFATc1 Pathways in Rats
Authors: Ju Linjie , Hu Peipei , Chen Ping , Wu Jiejie , Li Zhuoqun , Qiu Zhixia , Cheng Jun , Huang Fang
Published: January 2021

Metastatic bone pain is characterized by insufferable bone pain and abnormal bone structure. A major goal of bone cancer treatment is to ameliorate osteolytic lesion induced by tumor cells. Corydalis saxicola Bunting total alkaloids (CSBTA), the alkaloid compounds extracted from the root of C. saxicola Bunting, have been shown to possess anticancer and analgesic properties. In this study, we aimed to verify whether CSBTA could relieve cancer induced bone pain and inhibit osteoclastogenesis. The in vivo results showed that CSBTA ameliorated Walker 256 induced bone pain and osteoporosis in rats. Histopathological changes also supported that CSBTA inhibited Walker 256 cell-mediated osteolysis. Further in vitro analysis confirmed that CSBTA reduced the expression of RANKL and downregulate the level of RANKL/OPG ratio in breast cancer cells. Moreover, CSBTA could inhibit osteoclastogenesis by suppressing RANKL-induced NF-κB and c-Fos/NFATc1 pathways. Collectively, this study demonstrated that CSBTA could attenuate cancer induced bone pain via a novel mechanism. Therefore, CSBTA might be a promising candidate drug for metastatic bone pain patients.
Cost-Effectiveness of Genomic Test-Directed Olaparib for Metastatic Castration-Resistant Prostate Cancer
Authors: Su Dan , Wu Bin , Shi Lizheng
Published: January 2021

Purpose: The effectiveness of poly (adenosine diphosphate–ribose) polymerase (PARP) inhibitor olaparib for metastatic castration-resistant prostate cancer (MCRPC) with multiple loss-of-function alterations in genes that are involved in DNA repair has been demonstrated. We aimed to evaluate the cost-effectiveness of genomic test-directed olaparib on MCRPC from the US payer perspective.

Methods: A partitioned survival model was adopted to project the disease course of MCRPC had at least one gene alteration in BRCA1, BRCA2 and ATM (Scenario A) and has alterations in any of all 15 prespecified genes (Scenario B) after next-generation sequencing test. The efficacy and toxicity data were gathered from the PROfound trial. Clinical probabilities related to survival were estimated from the reported survival probabilities in each PROfound group. Cost and health preference data were derived from the literature. The incremental cost-effectiveness ratio (ICER) was measured. Subgroup analysis and sensitivity analysis were performed for exploring the model uncertainties.

Results: Olaparib yielded an additional 0.063 and 0.068 of quality-adjusted life year (QALY) with the augmented cost of $7,382 and saved the cost of $ 1,980 compared to standard care in scenario A and B, respectively, which yielded an ICER of $116,903/QALY and a cost-saving option. The lower weekly cost related to olaparib treatment led to the dominant findings in scenario B. The varied results between scenario A and B could be partly explained by different the number need to screen for identifying eligible patients who could be administered with olaparib, which sharply augmented the costs of the olaparib arm in scenario A. Subgroup analysis and sensitivity analysis revealed the results were generally robust in both of two scenarios.

Conclusion: The genomic test-directed olaparib is a preferred option compared with standard care strategy for men with MCRPC who had any of all 15 prespecified genes.
Interleukin-1 Blockade in Polygenic Autoinflammatory Disorders: Where Are We now?
Authors: Malcova Hana , Milota Tomas , Strizova Zuzana , Cebecauerova Dita , Striz Ilja , Sediva Anna , Horvath Rudolf
Published: January 2021

Polygenic autoinflammatory diseases (AIDs), such as systemic juvenile idiopathic arthritis (sJIA), adult-onset Still's disease, Kawasaki disease, idiopathic recurrent pericarditis (IRP), Behçet’s Syndrome, Crystal-induced arthropatihes such as gout or Calcium pyrophosphate deposition disease are characterized by the overexpression of inflammasome-associated genes, leading to a dysregulation of the innate immune response. The IL-1 cytokine family (IL-1α, IL-1β, IL-1Ra, IL-18, IL-36Ra, IL-36α, IL-37, IL-36β, IL-36g, IL-38, IL-33) was defined to be principally responsible for the inflammatory nature of polygenic AIDs. Several clinical trials were initiated, and IL-1 blockade has been proven to cause a rapid reduction of clinical symptoms and normalization of laboratory parameters in the majority of cases. Randomized, placebo-controlled, clinical trials, together with registry-based clinical trials and open-label, retrospective and prospective observational studies, supported the efficacy and safety of IL-1 inhibitors in the treatment of polygenic AIDs. Most of the current data are focused on the therapeutic use of anakinra, an IL-1 receptor antagonist, canakinumab, an anti-IL-1β monoclonal antibody, and rilonacept, a soluble decoy receptor. However, other promising agents, such as gevokizumab, IL-1β blocking monoclonal antibody, tadekinig alfa, a human recombinant IL-18-binding protein, and tranilast, an analog of a tryptophan metabolite, are currently being tested. Anakinra, canakinumab and rilonacept caused impressive improvements in both systemic and musculoskeletal symptoms. Furthermore, the anti-IL-1 therapy allowed corticosteroid tapering and, in some cases, even withdrawal. This article reviews the current IL-1 inhibitors and the results of all clinical trials in which they have been tested for the management of broad spectrum of polygenic AIDs.
Osthole Alleviates Neointimal Hyperplasia in Balloon-Induced Arterial Wall Injury by Suppressing Vascular Smooth Muscle Cell Proliferation and Downregulating Cyclin D1/CDK4 and Cyclin E1/CDK2 Expression
Authors: Li Yi-Qi , Li Ye-Li , Li Xiao-Tong , Lv Jun-Yuan , Gao Yang , Li Wen-Na , Gong Qi-Hai , Yang Dan-Li
Published: January 2021

Percutaneous coronary intervention (PCI) is the most widely used therapy for treating ischemic heart disease. However, intimal hyperplasia and restenosis usually occur within months after angioplasty. Modern pharmacological researchers have proven that osthole, the major active coumarin of Cnidium monnieri (L.) Cusson, exerts potent antiproliferative effects in lung cancer cells, the human laryngeal cancer cell line RK33 and TE671 medulloblastoma cells, and its mechanism of action is related to cell cycle arrest. The goal of the present study was to observe the effect of osthole on vascular smooth muscle cell (VSMC) proliferation using platelet-derived growth factor-BB (PDGF-BB)-stimulated VSMCs isolated from rats and vascular balloon injury as models to further elucidate the molecular mechanisms underlying this activity. We detected the relative number of VSMCs by the MTT assay and EdU staining and examined cell cycle progression by flow cytometry. To more deeply probe the mechanisms, the protein expression levels of PCNA, the cyclin D1/CDK4 complex and the cyclin E1/CDK2 complex in balloon-treated rat carotid arteries and the mRNA and protein expression levels of the cyclin D1/CDK4 and cyclin E1/CDK2 complexes in VSMCs were detected by real-time RT-PCR and western blotting. The data showed that osthole significantly inhibited the proliferation of VSMCs induced by PDGF-BB. Furthermore, osthole caused apparent VSMC cycle arrest early in G0/G1 phase and decreased the expression of cyclin D1/CDK4 and cyclin E1/CDK2. Our results demonstrate that osthole can significantly inhibit PDGF-BB-induced VSMC proliferation and that its regulatory effects on cell cycle progression and proliferation may be related to the downregulation of cyclin D1/CDK4 and cyclin E1/CDK2 expression as well as the prevention of cell cycle progression from G0/G1 phase to S phase. The abovementioned mechanism may be responsible for the alleviation of neointimal hyperplasia in balloon-induced arterial wall injury by osthole.
Ketones for Post-exercise Recovery: Potential Applications and Mechanisms
Authors: Mansor Latt Shahril , Woo Geoffrey Hubert
Published: January 2021

Ketogenic diet has been introduced in therapeutic areas for more than a century, but the role of ketones in exercise performance has only been explored in the past decade. One of the main reasons that allows the investigation of the role of ketones in exercise performance is the emergence of exogenous ketones, allowing athletes to achieve the state of ketosis acutely, and independent of their metabolic states. While there are mixed results showing either exogenous ketones improve exercise performance or no effect, the mechanisms of action are still being heavily researched. Moreover, these early data from exercise physiology studies suggested that exogenous ketones may play a more prominent role in post-exercise recovery, leading to a more pronounced cumulative impact over subsequent exercise performance. This review will look at existing evidence on the role of ketones in recovery and attempt to identify the current best practices and potential mechanisms that drive improved recovery.
Modulation of Ion Transport Across Plant Membranes by Polyamines: Understanding Specific Modes of Action Under Stress
Authors: Pottosin Igor , Olivas-Aguirre Miguel , Dobrovinskaya Oxana , Zepeda-Jazo Isaac , Shabala Sergey
Published: January 2021

This work critically discusses the direct and indirect effects of natural polyamines and their catabolites such as reactive oxygen species and γ-aminobutyric acid on the activity of key plant ion-transporting proteins such as plasma membrane H+ and Ca2+ ATPases and K+-selective and cation channels in the plasma membrane and tonoplast, in the context of their involvement in stress responses. Docking analysis predicts a distinct binding for putrescine and longer polyamines within the pore of the vacuolar TPC1/SV channel, one of the key determinants of the cell ionic homeostasis and signaling under stress conditions, and an additional site for spermine, which overlaps with the cytosolic regulatory Ca2+-binding site. Several unresolved problems are summarized, including the correct estimates of the subcellular levels of polyamines and their catabolites, their unexplored effects on nucleotide-gated and glutamate receptor channels of cell membranes and Ca2+-permeable and K+-selective channels in the membranes of plant mitochondria and chloroplasts, and pleiotropic mechanisms of polyamines’ action on H+ and Ca2+ pumps.
Psychological Predictors of COVID-19 Prevention Behavior in Hungarian Women Across Different Generations
Authors: Marschalko Eszter Eniko , Kotta Ibolya , Kalcza-Janosi Kinga , Szabo Kinga , Jancso-Farcas Susana
Published: January 2021

Background

Age related differences were found in prevention behavior, showing that older individuals tend to be the most proactive. The aim of the study was the identification of psychological predictors on COVID-19 prevention behavior in women, across four generations. In addition, the predictive role of the psychological variables was explored through the lens of negative and positive information processing perspective on total and domain-specific COVID-19 prevention behavior.

Methods

A cross-sectional research was conducted. The sample included 834 Hungarian speaking women. The assessed variables were: COVID-19 knowledge, risk perception, COVID-19 health anxiety, negative automatic thoughts, psychological flexibility, and four domains of COVID-19 prevention behavior (social distancing, general hygiene, information seeking, health behavior). A three-level hierarchical linear regression analysis was conducted to investigate the predictors of preventive behavior in each generation.

Results

A diversity across generations was found. In case of baby boomer generation, the final model explained 32.4% of the variance for total prevention behavior [F(14,215) = 8.847,p< 0.001], and only perceived risk made a significant contribution. For Gen X the final model accounted for 21.1% of variance of total prevention behavior [F(14,341) = 7.788,p< 0.001], marital status, perceived risk, COVID-19 health anxiety, and negative automatic thoughts made significant contributions. In case of Gen Y the final model accounted for 6.2% of variance on total prevention behavior [F(14,147) = 1.761,p= 0.05], only perceived risk had a contribution to the final model. For Gen Z the final model accounted for 23.4% of variance on total preventive behavior [F(13,71) = 2.979,p= 0.002], and only psychological flexibility made a contribution to the model. The results on the distinct domains of COVID-19 prevention behavior emphasized details in the dissimilarity among generations.

Conclusion

The role of generational identity on COVID-19 prevention behavior is relevant. The coexistence of negative and positive information processing may have its beneficial role in certain areas of prevention.
Understanding the Transient Nature of STEM Doctoral Students’ Research Self-Efficacy Across Time: Considering the Role of Gender, Race, and First-Generation College Status
Authors: Litson Kaylee , Blaney Jennifer M. , Feldon David F.
Published: January 2021

Developing research self-efficacy is an important part of doctoral student preparation. Despite the documented importance of research self-efficacy, little is known about the progression of doctoral students’ research self-efficacy over time in general and for students from minoritized groups. This study examined both within- and between-person stability of research self-efficacy from semester to semester over 4 years, focusing on doctoral students in biological sciences (N = 336). Using random intercept autoregressive analyses, we evaluated differences in stability across gender, racially minoritized student status, and first-generation student status. Results showed similar mean levels of self-efficacy across demographic groups and across time. However, there were notable differences in between-person and within-person stability over time, specifically showing higher between-person and lower within-person stability for racially minoritized and first-generation students. These findings indicate that racially minoritized and first-generation students’ research self-efficacy reports were less consistent from semester to semester. Such results may indicate that non-minoritized and continuing-generation students’ experiences from semester to semester typically reinforce their beliefs about their own abilities related to conducting research, while such is not the case for racially minoritized nor first-generation students. Future research should examine what types of experiences impact self-efficacy development across doctoral study to offer more precise insights about factors that influence these differences in within-person stability.
Nonverbal Behaviors “Speak” Relational Messages of Dominance, Trust, and Composure
Authors: Burgoon Judee K. , Wang Xinran , Chen Xunyu , Pentland Steven J. , Dunbar Norah E.
Published: January 2021

Nonverbal signals color the meanings of interpersonal relationships. Humans rely on facial, head, postural, and vocal signals to express relational messages along continua. Three of relevance are dominance-submission, composure-nervousness and trust-distrust. Machine learning and new automated analysis tools are making possible a deeper understanding of the dynamics of relational communication. These are explored in the context of group interactions during a game entailing deception. The “messiness” of studying communication under naturalistic conditions creates many measurement and design obstacles that are discussed here. Possibilities for their mitigation are considered.
Respiratory Symptoms and Urinary Cotinine Levels in Pre-school Children Exposed to Environmental Tobacco Smoke
Authors: Wang Yun , Huang Zhiqiang , Luo Dan , Tian Lang , Hu Mi , Xiao Shuiyuan
Published: January 2021

Objective: Preschool children exposed to environmental tobacco smoke (ETS) are at risk of developing adverse respiratory health effects. The present study aimed to investigate the relationship between the effects of cigarette-smoking caregivers on respiratory symptoms and urinary cotinine (UC) levels in children.

Methods: A cross-sectional study consisting of 543 children (aged between 5 and 6 years) from 5 kindergartens in central China was conducted using a structured questionnaire. We also analyzed UC levels to investigate the relationship between respiratory symptoms and ETS exposure. We further performed logistic regression analyses to establish the relationship between respiratory symptoms (coughing, rhinorrhea, and sneezing) and UC levels.

Results: A total of 71 (13.08%) children had a history of hospital admission with respiratory illnesses including bronchitis and pneumonia over the last 6 months. In addition, 102 (18.78%) children presented coughing symptoms, 114 (20.99%) experienced rhinorrhea and 79 (14.55%) presented sneezing symptoms over the last 6 months. After adjusting the confounders, odds ratio (OR) indicated that the number of cigarettes smoked by a caregiver was associated with coughing (OR = 11.02; 95% CI, 3.72–33.66), rhinorrhea (OR = 41.83; 95% CI, 5.58–313.05) and sneezing (OR = 4.71; 95% CI, 1.33–16.48). Furthermore, UC levels in children with coughing, rhinorrhea and sneezing were significantly higher than in children without respiratory symptoms (P = 0.002, P < 0.001, P < 0.001, respectively).

Conclusions: This study reveals that children exposed to ETS have higher levels of UC. Compared with caregiver who non-smoked live with children, smoked cigarettes were highly risk of developing respiratory illnesses in children. Notably, the higher the UC levels the greater the respiratory risk. Our results also signify that UC can be used as an indicator of ETS exposure to inform caregivers of the associated risks, and inform efforts to reduce related effects.
Sensitivity of SARS-CoV-2 Detection With Nasopharyngeal Swabs
Authors: Clerici Bianca , Muscatello Antonio , Bai Francesca , Pavanello Donatella , Orlandi Michela , Marchetti Giulia C. , Castelli Valeria , Casazza Giovanni , Costantino Giorgio , Podda Gian Marco
Published: January 2021

Background: SARS-CoV-2-infected subjects have been proven contagious in the symptomatic, pre-symptomatic and asymptomatic phase. The identification of these patients is crucial in order to prevent virus circulation. No reliable data on the sensitivity of nasopharyngeal swabs (NPS) are available because of the lack of a shared reference standard to identify SARS-CoV-2 infected patients. The aim of our study was to collect data on patients with a known diagnosis of COVID-19 who underwent serial testing to assess NPS sensitivity.

Methods: The study was a multi-center, observational, retrospective clinical study with consecutive enrollment. We enrolled patients who met all of the following inclusion criteria: clinical recovery, documented SARS-CoV-2 infection (≥1 positive rRT-PCR result) and ≥1 positive NPS among the first two follow-up swabs. A positive NPS not preceded by a negative nasopharyngeal swab collected 24–48 h earlier was considered a true positive. A negative NPS followed by a positive NPS collected 24–48 h later was regarded as a false negative. The primary outcome was to define sensitivity of SARS-CoV-2 detection with NPS.

Results: Three hundred and ninety three NPS were evaluated in 233 patients; the sensitivity was 77% (95% CI, 73 to 81%). Sensitivity of the first follow-up NPS (n = 233) was 79% (95% CI, 73 to 84%) with no significant variations over time. We found no statistically significant differences in the sensitivity of the first follow-up NPS according to time since symptom onset, age, sex, number of comorbidities, and onset symptoms.

Conclusions: NPS utility in the diagnostic algorithm of COVID-19 should be reconsidered.