bluuebunny/crossref_metadata_2025_split huggingface dataset:
Magnetic Resonance Guided Radiation Therapy for Pancreatic Adenocarcinoma, Advantages, Challenges, Current Approaches, and Future Directions
Authors: Hall William A. , Small Christina , Paulson Eric , Koay Eugene J. , Crane Christopher , Intven Martijn , Daamen Lois A. , Meijer Gert J. , Heerkens Hanne D. , Bassetti Michael , Rosenberg Stephen A. , Aitken Katharine , Myrehaug Sten , Dawson Laura A. , Lee Percy , Gani Cihan , Chuong Michael David , Parikh Parag J. , Erickson Beth A. 
Published: May 2021

IntroductionPancreatic adenocarcinoma (PAC) has some of the worst treatment outcomes for any solid tumor. PAC creates substantial difficulty for effective treatment with traditional RT delivery strategies primarily secondary to its location and limited visualization using CT. Several of these challenges are uniquely addressed with MR-guided RT. We sought to summarize and place into context the currently available literature on MR-guided RT specifically for PAC.MethodsA literature search was conducted to identify manuscript publications since September 2014 that specifically used MR-guided RT for the treatment of PAC. Clinical outcomes of these series are summarized, discussed, and placed into the context of the existing pancreatic literature. Multiple international experts were involved to optimally contextualize these publications.ResultsOver 300 manuscripts were reviewed. A total of 6 clinical outcomes publications were identified that have treated patients with PAC using MR guidance. Successes, challenges, and future directions for this technology are evident in these publications. MR-guided RT holds theoretical promise for the treatment of patients with PAC. As with any new technology, immediate or dramatic clinical improvements associated with its use will take time and experience. There remain no prospective trials, currently publications are limited to small retrospective experiences. The current level of evidence for MR guidance in PAC is low and requires significant expansion. Future directions and ongoing studies that are currently open and accruing are identified and reviewed.ConclusionsThe potential promise of MR-guided RT for PAC is highlighted, the challenges associated with this novel therapeutic intervention are also reviewed. Outcomes are very early, and will require continued and long term follow up. MR-guided RT should not be viewed in the same fashion as a novel chemotherapeutic agent for which dosing, administration, and toxicity has been established in earlier phase studies. Instead, it should be viewed as a novel procedural intervention which must be robustly tested, refined and practiced before definitive conclusions on the potential benefits or detriments can be determined. The future of MR-guided RT for PAC is highly promising and the potential implications on PAC are substantial.
Percutaneous Microwave Ablation Versus Open Surgical Resection for Colorectal Cancer Liver Metastasis
Authors: Zhao Qinxian , Cheng Zhigang , Han Zhiyu , Liu Fangyi , Yu Xiaoling , Tan Xianliang , Han Bin , Dou Jianping , Yu Jie , Liang Ping 
Published: May 2021

PurposeTo compare the therapeutic outcomes between open surgical resection (OSR) and percutaneous microwave ablation (PMWA) for colorectal liver metastasis (CRLM) ≤3 cm.MethodsIn this retrospective study, 200 consecutive patients with 306 CRLMs were reviewed. Overall survival (OS), disease-free survival (DFS), local tumour progression (LTP), intrahepatic distant recurrence, and extrahepatic metastasis were analysed to compare the therapeutic efficacy. Cox proportional hazards regression analysis was used to identify the prognostic factors for OS and DFS. Major complications and postoperative hospital stay were also assessed.ResultThe 1-, 3-, and 5-year OS rates were 91.6%, 64.1%, and 46.3%, respectively, in the PMWA group and 89.7%, 62.4% and 44.7%, respectively, in the OSR group (P=0.839). The 1-, 3-, and 5-year DFS rates were 61.9%, 44.8%, and 41.3%, respectively, in the PMWA group and 58.1%, 24.4%, and 18.3%, respectively, in the OSR group (P =0.066). The two groups had comparable 5-year cumulative rates of intrahepatic distant recurrence (P=0.627) and extrahepatic metastasis (P=0.884). The 5-year cumulative LTP rate was lower in the OSR group than in the PMWA group (P=0.023). The rate of major complications was higher in the OSR group than in the PMWA group (P =0.025), and the length of hospital stay after treatment was shorter in the PMWA group (P&lt;0.001).ConclusionThere were no significant differences in OS or DFS between the two groups. PMWA was associated with increased LTP, fewer postoperative days and fewer major complications.
Targeted Therapy With PI3K and FGFR Inhibitors on Human Papillomavirus Positive and Negative Tonsillar and Base of Tongue Cancer Lines With and Without Corresponding Mutations
Authors: Holzhauser Stefan , Wild Nicole , Zupancic Mark , Ursu Ramona G. , Bersani Cinzia , Näsman Anders , Kostopoulou Ourania N. , Dalianis Tina 
Published: May 2021

ObjectivesHuman papillomavirus positive (HPV+) tonsillar and base of tongue squamous cell carcinoma (TSCC/BOTSCC), the major subsites of oropharyngeal squamous cell carcinoma (OPSCC) have favorable outcome, but upon relapse, outcome is poor and new therapies needed. Since, phosphatidyl-inositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) and fibroblast-growth-factor-receptor-3 (FGFR3) mutations often occur in such tumors, here, we tested targeted therapy directed to such genes in TSCC/BOTSCC cell lines. We also combined the two types of inhibitors with each other, and cisplatin or docetaxel that are used clinically.MethodsThe HPV+ CU-OP-2, -3, -20, UPCI-SCC-154, and HPV- CU-OP-17 and UT-SCC-60A cell lines were first tested for common PIK3CA/FGFR3 mutations by competitive-allele-specific TaqMan-PCR. They were then treated with the food and drug administration (FDA) approved drugs, alpelisib (BYL719) and erdafitinib (JNJ-42756493) alone and in combination with cisplatin or docetaxel. Viability, proliferation, apoptosis and cytotoxicity responses were thereafter followed by WST-1 assays and the IncuCyte S3 Live® Cell Analysis System.ResultsHPV+ CU-OP-2 had a pS249C-FGFR3, and like CU-OP-20, a pE545K-PIK3CA mutation, while no other lines had such mutations. Irrespectively, dose dependent responses to all PI3K/FGFR inhibitors were obtained, and upon combining the inhibitors, positive effects were observed. Cisplatin and docetaxel also induced dose dependent responses, and upon combination with the inhibitors, both positive and neutral effects were found.ConclusionsThe data suggest that FDA approved drugs alpelisib and erdafitinib efficiently inhibit TSCC/BOTSCC cell line growth, especially when combined irrespective of presence of corresponding mutations and should be further explored, for use upon recurrent disease.
A Comparison Between Chemo-Radiotherapy Combined With Immunotherapy and Chemo-Radiotherapy Alone for the Treatment of Newly Diagnosed Glioblastoma: A Systematic Review and Meta-Analysis
Authors: Lara-Velazquez Montserrat , Shireman Jack M. , Lehrer Eric J. , Bowman Kelsey M. , Ruiz-Garcia Henry , Paukner Mitchell J. , Chappell Richard J. , Dey Mahua 
Published: May 2021

BackgroundImmunotherapy for GBM is an emerging field which is increasingly being investigated in combination with standard of care treatment options with variable reported success rates.ObjectiveTo perform a systematic review of the available data to evaluate the safety and efficacy of combining immunotherapy with standard of care chemo-radiotherapy following surgical resection for the treatment of newly diagnosed GBM.MethodsA literature search was performed for published clinical trials evaluating immunotherapy for GBM from January 1, 2000, to October 1, 2020, in PubMed and Cochrane using PICOS/PRISMA/MOOSE guidelines. Only clinical trials with two arms (combined therapy vs. control therapy) were included. Outcomes were then pooled using weighted random effects model for meta-analysis and compared using the Wald-type test. Primary outcomes included 1-year overall survival (OS) and progression-free survival (PFS), secondary outcomes included severe adverse events (SAE) grade 3 or higher.ResultsNine randomized phase II and/or III clinical trials were included in the analysis, totaling 1,239 patients. The meta-analysis revealed no statistically significant differences in group’s 1-year OS [80.6% (95% CI: 68.6%–90.2%) vs. 72.6% (95% CI: 65.7%–78.9%), p = 0.15] or in 1-year PFS [37% (95% CI: 26.4%–48.2%) vs. 30.4% (95% CI: 25.4%–35.6%) p = 0.17] when the immunotherapy in combination with the standard of care group (combined therapy) was compared to the standard of care group alone (control). Severe adverse events grade 3 to 5 were more common in the immunotherapy and standard of care group than in the standard of care group (47.3%, 95% CI: 20.8–74.6%, vs 43.8%, 95% CI: 8.7–83.1, p = 0.81), but this effect also failed to reach statistical significance.ConclusionOur results suggests that immunotherapy can be safely combined with standard of care chemo-radiotherapy without significant increase in grade 3 to 5 SAE; however, there is no statistically significant increase in overall survival or progression free survival with the combination therapy.
Long-Term Renal Transplant Outcome in Patients With Posterior Urethral Valves. Prognostic Factors Related to Bladder Dysfunction Management
Authors: Amesty María Virginia , García-Vaz Claudia , Espinosa Laura , Martínez-Urrutia María José , López-Pereira Pedro 
Published: May 2021

Introduction: To obtain a successful renal transplant (RT) outcome in patients with posterior urethral valves (PUV), it is necessary to accomplish an adequate bladder dysfunction treatment. Our aim was to determine prognostic factors related to bladder dysfunction management in long-term RT outcome in patients with PUV.Methods: A retrospective review of patients with PUV who received a first RT after 1985 in our institution with at least 5 years of follow-up was performed. Variables analyzed included prenatal diagnosis, age of diagnosis, initial presentation and management, bladder dysfunction treatment, other surgical treatments, pre-transplant dialysis, age of transplantation, type of donor, immunosuppression regimen, vascular and urological complications, rejections episodes, and graft survival.Results: Fifty-one patients were included in the analysis. Prenatal diagnosis was done in 37.3%. Median age of diagnosis was 0.30 (0–88) months. Initial presentation was vesicoureteral reflux (VUR) in 78% and obstructive ureterohydronefrosis in 35.3%. Initial management was valve ablation (29.4%), pyelo-ureterostomy (64.7%), and vesicostomy (5.9%). In 33.3%, a type of bladder dysfunction treatment was performed: 21.6% bladder augmentation (BA), 15.7% Mitrofanoff procedure, 17.6% anticholinergic drugs, and 27.5% clean intermittent catheterization (CIC). Pre-transplant dialysis was received by 66.7%. Transplantation was performed at 6.28 ± 5.12 years, 62.7% were cadaveric and 37.3% living-donor grafts. Acute rejection episodes were found in 23.6%. Urological complications included recurrent urinary tract infections (UTIs) (31.4%); native kidneys VUR (31.4%); graft VUR (45.1%); and ureteral obstruction (2%). Vascular complications occurred in 3.9%. Mean graft survival was 11.1 ± 6.9 years. Analyzing the prognostic factor that influenced graft survival, patients with had CIC or a Mitrofanoff procedure had a significant better long-term graft survival after 10 years of follow-up (p &lt; 0.05), despite of the existence of more recurrent UTIs in them. A better graft survival was also found in living-donor transplants (p &lt; 0.05). No significant differences were observed in long-term graft survival regarding native kidneys or graft VUR, BA, immunosuppression regimen, or post-transplant UTIs.Conclusion: Optimal bladder dysfunction treatment, including CIC with or without a Mitrofanoff procedure, might result in better long-term graft survival in patients with PUV. These procedures were not related to a worse RT outcome in spite of being associated with more frequent UTIs.
Development of a Virtual Chinese Pediatric Population Physiological Model Targeting Specific Metabolism and Kidney Elimination Pathways
Authors: Yao Xueting , Liu Xuanlin , Tu Siqi , Li Xiaobei , Lei Zihan , Hou Zhe , Yu Zhiheng , Cui Cheng , Dong Zhongqi , Salem Farzaneh , Li Haiyan , Liu Dongyang 
Published: May 2021

Background: Physiologically based pharmacokinetic (PBPK) modeling and simulating may be a powerful tool in predicting drug behaviors in specific populations. It is a mathematical model that relates the pharmacokinetic (PK) profile of a compound with human anatomical characteristics, physiological characteristics, and biochemical parameters. Predictions using PBPK models offer a promising way to guide drug development and can be used to optimize clinical dosing regimens. However, PK data of new drugs in the pediatric population are too limited to guide clinical therapy, which may lead to frequent adverse events or insufficient efficacy for pediatric patients, particularly in neonates and infants.Objective: The objective of this study was to establish a virtual Chinese pediatric population based on the physiological parameters of Chinese children that could be utilized in PBPK models.Methods: A Chinese pediatric PBPK model was developed in Simcyp Simulator by collecting published Chinese pediatric physiological and anthropometric data to use as system parameters. This pediatric population model was then evaluated in the Chinese pediatric population by predicting the pharmacokinetic characteristics of four probe drugs: theophylline (major CYP1A2 substrate), fentanyl (major CYP3A4 substrate), vancomycin, and ceftazidime (renal-eliminated).Results: The predicted maximum concentration (Cmax), area under the curve of concentration-time (AUC), and clearance (CL) for theophylline (CYP1A2 metabolism pathway) and fentanyl (CYP3A4 metabolism pathway) were within two folds of the observed data. For drugs mainly eliminated by renal clearance (vancomycin and ceftazidime) in the Chinese pediatric population, the ratio of prediction to observation for major PK parameters was within a 2-fold error range.Conclusion: The model is a supplement to the previous Chinese population PBPK model. We anticipate the model to be a better representative of the pediatric Chinese population for drugs PK, offering greater clinical precision for medication given to the pediatric population, ultimately advancing clinical development of pediatric drugs. We can refine this model further by collecting more physiological parameters of Chinese children.
Microbiome-Metabolomics Analysis Reveals the Protection Mechanism of α-Ketoacid on Adenine-Induced Chronic Kidney Disease in Rats
Authors: Mo Yenan , Sun Huang , Zhang Lei , Geng Wenjia , Wang Lixin , Zou Chuan , Wu Yuchi , Ji Chunlan , Liu Xusheng , Lu Zhaoyu 
Published: May 2021

Objectives: As nitrogen-free precursors of corresponding essential amino, α-ketoacid have been widely prescribed to end-stage renal disease patients together with a low protein diet However, the impact of α-ketoacid on intestinal microbiota in chronic kidney disease (CKD) individuals is unknown. The study aims at investigating the variation in the intestinal microbiota and metabolic profile in response to α-ketoacid treatment in an adenine-induced CKD rat model.Design: Rats in the treatment groups were given solution of compound α-ketoacid tablets. At the end of the study, blood, feces, colon tissues and kidney tissues were collected and processed for biochemical analyses, histological and western blot analyses, 16S rRNA sequence and untargeted metabolomic analyses.Results:α-Ketoacid treatment reduced serum creatinine, blood urea nitrogen and 24 h urine protein, and alleviated tubular atrophy, glomerulosclerosis and interstitial fibrosis in adenine-induced CKD rats. Moreover, α-ketoacid significantly improved intestinal barrier and increased the abundance of Methanobrevibacter, Akkermansia, Blautia and Anaerositipes while reduced the abundance of Anaerovorax and Coprococcus_3 at the genus level. In addition, our results also demonstrated that α-ketoacid significantly reduced the concentrations of indoxyl sulfate, betaine, choline and cholesterol. Spearman’s correlation analysis revealed that the abundance of Coprococcus_3 was positively correlated with serum level of betaine, trimethylamine N-oxide, indoxyl sulfate, cholic acid and deoxycholic acid.Conclusion:α-Ketoacid has a reno-protective effect against adenine-induced CKD, which may be mediated regulation of serum metabolic profiles via affecting intestinal microbial community.
Gravity Threshold and Dose Response Relationships: Health Benefits Using a Short Arm Human Centrifuge
Authors: Kourtidou-Papadeli Chrysoula , Frantzidis Christos A. , Gilou Sotiria , Plomariti Christina E. , Nday Christiane M. , Karnaras Dimitrios , Bakas Lefteris , Bamidis Panagiotis D. , Vernikos Joan 
Published: May 2021

PurposeIncreasing the level of gravity passively on a centrifuge, should be equal to or even more beneficial not only to astronauts living in a microgravity environment but also to patients confined to bed. Gravity therapy (GT) may have beneficial effects on numerous conditions, such as immobility due to neuromuscular disorders, balance disorders, stroke, sports injuries. However, the appropriate configuration for administering the Gz load remains to be determined.MethodsTo address these issues, we studied graded G-loads from 0.5 to 2.0g in 24 young healthy, male and female participants, trained on a short arm human centrifuge (SAHC) combined with mild activity exercise within 40–59% MHR, provided by an onboard bicycle ergometer. Hemodynamic parameters, as cardiac output (CO), stroke volume (SV), mean arterial pressure (MAP), systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) were analyzed, as well as blood gas analysis. A one-way repeated measures ANOVA and pairwise comparisons were conducted with a level of significancep&lt; 0.05.ResultsSignificant changes in heart rate variability (HRV) and its spectral components (Class, Fmax, and VHF) were found in all g loads when compared to standing (p&lt; 0.001), except in 1.7 and 2.0g. There were significant changes in CO, cardiac index (CI), and cardiac power (CP) (p&lt; 0.001), and in MAP (p= 0.003) at different artificial gravity (AG) levels. Dose-response curves were determined based on statistically significant changes in cardiovascular parameters, as well as in identifying the optimal G level for training, as well as the optimal G level for training. There were statistically significant gender differences in Cardiac Output/CO (p= 0.002) and Cardiac Power/CP (p= 0.016) during the AG training as compared to standing. More specifically, these cardiovascular parameters were significantly higher for male than female participants. Also, there was a statistically significant (p= 0.022) gender by experimental condition interaction, since the high-frequency parameter of the heart rate variability was attenuated during AG training as compared to standing but only for the female participants (p= 0.004).ConclusionThe comprehensive cardiovascular evaluation of the response to a range of graded AG loads, as compared to standing, in male and female subjects provides the dose-response framework that enables us to explore and validate the usefulness of the centrifuge as a medical device. It further allows its use in precisely selecting personalized gravity therapy (GT) as needed for treatment or rehabilitation of individuals confined to bed.
Screening of Key Proteins Affecting Floral Initiation of Saffron Under Cold Stress Using iTRAQ-Based Proteomics
Authors: Chen Jing , Zhou Guifen , Dong Yan , Qian Xiaodong , Li Jing , Xu Xuting , Huang Huilian , Xu Limin , Li Liqin 
Published: May 2021

BackgroundSaffron crocus (Crocus sativus) is an expensive and valuable species that presents preventive and curative effects. This study aimed to screen the key proteins affecting the floral initiation of saffron under cold stress and thus increasing yield by regulating the temperature.ResultsProtein expression profiles in flowering and non-flowering saffron buds were established using isobaric tags for relative or absolute quantitation (iTRAQ). A total of 5,624 proteins were identified, and 201 differentially abundant protein species (DAPs) were further obtained between the flowering and non-flowering groups. The most important functions of the upregulated DAPs were “sucrose metabolic process,” “lipid transport,” “glutathione metabolic process,” and “gene silencing by RNA.” Downregulated DAPs were significantly enriched in “starch biosynthetic process” and several oxidative stress response pathways. Three new flower-related proteins, CsFLK, CseIF4a, and CsHUA1, were identified in this study. The following eight key genes were validated by real-time qPCR in flowering and non-flowering top buds from five different growth phases: floral induction- and floral organ development-related genes CsFLK, CseIF4A, CsHUA1, and CsGSTU7; sucrose synthase activity-related genes CsSUS1 and CsSUS2; and starch synthase activity-related genes CsGBSS1 and CsPU1. These findings demonstrate the important roles played by sucrose/starch biosynthesis pathways in floral development at the mRNA level. During normal floral organ development, the sucrose contents in the top buds of saffron increased, and the starch contents decreased. In contrast, non-flowering buds showed significantly decreased sucrose contents under cold stress and no significant changes in starch contents compared with those in the dormancy stage.ConclusionIn this report, the protein profiles of saffron under cold stress and a normal environment were revealed for the first time by iTRAQ. A possible “reactive oxygen species–antioxidant system–starch/sugar interconversion flowering pathway” was established to explain the phenomenon that saffron does not bloom due to low temperature treatment.