bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prediction Model for Cereblon Expression in Bone Marrow Plasma Cells Based on Blood Markers in Multiple Myeloma Patients
Authors: Lee Byung-Hyun , Kang Ka-Won , Jeon Min Ji , Yu Eun Sang , Kim Dae Sik , Lee Se Ryeon , Sung Hwa Jung , Park Yong , Choi Chul Won , Kim Byung Soo 
Published: July 2021

BackgroundCereblon (CRBN) is a direct target of immunomodulatory drugs (IMiDs) and is known to be sensitive and responsive to IMiD therapy. We evaluated CRBN expression in bone marrow plasma cells and analyzed whether CRBN expression was associated with multiple myeloma prognosis. Lastly, we developed a nomogram model for predicting high CRBN expression based on clinically significant blood markers.MethodsWe evaluated 143 multiple myeloma patients (internal dataset) who underwent bone marrow examinations. For evaluating the prognostic ability of the nomogram model, two external cohorts (235 patients in external dataset 1 and 156 patients in external dataset 2) were analyzed. The expression of CRBN in bone marrow aspirate samples was evaluated using immunohistochemistry. High CRBN expression was defined as the study-defined H-score ≥6.ResultsIn the high CRBN group, the median progression-free survival (PFS) and overall survival (OS) of patients receiving the IMiD-based therapy and non-IMiD therapy were 29 and 10 months for PFS, and NR (not reached) and 54 months for OS, respectively. IMiD-based therapy was significantly associated with better PFS and OS outcomes. High CRBN expression was independently predicted by female sex, high serum free-light chain (FLC) ratio, higher serum M-protein level, and higher β2-microglobulin level. Based on these results, we constructed a new nomogram model to predict high CRBN expression and the effectiveness of IMiD therapy in multiple myeloma.ConclusionThis nomogram could improve the prognostic evaluation of myeloma patients exhibiting high CRBN expression treated with IMiD therapy and might help provide personalized treatment strategies to clinicians.
The Basic Research of the Combinatorial Therapy of ABT-199 and Homoharringtonine on Acute Myeloid Leukemia
Authors: Shi Yuanfei , Ye Jing , Yang Ying , Zhao Yanchun , Shen Huafei , Ye Xiujin , Xie Wanzhuo 
Published: July 2021

BackgroundExisting research shows that ABT-199, as a first-line drug, have been widely used in hematological malignancies, especially in leukemia, but the clinical efficacy of single drug therapy was limited part of the reason was that BCL-2 inhibitors failure to target other anti-apoptotic BCL-2 family proteins, such as MCL-1. In this case, combination therapy may be a promising way to overcome this obstacle. Here, we investigate the preclinical efficacy of a new strategy combining ABT-199 with homoharringtonine (HHT), a selective inhibitor of MCL-1 may be a promising approach for AML treatment as these two molecules are important in apoptosis.MethodsA Cell Counting Kit-8 (CCK8) assay and flow cytometry were used to determine the half-maximal inhibitory concentration (IC50) value and cell apoptosis rate, respectively. The flow cytometry results showed that combined treatment with HHT and ABT-199 caused apoptosis in AML patient samples (n=5) but had no effect on normal healthy donor samples (n=11). Furthermore, we used a Western blot assay to explore the mechanism underlying the efficacy of HHT combined with ABT-199. Finally, antileukemic activity was further evaluated in vivo xenograft model.ResultsOur results indicated that ABT-199 combined with HHT significantly inhibited cell growth and promoted apoptosis in both AML cell lines and primary AML tumors in a dose- and time-dependent manner. Moreover, HHT combined with ABT-199 suppressed AML cell growth and progression in vivo xenograft model.ConclusionsOur research found that HHT combined with ABT-199 exerted its anti-leukemia effect by inducing apoptosis through the treatment of AML in vitro and in vivo.
Radical Versus Non-Radical Resection for Early-Stage Retroperitoneal Sarcoma: A Propensity Score-Matched Analysis
Authors: Weng Chengxin , Wang Jiarong , Zhao Jichun , Yuan Ding , Huang Bin , Wang Tiehao 
Published: July 2021

BackgroundThe appropriate surgical procedure for early-stage retroperitoneal sarcoma (RPS) is unclear. Thus, we used a national database to compare the outcomes of radical and non-radical resection in patients with early stage RPS.MethodsThis retrospective study included 886 stage I RPS patients from 2004 to 2015 in the SEER database. Outcomes were compared using the multivariate Cox proportional hazards models and the results were presented as adjusted hazards ratio (AHR) with corresponding 95% confidence intervals (95%CIs). Propensity score-matched analyses were also performed for sensitive analyses.ResultsFor the 886 stage I RPS patients, 316 underwent radical resection, and 570 underwent non-radical resection, with a median follow-up of 4.58 (2.73-8.35) years. No difference was observed in overall mortality (AHR 0.84, 95%CI 0.62-1.15; P = 0.28) or RPS-specific mortality (AHR 0.88, 95%CI 0.57-1.36; P = 0.56) between groups. The results were similar in propensity score-matching analyses. However, subgroup analysis revealed that radical resection was associated with significantly decreased risks of overall mortality in male (AHR 0.61, 95%CI 0.38-0.98; P = 0.04) and in patients with radiotherapy (AHR 0.56, 95%CI 0.32-0.98; P = 0.04).ConclusionRadical resection did not improve midterm survival outcomes compared with non-radical resection in overall patients with early stage RPS. However, male patients or patients who received radiotherapy might benefit from radical resection with improved overall survival.
Effectiveness of Carbon Ion Radiation in Locally Advanced Pancreatic Cancer
Authors: Liermann Jakob , Naumann Patrick , Weykamp Fabian , Hoegen Philipp , Debus Juergen , Herfarth Klaus 
Published: July 2021

PurposeEffective treatment strategies for unresectable locally advanced pancreatic cancer (LAPC) patients are eagerly warranted. Recently, convincing oncological outcomes were demonstrated by carbon ion radiotherapy. Nevertheless, there is a lack of evidence for this modern radiation technique due to the limited number of carbon ion facilities worldwide. Here, we analyze feasibility and efficacy of carbon ion radiotherapy in the management of LAPC at Heidelberg Ion Beam Therapy Center (HIT).MethodsBetween 2015 and 2020, 21 LAPC patients were irradiated with carbon ions with a total dose of 48 Gy (RBE) in single doses of 4 Gy (RBE). Three patients (14%) were treated with concomitant chemotherapy with gemcitabine 300 mg/m2 body surface weekly. Toxicity rates were extracted from the charts. Overall survival, progression free survival, local control, and locoregional control were evaluated using Kaplan–Meier estimates.ResultsOne patient developed ascites CTCAE grade III during radiotherapy, which was related to a later histologically confirmed metachronous peritoneal carcinomatosis. No further higher-graded toxicity could be observed. The most common symptoms were nausea and abdominal pain. After a median estimated follow-up time of 19.1 months, the median progression free survival was 3.7 months, and the median overall survival was 11.9 months. The estimated 1-year local control and locoregional control rates were 89 and 84%, respectively.ConclusionCarbon ion radiotherapy of LAPC patients is safely feasible. Local tumor control rates were high. Nevertheless, compared to historical data, an overall survival improvement could not be observed. This could be explained by the poor prognosis of the selected underlying patients that mostly did not respond to prior chemotherapy as well as the early and frequent emergence of distant metastases that demonstrate the necessity of additional chemotherapy in further studies.
Acupuncture Treatment for Nocturnal Crying in Pediatric Patients: A Systematic Review of Clinical Studies
Authors: Ang Lin , Song Eunhye , Lee Hye Won , Kim Jung Tae , Kim Eunseop , Lee Myeong Soo 
Published: July 2021

Background:Nocturnal crying is a common condition in which children intermittently or continuously cry and fuss during the night, at certain times or throughout the night. It is a common pediatric sleep disturbance for which medical assistance is highly sought by parents, and one of the non-pharmacologic treatments for nocturnal crying is pediatric acupuncture. This review aimed to review the literature about the effectiveness and safety of pediatric acupuncture for nocturnal crying.Methods:Literature searches were performed on PubMed, the Cochrane Controlled Register of Trials (CENTRAL), Allied and Complementary Medicine Database (AMED), Chinese National Knowledge Infrastructure Database (CNKI), Wanfang Database, and Chinese Science and Technique Journals Database (VIP), OASIS, the Research Information Service System (RISS), and National Digital Science Library (NDSL) from the available date of inception until December 28, 2020. Two review authors independently screened the titles and abstracts of all relevant articles from the search to select eligible articles. All variants of clinical studies on acupuncture treatment for nocturnal crying, including case reports and case studies, were eligible. Data were independently extracted by two review authors using a standard data extraction form. Retrieved data are presented in a tabular form and narratively discussed.Results:We included 12 studies (10 case series and two case reports) with a total sample size of 2,324 children recruited from the hospital outpatient department. All of the included studies were conducted in mainland China and administered acupuncture as the sole intervention. For the primary outcome, the total efficacy rate of acupuncture treatment for nocturnal crying was reported as 100% in 9 studies, 95% in one study, 94% in another study, and 86% in the remaining study. For the secondary outcome, one study reported a 14% recurrence rate, whereas another study reported an 11% recurrence rate after treatment. There were no follow-ups in most of the studies. None of the studies reported possible adverse events. Most children recovered after one treatment. Generally, the acupoints that were most frequently selected were acupoints EM30 and PC9.Conclusions:This comprehensive review suggested that pediatric acupuncture may be an effective treatment for nocturnal crying, which could be worth investigating further.
Capacity Building for a New Multicenter Network Within the ECHO IDeA States Pediatric Clinical Trials Network
Authors: Annett Robert D. , Bickel Scott , Carlson John C. , Cowan Kelly , Cox Sara , Fisher Mark J. , Jarvis J. Dean , Kong Alberta S. , Kosut Jessica S. , Kulbeth Kurtis R. , Laptook Abbot , McElfish Pearl A. , McNally Mary M. , Pachter Lee M. , Pahud Barbara A. , Pyles Lee A. , Shaw Jennifer , Simonsen Kari , Snowden Jessica , Turley Christine B. , Atz Andrew M. 
Published: July 2021

Introduction: Research capacity building is a critical component of professional development for pediatrician scientists, yet this process has been elusive in the literature. The ECHO IDeA States Pediatric Clinical Trials Network (ISPCTN) seeks to implement pediatric trials across medically underserved and rural populations. A key component of achieving this objective is building pediatric research capacity, including enhancement of infrastructure and faculty development. This article presents findings from a site assessment inventory completed during the initial year of the ISPCTN.Methods: An assessment inventory was developed for surveying ISPCTN sites. The inventory captured site-level activities designed to increase clinical trial research capacity for pediatrician scientists and team members. The inventory findings were utilized by the ISPCTN Data Coordinating and Operations Center to construct training modules covering 3 broad domains: Faculty/coordinator development; Infrastructure; Trials/Research concept development.Results: Key lessons learned reveal substantial participation in the training modules, the importance of an inventory to guide the development of trainings, and recognizing local barriers to clinical trials research.Conclusions: Research networks that seek to implement successfully completed trials need to build capacity across and within the sites engaged. Our findings indicate that building research capacity is a multi-faceted endeavor, but likely necessary for sustainability of a unique network addressing high impact pediatric health problems. The ISPCTN emphasis on building and enhancing site capacity, including pediatrician scientists and team members, is critical to successful trial implementation/completion and the production of findings that enhance the lives of children and families.
Perampanel Reduces Hyperthermia-Induced Seizures in Dravet Syndrome Mouse Model
Authors: Ho Shih-Yin , Lin Li , Chen I-Chun , Tsai Che-Wen , Chang Fang-Chia , Liou Horng-Huei 
Published: July 2021

Treatment options for Dravet syndrome are limited. The aim of this study was to evaluate the antiepileptic effect of the AMPA receptor antagonist perampanel (PER) on a mouse model of Dravet syndrome (Scn1aE1099X/+). We report here that the PER (2 mg/kg) treatment inhibited the spontaneous recurrent seizures and attenuated epileptic activity in Scn1aE1099X/+ mice. In the hyperthermia-induced seizure experiment, PER clearly increased temperature tolerance and significantly ameliorated seizure frequency and discharge duration. PER also demonstrated antiepileptic effects in a cross-over study and a synergistic effect for attenuating heat-induced seizure when given in combination with stiripentol or valproic acid. The results showed that PER effectively decreased the occurrence of spontaneous recurrent seizures and showed significant therapeutic potential for hyperthermia-induced seizures with regard to both susceptibility and severity in a Dravet syndrome mouse model. Potential therapeutic effects of PER for treatment of Dravet syndrome were demonstrated.
Toxicological Assessment of Bromochlorophene: Single and Repeated-Dose 28-Day Oral Toxicity, Genotoxicity, and Dermal Application in Sprague–Dawley Rats
Authors: Won Hansol , Jeong Da Hye , Shin Hyo-Sook , Lee Jin Hee , Lee Jeong Pyo , Yang Jun-Young , Jung Kikyung , Jeong Jayoung , Oh Jae Ho 
Published: July 2021

Bromochlorophene (BCP) has shown good properties in sterilization and antibacterial activity and is widely used as a household chemical. We evaluated the genotoxicity, single and repeated-dose 28-day oral toxicity, and dermal application of a BCP suspension in Sprague–Dawley (SD) rats. For the single-dose toxicity study, a dose of 25–1,000 mg per kg of bodyweight (mg/kg b.w.) of BCP was given once orally to SD rats. Mortality and clinical signs were observed and recorded for the first 30 min after treatment, at 4 h post-administration, and then at least once daily for 14 days after administration. For the repeated-dose 28-day toxicity study, the high dose was set at 1,000 mg/kg b.w. and the middle, middle-low, and low dose were set to 500, 250, and 125 mg/kg, respectively. Hematology and biochemistry parameters were examined. Gross pathologic and histopathologic examinations were performed on selected tissues from all animals. A bacterial reverse mutation assay, in vitro chromosomal aberration assay, and in vivo micronucleus assay were performed to assess genotoxicity-dermal application exposure assessment of BCP in rats. A high oral approximate lethal dose (ALD) of 1,000 mg/kg was observed in the single-dose toxicity test. During the repeated-dose 28-day time period, most animal deaths after administration occurred during the first 3 weeks. The 1,000 mg/kg b.w. oral dose caused the death of six male rats (6/7) and four female rats (4/7). At 500 mg/kg b.w., the female rats showed mortality (1/7). For the biochemistry assays, cholesterol was increased significantly compared to vehicle in both sexes in the 250 and 500 mg/kg groups. Histopathological changes with treatment-related findings were observed in the pancreas in female rats treated with a high dose of BCP compared with the vehicle group. BCP showed no genotoxic effect. These data suggested that the ALD of BCP, estimated as a non-genotoxic substance, was over 1,000 mg/kg b.w. in the single-dose toxicity study, and the NOAEL of BCP was considered to be 250 mg/kg b.w. for male and female rats after repeated oral administration for 28 days under the present study conditions.
Characterization of the Electrophysiologic Remodeling of Patients With Ischemic Cardiomyopathy by Clinical Measurements and Computer Simulations Coupled With Machine Learning
Authors: Aronis Konstantinos N. , Prakosa Adityo , Bergamaschi Teya , Berger Ronald D. , Boyle Patrick M. , Chrispin Jonathan , Ju Suyeon , Marine Joseph E. , Sinha Sunil , Tandri Harikrishna , Ashikaga Hiroshi , Trayanova Natalia A. 
Published: July 2021

RationalePatients with ischemic cardiomyopathy (ICMP) are at high risk for malignant arrhythmias, largely due to electrophysiological remodeling of the non-infarcted myocardium. The electrophysiological properties of the non-infarcted myocardium of patients with ICMP remain largely unknown.ObjectivesTo assess the pro-arrhythmic behavior of non-infarcted myocardium in ICMP patients and couple computational simulations with machine learning to establish a methodology for the development of disease-specific action potential models based on clinically measured action potential duration restitution (APDR) data.Methods and ResultsWe enrolled 22 patients undergoing left-sided ablation (10 ICMP) and compared APDRs between ICMP and structurally normal left ventricles (SNLVs). APDRs were clinically assessed with a decremental pacing protocol. Using genetic algorithms (GAs), we constructed populations of action potential models that incorporate the cohort-specific APDRs. The variability in the populations of ICMP and SNLV models was captured by clustering models based on their similarity using unsupervised machine learning. The pro-arrhythmic potential of ICMP and SNLV models was assessed in cell- and tissue-level simulations. Clinical measurements established that ICMP patients have a steeper APDR slope compared to SNLV (by 38%, p &lt; 0.01). In cell-level simulations, APD alternans were induced in ICMP models at a longer cycle length compared to SNLV models (385–400 vs 355 ms). In tissue-level simulations, ICMP models were more susceptible for sustained functional re-entry compared to SNLV models.ConclusionMyocardial remodeling in ICMP patients is manifested as a steeper APDR compared to SNLV, which underlies the greater arrhythmogenic propensity in these patients, as demonstrated by cell- and tissue-level simulations using action potential models developed by GAs from clinical measurements. The methodology presented here captures the uncertainty inherent to GAs model development and provides a blueprint for use in future studies aimed at evaluating electrophysiological remodeling resulting from other cardiac diseases.
Comparison Between 5- and 1-Year Outcomes Using Cutoff Values of Pressure Drop Coefficient and Fractional Flow Reserve for Diagnosing Coronary Artery Diseases
Authors: Banerjee Rupak K. , Ramadurai Sruthi , Manegaonkar Shreyash M. , Rao Marepalli B. , Rakkimuthu Sathyaprabha , Effat Mohamed A. 
Published: July 2021

BackgroundThe current pressure-based coronary diagnostic index, fractional flow reserve (FFR), has a limited efficacy in the presence of microvascular disease (MVD). To overcome the limitations of FFR, the objective is to assess the recently introduced pressure drop coefficient (CDP), a fundamental fluid dynamics-based combined pressure–flow index.MethodsWe hypothesize that CDP will result in improved clinical outcomes in comparison to FFR. To test the hypothesis, chi-square test was performed to compare the percent major adverse cardiac events (%MACE) at 5 years between (a) FFR &lt; 0.75 and CDP &gt; 27.9 and (b) FFR &lt; 0.80 and CDP &gt; 25.4 groups using a prospective cohort study. Furthermore, Kaplan–Meier survival curves were compared between the FFR and CDP groups. The results were considered statistically significant for p &lt; 0.05. The outcomes of the CDP arm were presumptive as clinical decision was solely based on the FFR.ResultsFor the complete patient group, the %MACE in the CDP &gt; 27.9 group (10 out of 35, 29%) was lower in comparison to the FFR &lt; 0.75 group (11 out of 20, 55%), and the difference was near significant (p = 0.05). The survival analysis showed a significantly higher survival rate (p = 0.01) in the CDP &gt; 27.9 group (n = 35) when compared to the FFR &lt; 0.75 group (n = 20). The results remained similar for the FFR = 0.80 cutoff. The comparison of the 5-year MACE outcomes with the 1-year outcomes for the complete patient group showed similar trends, with a higher statistical significance for a longer follow-up period of 5 years.ConclusionBased on the MACE and survival analysis outcomes, CDP could possibly be an alternate diagnostic index for decision-making in the cardiac catheterization laboratory.Clinical Trial Registrationwww.ClinicalTrials.gov, identifier NCT01719016.
Spatial and Ecological Drivers of Genetic Structure in Greek Populations of Alkanna tinctoria (Boraginaceae), a Polyploid Medicinal Herb
Authors: Ahmad Muhammad , Leroy Thibault , Krigas Nikos , Temsch Eva M. , Weiss-Schneeweiss Hanna , Lexer Christian , Sehr Eva Maria , Paun Ovidiu 
Published: July 2021

Background and Aims:Quantifying genetic variation is fundamental to understand a species’ demographic trajectory and its ability to adapt to future changes. In comparison with diploids, however, genetic variation and factors fostering genetic divergence remain poorly studied in polyploids due to analytical challenges. Here, by employing a ploidy-aware framework, we investigated the genetic structure and its determinants in polyploidAlkanna tinctoria(Boraginaceae), an ancient medicinal herb that is the source of bioactive compounds known as alkannin and shikonin (A/S). From a practical perspective, such investigation can inform biodiversity management strategies.Methods:We collected 14 populations ofA. tinctoriawithin its main distribution range in Greece and genotyped them using restriction site-associated DNA sequencing. In addition, we included two populations ofA. sieberi. By using a ploidy-aware genotype calling based on likelihoods, we generated a dataset of 16,107 high-quality SNPs. Classical and model-based analysis was done to characterize the genetic structure within and between the sampled populations, complemented by genome size measurements and chromosomal counts. Finally, to reveal the drivers of genetic structure, we searched for associations between allele frequencies and spatial and climatic variables.Key Results:We found support for a marked regional structure inA. tinctoriaalong a latitudinal gradient in line with phytogeographic divisions. Several analyses identified interspecific admixture affecting both mainland and island populations. Modeling of spatial and climatic variables further demonstrated a larger contribution of neutral processes and a lesser albeit significant role of selection in shaping the observed genetic structure inA. tinctoria.Conclusion:Current findings provide evidence of strong genetic structure inA. tinctoriamainly driven by neutral processes. The revealed natural genomic variation in GreekAlkannacan be used to further predict variation in A/S production, whereas our bioinformatics approach should prove useful for the study of other non-model polyploid species.