bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasma protein changes reflect colorectal cancer development and associated inflammation
Authors: Urbiola-Salvador Víctor , Jabłońska Agnieszka , Miroszewska Dominika , Huang Qianru , Duzowska Katarzyna , Drężek-Chyła Kinga , Zdrenka Marek , Śrutek Ewa , Szylberg Łukasz , Jankowski Michał , Bała Dariusz , Zegarski Wojciech , Nowikiewicz Tomasz , Makarewicz Wojciech , Adamczyk Agnieszka , Ambicka Aleksandra , Przewoźnik Marcin , Harazin-Lechowicz Agnieszka , Ryś Janusz , Filipowicz Natalia , Piotrowski Arkadiusz , Dumanski Jan P. , Li Bin , Chen Zhi 
Published: May 2023

IntroductionColorectal cancer (CRC) is the third most common malignancy and the second leading cause of death worldwide. Efficient non-invasive blood-based biomarkers for CRC early detection and prognosis are urgently needed.MethodsTo identify novel potential plasma biomarkers, we applied a proximity extension assay (PEA), an antibody-based proteomics strategy to quantify the abundance of plasma proteins in CRC development and cancer-associated inflammation from few μL of plasma sample.ResultsAmong the 690 quantified proteins, levels of 202 plasma proteins were significantly changed in CRC patients compared to age-and-sex-matched healthy subjects. We identified novel protein changes involved in Th17 activity, oncogenic pathways, and cancer-related inflammation with potential implications in the CRC diagnosis. Moreover, the interferon γ (IFNG), interleukin (IL) 32, and IL17C were identified as associated with the early stages of CRC, whereas lysophosphatidic acid phosphatase type 6 (ACP6), Fms-related tyrosine kinase 4 (FLT4), and MANSC domain-containing protein 1 (MANSC1) were correlated with the late-stages of CRC.DiscussionFurther study to characterize the newly identified plasma protein changes from larger cohorts will facilitate the identification of potential novel diagnostic, prognostic biomarkers for CRC.
Preclinical investigations of the efficacy of the glutaminase inhibitor CB-839 alone and in combinations in chronic lymphocytic leukemia
Authors: Timofeeva Natalia , Ayres Mary L. , Baran Natalia , Santiago-O’Farrill Janice M. , Bildik Gamze , Lu Zhen , Konopleva Marina , Gandhi Varsha 
Published: May 2023

IntroductionChronic lymphocytic leukemia (CLL) cells are metabolically flexible and adapt to modern anticancer treatments. Bruton tyrosine kinase (BTK) and B-cell lymphoma-2 (BCL-2) inhibitors have been widely used to treat CLL, but CLL cells become resistant to these treatments over time. CB-839 is a small-molecule glutaminase-1 (GLS-1) inhibitor that impairs glutamine use, disrupts downstream energy metabolism, and impedes the elimination of reactive oxygen species.MethodsTo investigate the in vitro effects of CB-839 on CLL cells, we tested CB-839 alone and in combination with ibrutinib, venetoclax, or AZD-5991 on the HG-3 and MEC-1 CLL cell lines and on primary CLL lymphocytes.ResultsWe found that CB-839 caused dose-dependent decreases in GLS-1 activity and glutathione synthesis. CB-839–treated cells also showed increased mitochondrial superoxide metabolism and impaired energy metabolism, which were reflected in decreases in the oxygen consumption rate and depletion of the adenosine triphosphate pool and led to the inhibition of cell proliferation. In the cell lines, CB-839 combined with venetoclax or AZD-5991, but not with ibrutinib, demonstrated synergism with an increased apoptosis rate and cell proliferation inhibition. In the primary lymphocytes, no significant effects of CB-839 alone or in combination with venetoclax, ibrutinib, or AZD-5991 were observed.DiscussionOur findings suggest that CB-839 has limited efficacy in CLL treatment and shows limited synergy in combination with widely used CLL drugs.
Sustained delivery of PARP inhibitor Talazoparib for the treatment of BRCA-deficient ovarian cancer
Authors: Yang Shicheng , Green Allen , Brown Needa , Robinson Alexis , Senat Merline , Testino Bryanna , Dinulescu Daniela M. , Sridhar Srinivas 
Published: May 2023

BackgroundOvarian cancer has long been known to be the deadliest cancer associated with the female reproductive system. More than 15% of ovarian cancer patients have a defective BRCA-mediated homologous recombination repair pathway that can be therapeutically targeted with PARP inhibitors (PARPi), such as Talazoparib (TLZ). The expansion of TLZ clinical approval beyond breast cancer has been hindered due to the highly potent systemic side effects resembling chemotherapeutics. Here we report the development of a novel TLZ-loaded PLGA implant (InCeT-TLZ) that sustainedly releases TLZ directly into the peritoneal (i.p.) cavity to treat patient-mimicking BRCA-mutated metastatic ovarian cancer (mOC).MethodsInCeT-TLZ was fabricated by dissolving TLZ and PLGA in chloroform, followed by extrusion and evaporation. Drug loading and release were confirmed by HPLC. The in vivo therapeutic efficacy of InCeT-TLZ was carried out in a murine Brca2-/-p53R172H/-Pten-/- genetically engineered peritoneally mOC model. Mice with tumors were divided into four groups: PBS i.p. injection, empty implant i.p. implantation, TLZ i.p. injection, and InCeT-TLZ i.p. implantation. Body weight was recorded three times weekly as an indicator of treatment tolerance and efficacy. Mice were sacrificed when the body weight increased by 50% of the initial weight.ResultsBiodegradable InCeT-TLZ administered intraperitoneally releases 66 μg of TLZ over 25 days. In vivo experimentation shows doubled survival in the InCeT-TLZ treated group compared to control, and no significant signs of toxicity were visible histologically in the surrounding peritoneal organs, indicating that the sustained and local delivery of TLZ greatly maximized therapeutic efficacy and minimized severe clinical side effects. The treated animals eventually developed resistance to PARPi therapy and were sacrificed. To explore treatments to overcome resistance, in vitro studies with TLZ sensitive and resistant ascites-derived murine cell lines were carried out and demonstrated that ATR inhibitor and PI3K inhibitor could be used in combination with the InCeT-TLZ to overcome acquired PARPi resistance.ConclusionCompared to intraperitoneal PARPi injection, the InCeT-TLZ better inhibits tumor growth, delays the ascites formation, and prolongs the overall survival of treated mice, which could be a promising therapy option that benefits thousands of women diagnosed with ovarian cancer.
Effect of hip CPM on gross motor function and development of the hip joint: a single-center randomized controlled study on spastic cerebral palsy children with hip dysplasia
Authors: Wang Lulu , Zhang Nuochen , Fang Liwei , Cui Zhenzhen , Niu Huihui , Lv Fuli , Hu Dayong , Wu De 
Published: May 2023

ObjectiveTo investigate the effectiveness of hip continuous passive motion (hCPM) on hip development at skeletal maturity and gross motor function for spastic cerebral palsy children with hip dysplasia.MethodsProspective case–control research of hCPM with goal-directed training versus merely goal-directed training. On the basis of goal-directed training, the hCPM group used the hip joint CPM instrument (the external fixator was connected to the power device to make the hip joint carry out continuous passive movement) for 40–60 min, twice a day, and five times a week, and received continuous training for 8 weeks simultaneously. The control group received only goal-directed training for 8 weeks. Functional outcomes pertaining to the affected hip joints were assessed via gross motor function measure (GMFM), migration percentage (MP), acetabular index (AI), and Harris hip functional score (HHS) at the time of enrollment and the end of the intervention.ResultsThe case–control research included 65 participants (mean age = 46.20 months, SD = 17.09 months; Gross Motor Function Grading System level: III = 41, IV = 24) who were randomly selected to either the hCPM (n = 45) or the control group (n = 20). No differences were found in baseline (acquisition phase) GMFM, MP, AI, or HHS (t = −1.720, P = 0.090; t* = 1.836, P* = 0.071; t# = −1.517, P# = 0.139; t* = −1.310, P* = 0.195; t# = −1.084, P# = 0.097; t = −1.041, P = 0.301). At the 8-week follow-up, GMFM, MP, AI, and HHS significantly improved over baseline in the hCPM group (hCPM group: t = 18.59, 20.172*, 40.291#, 16.820*, 32.900#, 28.081; P &lt; 0.001). Between-group differences at 8-week follow-up times points favored the hCPM group for GMFM (t = −2.637, P = 0.011), MP (t* = 2.615, P* = 0.014; t# = 3.000, P# = 0.006), AI (t* = 2.055, P* = 0.044; t# = 2.223, P# = 0.030), HHS (t = −4.685, P &lt; 0.001) (*: left side; #: right side).ConclusionSpastic cerebral palsy children with hip dysplasia achieved meaningful functional improvement after 8 weeks of goal-directed training with hCPM therapy.
Changes in behavior and quality of life in German young children during the COVID-19 pandemic—results from the COVID kids bavaria study
Authors: Schillok Hannah , Coenen Michaela , Rehfuess Eva A. , Kuhlmann Pia H. , Matl Stefan , Kindermann Hannah , Maison Nicole , Eckert Jana , von Both Ulrich , Behrends Uta , Frühwald Michael C. , Neubert Antje , Woelfle Joachim , Melter Michael , Liese Johannes , Hübner Johannes , Klein Christoph , Kern Anna , Jung-Sievers Caroline 
Published: May 2023

IntroductionThe COVID-19 pandemic with its containment measures such as closures of schools and daycare facilities led to numerous restrictions in daily life, putting developmental opportunities and health-related quality of life in children at risk. However, studies show that not every family was impacted equally by the pandemic and that this exceptional health and societal situation reinforced pre-existing health inequalities among the vulnerable. Our study aimed at analyzing changes in behavior and health-related quality of life of children attending elementary schools and daycare facilities in Bavaria, Germany in spring 2021. We also sought to identify associated factors contributing to inequalities in quality of life.MethodsData from a multi-center, open cohort study (“COVID Kids Bavaria”) conducted in 101 childcare facilities and 69 elementary schools across all electoral districts of Bavaria were analyzed. Children attending these educational settings (aged 3-10 years) were eligible for participation in a survey on changes in behavior and health-related quality of life. The KINDLR questionnaire (based on children’s self-report and parental report) was administered about one year after the onset of the pandemic (spring 2021). Descriptive and logistic regression analyses and comparisons to pre-pandemic KiGGS (German Health Interview and Examination Survey for Children and Adolescents) data were undertaken.ResultsAmong respondents, a high percentage of parents reported changes in their children's eating and sleeping behavior, sports and outdoor activities as well as altered screen time. Health-related quality of life in KINDLR analyses compared to pre-pandemic population averages were lower in all age groups (for 3–6-year-old KINDLR-total score: COVID Kids Bavaria MD 74.78 ± 10.57 vs KiGGS data 80.0 ± 8.1; 7-10 years-old KINDLR-total score: COVID Kids Bavaria MD 73.88 ± 12.03 vs KiGGS data 79.30 ± 9.0). No significant differences were detected with regard to associated factors, namely type of institution, sex of the child, migration background, household size and parental education.ConclusionThese findings suggest a relevant impact of the COVID-19 pandemic on children’s behavior and health-related quality of life one year after the onset of the pandemic. Further analyses in large-scale longitudinal studies are needed to determine the effects of specific pandemic or crisis associated factors contributing to health inequalities.
Association of pharmaceutical care barriers and role ambiguity and role conflict of clinical pharmacists
Authors: Sun Qingran , Wan Chuchuan , Xu Zhaoqi , Huang Yuankai , Xi Xiaoyu 
Published: May 2023

Objectives: This study aimed to understand current status of pharmaceutical care barriers and explore the impact of them on the role ambiguity and role conflict of clinical pharmacists in secondary and tertiary hospitals in mainland China.Methods: The Chinese version of Role Conflict and Role Ambiguity Scale was used to measure clinical pharmacists’ role ambiguity and role conflict. A questionnaire for clinical pharmacists’ pharmaceutical care barriers was established to determine whether clinical pharmacists encounter barriers. Multiple linear regression model was used to analyze the influence of various pharmaceutical care barriers on the role ambiguity and role conflict of clinical pharmacists.Results: 1,300 clinical pharmacists from 31 provinces were eventually included. The results revealed that commonly perceived barriers to pharmaceutical care by clinical pharmacists include the lack of financial compensation and dedicated time for pharmaceutical care. Barriers such as clinical pharmacists’ unawareness of the importance of pharmaceutical care increase the degree of clinical pharmacists’ role conflict. And the lack of financial compensation for pharmaceutical care decreases the degree of role ambiguity, while barriers such as the lack of dedicated time for pharmaceutical care, the failure to standardize the service procedures and contents of related documents in healthcare institutions increase the degree of role ambiguity.Conclusion: Increased focus on enhancing financial compensation, responsibility cognition, education and training, and greater consideration of institutional factors could help clinical pharmacists better manage their work environments and provide higher-quality pharmaceutical care.
Deuterated buprenorphine retains pharmacodynamic properties of buprenorphine and resists metabolism to the active metabolite norbuprenorphine in rats
Authors: Janganati Venumadhav , Salazar Paloma , Parks Brian J. , Gorman Gregory S. , Prather Paul L. , Peterson Eric C. , Alund Alexander W. , Moran Jeffery H. , Crooks Peter A. , Brents Lisa K. 
Published: May 2023

Introduction: An active metabolite of buprenorphine (BUP), called norbuprenorphine (NorBUP), is implicated in neonatal opioid withdrawal syndrome when BUP is taken during pregnancy. Therefore, reducing or eliminating metabolism of BUP to NorBUP is a novel strategy that will likely lower total fetal exposure to opioids and thus improve offspring outcomes. Precision deuteration alters pharmacokinetics of drugs without altering pharmacodynamics. Here, we report the synthesis and testing of deuterated buprenorphine (BUP-D2).Methods: We determined opioid receptor affinities of BUP-D2 relative to BUP with radioligand competition receptor binding assays, and the potency and efficacy of BUP-D2 relative to BUP to activate G-proteins via opioid receptors with [35S]GTPγS binding assays in homogenates containing the human mu, delta, or kappa opioid receptors. The antinociceptive effects of BUP-D2 and BUP were compared using the warm-water tail withdrawal assay in rats. Blood concentration versus time profiles of BUP, BUP-D2, and NorBUP were measured in rats following intravenous BUP-D2 or BUP injection.Results: The synthesis provided a 48% yield and the product was ≥99% deuterated. Like BUP, BUP-D2 had sub-nanomolar affinity for opioid receptors. BUP-D2 also activated opioid receptors and induced antinociception with equal potency and efficacy as BUP. The maximum concentration and the area under the curve of NorBUP in the blood of rats that received BUP-D2 were over 19- and 10-fold lower, respectively, than in rats that received BUP.Discussion: These results indicate that BUP-D2 retains key pharmacodynamic properties of BUP and resists metabolism to NorBUP and therefore holds promise as an alternative to BUP.
Yue-bi-tang attenuates adriamycin-induced nephropathy edema through decreasing renal microvascular permeability via inhibition of the Cav-1/ eNOS pathway
Authors: Li Tingting , Cheng Su , Xu Lin , Lin Pinglan , Shao Minghai 
Published: May 2023

Edema is one of the most typical symptoms of nephrotic syndrome. Increased vascular permeability makes a significant contribution to the progression of edema. Yue-bi-tang (YBT) is a traditional formula with excellent clinical efficacy in the treatment of edema. This study investigated the effect of YBT on renal microvascular hyperpermeability-induced edema in nephrotic syndrome and its mechanism. In our study, the content of target chemical components of YBT was identified using UHPLC-Q-Orbitrap HRMS analysis. A nephrotic syndrome model was replicated based on male Sprague-Dawley rats with Adriamycin (6.5 mg/kg) by tail vein injection. The rats were randomly divided into control, model, prednisone, and YBT (22.2 g/kg, 11.1 g/kg, and 6.6 g/kg) groups. After 14 d of treatment, the severity of renal microvascular permeability, edema, the degree of renal injury, and changes in the Cav-1/eNOS pathway were assessed. We found that YBT could regulate renal microvascular permeability, alleviate edema, and reduce renal function impairment. In the model group, the protein expression of Cav-1 was upregulated, whereas VE-cadherin was downregulated, accompanied by the suppression of p-eNOS expression and activation of the PI3K pathway. Meanwhile, an increased NO level in both serum and kidney tissues was observed, and the above situations were improved with YBT intervention. It thus indicates YBT exerts therapeutic effects on the edema of nephrotic syndrome, as it improves the hyperpermeability of renal microvasculature, and that YBT is engaged in the regulation of Cav-1/eNOS pathway-mediated endothelial function.
Pharmacist-led iodinated contrast media infusion risk assessment service
Authors: Jiang Huiyan , Li Yuan , Wu Xiaoyan , Yu Hongming , Zhang Xin , Ge Weihong , Yan Simin 
Published: May 2023

Background: With the increasing development of medical imaging, the use of iodinated contrast media has become more widespread. Adverse reactions caused by iodinated contrast media have drawn much attention. Despite this, there is still a lack of unified standards for the safe infusion process of iodinated contrast media in clinical practice both domestically and internationally.Objectives: Establishing a risk management service system to better predict the risks associated with iodinated contrast media infusion, reduce the incidence of adverse reactions and minimize patient harm.Method: A prospective interventional study was carried out from April 2021 to December 2021 at Nanjing Drum Tower Hospital in China. During this study, a service system was established to manage the risks associated with the infusion of iodinated contrast media. Personalized risk identification and assessment were performed by a pharmacist-led multidisciplinary team before iodinated contrast media infusion. Early warning, prevention, and adverse reaction management were performed according to different risk levels during and after infusion.Results: A multidisciplinary team led by pharmacists was established to evaluate the risks associated with infusion of iodinated contrast media. A total of 157 patients with risk factors related to the iodinated contrast media were screened out, which prevented 22 serious adverse events and enhanced the quality of medical care. All participants expressed high satisfaction with the service.Conclusion: Through practical exploration, the pharmacist-led multidisciplinary team can provide advance warning and effectively limit the risks of adverse reactions caused by iodinated contrast media to a preventable and controllable level. This approach serves as a valuable reference for developing strategies and schemes to reduce the incidence of such reactions. Therefore, we encourage the implementation of this intervention in other areas of China.
Association of periconceptional or pregnancy exposure of HPV vaccination and adverse pregnancy outcomes: a systematic review and meta-analysis with trial sequential analysis
Authors: Yan Xiaoli , Li Hongyu , Song Bin , Huang Ge , Chang Qing , Wang Dan , Yan Ping 
Published: May 2023

Objective: To evaluate whether periconceptional or pregnancy exposure of human papillomavirus (HPV) vaccination would increase the risk of adverse pregnancy outcomes.Methods: The PubMed, Web of Science, Embase, the Cochrane Library of clinical trials were searched from inception to March 2023. We computed relative risk (RR) and 95% confidence intervals (CIs) and prediction intervals (PIs) regarding the association between HPV vaccination in periconceptional period or during pregnancy and the risks of adverse pregnancy outcomes by using R software Version 4.1.2 and STATA Version 12.0. A trial sequential analysis (TSA) was performed with TSA v0.9.5.10 Beta software.Results: Four randomized controlled trials (RCTs) and eight cohort studies were included in this meta-analysis. Analysis of RCTs showed that HPV vaccination in periconceptional period or during pregnancy did not increase the risks of spontaneous abortion (RR = 1.152, 95% CI: 0.909–1.460, 95% PI: 0.442–3.000), birth defects (RR = 1.171, 95% CI: 0.802–1.709, 95% PI: 0.320–4.342), stillbirth (RR = 1.053, 95% CI: 0.616–1.800, 95% PI: 0.318–3.540), preterm birth (RR = 0.940, 95% CI: 0.670–1.318) and ectopic pregnancy (RR = 0.807, 95% CI: 0.353–1.842, 95% PI: 0.128–5.335). In cohort studies, periconceptional or pregnancy exposures of HPV vaccine were not associated with the increased risk of spontaneous abortion (RR = 0.987, 95% CI: 0.854–1.140, 95% PI: 0.652–1.493), birth defects (RR = 0.960, 95% CI: 0.697–1.322, 95% PI: 0.371–2.480), stillbirth (RR = 1.033, 95% CI: 0.651–1.639, 95% PI: 0.052–21.064), small size for gestational age (SGA) (RR = 0.971, 95% CI: 0.873–1.081, 95% PI: 0.657–1.462) and preterm birth (RR = 0.977, 95% CI: 0.874–1.092, 95% PI: 0.651–1.444).Conclusion: HPV vaccine exposures in periconceptional period or during pregnancy did not increase the risks of adverse pregnancy outcomes, including spontaneous abortion, birth defects, stillbirth, SGA, preterm birth and ectopic pregnancy.Systematic Review Registration:https://www.crd.york.ac.uk/prospero/, identifier CRD42023399777.
Potential impact of mepolizumab in stepping down anti-osteporotic treatment in corticosteroid-dependent asthma
Authors: Domingo Christian , Sogo Ana , Casado Enrique , Martínez-Moragón Eva , Blanco-Aparicio Marina , Carrillo Teresa , Bañas-Conejero David , Sánchez-Herrero María-Guadalupe 
Published: May 2023

Oral corticosteroids (OCS) are commonly used for the acute management of severe asthma exacerbations or as maintenance therapy; however, chronic use is associated with significant toxicities, e.g., osteoporosis. In the REal worlD Effectiveness and Safety (REDES) study of mepolizumab in a multicentric Spanish cohort of asthma patients, mepolizumab effectively reduced clinically severe asthma exacerbations and decreased OCS dependence. This post-hoc analysis further evaluates mepolizumab’s de-escalation effect on OCS dose. Patients enrolled in REDES who had OCS consumption data available for 12 months pre- and post-mepolizumab treatment were included in this analysis. Primary outcomes were to determine the change in the proportion of patients eligible for anti-osteoporotic treatment due to the changes in OCS consumption before and after 1 year of mepolizumab treatment. All analyses are descriptive. Approximately one-third (98/318; 30.8%) of patients in REDES were on maintenance OCS at the time of mepolizumab treatment initiation. In REDES, mean cumulative OCS exposure decreased by 54.3% after 1 year of treatment. The proportion of patients on high-dose OCS (≥7.5 mg/day) fell from 57.1% at baseline to 28.9% after 12 months of mepolizumab treatment. Thus, 53.6% of OCS-dependent asthma patients treated with mepolizumab would cease to be candidates for anti-osteoporotic treatment according to guidelines thresholds.