bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor grade-associated genomic mutations in Chinese patients with non-small cell lung cancer
Authors: Wang Yang , Qin Shilei , Liang Yuepei , Yan Ling , Zheng Min , Zeng Yanwu , Lu Leilei 
Published: March 2023

BackgroundLung cancer is the most prevalent cancer worldwide and accounts for approximately 20% of cancer-related death in China every year. High-grade lung cancer poses a significant threat to patients, and developing a novel treatment for these patients requires an understanding of its underlying mechanism.MethodsChinese patients with lung cancer were enrolled. The tumor samples were collected by surgery or puncture and applied for next-generation sequencing. A panel of pan-cancer genes was targeted, and the sequencing depth was set to over 1,000 to improve the sensitivity of detecting mutations. Short-length mutations (substitution, insertion, and deletion), copy number variation, and gene fusion were called. Gene mutations were compared between low-grade, middle-grade, and high-grade tumors using Fisher’s exact test. The enriched pathways in each grade of tumors were also inferred.ResultsThe study included 173 Chinese patients with non-small cell lung cancer, of whom 98 (56.6%) patients were female and 75 (43.4%) were male, with a mean age of 56.8 years. All patients were microsatellite stable; 66.4% were at the early stages (Stages 0, I, and II) with a tumor mutational burden of approximately 2.5 (confidence interval = [0, 48.3]). Compared to low-grade tumors, high-grade tumors had a significantly higher percentage of mutations in TP53 (75.9% vs 34.4%, p = 1.86e-3) and PIK3CA (24.1% vs. 0%, p = 3.58e-3). Pathway analysis found that high-grade tumors were enriched with mutations in bacterial invasion of epithelial cells (31% vs. 0%, p = 5.8e-4), Epstein–Barr virus infection (79.3% vs. 37.5%, p = 1.72e-3), and the Wnt signaling pathway (75.9% vs. 34.4%, p = 1.91e-3). High-grade tumors had a significantly higher tumor mutational burden than low-grade tumors (p-value = 0.0017). However, actionable mutations with high-level evidence were lower in high-grade tumors.ConclusionPatients with high-grade tumors from lung cancer may be more affected by bacteria and Epstein–Barr virus than low-grade tumors. High-grade tumors were specially mutated in TP53 and PIK3CA and may benefit more from immunotherapy. Further research on the underlying mechanism of high-grade lung cancer is necessary to develop new therapeutic options. Lung cancer, tumor grade, genomic mutations, Epstein–Barr virus, pathway analysis
Time interval from diagnosis to treatment of brain metastases with stereotactic radiosurgery is not associated with radionecrosis or local failure
Authors: Leu Justin , Akerman Meredith , Mendez Christopher , Lischalk Jonathan W. , Carpenter Todd , Ebling David , Haas Jonathan A. , Witten Matthew , Barbaro Marissa , Duic Paul , Tessler Lee , Repka Michael C. 
Published: March 2023

IntroductionBrain metastases are the most common intracranial tumor diagnosed in adults. In patients treated with stereotactic radiosurgery, the incidence of post-treatment radionecrosis appears to be rising, which has been attributed to improved patient survival as well as novel systemic treatments. The impacts of concomitant immunotherapy and the interval between diagnosis and treatment on patient outcomes are unclear.MethodsThis single institution, retrospective study consisted of patients who received single or multi-fraction stereotactic radiosurgery for intact brain metastases. Exclusion criteria included neurosurgical resection prior to treatment and treatment of non-malignant histologies or primary central nervous system malignancies. A univariate screen was implemented to determine which factors were associated with radionecrosis. The chi-square test or Fisher’s exact test was used to compare the two groups for categorical variables, and the two-sample t-test or Mann-Whitney test was used for continuous data. Those factors that appeared to be associated with radionecrosis on univariate analyses were included in a multivariable model. Univariable and multivariable Cox proportional hazards models were used to assess potential predictors of time to local failure and time to regional failure.ResultsA total of 107 evaluable patients with a total of 256 individual brain metastases were identified. The majority of metastases were non-small cell lung cancer (58.98%), followed by breast cancer (16.02%). Multivariable analyses demonstrated increased risk of radionecrosis with increasing MRI maximum axial dimension (OR 1.10, p=0.0123) and a history of previous whole brain radiation therapy (OR 3.48, p=0.0243). Receipt of stereotactic radiosurgery with concurrent immunotherapy was associated with a decreased risk of local failure (HR 0.31, p=0.0159). Time interval between diagnostic MRI and first treatment, time interval between CT simulation and first treatment, and concurrent immunotherapy had no impact on incidence of radionecrosis or regional failure.DiscussionAn optimal time interval between diagnosis and treatment for intact brain metastases that minimizes radionecrosis and maximizes local and regional control could not be identified. Concurrent immunotherapy does not appear to increase the risk of radionecrosis and may improve local control. These data further support the safety and synergistic efficacy of stereotactic radiosurgery with concurrent immunotherapy.
Urinary KIM-1 is not correlated with gestational age among 5-year-old children born prematurely
Authors: Restrepo Jaime M. , Torres-Canchala Laura , Bonventre Joseph V. , Arias Juan C. , Ferguson Michael , Villegas Adriana , Ramirez Oscar , Filler Guido 
Published: March 2023

BackgroundPreterm birth is associated with decreased nephron endowment. Currently, there is no reliable non-invasive biomarker to identify or monitor decreased nephron number in at-risk patients. Urinary Kidney Injury Molecule-1 (KIM-1) is a biomarker of acute and chronic renal injury. We measured urinary KIM-1 among a wide array of other potential biomarkers.MethodsWe conducted an ambispective cohort study of 5-years-old children born prematurely and healthy controls identified from city schools. Detailed anthropometrics, renal ultrasound dimensions, and biochemical parameters were measured. Urinary KIM-1 was measured using Luminex® technology. Age independent z-scores were calculated and compared. Spearman correlations were used for estimating the association between measures and KIM-1.ResultsWe enrolled 129 children, 97 (75.2%) born pre-term and 32 (24.8%) healthy controls born at full-term. Pre-term patients had significantly lower weight and body surface area than controls. Pre-term patients and controls did not differ in current age, sex, race, height, blood pressure, urinary sodium, fractional sodium excretion, serum creatinine and estimated GFR. All spearman correlation between KIM-1 and gestational age, renal and serum measurements were weak without statistical significanceConclusionIn 5-year-old children born prematurely, KIM-1 was not correlated with gestational age. Further prospective studies need to confirm this finding.
Outcomes of and factors associated with the development of bronchopulmonary dysplasia with pulmonary hypertension in very low birth weight infants: A retrospective study in a medical center
Authors: Chang Han-Pi , Lien Reyin , Chu Shih-Ming , Lin Jainn-Jim , Chiang Ming-Chou 
Published: March 2023

IntroductionBronchopulmonary dysplasia (BPD) with pulmonary hypertension (PH) leads to increased morbidity and mortality in extremely preterm infants. Recent studies have analyzed factors associated with development of PH in BPD; however, this research remains inconclusive, and controversy exists regarding the correlation between BPD and PH. This study aimed to investigate potential associated factors, clinical characteristics, and outcomes of BPD with pulmonary hypertension in very low birth weight (VLBW) preterm infants.MethodsWe conducted a retrospective study, reviewing the records of infants with gestational age (GA) &lt;32 weeks and birth weight &lt;1,500 g admitted to a tertiary neonatal intensive care unit between January 2020 and October 2021 who were diagnosed with moderate to severe BPD. Echocardiogram was performed at the postmenstrual age of 36 weeks or before discharge. The diagnosis of PH was based on the findings of echocardiogram. Prenatal and postnatal characteristics, demographic data, treatment details, and outcomes were collected and analyzed.ResultsA total of 139 VLBW infants with BPD were enrolled and divided into a PH group (n = 25) and a non-PH group (n = 114). The mean GA was 27.3 ± 2.3 weeks and the mean birth weight of infants with BPD was 927.3 ± 293.3 g. A multivariate logistic regression model revealed that a high positive end-expiratory pressure (PEEP) setting (OR: 2.105; 95% CI: 1.472–3.011; p &lt; 0.001) in established BPD and surgical closure of patent ductus arteriosus (PDA; OR: 6.273; 95% CI: 1.574–24.977; p = 0.009) were associated with BPD–PH. Neonates with BPD who developed pulmonary hypertension remained hospitalized for longer (p &lt; 0.001), received invasive mechanical ventilation support for longer (p &lt; 0.001), had a higher incidence of retinopathy of prematurity (ROP; OR: 4.201; 95% CI: 1.561–11.304; p = 0.003), were more likely to require oxygen support at discharge (OR: 5.600; 95% CI: 2.175–14.416; p &lt; 0.001), and were more likely to undergo tracheostomy (OR: 35.368; 95% CI: 4.03–310.43; p &lt; 0.001).ConclusionPDA ligation and a higher PEEP setting were associated with BPD–PH in our cohort study. Compared with VLBW infants with BPD but without PH, infants with BPD and PH were hospitalized for longer, and also had a higher incidence of oxygen support after discharge, ROP, and tracheostomy.
Complete and incomplete Kawasaki disease: Clinical differences and coronary artery outcome from a national prospective surveillance study in Switzerland
Authors: Bressieux-Degueldre S. , Gradoux E. , Di Bernardo S. , Sekarski N. 
Published: March 2023

IntroductionThe aim of this national prospective surveillance study was to compare the clinical presentation, laboratory findings, treatment, and coronary artery outcome in patients with incomplete and complete Kawasaki disease (KD).MethodsBetween March 2013 and February 2019, children with a diagnosis of complete and incomplete KD were reported by the Swiss Paediatric Surveillance Unit and prospectively enrolled. Clinical data, laboratory values, treatment, and echocardiographic features were collected at diagnosis and 1 year of follow-up. Data were compared between children with complete or incomplete KD.ResultsA total of 351 questionnaires were registered from children with a diagnosis of KD. Of them, 219 (62.4%) children had complete KD, and 132 (37.6%) children had incomplete KD. Children with incomplete KD were younger and had a longer-lasting fever; however, there were no differences in the level of C-reactive protein. All but four children received intravenous immunoglobulin treatment, whereas 14% of children were treated with corticosteroids. Children with incomplete KD were more often treated with corticosteroids than children with incomplete KD (p = 0.01). At diagnosis, 39 (11.1%) patients had only coronary artery dilation and 57 (16.2%) had at least one coronary artery aneurysm. There were no differences in coronary artery involvement between the two groups. At follow-up, 273 of 294 (92.8%) patients had no coronary artery involvement, with no difference between the two groups (p = 0.609). The overall incidence of coronary artery aneurysms at diagnosis was 16.2%. At follow-up, most coronary artery aneurysms had regressed, and coronary artery aneurysms were present in only 5.8% of the patients. Coronary artery aneurysms were slightly more frequent in patients with incomplete KD at follow-up (p = 0.039) but not at diagnosis (p = 0.208).ConclusionAlthough the clinical presentation in children with incomplete and complete KD differs, the absence of coronary artery involvement does not. The use of corticosteroids appears to be preventive against the development of coronary artery aneurysms in these patients. However, the results of this study suggest a lower rate of coronary artery aneurysm regression in patients with incomplete KD. Further studies on a larger scale are needed to assess the risk of non-regression of coronary artery aneurysms in this particular group of patients.
Genotypic spectrum of α-thalassemia and β-thalassemia in newborns of the Li minority in Hainan province, China
Authors: Zhong Kun , Shi Haijie , Wu Wenli , Xu Haizhu , Wang Hui , Zhao Zhendong 
Published: March 2023

PurposeTo explore the genotypes and allele frequencies of α, β and α+β thalassemias in Li minorities, which resided in Hainan Province of China for a long time.MethodsIn the present study, 1,438 newborns of the Li minority were collected from January 2020 to April 2021. The genotypes of thalassemia were detected by fluorescence PCR and verified by flow-through hybridization PCR analyses. Rare genotypes were detected by restriction fragment length polymorphism electrophoresis and Sanger DNA sequencing.ResultsAmong 1,438 participants, 1,024 (71.2%) were diagnosed with any kind of thalassemia. Among all thalassemia carriers, 902 (88.09%) subjects were diagnosed with α-thalassemia, and 18 subtypes of α-thalassemia were detected, with the top three genotypes being −α4.2/αα (25.39%), −α3.7/αα (22.62%) and αWSα/αα (16.96%). Thirty-two (3.13%) patients were β-thalassemia carriers, and 6 types of β-thalassemia genotypes were detected. The top two genotypes were βCD41–42/βN (46.88%) and β−28/βN (18.75%). Additionally, 90 (8.79%) cases were α + β-thalassemia, and the top two genotypes were −α3.7/αα, βCD41–42/βN (30.00%) and −α4.2/αα, βCD41–42/βN (26.67%). Furthermore, two genotypes (−α4.2/HKαα and βCD76 GCT &gt; CCT/βN) were first identified in Hainan Province, and βCD76 GCT &gt; CCT/βN was first identified in China.ConclusionNewborns of Li have a higher prevalence of thalassemia for a long period, and further education on the impact of thalassemia, follow-up studies of the clinical manifestation and treatment and proper intervention methods should be designed to reduce the burden of thalassemia and enhance the quality of life in Li newborns.
Neutrophil extracellular traps in urinary tract infection
Authors: Krivošíková Katarína , Šupčíková Nadja , Gaál Kovalčíková Alexandra , Janko Jakub , Pastorek Michal , Celec Peter , Podracká Ľudmila , Tóthová Ľubomíra 
Published: March 2023

BackgroundUrinary tract infections (UTI) are common types of bacterial infection in children. UTI treatment is aimed to prevent complications including hypertension, proteinuria, and progression to chronic kidney disease. Activated neutrophils release chromatin-based structures associated with antimicrobial proteins called neutrophil extracellular traps (NETs). We aimed to describe the role of NET-associated markers in children with UTI as well as the role of NETs formation in a mouse model of UTI.Materials and methodsMarkers of NETs including extracellular DNA (ecDNA), myeloperoxidase (MPO) and cathelicidin were analyzed in children with febrile UTI caused by E.coli (n = 98, aged 0.3–1.3 years) and in healthy controls (n = 50, 0.5–5.2 years). Moreover, an acute experimental model of UTI was performed on PAD4 knock-out mice with diminished NETs formation (n = 18), and on wild-type mice (n = 15).ResultsChildren with UTI had significantly higher urinary NETs markers including total ecDNA, nuclear DNA and mitochondrial DNA, altogether with MPO and cathelicidin. The concentrations of MPO and cathelicidin positively correlated with ecDNA (r = 0.53, p ≤ 0.001; r = 0.56, p ≤ 0.001, respectively) and the number of leukocytes in the urine (r = 0.29, p ≤ 0.05; r = 0.27, p ≤ 0.05, respectively). Moreover, urinary MPO was positively associated with cathelicidin (r = 0.61, p ≤ 0.001). In the experimental model, bacterial load in the bladder (20-fold) and kidneys (300-fold) was significantly higher in PAD4 knock-out mice than in wild-type mice.ConclusionHigher urinary NETs makers—ecDNA, MPO and cathelicidin and their correlation with leukocyturia in children with UTI confirmed our hypothesis about the association between NETs and UTI in children. Higher bacterial load in mice with diminished NETs formation suggests that NETs are not only a simple consequence of UTI, but might play a direct role in the prevention of pyelonephritis and other UTI complications.
Resistance of Vibrio cholera to antibiotics that inhibit cell wall synthesis: A systematic review and meta-analysis
Authors: Nateghizad Hossein , Sajadi Rojina , Shivaee Ali , Shirazi Omid , Sharifian Mohadeseh , Tadi Danyal Abbasi , Amini Kumarss 
Published: March 2023

Objective:Cholera is a challenging ancient disease caused byVibrio cholera(V. cholera). Antibiotics that prevent cell wall synthesis are among the first known antibiotic groups. Due to its high consumption,V. cholerahas developed resistance to the majority of antibiotics in this class. Resistance to recommended antibiotics for the treatment ofV. cholerahas also increased. In light of the decrease in consumption of certain antibiotics in this group that inhibit cell wall synthesis and the implementation of new antibiotics, it is necessary to determine the antibiotic resistance pattern ofV. choleraand to employ the most effective treatment antibiotic.Method:An comprehensive systematic search for relevant articles was conducted in PubMed, Web of Science, Scopus, and EMBASE through October 2020. Stata version 17.1 utilized the Metaprop package to execute a Freeman-Tukey double arcsine transformation in order to estimate weighted pooled proportions.Results:A total of 131 articles were included in the meta-analysis. Ampicillin was the most investigated antibiotic. The prevalence of antibiotic resistance was in order aztreonam (0%), cefepime (0%), imipenem (0%), meropenem (3%), fosfomycin (4%), ceftazidime (5%), cephalothin (7%), augmentin (8%), cefalexin (8%), ceftriaxone (9%), cefuroxime (9%), cefotaxime (15%), cefixime (37%), amoxicillin (42%), penicillin (44%), ampicillin (48%), cefoxitin (50%), cefamandole (56%), polymyxin-B (77%), carbenicillin (95%) respectively.Discussion:Aztreonam, cefepime, and imipenem are the most efficientV. choleracell wall synthesis inhibitors. There has been an increase in resistance to antibiotics such as cephalothin, ceftriaxone, amoxicillin, and meropenem. Over the years, resistance to penicillin, ceftazidime, and cefotaxime, has decreased.
Pharmacogenomic profile of actionable molecular variants related to drugs commonly used in anesthesia: WES analysis reveals new mutations
Authors: Parada-Márquez Juan Fernando , Maldonado-Rodriguez Nicolás David , Triana-Fonseca Paula , Contreras-Bravo Nora Constanza , Calderón-Ospina Carlos Alberto , Restrepo Carlos M. , Morel Adrien , Ortega-Recalde Oscar Javier , Silgado-Guzmán Daniel Felipe , Angulo-Aguado Mariana , Fonseca-Mendoza Dora Janeth 
Published: March 2023

Background: Genetic interindividual variability is associated with adverse drug reactions (ADRs) and affects the response to common drugs used in anesthesia. Despite their importance, these variants remain largely underexplored in Latin-American countries. This study describes rare and common variants found in genes related to metabolism of analgesic and anaesthetic drug in the Colombian population.Methods: We conducted a study that included 625 Colombian healthy individuals. We generated a subset of 14 genes implicated in metabolic pathways of common medications used in anesthesia and assessed them by whole-exome sequencing (WES). Variants were filtered using two pipelines: A) novel or rare (minor allele frequency—MAF &lt;1%) variants including missense, loss-of-function (LoF, e.g., frameshift, nonsense), and splice site variants with potential deleterious effect and B) clinically validated variants described in the PharmGKB (categories 1, 2 and 3) and/or ClinVar databases. For rare and novel missense variants, we applied an optimized prediction framework (OPF) to assess the functional impact of pharmacogenetic variants. Allelic, genotypic frequencies and Hardy-Weinberg equilibrium were calculated. We compare our allelic frequencies with these from populations described in the gnomAD database.Results: Our study identified 148 molecular variants potentially related to variability in the therapeutic response to 14 drugs commonly used in anesthesiology. 83.1% of them correspond to rare and novel missense variants classified as pathogenic according to the pharmacogenetic optimized prediction framework, 5.4% were loss-of-function (LoF), 2.7% led to potential splicing alterations and 8.8% were assigned as actionable or informative pharmacogenetic variants. Novel variants were confirmed by Sanger sequencing. Allelic frequency comparison showed that the Colombian population has a unique pharmacogenomic profile for anesthesia drugs with some allele frequencies different from other populations.Conclusion: Our results demonstrated high allelic heterogeneity among the analyzed sampled, enriched by rare (91.2%) variants in pharmacogenes related to common drugs used in anesthesia. The clinical implications of these results highlight the importance of implementation of next-generation sequencing data into pharmacogenomic approaches and personalized medicine.
Leveraging in vitro and pharmacokinetic models to support bench to bedside investigation of XTMAB-16 as a novel pulmonary sarcoidosis treatment
Authors: Offman Elliot , Singh Noopur , Julian Mark W. , Locke Landon W. , Bicer Sabahattin , Mitchell Jonah , Matthews Thomas , Anderson Kirsten , Crouser Elliott D. 
Published: March 2023

Background: Sarcoidosis is a chronic, multisystem inflammatory disorder characterized by non-caseating epithelioid granulomas; infiltration of mononuclear cells; and destruction of microarchitecture in the skin, eye, heart, and central nervous system, and the lung in &gt;90% of cases. XTMAB-16 is a chimeric anti-tumor necrosis factor alpha (TNFα) antibody, distinct from other anti-TNF antibodies based on its molecular structure. The efficacy of XTMAB-16 has not been clinically demonstrated, and it is still undergoing clinical development as a potential treatment for sarcoidosis. The current study demonstrates the activity of XTMAB-16 in a well-established in vitro sarcoidosis granuloma model, although XTMAB-16 is not yet approved by the United States Food and Drug Administration (FDA) for treatment of sarcoidosis, or any other disease.Objective: To provide data to guide safe and efficacious dose selection for the ongoing clinical development of XTMAB-16 as a potential treatment for sarcoidosis.Methods: First, XTMAB-16 activity was evaluated in an established in vitro model of granuloma formation using peripheral blood mononuclear cells from patients with active pulmonary sarcoidosis to determine a potentially efficacious dose range. Second, data obtained from the first-in-human study of XTMAB-16 (NCT04971395) were used to develop a population pharmacokinetic (PPK) model to characterize the pharmacokinetics (PK) of XTMAB-16. Model simulations were performed to evaluate the sources of PK variability and to predict interstitial lung exposure based on concentrations in the in vitro granuloma model.Results: XTMAB-16 dose levels of 2 and 4 mg/kg, once every 2 weeks (Q2W) or once every 4 weeks (Q4W) for up to 12 weeks, were supported by data from the non-clinical, in vitro secondary pharmacology; the Phase 1 clinical study; and the PPK model developed to guide dose level and frequency assumptions. XTMAB-16 inhibited granuloma formation and suppressed interleukin-1β (IL-1β) secretion in the in vitro granuloma model with a half maximal inhibitory concentration (IC50) of 5.2 and 3.5 μg/mL, respectively. Interstitial lung concentrations on average, following 2 or 4 mg/kg administered Q2W or Q4W, are anticipated to exceed the in vitro IC50 concentrations.Conclusion: The data presented in this report provide a rationale for dose selection and support the continued clinical development of XTMAB-16 for patients with pulmonary sarcoidosis.