bluuebunny/crossref_metadata_2025_split huggingface dataset:
GrlR, a negative regulator in enteropathogenic E. coli, also represses the expression of LEE virulence genes independently of its interaction with its cognate partner GrlA
Authors: Lara-Ochoa Cristina , Huerta-Saquero Alejandro , Medrano-López Abraham , Deng Wanyin , Finlay B. Brett , Martínez-Laguna Ygnacio , Puente José L. 
Published: February 2023

IntroductionEnteropathogenic Escherichia coli (EPEC), enterohemorrhagic E. coli (EHEC) and Citrobacter rodentium (CR) belong to a group of pathogens that share the ability to form “attaching and effacing” (A/E) lesions on the intestinal epithelia. A pathogenicity island known as the locus of enterocyte effacement (LEE) contains the genes required for A/E lesion formation. The specific regulation of LEE genes relies on three LEE-encoded regulators: Ler activates the expression of the LEE operons by antagonizing the silencing effect mediated by the global regulator H-NS, GrlA activates ler expression and GrlR represses the expression of the LEE by interacting with GrlA. However, despite the existing knowledge of LEE regulation, the interplay between GrlR and GrlA and their independent roles in gene regulation in A/E pathogens are still not fully understood.MethodsTo further explore the role that GrlR and GrlA in the regulation of the LEE, we used different EPEC regulatory mutants and cat transcriptional fusions, and performed protein secretion and expression assays, western blotting and native polyacrylamide gel electrophoresis.Results and discussionWe showed that the transcriptional activity of LEE operons increased under LEE-repressing growth conditions in the absence of GrlR. Interestingly, GrlR overexpression exerted a strong repression effect over LEE genes in wild-type EPEC and, unexpectedly, even in the absence of H-NS, suggesting that GrlR plays an alternative repressor role. Moreover, GrlR repressed the expression of LEE promoters in a non-EPEC background. Experiments with single and double mutants showed that GrlR and H-NS negatively regulate the expression of LEE operons at two cooperative yet independent levels. In addition to the notion that GrlR acts as a repressor by inactivating GrlA through protein-protein interactions, here we showed that a DNA-binding defective GrlA mutant that still interacts with GrlR prevented GrlR-mediated repression, suggesting that GrlA has a dual role as a positive regulator by antagonizing GrlR’s alternative repressor role. In line with the importance of the GrlR-GrlA complex in modulating LEE gene expression, we showed that GrlR and GrlA are expressed and interact under both inducing and repressing conditions. Further studies will be required to determine whether the GrlR alternative repressor function depends on its interaction with DNA, RNA, or another protein. These findings provide insight into an alternative regulatory pathway that GrlR employs to function as a negative regulator of LEE genes.
Cerebral white matter lesions and regional blood flow are associated with reduced cognitive function in early-stage cognitive impairment
Authors: Kuroda Takeshi , Ono Kenjiro , Honma Motoyasu , Asano Miki , Mori Yukiko , Futamura Akinori , Yano Satoshi , Kanemoto Mizuki , Hieda Sotaro , Baba Yasuhiko , Izumizaki Masahiko , Murakami Hidetomo 
Published: February 2023

BackgroundDifferences in the extent of cerebral white matter lesions (WML) and regional cerebral blood flow (rCBF) in early-stage cognitive impairment (ESCI) contribute to the prognosis of cognitive decline; however, it is unclear precisely how WML and rCBF affect cognitive decline in ESCI.ObjectiveWe examined the association between WML, rCBF, and cognitive impairment in the ESCI, using path analysis to clarify how these variables affect each other.MethodsEighty-three patients who consulted our memory clinic regarding memory loss were included in this study based on the Clinical Dementia Rating. Participants underwent the Mini-Mental State Examination (MMSE), brain magnetic resonance imaging (MRI) for voxel-based morphometry analysis, and brain perfusion single-photon emission computed tomography (SPECT) for rCBF evaluation in cortical regions, using 3D stereotactic surface projection (3D-SSP) analysis.ResultsPath analysis was performed on the MRI voxel-based morphometry and SPECT 3D-SSP data, showing a significant correlation between both and MMSE scores. In the most suitable model (GFI = 0.957), correlations were observed between lateral ventricular (LV-V) and periventricular WML (PvWML-V) volumes [standardized coefficient (SC) = 0.326, p = 0.005], LV-V and rCBF of the anterior cingulate gyrus (ACG-rCBF; SC = 0.395, p &lt; 0.0001), and ACG-rCBF and PvWML-V (SC = 0.231, p = 0.041). Furthermore, a direct relationship between PvWML-V and MMSE scores was identified (SC = −0.238, p = 0.026).ConclusionSignificant interrelationships were observed among the LV-V, PvWML-V, and ACG-rCBF that directly affected the MMSE score in the ESCI. The mechanisms behind these interactions and the impact of PvWML-V on cognitive function require further investigation.
Effects of percutaneously-implanted epidural stimulation on cardiovascular autonomic function and spasticity after complete spinal cord injury: A case report
Authors: Gorgey Ashraf S. , Goldsmith Jacob , Alazzam Ahmad , Trainer Robert 
Published: February 2023

ImportanceThere is a revived interest to explore spinal cord epidural stimulation (SCES) to improve physical function after spinal cord injury (SCI). This case report highlights the potential of eliciting multiple functional improvements with a single SCES configuration, a strategy which could improve clinical translation.ObjectiveTo determine whether SCES intended to facilitate walking also acutely yields benefits in cardiovascular autonomic regulation and spasticity.DesignCase report from data collected at two timepoints 15 weeks apart from March to June 2022 as part of a larger clinical trial.SettingResearch lab at Hunter Holmes McGuire VA Medical Center.Participant27-year-old male, 7 years post a C8 motor complete spinal cord injury.InterventionA SCES configuration intended to enhance exoskeleton-assisted walking training applied for autonomic and spasticity management.Main outcomes and measuresThe primary outcome was cardiovascular autonomic response to a 45-degree head-up-tilt test. Systolic blood pressure (SBP), heart rate (HR), and absolute power of the low-frequency (LF) and high-frequency (HF) components of a heart-rate variability analysis were collected in supine and tilt with and without the presence of SCES. Right knee flexor and knee extensor spasticity was assessed via isokinetic dynamometry with and without SCES.ResultsAt both assessments with SCES off, transitioning from supine to tilt decreased SBP (assessment one: 101.8 to 70 mmHg; assessment two: 98.9 to 66.4 mmHg). At assessment one, SCES on in supine (3 mA) increased SBP (average 117 mmHg); in tilt, 5 mA stabilized SBP near baseline values (average 111.5 mmHg). At assessment two, SCES on in supine (3 mA) increased SBP (average 140 mmHg in minute one); decreasing amplitude to 2 mA decreased SBP (average 119 mmHg in minute five). In tilt, 3 mA stabilized SBP near baseline values (average 93.2 mmHg). Torque-time integrals at the right knee were reduced at all angular velocities for knee flexors (range: −1.9 to −7.8%) and knee extensors (range: −1 to −11.4%).Conclusions and relevanceThese results demonstrate that SCES intended to facilitate walking may also enhance cardiovascular autonomic control and attenuate spasticity. Using one configuration to enhance multiple functions after SCI may accelerate clinical translation.Clinical trial registrationhttps://clinicaltrials.gov/ct2/show/, identifier NCT04782947.
Health effects of the time-restricted eating in adults with obesity: A systematic review and meta-analysis
Authors: Chen Weiyi , Liu Xiaoli , Bao Lei , Yang Ping , Zhou Huihui 
Published: February 2023

BackgroundThe number of people suffering from overweight or obesity has been steadily increasing in recent years. As a new form of diet, the efficacy of time-restricted eating (TRE) remains debatable.ObjectiveThis meta-analysis quantified the effect of TRE on weight change and other physical parameters in obese and overweight adults.MethodsWe did a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing the TRE interventions on weight loss and other metabolic parameters by searching PubMed, Embase, and Cochrane Central Register of Controlled Trials to identify eligible trials published from database inception up until 23 August 2022. The risk of bias was assessed using the Revised Cochrane risk-of-bias tool (ROB-2.0). Meta-analysis was performed using Review Manager 5.4.1 software.ResultsNine RCTs with 665 individuals (345 in the TRE group while 320 in the control group) were included. Results indicated that TRE had a greater decrease in body weight (−1.28 kg; 95% CI [−2.05, −0.52], p = 0.001), fat mass (−0.72 kg; 95% CI [−1.40, −0.03], p = 0.04), body mass index (−0.34 kg/m2; 95% CI [−0.64, −0.04], p = 0.03) and diastolic blood pressure (−2.26 mmHg 95% CI [−4.02, −0.50], p = 0.01). However, the meta-analysis demonstrated that there was no significant difference between TRE and the control group in lean mass, systolic blood pressure, waist circumference, fasting glucose, fasting insulin, homeostasis model assessment-insulin resistance (HOMA-IR), total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglycerides. Besides, the duration of the study and daily eating window also had an impact on weight change.ConclusionTRE was associated with reductions in weight and fat mass and can be a dietary intervention option for adults with obesity. But high-quality trials and longer follow-ups are needed to draw definitive conclusions.
Artificial intelligence-based prediction of overall survival in metastatic renal cell carcinoma
Authors: Barkan Ella , Porta Camillo , Rabinovici-Cohen Simona , Tibollo Valentina , Quaglini Silvana , Rizzo Mimma 
Published: February 2023

Background and objectivesInvestigations of the prognosis are vital for better patient management and decision-making in patients with advanced metastatic renal cell carcinoma (mRCC). The purpose of this study is to evaluate the capacity of emerging Artificial Intelligence (AI) technologies to predict three- and five-year overall survival (OS) for mRCC patients starting their first-line of systemic treatment.Patients and methodsThe retrospective study included 322 Italian patients with mRCC who underwent systemic treatment between 2004 and 2019. Statistical analysis included the univariate and multivariate Cox proportional-hazard model and the Kaplan-Meier analysis for the prognostic factors’ investigation. The patients were split into a training cohort to establish the predictive models and a hold-out cohort to validate the results. The models were evaluated by the area under the receiver operating characteristic curve (AUC), sensitivity, and specificity. We assessed the clinical benefit of the models using decision curve analysis (DCA). Then, the proposed AI models were compared with well-known pre-existing prognostic systemsResultsThe median age of patients in the study was 56.7 years at RCC diagnosis and 78% of participants were male. The median survival time from the start of systemic treatment was 29.2 months; 95% of the patients died during the follow-up that finished by the end of 2019. The proposed predictive model, which was constructed as an ensemble of three individual predictive models, outperformed all well-known prognostic models to which it was compared. It also demonstrated better usability in supporting clinical decisions for 3- and 5-year OS. The model achieved (0.786 and 0.771) AUC and (0.675 and 0.558) specificity at sensitivity 0.90 for 3 and 5 years, respectively. We also applied explainability methods to identify the important clinical features that were found to be partially matched with the prognostic factors identified in the Kaplan-Meier and Cox analyses.ConclusionsOur AI models provide best predictive accuracy and clinical net benefits over well-known prognostic models. As a result, they can potentially be used in clinical practice for providing better management for mRCC patients starting their first-line of systemic treatment. Larger studies would be needed to validate the developed model
Whole-genome sequencing identified novel mutations in a Chinese family with lynch syndrome
Authors: He Wan , Dong Shaowei , Shen Jing , Wu Jiutong , Zhao Pan , Li Dongbing , Wang Dongliang , Tang Na , Zou Chang 
Published: February 2023

BackgroundLynch syndrome (LS) is caused by a germline mutation in one of the mismatch repair genes (MLH1, MSH2, MSH6, and PMS2) or in the EPCAM gene. The definition of Lynch syndrome is based on clinical, pathological, and genetic findings. Therefore, the identification of susceptibility genes is essential for accurate risk assessment and tailored screening programs in LS monitoring.Patients and methodsIn this study, LS was diagnosed clinically in a Chinese family using Amsterdam II criteria. To further explore the molecular characteristics of this LS family, we performed whole genome sequencing (WGS) to 16 members in this family and summarized the unique mutational profiles within this family. We also used Sanger sequencing technology and immunohistochemistry (IHC) to verify some of the mutations identified in the WGS analysis.ResultsWe showed that mutations in mismatch repair (MMR) related genes, as well as pathways including DNA replication, base excision repair, nucleotide excision repair, and homologous recombination were enhanced in this family. Two specific variants, MSH2 (p.S860X) and FSHR (p.I265V) were identified in all five members with LS phenotypes in this family. The MSH2 (p.S860X) variant is the first reported variant in a Chinese LS family. This mutation would result in a truncated protein. Theoretically, these patients might benefit from PD-1 (Programmed death 1) immune checkpoint blockade therapy. The patients who received nivolumab in combination with docetaxel treatments are currently in good health.ConclusionOur findings extend the mutation spectrum of genes associated with LS in MLH2 and FSHR, which is essential for future screening and genetic diagnosis of LS.
Post-transplant cyclophosphamide versus anti-thymocyte globulin in allogeneic hematopoietic stem cell transplantation from unrelated donors: A systematic review and meta-analysis
Authors: Tang Lu , Liu Zhigang , Li Tao , Dong Tian , Wu Qiuhui , Niu Ting , Liu Ting , Ji Jie 
Published: February 2023

BackgroundPost-transplant cyclophosphamide (PTCy) and anti-thymocyte globulin (ATG) are both common graft-versus-host disease (GVHD) prophylaxis strategies in allo-HSCT from unrelated donors. However, no consensus has reached on which regimen is optimal. Although several studies concerning this topic exist, the outcomes of different studies still conflict with each other. Therefore, an overall comparison of the two regimens is urgently needed to help make informed clinical decisions.MethodsStudies comparing PTCy and ATG regimens in unrelated donor (UD) allo-HSCT were searched in four critical medical databases from inception to April 17, 2022. The primary outcome was grade II-IV aGVHD, grade III-IV aGVHD and chronic GVHD (cGVHD), and the secondary outcomes included overall survival (OS), relapse incidence (RI), non-relapse mortality (NRM), and several severe infectious complications. The quality of articles was assessed by the Newcastle-Ottawa scale (NOS), and data were extracted by two independent investigators and then analyzed by RevMan 5.4.ResultsSix out of 1091 articles were eligible for this meta-analysis. Compared with the ATG regimen, prophylaxis based on PTCy achieved a lower incidence of grade II-IV aGVHD incidence (RR=0.68, 95% CI 0.50-0.93, P=0.010, I2 = 67%), grade III-IV aGVHD (RR=0.32, 95% CI 0.14-0.76, P=0.001, I2 = 75%), NRM (RR=0.67, 95% CI 0.53-0.84, P=0.17, I2 = 36%), EBV-related PTLD (RR=0.23, 95% CI 0.09-0.58, P=0.85, I2 = 0%) and better OS (RR=1.29, 95% CI 1.03-1.62, P=0.0001, I2 = 80%). The cGVHD, RI, CMV reactivation and BKV-related HC showed no significant difference between the two groups (RR=0.66, 95% CI 0.35-1.26, P&lt;0.00001, I2 = 86%; RR=0.95, 95% CI 0.78-1.16, P=0.37, I2 = 7%; RR=0.89, 95% CI 0.63-1.24, P=0.07, I2 = 57%; RR=0.88, 95% CI 0.76-1.03, P=0.44, I2 = 0%).ConclusionIn the setting of unrelated donor allo-HSCT, prophylaxis based on PTCy can lower the incidence of grade II-IV aGVHD, grade III-IV aGVHD, NRM and EBV-related complication, achieve better OS compared to ATG-based regimen. And cGVHD, RI, CMV reactivation and BKV-related HC were comparable in the two groups.
Sintilimab plus Lenvatinib conversion therapy for intermediate/locally advanced hepatocellular carcinoma: A phase 2 study
Authors: Wang Lijun , Wang Hongwei , Cui Yong , Liu Ming , Jin Kemin , Xu Da , Wang Kun , Xing Baocai 
Published: February 2023

IntroductionPatients with intermediate or locally advanced hepatocellular carcinoma (HCC) who are not eligible for radical treatment typically have a poor overall prognosis. Treatment strategies that can convert unresectable HCC into resectable HCC may improve patient survival. We conducted a single arm phase 2 trial to evaluate the efficacy and safety of Sintilimab plus Lenvatinib as conversion therapy for HCC.MethodsA single-arm, single-center study conducted in China (NCT04042805). Adults (≥18 years) with Barcelona Clinic Liver Cancer (BCLC) Stage B or C HCC ineligible for radical surgery with no distant/lymph node metastasis received Sintilimab 200 mg IV on day 1 of a 21-day cycle plus Lenvatinib 12 mg (body weight ≥60 kg) or 8 mg (body weight &lt;60 kg) orally once daily. Resectability was based on imaging and liver function. The primary endpoint was objective response rate (ORR), assessed using RECIST v1.1. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), event-free survival (EFS) in patients who underwent resection, surgical conversion rate, and safety.ResultsOverall, 36 patients were treated between August 1, 2018, and November 25, 2021; the median age was 58 years (range, 30–79), and 86% were male. The ORR (RECIST v1.1) was 36.1% (95% CI, 20.4–51.8) and the DCR was 94.4% (95% CI, 86.9–99.9). Eleven patients underwent radical surgery and one received radiofrequency ablation and stereotactic body radiotherapy; after a median follow up of 15.9 months, all 12 were alive and four had recurrence, median EFS was not reached. Median PFS among 24 patients who did not undergo surgery was 14.3 months (95% CI, 6.3–26.5). Treatment was generally well tolerated; two patients had serious adverse events; there were no treatment-related deaths.ConclusionsSintilimab plus Lenvatinib is safe and feasible for the conversion treatment of intermediate to locally advanced HCC initially unsuitable for surgical resection.
Use of proton pump inhibitors in scandinavian children and adolescents: An observational study
Authors: Closs Emilie Raaum , Mårild Karl , Nielsen Rasmus Gaardskær , Størdal Ketil 
Published: February 2023

AimsTo examine the use of proton pump inhibitors (PPIs) in Scandinavian children with focus on the geographical variation, temporal changes and possible contributing factors to observed changes.MethodsAn observational population-based study of children and adolescents (1-17 years) in Norway, Sweden, and Denmark during the period 2007-2020. Information concerning dispensed PPIs was obtained from the national prescription databases of each country and presented as means per 1,000 children for each country and calendar year in four age categories (1-4, 5-9, 10-13 and 14-17 years).ResultsIn 2007, the PPI use in children was similar across Scandinavian countries. An increased PPI use was observed in all countries during the study period, with gradually increasing differences between the countries. In general, Norway showed both the largest total increase and the largest increase in each age category compared to Sweden and Denmark. In 2020 Norwegian children showed, on average, a 59% higher PPI use compared to Swedish children and a more than double the overall dispensation rate than Denmark. In Denmark there was a 19% reduction in dispensed PPIs from 2015 to 2020.ConclusionDespite being countries with similar health care systems and without indications of increased incidence of gastroesophageal reflux disease (GERD), we observed considerable geographical variation and temporal changes of PPI use in children. Although this study did not contain data on the indication for PPI use, these large differences across countries and time may indicate a current overtreatment.
Dendrobium mixture ameliorates type 2 diabetes mellitus with non-alcoholic fatty liver disease through PPAR gamma: An integrated study of bioinformatics analysis and experimental verification
Authors: Zhuang Shuting , Zhang Jieping , Lin Xiaohui , Wang Xiaoning , Yu Wenzhen , Shi Hong 
Published: February 2023

Dendrobium mixture (DM) is a patented Chinese herbal medicine indicated which has anti-inflammatory and improved glycolipid metabolism. However, its active ingredients, targets of action, and potential mechanisms are still uncertain. Here, we investigate the role of DM as a prospective modulator of protection against non-alcoholic fatty liver disease (NAFLD) induced by type 2 diabetes mellitus (T2DM) and illustrate the molecular mechanisms potentially involved. The network pharmacology and TMT-based quantitative protomics analysis were conducted to identify potential gene targets of the active ingredients in DM against NAFLD and T2DM. DM was administered to the mice of DM group for 4 weeks, and db/m mice (control group) and db/db mice (model group) were gavaged by normal saline. DM was also given to Sprague-Dawley (SD) rats, and the serum was subjected to the palmitic acid-induced HepG2 cells with abnormal lipid metabolism. The mechanism of DM protection against T2DM-NAFLD is to improve liver function and pathological morphology by promoting peroxisome proliferator-activated receptor γ (PPARγ) activation, lowering blood glucose, improving insulin resistance (IR), and reducing inflammatory factors. In db/db mice, DM reduced RBG, body weight, and serum lipids levels, and significantly alleviated histological damage of liver steatosis and inflammation. It upregulated the PPARγ corresponding to the prediction from the bioinformatics analysis. DM significantly reduced inflammation by activating PPARγ in both db/db mice and palmitic acid-induced HepG2 cells.