bluuebunny/crossref_metadata_2025_split huggingface dataset:
A postbiotic fermented oat gruel may have a beneficial effect on the colonic mucosal barrier in patients with irritable bowel syndrome
Authors: Bednarska Olga , Biskou Olga , Israelsen Hans , Winberg Martin E. , Walter Susanna , Keita Åsa V. 
Published: December 2022

BackgroundImpaired intestinal permeability and microbial dysbiosis are important pathophysiological mechanisms underlying irritable bowel syndrome (IBS). ReFerm®, also called Profermin®, is a postbiotic product of oat gruel fermented with Lactobacillus plantarum 299v. In this study, we investigated whether ReFerm® has a beneficial effect on the intestinal epithelial barrier function in patients with IBS.Materials and methodsThirty patients with moderate to severe IBS-diarrhoea (IBS-D) or IBS-mixed (IBS-M) were treated with enema containing ReFerm® or placebo. The patients underwent sigmoidoscopy with biopsies obtained from the distal colon at baseline and after 14 days of treatment with ReFerm® or placebo twice daily. The biopsies were mounted in Ussing chambers, and paracellular and transcellular permeabilities were measured for 120 min. In addition, the effects of ReFerm® or placebo on the epithelial barrier were investigated in vitro using Caco-2 cells.ResultsReFerm® reduced paracellular permeability (p &lt; 0.05) and increased transepithelial resistance (TER) over time (p &lt; 0.01), whereas the placebo had no significant effect in patients. In ReFerm®-treated Caco-2 cells, paracellular and transcellular permeabilities were decreased compared to the control (p &lt; 0.05) and placebo (p &lt; 0.01). TER was increased in Caco-2 ReFerm®-treated cells, and normalised TER was increased in ReFerm®-treated Caco-2 cells compared to control (p &lt; 0.05) and placebo-treated (p &lt; 0.05) cells.ConclusionReFerm® significantly reduced paracellular permeability and improved TER in colonic biopsies collected from patients with IBS and in a Caco-2 cell model. Our results offer new insights into the potential benefits of ReFerm® in IBS management. Further studies are needed to identify the molecular mechanisms underlying the barrier-protective properties of ReFerm®.Clinical trial registration[https://clinicaltrials.gov/], identifier [NCT05475314].
Risk factors of cervical lymph node metastasis in multifocal papillary thyroid cancer
Authors: Zhang Ting , He Liang , Wang Zhihong , Dong Wenwu , Sun Wei , Zhang Ping , Zhang Hao 
Published: December 2022

IntroductionIdentifying risk variables for cervical lymph node metastases in multifocality papillary thyroid cancer (MPTC) could assist surgeons in determining whether cervical lymph node dissection would be an appropriate surgical option.MethodsA retrospective cohort of 2006 patients with papillary thyroid cancer were selected. MPTC (N = 460) was defined as the presence of two or more foci of PTC. The risk factors for central lymph node metastasis (CLNM) and lateral lymph node metastasis (LLNM) in MPTC were investigated by univariate and multivariate analyses, including the following items: age at diagnosis, gender, Hashimoto’s thyroiditis, extrathyroidal extension (ETE), maximal axial diameter (MAD) and the sum of axial diameters (SAD) of tumor. In addition, CLNM was used to evaluate LLNM.ResultsThe incidence of CLNM and LLNM was 44.57% and 17.17%, respectively. The multivariate analysis demonstrated that gender, extrathyroidal extension (ETE), age, maximal axial diameter (MAD), and the sum of axial diameters (SAD) were related to increased risk for CLNM in MPTC (p &lt; 0.05). The area under the receiver operating characteristic (ROC) curve (AUC) for age at diagnosis of CLNM was 0.647, the cut-off value was 50 years old. Additionally, by multivariate analysis, CLNM, ETE, MAD, and SAD were independent risk factors for LLNM in MPTC (p &lt; 0.05). ROC curve analysis demonstrates that AUC for MAD and SAD diagnosis of LLNM were 0.639 and 0.757, and the cut-off values were 16 and 26 mm, respectively.ConclusionsMPTC patients who have risk factors for CLNM were advised to perform prophylactic central lymph node dissection (CLND). Additionally, the presence of risk factors for LLNM should be individually evaluated and analyzed for the necessity of lateral lymph node dissection.
Endoscopic and pathohistologic features of early gastric signet ring cell carcinoma presented as elevated type: A case report
Authors: Di Lianjun , Wu Xinglong , Tuo Biguang 
Published: December 2022

BackgroundAlmost all early gastric signet ring cell carcinomas (SRCCs) are the flat or depressed type, and the elevated type is rare. Here, we report the endoscopic and pathohistologic features of a rare case of SRCCs presented as the elevated type.Case presentationA 54-year-old man underwent esophagogastroduodenoscopy in our hospital because of intermittent upper abdominal pain for 6 years. White light endoscopy revealed an elevated lesion that is smooth and reddish and covered with normal mucosa and looked like a polyp. Magnifying endoscopy with narrow-band imaging showed broadened intervening parts, an elongated pit, and a dense microvascular network with focal irregularity. The lesion was considered as early gastric cancer and completely resected with endoscopic submucosal dissection. Pathohistological examination confirmed that the lesion was pure early SRCC that was limited within the mucosal lamina propria (T1a).ConclusionElevated pure gastric SRCC is rare. This is a report of early pure gastric SRCC presented as the elevated type and the description of its endoscopic and pathohistologic features, which will contribute to the early detection of gastric SRCC.
DDB2 represses epithelial-to-mesenchymal transition and sensitizes pancreatic ductal adenocarcinoma cells to chemotherapy
Authors: Dardare Julie , Witz Andréa , Betz Margaux , Francois Aurélie , Meras Morgane , Lamy Laureline , Lambert Aurélien , Grandemange Stéphanie , Husson Marie , Rouyer Marie , Demange Jessica , Merlin Jean-Louis , Harlé Alexandre , Gilson Pauline 
Published: December 2022

IntroductionDamage specific DNA binding protein 2 (DDB2) is an UV-indiced DNA damage recognition factor and regulator of cancer development and progression. DDB2 has dual roles in several cancers, either as an oncogene or as a tumor suppressor gene, depending on cancer localization. Here, we investigated the unresolved role of DDB2 in pancreatic ductal adenocarcinoma (PDAC). MethodsThe expression level of DDB2 in pancreatic cancer tissues and its correlation with patient survival were evaluated using publicly available data. Two PDAC cell models with CRISPR-modified DDB2 expression were developed: DDB2 was repressed in DDB2-high T3M4 cells (T3M4 DDB2-low) while DDB2 was overexpressed in DDB2-low Capan-2 cells (Capan-2 DDB2-high). Immunofluorescence and qPCR assays were used to investigate epithelial-to-mesenchymal transition (EMT) in these models. Migration and invasion properties of the cells were also determined using wound healing and transwell assays. Sensitivity to 5-fluorouracil (5-FU), oxaliplatin, irinotecan and gemcitabine were finally investigated by crystal violet assays.ResultsDDB2 expression level was reduced in PDAC tissues compared to normal ones and DDB2-low levels were correlated to shorter disease-free survival in PDAC patients. DDB2 overexpression increased expression of E-cadherin epithelial marker, and decreased levels of N-cadherin mesenchymal marker. Conversely, we observed opposite effects in DDB2 repression and enhanced transcription of SNAIL, ZEB1, and TWIST EMT transcription factors (EMT-TFs). Study of migration and invasion revealed that these properties were negatively correlated with DDB2 expression in both cell models. DDB2 overexpression sensitized cells to 5-fluorouracil, oxaliplatin and gemcitabine.ConclusionOur study highlights the potential tumor suppressive effects of DDB2 on PDAC progression. DDB2 could thus represent a promising therapeutic target or biomarker for defining prognosis and predicting chemotherapy response in patients with PDAC.
High efficacy of azacitidine combined with homoharringtonine, idarubicin, and cytarabine in newly diagnosed patients with AML: A single arm, phase 2 trial
Authors: Li Jun , Huang Yanqing , Hou Yue , Gu Yan , Song Chunhua , Ge Zheng 
Published: December 2022

IntroductionThis study aims to evaluate the efficacy and safety of the novel combination of Aza and HIA as the frontline induction therapy in newly diagnosed AML patients eligible for intensive chemotherapy (IC) (registered on ClinicalTrials.gov, number NCT04248595).MethodsAza (75mg/m2/d on days1-5 subcutaneous) is administered in combination with HIA [HHT 2mg/m2/d on days 4-8 intravenous over 3 hours, idarubicin 6mg/m2/d on days 4-6 intravenous, and cytarabine 100mg/m2/d on days 4-10 intravenous]. The primary endpoint was complete remission (CR) or CR with incomplete blood count recovery (CRi). Secondary endpoints were overall survival (OS), relapse-free survival (RFS), and adverse events (AEs).ResultsA total of 20 AML patients (aged 18-70 years) were enrolled between Jan 2020 and Sep 2022. 95% (19/20) of patients achieved CR/CRi, and 89.5% (17/19) had undetectable MRD, in which 94.7% (18/19) reached CR/CRi, and 88.9% (16/18) obtained MRD negative after the 1st cycle of induction therapy. Median OS and RFS were both not reached during the follow-up. The estimated 2-year OS and RFS were 87.5% (95%CI, 58.6% to 96.7%) and 87.1% (95%CI, 57.3% to 96.6%), respectively. No patient discontinued the treatment for AEs.DiscussionThis study provides preliminary evidence for this novel combination therapy as the first-line induction therapy for young or older AML patients fit for IC.
Treatment- and immune-related adverse events of immune checkpoint inhibitors in esophageal or gastroesophageal junction cancer: A network meta-analysis of randomized controlled trials
Authors: Zheng Jianqing , Huang Bifen , Xiao Lihua , Wu Min , Li Jiancheng 
Published: December 2022

ObjectiveTo systematically evaluate the safety and adverse event profiles of immune checkpoint inhibitors (ICIs) in patients with esophageal cancer (EPC) or gastroesophageal junction cancer (GEJC).MethodsPubMed, Web of Science, Cochrane Library, and major conference proceedings were systematically searched for all phase II or phase III randomized controlled trials (RCTs) in EPC or GEJC using ICIs. Safety outcomes including treatment-related adverse events (trAEs), immune-related adverse events (irAEs), and serious trAEs were evaluated by network meta-analysis or dichotomous meta-analysis based on the random-effects model.ResultsEleven RCTs involving EPC (five RCTs) and GEJC (six RCTs) were included in the final meta-analysis. NMA showed that placebo was associated with the best safety ranking for grade 3–5 trAEs (SUCRA = 96.0%), followed by avelumab (78.6%), nivolumab (73.9%), ipilimumab (57.0%), and pembrolizumab (56.6%). Conventional pairwise meta-analysis (CPM) showed that ICIs have similar grade 3–5 trAE risk compared with chemotherapy (RR = 0.764, 95% CI: 0.574 to 1.016, I2 = 95.7%, Z = 1.85, P = 0.065). NMA showed that the general safety of grade 3–5 irAEs ranked from high to low is as follows: ChT (85.1%), placebo (76.5%), ipilimumab (56.0%), nivolumab (48.5%), avelumab (48.4%), camrelizumab (41.8%), pembrolizumab (36.4%), and nivolumab + ipilimumab (21.6%). CPM showed that the rates of grade 3–5 irAEs in the ICI group and the chemotherapy group were 7.35% (154/2,095, 95% CI: [6.23%, 8.47%]) versus 2.25% (42/1,869, 95% CI: [1.58%, 2.92%]), with statistical significance (RR = 3.151, 95% CI = 2.175 to 4.563, Z = 6.07, P = 0.000). The most common irAEs in the ICI group were skin reaction (15.76%, 95% CI: [13.67%, 17.84%]), followed by hypothyroidism (9.73%, 95% CI: [8.07%, 11.39%]), infusion-related reactions (5.93%, 95% CI: [4.29%, 7.58%]), hepatitis (5.25%, 95% CI: [4.28%, 6.22%]), and pneumonitis (4.45%, 95% CI: [3.5%, 5.4%]).ConclusionDifferent ICIs had different toxicity manifestations and should not be considered as an entity. Compared with chemotherapy, ICIs were more prone to irAEs, but the overall rates remained low and acceptable. For clinicians, it is important to recognize and monitor the adverse events caused by ICIs for patients with EPC or GEJC.
The role of neo-adjuvant therapy in cholangiocarcinoma: A systematic review
Authors: Cremen Sinead , Kelly Michael E. , Gallagher Tom K. 
Published: December 2022

IntroductionCholangiocarcinoma (CCA) is the most common malignancy affecting the biliary tree. The only curative treatment is surgical resection, aiming for negative margins (R0). For those who have locally advanced disease, which is borderline resectable, neoadjuvant chemoradiation presents an opportunity to reduce tumour size and allow for surgical resection. The aim of this review is to establish the role of neoadjuvant therapy in each subtype of CCA and establish its impact on survival.MethodsSearch terms such as ‘neoadjuvant therapy’ and ‘cholangiocarcinoma’ were searched on multiple databases, including Pubmed, Ovid and Embase. They were then reviewed separately by two reviewers for inclusion criteria. 978 studies were initially identified from the search strategy, with 21 being included in this review.Results5,009 patients were included across 21 studies. 1,173 underwent neoadjuvant therapy, 3,818 had surgical resection alone. 359 patients received Gemcitabine based regimes, making it the most commonly utilised regimen for patients CCA and Biliary Tract Cancer (BTC). Data on tolerability of regimes was limited. All included papers were found to have low risk of bias when assessed using The Newcastle Ottawa Scale. Patients who underwent neoadjuvant therapy had a similar median overall survival compared to those who underwent upfront surgery (38.4 versus 35.1 months respectively). Pre-operative CA19-9, microvascular invasion, perineurial invasion and positive lymph nodes were of prognostic significance across BTC and CCA subtypes.ConclusionNeoadjuvant therapy and surgical resection is associated with improved patient outcomes and longer median overall survival compared to therapy and upfront surgery, however heterogeneity between research papers limited the ability to further analyse the significance of these results. Although initial studies are promising, further research is required in order to define suitable treatment protocols and tolerability of neoadjuvant regimes.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42020164781.
Correlation between serum cytokines and clinicopathological features in patients with drug-induced liver injury
Authors: Zhang Yu , Gao Hui , Zhang Yu , Shao Yue-Ming , Zhang Rui-Hua , Wen Xiao-Yu 
Published: December 2022

Objectives: Changes in serum levels of cytokines have been proposed as possible biological markers of tissue damage, including drug-induced liver injury (DILI). Here, we aimed to screen cytokine markers that have guiding significance for the degree of inflammation of DILI.Patients and methods: 54 patients with DILI were retrospectively analyzed as the experimental group, and 14 healthy subjects were randomly selected as the control group. A total of 20 cytokines were detected by using a cytokine protein antibody chip, and differentially expressed proteins were screened.Results: There were significant differences in serum cytokines between DILI patients and healthy controls. Compared with the control group, the DILI group expressed 11 differential proteins. IL-8, TNF RII, TNFα, TNF RI, MIP-1β, MIP-1α, and IL-1β were differentially expressed in DILI patients with different degrees of inflammation from G1 to G4. MIG, IL-12p40, and IL-10 were differentially expressed in the higher degree of inflammation groups (G2, G3, and G4 groups). Tissue inhibitor of metalloproteinases-1 (TIMP-1) was differentially expressed in the group with the highest inflammation degree (G4 group). Chemokine C-C motif ligand 1 (I-309) was only differentially expressed in the lowest inflammation group (G1 group).Conclusion: The changes and differential expression of specific cytokine levels were helpful for evaluating different degrees of inflammation of DILI.
Plasma apixaban levels in Chinese patients with chronic kidney disease—Relationship with renal function and bleeding complications
Authors: Sin Chun-fung , Wong Ka-ping , Wong Tsz-fu , Siu Chung-wah , Yap Desmond Y. H. 
Published: December 2022

Introduction: Accumulation of apixaban in plasma is a major concern in patients with chronic kidney disease (CKD). Studies that investigated plasma apixaban level in CKD patients and its association with clinically significant events are scarce.Methods: Patients with CKD Stage 1–4 who were taking apixaban, either 2.5 mg BD or 5 mg BD were recruited. The peak and trough plasma apixaban level were measured after 2 h and 12 h of last dose respectively. The results were correlated with renal function and clinical events during the period of follow-up from 1 January 2018 to 31 October 2021.Results: 141 patients (CKD Stage 1, n = 12; Stage 2, n = 74; Stage 3, n = 48, stage 4, n = 7) were included for analysis. The plasma peak and trough apixaban were significantly higher in patients with CKD stage 3 when compared with those having CKD stage 2 and 1 (peak levels: 223.4 ± 107.8 ng/ml vs. 161.0 ± 55.2 ng/ml vs. 126.6 ± 30.2 ng/ml; trough levels: 118.3 ± 67.9 ng/ml vs. 81.2 ± 33.0 ng/ml vs. 51.9 ± 31.1 ng/ml, p &lt; 0.05 or all) in patients taking 5 mg BD. Plasma trough apixaban level was negatively correlated with eGFR in patients taking 5 mg BD (r2 = −0.174, p &lt; 0.001) and 2.5 mg BD (r2 = −0.215, p &lt; 0.05). The plasma peak and trough apixaban level correlated with PT (r2 = 0.065, p = 0.003 and r2 = 0.096, p &lt; 0.01 respectively). Multivariate analysis showed that plasma trough apixaban levels were associated with the risk of bleeding complications (Odd ratio: 1.011, 95% CI:1.002–1.021, p = 0.023).Conclusion: The plasma apixaban level shows a trend of increase with worsening renal function, and an increase in the plasma apixaban level is suggestive of an increased risk of bleeding complications in patients with CKD. Further large-scale prospective studies are needed to evaluate relationship between plasma apixaban level and renal function as well as safety outcome in CKD patients. Moreover, the role of drug level monitoring should be prospectively evaluated for dosage optimization and the minimization of bleeding risks in CKD patients.
Joint population pharmacokinetic modeling of venlafaxine and O-desmethyl venlafaxine in healthy volunteers and patients to evaluate the impact of morbidity and concomitant medication
Authors: Wang Zhanzhang , Li Lu , Huang Shanqing , Wang Xipei , Liu Shujing , Li Xiaolin , Kong Wan , Ni Xiaojia , Zhang Ming , Huang Shanshan , Tan Yaqian , Wen Yuguan , Shang Dewei 
Published: December 2022

Introduction:Venlafaxine (VEN) is a widely used dual selective serotonin/noradrenaline reuptake inhibitor indicated for depression and anxiety. It undergoes first-pass metabolism to its active metabolite, O-desmethyl venlafaxine (ODV). The aim of the present study was to develop a joint population pharmacokinetic (PPK) model to characterize their pharmacokinetic characters simultaneously.Methods:Plasma concentrations with demographic and clinical data were derived from a bioequivalence study in 24 healthy subjects and a naturalistic TDM setting containing 127 psychiatric patients. A parent-metabolite PPK modeling was performed with NONMEM software using a non-linear mixed effect modeling approach. Goodness of fit plots and normalized prediction distribution error method were used for model validation.Results and conclusion:Concentrations of VEN and ODV were well described with a one-compartment model incorporating first-pass metabolism. The first-pass metabolism was modeled as a first-order conversion. The morbid state and concomitant amisulpride were identified as two significant covariates affecting the clearance of VEN and ODV, which may account for some of the variations in exposure. This model may contribute to the precision medication in clinical practice and may inspire other drugs with pre-system metabolism.
Highly acidic pH facilitates enamel protein self-assembly, apatite crystal growth and enamel protein interactions in the early enamel matrix
Authors: Zhang Youbin , Jin Tianquan , Zhu Weiying , Pandya Mirali , Gopinathan Gokul , Allen Michael , Reed David , Keiderling Timothy , Liao Xiubei , Diekwisch Thomas G. H. 
Published: December 2022

Tooth enamel develops within a pH sensitive amelogenin-rich protein matrix. The purpose of the present study is to shed light on the intimate relationship between enamel matrix pH, enamel protein self-assembly, and enamel crystal growth during early amelogenesis. Universal indicator dye staining revealed highly acidic pH values (pH 3–4) at the exocytosis site of secretory ameloblasts. When increasing the pH of an amelogenin solution from pH 5 to pH 7, there was a gradual increase in subunit compartment size from 2 nm diameter subunits at pH 5 to a stretched configuration at pH6 and to 20 nm subunits at pH 7. HSQC NMR spectra revealed that the formation of the insoluble amelogenin self-assembly structure at pH6 was critically mediated by at least seven of the 11 histidine residues of the amelogenin coil domain (AA 46–117). Comparing calcium crystal growth on polystyrene plates, crystal length was more than 20-fold elevated at pH 4 when compared to crystals grown at pH 6 or pH 7. To illustrate the effect of pH on enamel protein self-assembly at the site of initial enamel formation, molar teeth were immersed in phosphate buffer at pH4 and pH7, resulting in the formation of intricate berry tree-like assemblies surrounding initial enamel crystal assemblies at pH4 that were not evident at pH7 nor in citrate buffer. Amelogenin and ameloblastin enamel proteins interacted at the secretory ameloblast pole and in the initial enamel layer, and co-immunoprecipitation studies revealed that this amelogenin/ameloblastin interaction preferentially takes place at pH 4—pH 4.5. Together, these studies highlight the highly acidic pH of the very early enamel matrix as an essential contributing factor for enamel protein structure and self-assembly, apatite crystal growth, and enamel protein interactions.