bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protein arginine methyltransferase 4 modulates nitric oxide synthase uncoupling and cerebral blood flow in Alzheimer's disease
Authors: Clemons Garrett A. , Silva Alexandre Couto e , Acosta Christina H. , Udo Mariana Sayuri Berto , Tesic Vesna , Rodgers Krista M. , Wu Celeste Yin‐Chieh , Citadin Cristiane T. , Lee Reggie Hui‐Chao , Neumann Jake T. , Allani Shailaja , Prentice Howard , Zhang Quanguang , Lin Hung Wen 
Published: August 2022

AbstractAlzheimer's disease (AD) is the leading cause of mortality, disability, and long‐term care burden in the United States, with women comprising the majority of AD diagnoses. While AD‐related dementia is associated with tau and amyloid beta accumulation, concurrent derangements in cerebral blood flow have been observed alongside these proteinopathies in humans and rodent models. The homeostatic production of nitric oxide synthases (NOS) becomes uncoupled in AD which leads to decreased NO‐mediated vasodilation and oxidative stress via the production of peroxynitrite (ONOO−∙) superoxide species. Here, we investigate the role of the novel protein arginine methyltransferase 4 (PRMT4) enzyme function and its downstream product asymmetric dimethyl arginine (ADMA) as it relates to NOS dysregulation and cerebral blood flow in AD. ADMA (type‐1 PRMT product) has been shown to bind NOS as a noncanonic ligand causing enzymatic dysfunction. Our results from RT‐qPCR and protein analyses suggest that aged (9−12 months) female mice bearing tau‐ and amyloid beta‐producing transgenic mutations (3xTg‐AD) express higher levels of PRMT4 in the hippocampus when compared to age‐ and sex‐matched C57BL6/J mice. In addition, we performed studies to quantify the expression and activity of different NOS isoforms. Furthermore, laser speckle contrast imaging analysis was indicative that 3xTg‐AD mice have dysfunctional NOS activity, resulting in reduced production of NO metabolites, enhanced production of free‐radical ONOO−, and decreased cerebral blood flow. Notably, the aforementioned phenomena can be reversed via pharmacologic PRMT4 inhibition. Together, these findings implicate the potential importance of PRMT4 signaling in the pathogenesis of Alzheimer's‐related cerebrovascular derangement.
Hepatogenesis and hepatocarcinogenesis: Alignment of the main signaling pathways
Authors: Shokouhian Bahare , Aboulkheyr Es Hamidreza , Negahdari Babak , Tamimi Atena , Shahdoust Maryam , Shpichka Anastasia , Timashev Peter , Hassan Moustapha , Vosough Massoud 
Published: August 2022

AbstractDevelopment is a symphony of cells differentiation in which different signaling pathways are orchestrated at specific times and periods to form mature and functional cells from undifferentiated cells. The similarity of the gene expression profile in malignant and undifferentiated cells is an interesting topic that has been proposed for many years and gave rise to the differentiation‐therapy concept, which appears a rational insight and should be reconsidered. Hepatocellular carcinoma (HCC), as the sixth common cancer and the third leading cause of cancer death worldwide, is one of the health‐threatening complications in communities where hepatotropic viruses are endemic. Sedentary lifestyle and high intake of calories are other risk factors. HCC is a complex condition in which various dimensions must be addressed, including heterogeneity of cells in the tumor mass, high invasiveness, and underlying diseases that limit the treatment options. Under these restrictions, recognizing, and targeting common signaling pathways during liver development and HCC could expedite to a rational therapeutic approach, reprograming malignant cells to well‐differentiated ones in a functional state. Accordingly, in this review, we highlighted the commonalities of signaling pathways in hepatogenesis and hepatocarcinogenesis, and comprised an update on the current status of targeting these pathways in laboratory studies and clinical trials.
Risk factors for liver‐related mortality of patients with hepatitis C virus after sustained virologic response to direct‐acting antiviral agents
Authors: Hattori Nobuhiro , Ikeda Hiroki , Watanabe Tsunamasa , Satta Yosuke , Ehira Takuya , Suzuki Tatsuya , Kiyokawa Hirofumi , Nakahara Kazunari , Takahashi Hideaki , Matsunaga Kotaro , Matsumoto Nobuyuki , Yasuda Hiroshi , Suzuki Michihiro , Itoh Fumio , Tateishi Keisuke 
Published: August 2022

AbstractBackground and AimThe aim of this study was to identify the factors associated with liver‐related and non‐liver‐related mortality of patients with hepatitis C virus (HCV) after sustained virologic response (SVR) to direct‐acting antiviral agents (DAAs).MethodsWe conducted a retrospective, single‐center cohort study of HCV patients cured by DAAs.ResultsA total of 330 patients with SVR to DAAs were eligible. The median follow‐up period was 3.38 years (inter‐quartile range: 2.03–4.58). The cumulative liver‐related or non‐liver‐related mortality rates at 1, 3, and 5 years were 0.00 or 1.29%, 2.87 or 3.60%, and 5.10 or 9.46, respectively. Among the liver‐related deaths, 9 of the 10 were from liver cancer. Among the non‐liver‐related deaths, the most common cause was malignancy. Through multivariate analysis using the Cox proportional hazard model, diabetes mellitus (DM, hazard ratio 13.1, 95% confidence interval 2.81–61.3) and a history of hepatocellular carcinoma (HCC, 12.8, 2.76–59.2), independently predicted liver‐related death. No variables were associated with non‐liver‐related death.ConclusionOur findings suggest that DM and a history of HCC are risk factors for liver‐related mortality of HCV patients cured by DAAs. These results indicate that early management of HCV and HCC surveillance of diabetic patients after SVR are important to increase the chance of survival. Further studies are needed to confirm the association of DM and HCC history with survival.
The emergence, spread and vanishing of a French SARS‐CoV‐2 variant exemplifies the fate of RNA virus epidemics and obeys the Mistigri rule
Authors: Colson Philippe , Gautret Philippe , Delerce Jeremy , Chaudet Hervé , Pontarotti Pierre , Forterre Patrick , Tola Raphael , Bedotto Marielle , Delorme Léa , Bader Wahiba , Levasseur Anthony , Lagier Jean‐Christophe , Million Matthieu , Yahi Nouara , Fantini Jacques , La Scola Bernard , Fournier Pierre‐Edouard , Raoult Didier 
Published: August 2022

AbstractThe nature and dynamics of mutations associated with the emergence, spread, and vanishing of SARS‐CoV‐2 variants causing successive waves are complex. We determined the kinetics of the most common French variant (“Marseille‐4”) for 10 months since its onset in July 2020. Here, we analyzed and classified into subvariants and lineages 7453 genomes obtained by next‐generation sequencing. We identified two subvariants, Marseille‐4A, which contains 22 different lineages of at least 50 genomes, and Marseille‐4B. Their average lifetime was 4.1 ± 1.4 months, during which 4.1 ± 2.6 mutations accumulated. Growth rate was 0.079 ± 0.045, varying from 0.010 to 0.173. Most of the lineages exhibited a bell‐shaped distribution. Several beneficial mutations at unpredicted sites initiated a new outbreak, while the accumulation of other mutations resulted in more viral heterogenicity, increased diversity and vanishing of the lineages. Marseille‐4B emerged when the other Marseille‐4 lineages vanished. Its ORF8 gene was knocked out by a stop codon, as reported in SARS‐CoV‐2 of mink and in the Alpha variant. This subvariant was associated with increased hospitalization and death rates, suggesting that ORF8 is a nonvirulence gene. We speculate that the observed heterogenicity of a lineage may predict the end of the outbreak.
Therapeutic effects of MSCs, genetically modified MSCs, and NFĸB‐inhibitor on chronic inflammatory osteolysis in aged mice
Authors: Kushioka Junichi , Toya Masakazu , Shen Huaishuang , Hirata Hirohito , Zhang Ning , Huang Ejun , Tsubosaka Masanori , Gao Qi , Teissier Victoria , Li Xueping , Utsunomiya Takeshi , Goodman Stuart B. 
Published: August 2022

AbstractThe number of total joint replacements is increasing, especially in elderly patients, and so too are implant‐related complications such as prosthesis loosening. Wear particles from the prosthesis induce a chronic inflammatory reaction and subsequent osteolysis, leading to the need for revision surgery. This study investigated the therapeutic effect of NF‐ĸB decoy oligodeoxynucleotides (ODN), mesenchymal stem cells (MSCs), and genetically‐modified NF‐ĸB sensing interleukin‐4 over‐secreting MSCs (IL4‐MSCs) on chronic inflammation in aged mice. The model was generated by continuous infusion of contaminated polyethylene particles into the intramedullary space of the distal femur of aged mice (15−17 months old) for 6 weeks. Local delivery of ODN showed increased bone mineral density (BMD), decreased osteoclast‐like cells, increased alkaline phosphatase (ALP)‐positive area, and increased M2/M1 macrophage ratio. Local injection of MSCs and IL4‐MSCs significantly decreased osteoclast‐like cells and increased the M2/M1 ratio, with a greater trend for IL4‐MSCs than MSCs. MSCs significantly increased ALP‐positive area and BMD values compared with the control. The IL4‐MSCs demonstrated higher values for both ALP‐positive area and BMD. These findings demonstrated the therapeutic effects of ODN, MSCs, and IL4‐MSCs on chronic inflammatory osteolysis in aged mice. The two MSC‐based therapies were more effective than ODN in increasing the M2/M1 macrophage ratio, reducing bone resorption, and increasing bone formation. Specifically, MSCs were more effective in increasing bone formation, and IL4‐MSCs were more effective in mitigating inflammation. This study suggests potential therapeutic strategies for treating wear particle‐associated inflammatory osteolysis after arthroplasty in the elderly.
Botulinum neurotoxin type A improves vasti muscle balance, patellar tracking, and pain in patients with chronic patellofemoral pain
Authors: Pal Saikat , Choi Jang‐Hwan , Delp Scott L. , Fredericson Michael 
Published: August 2022

AbstractThe purpose of this study was to determine the effects of botulinum neurotoxin type A (BoNT‐A) on vastus lateralis:vastus medialis (VL:VM) muscle balance, patellar tracking, and pain in patients with chronic patellofemoral (PF) pain. We recruited 13 participants (9 females, 4 males) with recalcitrant PF pain who underwent ultrasound‐guided BoNT‐A injections into the distal third of the VL muscle, followed by a 6‐week home exercise program to strengthen their VM muscle. We imaged the participants in a C‐arm computed tomography (CT) scanner before and after the intervention. We calculated VL:VM ratios from CT images from a supine, nonweight‐bearing condition. We obtained patellar tilt and bisect offset values from CT images from an upright, weight‐bearing condition. We recorded functional pain scores before, immediately after, and 2–4 years after the intervention. We classified the participants into normal tracking and maltracking groups based on their patellar tilt and bisect offset values. BoNT‐A with home exercise reduced VL:VM ratio (18%; p < 0.001), patellar tilt (19%; p = 0.020), and bisect offset (5%; p = 0.025). Four participants classified as maltrackers before the intervention transitioned to normal tracking after the intervention. Functional pain scores improved immediately after the intervention (13%, p < 0.001) and remained improved at 2‐year follow‐up (12%, p = 0.011). Statement of Clinical Significance: This study provides new evidence in support of BoNT‐A for treatment of PF pain. Classification of patients under weight‐bearing conditions may identify individuals who will most benefit from a BoNT‐A treatment.
D‐mannose alleviated alveolar bone loss in mice with experimental periodontitis via regulating the anti‐inflammatory effect of amino acids
Authors: Yang Hua , Han Nannan , Luo Zhenhua , Xu Junji , Guo Lijia , Liu Yi 
Published: August 2022

AbstractBackgroundPeriodontitis is a chronic infectious disease caused by dysbiosis of oral microbiota, ultimately leading to periodontal alveolar bone loss. The oral subgingival microbiome, a key role in periodontitis pathogenesis, could alter the composition of gut microbiomes resulting in intestinal microbiota disorder. D‐mannose plays an important role in glucose metabolism; whether it is beneficial to prevention and treatment of periodontitis and the regulation of oral and intestinal microbiota changes is still unknown.MethodsTo explore the effect of D‐mannose, we established experimental periodontitis models in mice and then treated with supplementation of D‐mannose in drinking water or gavage to examine the extent of periodontal bone loss using methylene blue staining. Moreover, the oral and fecal samples of mice were collected for 16S rRNA deep sequencing to analyze the changes of oral and gut microbiota after 14 days. Furthermore, amino acid content assays were used to test the concentration of amino acid of gingival tissues and intestinal tissues.ResultsWe found that D‐mannose could alleviate periodontal bone loss whether in the manner of drinking water or gavage. 16S rRNA results revealed that the abundance of Firmicutes changed significantly in oral samples, while Firmicutes and Akkermansia muciniphila were dominated in gut microbiota. In addition, we demonstrated that D‐mannose inhibited inflammation and alleviated alveolar bone loss in periodontitis via regulating amino acid metabolism of oral and gut microbiomes.ConclusionOur findings provided insight into the mechanism underlying the abilities of D‐mannose in improving periodontitis treatment, suggesting that D‐mannose has potential application in the dental clinic.
Large‐scale mass movements recorded in the sediments of Lake Hallstatt (Austria)–evidence for recurrent natural hazards at a UNESCO World Heritage site
Authors: Lauterbach Stefan , Strasser Michael , Kowarik Kerstin , Reschreiter Hans , Mandl Gerhard W. , Spötl Christoph , Plessen Birgit , Brauer Achim 
Published: August 2022

AbstractThe Bronze to Iron Age underground salt mining complex of Hallstatt (Austria) is widely recognised for its cultural importance and wealth of archaeological artefacts. However, while the daily life in the salt mines is archaeologically well documented and environmental effects of the mining activity have been investigated recently, the impact of natural hazards on the prehistoric mining community is still poorly understood. For instance, while it is well established that the prehistoric underground mines have repeatedly been destroyed by large‐scale mass movements, only little is known about the characteristics and extent of these events as well as about mass‐movement recurrence during more recent times. To shed light on past mass‐movement activity in the vicinity of the Hallstatt salt mines, we investigated sediment cores from adjacent Lake Hallstatt. Within the regular lake sediments we identified three large‐scale event deposits, which are interpreted to originate from spontaneous or seismically induced mass movements in the mid‐19th and late 9th century ce and the mid‐4th century bce. While the age of the latter event is in good agreement with the abandonment of the famous Iron Age cemetery at Hallstatt, the younger events indicate that large‐scale mass movements also occurred repeatedly during the Common Era.
Identifying and managing problematic trials: A research integrity assessment tool for randomized controlled trials in evidence synthesis
Authors: Weibel Stephanie , Popp Maria , Reis Stefanie , Skoetz Nicole , Garner Paul , Sydenham Emma 
Published: August 2022

AbstractEvidence synthesis findings depend on the assumption that the included studies follow good clinical practice and results are not fabricated or false. Studies which are problematic due to scientific misconduct, poor research practice, or honest error may distort evidence synthesis findings. Authors of evidence synthesis need transparent mechanisms to identify and manage problematic studies to avoid misleading findings. As evidence synthesis authors of the Cochrane COVID‐19 review on ivermectin, we identified many problematic studies in terms of research integrity and regulatory compliance. Through iterative discussion, we developed a research integrity assessment (RIA) tool for randomized controlled trials for the update of this Cochrane review. In this paper, we explain the rationale and application of the RIA tool in this case study. RIA assesses six study criteria: study retraction, prospective trial registration, adequate ethics approval, author group, plausibility of methods (e.g., randomization), and plausibility of study results. RIA was used in the Cochrane review as part of the eligibility check during screening of potentially eligible studies. Problematic studies were excluded and studies with open questions were held in awaiting classification until clarified. RIA decisions were made independently by two authors and reported transparently. Using the RIA tool resulted in the exclusion of >40% of studies in the first update of the review. RIA is a complementary tool prior to assessing “Risk of Bias” aiming to establish the integrity and authenticity of studies. RIA provides a platform for urgent development of a standard approach to identifying and managing problematic studies.
Polysaccharides from steam‐processed Polygonatum cyrtonema Hua protect against d‐galactose‐induced oxidative damage in mice by activation of Nrf2/HO‐1 signaling
Authors: Teng Huanhuan , Zhang Yi , Jin Chuanshan , Wang Tongsheng , Huang Shengzhuo , Li Lei , Xie Songzi , Wu Deling , Xu Fengqing 
Published: August 2022

AbstractBACKGROUNDPolygonatum cyrtonema Hua is cultivated for its edible and medical value. The steam‐processed rhizome of P. cyrtonema is the main form for daily consumption and it has been used traditionally in tonics for treating various age‐related disorders. The aim of our study was to compare the physicochemical properties and antioxidant activity of polysaccharides respectively extracted from crude P. Cyrtonema (PCPC), and steam‐processed P. cyrtonema (PCPS), and to explore a possible underlying antioxidant mechanism.RESULTSThe PCPC with a molecular weight of 4.35 × 103 Da mainly consisted of fructose and trace amounts of glucose, whereas PCPS with 4.24 × 104 Da was composed of fructose, arabinose, glucose, xylose, mannose, galacturonic acid and glucuronic acid. The PCPC had a triple‐helical conformation whereas PCPS was a random coil. Both exhibited free radicals‐ scavenging activity in vitro. In a mouse model of oxidative damage, PCPC or PCPS treatment significantly reversed histopathological alterations, reactive oxygen species (ROS) accumulation and the reduction of antioxidant enzyme activity. They both also promoted Nrf2 nuclear transport by decreasing Keap‐1 expression and increasing HO‐1 expression. Both in vitro and in vivo, PCPS exhibited more potent antioxidant activity than PCPC.CONCLUSIONOverall, the results suggest that PCPS has a stronger effect on the prevention of oxidative damage by activating Nrf2/HO‐1 antioxidant signaling. This study demonstrates the role of steam‐processed P. cyrtonema rhizome and provides valuable perspective for PCPS as a functional agent. © 2022 Society of Chemical Industry.
Utilization of lymph node evaluation at hysterectomy for cervical carcinoma in situ
Authors: Matsuo Koji , Tavakoli Amin , Donovan Kelly M. , Mandelbaum Rachel S. , Klar Maximilian , Roman Lynda D. , Wright Jason D. 
Published: August 2022

AbstractBackground and ObjectivesThis study examined the utilization and characteristics of lymph node evaluation at hysterectomy for carcinoma in situ of the uterine cervix.MethodsThis retrospective cohort study queried the Healthcare Cost and Utilization Project's National Inpatient Sample, evaluating 7395 patients with cervical carcinoma in situ who underwent hysterectomy from 2016 to 2019. A multivariable binary logistic regression model was fitted to identify independent characteristics related to lymph node evaluation. A classification‐tree was constructed with recursive partitioning analysis to examine utilization patterns of lymph node evaluation.ResultsLymph node evaluation at hysterectomy was performed in 4.6%. In amultivariable analysis, older age, higher income, use of robotic‐assisted hysterectomy, and surgery at large bed capacity or urban teaching centers in the northeast US region were associated with increased likelihood of lymph node evaluation (all, p < 0.05). Of those independent factors, robotic‐assisted surgery exhibited the largest effect size (adjusted odds ratio 3.23, 95% confidence interval 2.54–4.10). Utilization pattern analysis identified nine unique characteristics, of which robotic‐assisted surgery was the primary indicator for cohort allocation (12.4% vs. 3.2%, p < 0.001). The difference between the lowest–highest patterns was 33.3% (range, 0%–33.3%).ConclusionLymph node evaluation was rarely performed for cervical carcinoma in situ overall and robotic surgery was associated with increased utilization of lymph node evaluation.
Limited‐stage small cell carcinoma of the esophagus treated with curative esophagectomy: A multicenter retrospective cohort study
Authors: Gu Yi‐Min , Yang Yu‐Shang , Shi Gui‐Dong , Yan Cheng‐Yi , Shang Qi‐Xin , Zhang Han‐Lu , Wang Wen‐Ping , Yuan Yong , Chen Long‐Qi 
Published: August 2022

AbstractBackgroundThis study aimed to investigate the efficacy of surgery in the treatment of small cell carcinoma of the esophagus (SCCE) and explore potential prognostic factors.MethodsWe screened patients with SCCE who underwent esophagectomy from 2010 to 2018 at three institutes. Differences in survival were analyzed using the Kaplan–Meier method and log–rank test. The prognostic factors were identified using univariate and multivariate analyses.ResultsA total of 69 patients were included. Multivariate analysis showed that TNM stage (hazard ratio [HR]: 4.10, 95% confidence interval [CI]: 1.57–10.75, p = 0.004) and adjuvant therapy (HR: 0.28, 95% CI: 0.16–0.51, p < 0.001) were independent prognostic factors. Stage I, stage IIA, and stage IIB disease were merged into the surgery response disease (SRD), whereas stage III disease into the surgery nonresponse disease (SNRD). The SRD group had significantly improved survival compared to the SNRD group (HR: 0.33, 95% CI: 0.19–0.58, p < 0.001). In addition, adjuvant therapy increased survival benefit in the SNRD group (p < 0.001) but not in the SRD group (p = 0.061).ConclusionsSurgery alone appears to be adequate for disease control in the SRD group, whereas multimodality therapy was associated with improved survival in the SNRD group.