bluuebunny/crossref_metadata_2025_split huggingface dataset:
BI-907828, a novel potent MDM2 inhibitor, inhibits glioblastoma brain tumor stem cells in vitro and prolongs survival in orthotopic xenograft mouse models
Authors: Hao Xiaoguang , Bahia Ravinder K , Cseh Orsolya , Bozek Danielle A , Blake Sophia , Rinnenthal Jörg , Weyer-Czernilofsky Ulrike , Rudolph Dorothea , Artee Luchman H 
Published: December 2022

Abstract

Background
The tumor suppressor TP53 (p53) is frequently mutated, and its downstream effectors inactivated in many cancers, including glioblastoma (GBM). In tumors with wild-type status, p53 function is frequently attenuated by alternate mechanisms including amplification and overexpression of its key negative regulator, MDM2. We investigated the efficacy of the MDM2 inhibitor, BI-907828, in GBM patient-derived brain tumor stem cells (BTSCs) with different amplification statuses of MDM2, in vitro and in orthotopic xenograft models.

Methods
In vitro growth inhibition and on-target efficacy of BI-907828 were assessed by cell viability, co-immunoprecipitation assays, and western blotting. In vivo efficacy of BI-907828 treatments was assessed with qPCR, immunohistochemistry, and in intracranial xenograft models.

Results
BI-907828 decreases viability and induces cell death at picomolar concentrations in both MDM2 amplified and normal copy number TP53 wild-type BTSC lines. Restoration of p53 activity, including robust p21 expression and apoptosis induction, was observed in TP53 wild-type but not in TP53 mutant BTSCs. shRNA-mediated knock-down of TP53 in wild-type BTSCs abrogated the effect of BI-907828, confirming the specificity of the inhibitor. Pharmacokinetic-pharmacodynamic studies in orthotopic tumor-bearing severe combined immunodeficiency (SCID) mice demonstrated that a single 50 mg/kg p.o. dose of BI-907828 resulted in strong activation of p53 target genes p21 and MIC1. Long-term weekly or bi-weekly treatment with BI-907828 in orthotopic BTSC xenograft models was well-tolerated and improved survival both as a single-agent and in combination with temozolomide, with dose-dependent efficacy observed in the MDM2 amplified model.

Conclusions
BI-907828 provides a promising new therapeutic option for patients with TP53 wild-type primary brain tumors.
A time-varying threshold STAR model with applications
Authors: Dueker Michael , Jackson Laura E , Owyang Michael T , Sola Martin 
Published: December 2022

AbstractSmooth-transition autoregressive (STAR) models, competitors of Markov-switching models, are limited by an assumed time-invariant threshold level. We augment the STAR model with a time-varying threshold that can be interpreted as a ‘tipping level’ where the mean and dynamics of the VAR shift. Thus, the time-varying latent threshold level serves as a demarcation between regimes. We show how to estimate the model in a Bayesian framework using a Metropolis step and an unscented Kalman filter proposal. To show how allowing time variation in the threshold can affect the results, we present two applications: a model of the natural rate of unemployment and a model of regime-dependent government spending.
High-temperature two-layer integrated receiver storage for concentrating solar power systems
Authors: Li Xiuxiu , Yang Song , Wang Jun , Lund Peter D 
Published: December 2022

Abstract
An integrated receiver storage for a beam-down concentrating solar power (CSP) plant enables simplifying the system layout and reducing the costs. Here a two-layer integrated receiver storage (TLIRS) system design is proposed consisting of a cavity receiver and a two-layer packed-bed storage. The first layer is a porous ceramic and the second one is rocks. To enable performance optimization of the system, models for cavity radiation, two-phase transient heat transfer and local thermal nonequilibrium were derived and validated. The thermal performance of the TLIRS system was assessed and characterized by the absorbing, charging, discharging and overall efficiencies and by the solar-to-exergy conversion ratio. The results indicate that the porous ceramic layer significantly enhances the absorption of solar irradiance and thus improves the thermal efficiencies. For CSP applications, the TLIRS system potentially achieves high thermal performance in repetitive charging and discharging cycles.
Crowdfunding a life: how relationships shape requests for financial assistance
Authors: Halcomb Laura 
Published: December 2022

Abstract
How do relationships shape requests for financial assistance? I conducted a qualitative content analysis of 1666 US-based GoFundMe campaigns for patients with colorectal cancer. I identify three types of campaign organizers—self-funders, financially bonded campaigners and financially independent campaigners—who draw on different narratives of deservingness depending on their relationship to medical costs. I find that organizers use stories to create good matches, which vary depending on the organizer’s financial relationship with the patient. Financially independent campaigners, who do not experience the burden of medical bills, tell stories that counter dominant cultural beliefs about dependency. Self-funders and financially bonded campaigners both told stories that managed the stigma of dependency, where the former connects self-sufficiency to employment and the latter argues that medical prices make it impossible to prepare. These findings provide novel insights into theories of relational work and how financial relationships shape narratives of debt, dependency and deservingness.
Inflammatory Periodontal Ligament Stem Cells Drive M1 Macrophage Polarization via Exosomal miR-143-3p-Mediated Regulation of PI3K/AKT/NF-κB Signaling
Authors: Wang Yazheng , Zhang Xige , Wang Jinjin , Zhang Yang , Ye Qingyuan , Wang Yang , Fei Dongdong , Wang Qintao 
Published: December 2022

AbstractMacrophage polarization plays an important role in the progression of inflammation. Exosomes derived from stem cells are promising candidates for macrophage immunoregulation. However, how exosomes derived from periodontal ligament stem cells (PDLSCs) in an inflammatory environment influence macrophage polarization has yet to be fully elucidated. In this study, inflammatory PDLSCs were found to downregulate M2 macrophage polarization at the mRNA and protein levels in a Transwell coculture system of PDLSCs and THP-1-derived M0 macrophages. Furthermore, inflammatory PDLSC-derived exosomes shifted macrophages toward the M1 phenotype. The inhibition of inflammatory PDLSC-derived exosomes by GW4869 weakened inflammatory PDLSC-mediated M1 macrophage polarization. A miRNA microarray was used to determine the differential miRNAs shuttled by healthy and inflammatory PDLSC-derived exosomes. Compared with healthy exosomes, miR-143-3p was enriched in inflammatory PDLSC-derived exosomes, which targeted and inhibited the expression of PI3Kγ and promoted M1 macrophage polarization by suppressing PI3K/AKT signaling and activating NF-κB signaling, while an agonist of the PI3K pathway reversed this effect. Moreover, exosome-shuttled miR-143-3p from PDLSCs drove M1 macrophage polarization and aggravated periodontal inflammation in a mouse periodontitis model. In conclusion, these results demonstrate that inflammatory PDLSCs facilitate M1 macrophage polarization through the exosomal miR-143-3p-mediated regulation of PI3K/AKT/NF-κB signaling, providing a potential new target for periodontitis treatment.
Myclobutanil-mediated alteration of liver-gut FXR signaling in mice
Authors: Taylor Rulaiha , Armstrong Laura , Bhattacharya Anisha , Henry Zakiyah , Brinker Anita , Buckley Brian , Kong Bo , Guo Grace 
Published: December 2022

Abstract
The effects of exposure to Myclobutanil, a triazole fungicide, on the development and progression of nonalcoholic fatty liver disease (NAFLD) are unclear, but activation of nuclear receptors (NRs) is a known mechanism of azole-induced liver toxicity. Farnesoid X receptor (FXR) is a NR and is highly expressed in the liver and intestine. Activation of FXR tightly regulates bile acid (BA), lipid and glucose homeostasis, and inflammation partly through the induction of fibroblast growth factor 15 (FGF15; human ortholog FGF19). FXR activation is downregulated during NAFLD and agonists are currently being explored as potential therapeutic strategy. In this study, we aimed to clarify the effects of Myclobutanil exposure on FXR activation and NAFLD development. Reporter assay showed Myclobutanil treatment, following FXR activation with potent FXR agonist (GW4064), resulted in a dose-dependent decrease of FXR activity. Furthermore, a 10-day study in male mice demonstrated that cotreatment with Myclobutanil led to an 80% reduction of GW4064-induced ileal expression of Fgf15. In a diet-induced NAFLD study, low-fat diet (LFD) fed mice administered myclobutanil displayed decreased FXR activity in the liver and ileum, while high-fat-high-sugar-diet (HFHSD) fed mice showed an increase in hepatic FXR activity and an induction of target genes regulated by constitutive androstane receptor and/or pregnane X receptor. Our work demonstrates Myclobutanil inhibits FXR activity and modulates FXR activity differentially in mice fed LFD or HFHSD. Our studies suggest the importance of understanding how Myclobutanil could contribute to BA dysregulation in disease states such as NAFLD.
Genome Resource for Acinetobacter schindleri H4-3-C1: An Endophyte of Pseudostellaria heterophylla with Degradation Activity to Toxins Produced by Fungal Pathogens
Authors: Yuan Qing-Song , Deng Tao , Gao Yanping , Jiang Weike , Ou Xiaohong , Wang Yanhong , Guo Lanping , Zhou Tao 
Published: December 2022

Acinetobacter schindleri is an endophyte of Pseudostellaria heterophylla, a traditional Chinese herbal plant. It has high degradation activity to toxins produced by fungal pathogen Fusarium graminearum. Here, we deployed PacBio single-molecule real-time long-read sequencing technology to generate a complete genome assembly for the Acinetobacter schindleri H4-3-C1 strain and obtained 1.59 Gb of clean reads. These reads were assembled to a single circular DNA chromosome with a length of 3,265,024 bp, and no plasmid was found in the genome. Totals of 3,193 coding sequences, 91 transfer RNA, 21 ribosomal RNA, and 75 small RNAs were identified in the genome. This high-quality genome assembly and gene annotation resource will facilitate the excavation of the zearalenone degradation gene and provide valuable resources for preventing and controlling toxigenic fungal diseases of P. heterophylla. [Formula: see text] Copyright © 2022 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
Osteoarthritis gene therapy in 2022
Authors: Evans Christopher H. , Ghivizzani Steven C. , Robbins Paul D. 
Published: December 2022

Purpose of review
To assess the present status of gene therapy for osteoarthritis (OA).

Recent findings
An expanding list of cDNAs show therapeutic activity when introduced into the joints of animals with experimental models of OA. In vivo delivery with adenovirus or adeno-associated virus is most commonly used for this purpose. The list of encoded products includes cytokines, cytokine antagonists, enzymes, enzyme inhibitors, growth factors and noncoding RNA. Elements of CRISPR-Cas have also been delivered to mouse knees to ablate key genes. Several human trials have been initiated, using transgenes encoding transforming growth factor-β1, interleukin-1 receptor antagonist, interferon-β, the NKX3.2 transcription factor or variant interleukin-10. The first of these, using ex vivo delivery with allogeneic chondrocytes, gained approval in Korea which was subsequently retracted. However, it is undergoing Phase III clinical trials in the United States. The other trials are in Phase I or II. No gene therapy for OA has current marketing approval in any jurisdiction.

Summary
Extensive preclinical data support the use of intra-articular gene therapy for treating OA. Translation is beginning to accelerate and six gene therapeutics are in clinical trials. Importantly, venture capital has begun to flow and at least seven companies are developing products. Significant progress in the future can be expected.
Comparisons of minimally invasive esophagectomy and open esophagectomy in lymph node metastasis/dissection for thoracic esophageal cancer
Authors: Li Zhenhua , Gai Chunyue , Zhang Yuefeng , Wen Shiwang , Lv Huilai , Xu Yanzhao , Huang Chao , Zhao Bo , Tian Ziqiang 
Published: December 2022

Abstract

Background:
The study aimed to clarify the characteristics of lymph node metastasis (LNM) and to compare the oncologic outcomes of minimally invasive esophagectomy (MIE) with open esophagectomy (OE) in terms of lymph node dissection (LND) in thoracic esophageal cancer patients.

Methods:
The data from esophageal cancer patients who underwent MIE or OE from January 2016 to January 2019 were retrospectively reviewed. The characteristics of LNM in thoracic esophageal cancer were discussed, and the differences in numbers of LND, LND rate, and LNM rate/degree of upper mediastinum between MIE and OE were compared.

Results:
For overall characteristics of LNM in 249 included patients, the highest rate of LNM was found in upper mediastinum, while LNM rate in middle and lower mediastinum, and abdomen increased with the tumor site moving down. The patients were divided into MIE (n = 204) and OE groups (n = 45). In terms of number of LND, there were significant differences in upper mediastinum between MIE and OE groups (8 [5, 11] vs. 5 [3, 8], P < 0.001). The comparative analysis of regional lymph node showed there was no significant difference except the subgroup of upper mediastinal 2L and 4L group (3 [1, 5] vs. 0 [0, 2], P < 0.001 and 0 [0, 2] vs. 0, P = 0.012, respectively). Meanwhile, there was no significant difference in terms of LND rate except 2L (89.7% [183/204] vs. 71.1% [32/45], P = 0.001) and 4L (41.2% [84/204] vs. 22.2% [10/45], P = 0.018) groups. For LNM rate of T3 stage, there was no significant difference between MIE and OE groups, and the comparative analysis of regional lymph node showed that there was no significant difference except 2L group (11.1% [5/45] vs. 38.1% [8/21], P = 0.025). The LNM degree of OE group was significantly higher than that of MIE group (27.2% [47/173] vs. 7.6% [32/419], P < 0.001), and the comparative analysis of regional LNM degree showed that there was no significant difference except 2L (34.7% [17/49] vs. 7.7% [13/169], P < 0.001) and 4L (23.8% [5/21] vs. 3.9% [2/51], P = 0.031) subgroups.

Conclusion:
MIE may have an advantage in LND of upper mediastinum 2L and 4L groups, while it was similar to OE in other stations of LND.
Welfare practices for anaesthesiology trainees in Europe
Authors: Berger-Estilita Joana , Leitl Jacqueline , Vacas Susana , Neskovic Vojislava , Stüber Frank , Zdravkovic Marko 
Published: December 2022

BACKGROUND
Current regulations of anaesthesiology training programmes may affect gender equity, female representation and leadership.

OBJECTIVE
To describe the work regulations of anaesthesiology training programs and working conditions during the early period of child-rearing in European countries.

DESIGN
Cross-sectional survey.

SETTING
National Anesthesiologists Societies Committee (NASC) representatives of the European Society of Anesthesiology and Intensive Care.

PARTICIPANTS
Thirty-eight NASC representatives.

MAIN OUTCOME MEASURES
Basic specialist training working conditions, gender-related data, return to work after childbirth and workplace policies against discrimination during anaesthesiology specialist training.

INTERVENTION(S)
A 48-item questionnaire to explore the work patterns and conditions for trainees especially for new parents, professional development opportunities and work discrimination regulations in each representative country was distributed to NASC representatives of 44 European countries.

RESULTS
We collected the replies of each representative (38 representatives from 44 invited countries’ representatives, 86% response rate). The median [IQR] proportion of female trainees was 60% [50 to 68]. There were no reported pay differences between sexes. In eight European countries, pregnant trainees worked fewer hours and were excused from night shifts. Women could not be laid off during pregnancy in all 38 countries (100%). The countries offered a median of 18 weeks of paid (total or partial) maternity leave (range, 13 to 60 weeks). Most countries (89%) accommodate paid paternity leaves. A significant proportion of parental leave was unpaid (n=18, 42%). Twenty-one (55%) countries allowed part-time work after delivery. The UK was the only country with clear recommendations to formally complain after harassment.

CONCLUSION
European countries have a wide variety of regulations. On paper, numerous countries have various paid maternal, paternal and parental leave; however, it remains to be determined if such leave takes place in practice. The practical consequences of these regulations on female trainees during the child-rearing period need to be explored further.

TRIAL REGISTRATION
None
Thoracic Duct Lymphovenous Bypass: A Preliminary Case Series, Surgical Techniques, and Expected Physiologic Outcomes
Authors: Toyoda Yoshiko , Fowler Cody , Mazzaferro Daniel M. , McGraw J. Reed , Othman Sammy , Azoury Said C. , Itkin Maxim , Kovach III Stephen J. 
Published: December 2022

Background:
In patients with recalcitrant mechanical thoracic duct obstruction, microsurgical lymphovenous bypass is an emerging therapeutic option. We herein discuss the preoperative workup, share our current operative technique, and evaluate preliminary outcomes with an emphasis on changes in physiology.

Methods:
A retrospective review of adult patients who underwent thoracic duct lymphovenous bypass by a single surgeon and interventional radiologist from 2019 to 2022 was performed. Demographics, comorbidities, perioperative data, and postoperative outcomes were collected.

Results:
Nine patients were included in the study. Immediate postoperative heart rate increased significantly among this heterogeneous patient population, but within 4–6 hours the change in heart rate was no longer significant. Mean arterial pressure and oxygen requirement were not significantly different before and after bypass.

Conclusions:
Thoracic duct lymphovenous bypass seem to be well tolerated in the short-term even in patients with cardiopulmonary comorbidities. Further data are necessary to continue to better understand the resulting physiologic changes and to optimize patient outcomes.
Clinical Best Practices for Radiation Safety During Lutetium-177 Therapy
Authors: Cappon Derek John , Fang Susanna , Berry Kendall , Capone Gina , Carlton Gina L. , Chrétien Mario , Gough John , Kamen Jacob , Khoorshed Anne , Miller Andy , Nelli Stephen , Petric M. Peter , Tourneur Frank , Zic Josip J. 
Published: December 2022

Importance

177Lu therapy as part of theranostic treatment for cancer is expanding but it can be a challenge for sites with limited radiation protection staff to implement the radiation safety program required for therapeutic nuclear medicine.

Objective
To increase the adoption of 177Lu therapy, especially in smaller centers and clinics, by providing a collection of radiation safety best practices and operational experience. To provide a resource for radiation safety officers supporting the implementation of a 177Lu therapy program.

Methods
A panel of 11 radiation safety professionals representing sites across Canada and the United States with experience delivering 177Lu therapy was assembled and discussed their responses to a list of questions focused on the following radiation safety topics: facility layout and design; radiation safety program; and drug management and patient care.

Results
A comprehensive set of best practice guidelines for clinical radiation safety during 177Lu therapy has been developed based on the collective operational experience of a group of radiation safety professionals. Significant findings included that 177Lu therapy is often safely administered in unshielded rooms, that staff radiation exposure associated with 177Lu therapy is minimal relative to other nuclear medicine programs, and that some relatively simple preparation in advance including papering of common surfaces and planning for incontinence can effectively control contamination during therapy.

Conclusion
The guidance contained in this paper will assist radiation safety professionals in the implementation of safe, effective 177Lu therapy programs, even at smaller sites with limited to no experience in therapeutic nuclear medicine.
In vitro models to study Clostridioides difficile infection: current systems and future advances
Authors: Ewin Duncan , Birch William Davis , Moura Ines B. 
Published: December 2022

Purpose of review

Clostridioides difficile infection (CDI) is the most common cause of healthcare-associated diarrhoea in western countries, being categorized as an urgent healthcare threat. Historically, researchers have relied on the use of in vivo animal models to study CDI pathogenesis; however, differences in physiology and disease prognosis compared with humans limit their suitability to model CDI. In vitro models are increasingly being used as an alternative as they offer excellent process control, and some are able to use human ex-vivo prokaryotic and/or eukaryotic cells.

Recent findings
Simulating the colonic environment in vitro is particularly challenging. Bacterial fermentation models have been used to evaluate novel therapeutics, explore the re-modelling of the gut microbiota, and simulate disease progression. However, they lack the scalability to become more widespread. Models that co-culture human and bacterial cells are of particular interest, but the different conditions required by each cell type make these models challenging to run. Recent advancements in model design have allowed for longer culture times with more representative bacterial populations.

Summary
As in vitro models continue to evolve, they become more physiologically relevant, offering improved simulations of CDI, and extending their applicability.
<xhtml:span xmlns:xhtml="http://www.w3.org/1999/xhtml" xml:lang="en">Comparison of diagnostic accuracy of Xpert MTB/RIF and Geno type MTBDRplus line probe assayfor&#160;diagnosis of tuberculous pleural effusion
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Authors: Sharif Ayesha , Vaqar Maham , Jabeen Kauser , Irfan Muhammad 
Published: December 2022

Background :
Tuberculous pleural effusion (TPE) occurs in up to 25% of TB patients. Owing to the pauci-bacillary nature of the pleural fluid, the diagnosis of TPE is a challenge. Newer diagnostic tools are required for the rapid diagnosis of TPE.
Objectives :
To compare the sensitivity and specificity of Xpert MTB/RIF and Geno type MTBDRplus line probe assay (MTBDRplus) for diagnosing TPE.
Methods :
A prospective cross-sectional study was performed at Aga Khan University Hospital, Karachi, Pakistan from August 2014 to January 2016. Patients with suspected TPE were recruited on the basis of history, exudative lymphocytic nature of effusion and raised adenosine daminase level. Pleural fluid samples were tested for AFB smear, culture, Xpert MTB/RIFand MTBDR plus .
Results :
We enrolled 99 patients with mean age of 50.4±20.3 years. AFB culture was positive in 14 (14.14%) cases. Considering AFB culture as Gold standard, the sensitivity of Xpert MTB/RIF was found to be 57.14% (95% CI: 28.86 – 82.34%) and specificity was 97.65% (95% CI: 91.76 - 99.71%) and the sensitivity of MTBDR plus was 35.71% (95% CI: 12.76 – 64.86%) and specificity was 98.82% (95% CI: 93.62 - 99.90%).The sensitivity of Xpert MTB/RIF in TPE was higher than MTBDRplus (p 0.013), while specificity was similar.
Conclusion :
Xpert MTB/RIF is more sensitive for detecting TPE than MTBDRplus and AFB smear microscopy. A multicenter, large-sample study is needed to evaluate this method for early TPE diagnosis.