bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of PCR assays to detect signature circulating tumor DNA methylation markers and KRas mutations for pancreatic ductal adenocarcinoma (PDAC).
Authors: Guo Shiwei , Su Mingyang , Shi Xiaohan , Gao Suizhi , Wang Huan , Pan Yaqi , Gong Chengxiang , He Qiye , Liu Rui , Jin Gang 
Published: January 2022

524 Background: PDAC is a cancer of high mortality. Accurate and cost-effective PCR assays detecting diagnostic and prognostic PDAC markers in blood are desirable for conducting PDAC screening in high-risk populations, evaluating treatments for patients and surveying for post-treatment relapse. Methods: We combined PDAC-diagnosing ctDNA methylation markers with PDAC-driving Kras mutations as targets to develop said PCR tests. Methylation markers were previously validated to classify PDAC plasma at a high accuracy by a targeted methylation sequencing assay. Seven known PDAC driver mutations in KRas exon2 were selected. Taqman-based quantitative methylation-specific PCR (MSP) and ARMS PCR were designed for methylation markers and KRas mutations, respectively, and were validated for technical performances. A step of pre-amplification of input DNA by conventional PCR was included prior to quantitative PCR to improve sensitivity. Over 200 clinical PDAC and control tissue and plasma samples were used to determine their analytical performances in classifying PDAC plasma. Results: All targets were detected at a limit-of-detection of 0.25% or better on standards DNA in PCR. To test clinical plasma samples, methylation markers were first filtered by comparing their levels in PDAC-, para-tumor tissues and whole blood cells. Twenty-four most discriminatory markers for PDAC tissues were selected and used to classify 110 PDAC plasma samples from equal number of normal samples. They were evaluated for their sensitivity at a pre-set specificity of 90%. The 4 best-performing markers were selected to build and cross-validate a general-linear-model (GLM) PDAC classifier, which achieved a sensitivity of 66% at 90% specificity (AUC = 0.829) in cross-validation. Adding status of KRas mutations further improved prediction accuracy by increasing sensitivity to 75% (AUC = 0.89), demonstrating the methylation markers and KRas mutations complement each other in detection PDAC plasma. Conclusions: Our results suggest that a small number of our DNA methylation markers can classify PDAC plasma at a reasonably high accuracy by MSP. Incorporating KRas driver mutations further improved classification accuracy. Together they are promising to be further translated into diagnostics for PDAC early screening, treatment assessment and postoperative surveillance.
Real-world cost-effectiveness of first-line gemcitabine + nab-paclitaxel versus FOLFIRINOX in patients with advanced pancreatic cancer: A population-based retrospective cohort study in Ontario, Canada.
Authors: Arciero Vanessa , Luo Jin , Parmar Ambika , Dai Wei Fang , Beca Jaclyn M. , Raphael Michael J. , Isaranuwatchai Wanrudee , Habbous Steven , Tadrous Mina , Earle Craig , Biagi Jim , Mittmann Nicole , Arias Jessica , Gavura Scott , Chan Kelvin K. 
Published: January 2022

529 Background: Currently, there are no direct randomized control trials (RCTs) comparing gemcitabine and nab-paclitaxel (Gem-Nab) and FOLFIRINOX for advanced pancreatic cancer (APC). Thus, previous model-based cost-effectiveness analyses were based on indirect comparisons of RCT data. While it is well known that RCT-based efficacy does not often translate to real-world effectiveness, there is limited literature investigating the comparative cost-effectiveness of Gem-Nab versus FOLFIRINOX for APC in the real-world. The objective of this study is to examine the real-world cost-effectiveness of Gem-Nab versus FOLFIRINOX in patients with APC in Ontario, Canada. Methods: This population-based retrospective cohort study compared all patients treated with first-line Gem-Nab or FOLFIRINOX for APC with ECOG performance status 0-1 in Ontario from April 2015 to March 2019. Patients were linked to administrative databases to identify key characteristics and costing data. Using propensity scores and a stabilizing weights method, an inverse probability of treatment weighted cohort was developed. Mean survival and total costs were calculated over a 5-year time horizon, adjusted for censoring and discounted at 1.5% (per Canadian guidelines). Incremental cost-effectiveness ratio and net monetary benefit were computed (measured in life-years and quality-adjusted life years) to estimate cost-effectiveness from the public healthcare payer’s perspective. A sensitivity analysis was conducted using the propensity score matching method. Results: 1,988 patients were identified (Gem-Nab: 928, FOLFIRINOX: 1,060). Mean survival was lower for patients in the Gem-Nab group than the FOLFIRINOX group (0.98 versus 1.26 life-years, incremental -0.28 (95% confidence interval -0.47, -0.13)). Patients in the Gem-Nab group also incurred greater mean 5-year total costs (Gem-Nab: $103,884, FOLFIRINOX: $101,518). Key cost contributors include ambulatory cancer care, acute in-patient hospitalization, and systemic therapy drug acquisition. Gem-Nab was dominated by FOLFIRINOX, as it is less effective and more costly. Results from the sensitivity analysis were similar. Conclusions: In routinely treated unselected patients, Gem-Nab is likely more costly and less effective than FOLFIRINOX and therefore, not considered cost-effective at any commonly accepted willingness-to-pay threshold.
Phase II study of sitravatinib in combination with tislelizumab in patients with advanced biliary tract cancer who have failed to at least 1 prior systemic treatment: Trial in progress.
Authors: Oh Do-Youn , Kim Jin Won , Chon Hongjae , Lee Choong-kun , Kim Ji-Won , Kang Beodeul , Choi Hye Jin , Park Se Jun , Yoon Jeesun , Lee Myung Ah 
Published: January 2022

TPS490 Background: In biliary tract cancer (BTC), there was a positive association of overall survival (OS) with high levels of tumor-infiltrating CD4+, CD8+, and Foxp3+ T lymphocytes, whereas increases in PD-1+/CD8+ tumor-infiltrating lymphocytes had a negative association with OS (Tariq NU et al. 2018). Therefore, immune-modulating treatment can be promising option to overcome a dismal prognosis in BTC patients. However, immune checkpoint inhibitor (ICI) monotherapy, including tislelizumab (anti-PD-1 monoclonal antibody), has a modest effect in advanced BTC (Desai J et al. 2020). Thus, several combination strategies to improve the anti-tumor effect of ICI are being conducted. Anti-angiogenic agent in combination with ICI is one of the promising strategies in which anti-angiogenic agent induced improved anti-tumor immune responses by increasing tumor antigen presentation and promoting lymphocyte infiltration and migration (Song Y et al. 2020). However, this combination have not been widely tested in BTC patients. Sitravatinib is a potent inhibitor of multiple receptor tyrosine kinases including Axl, MER, MET, KIT, FLT3, RET, VEGFR1-3, PDGFRα, which targets are expressed in a number of immune cell types and promote an immunosuppressive tumor microenvironment. This study aim to evaluate the efficacy of the combination strategy of sitravatinib with tislelizumab in advanced BTC and to reveal the immune-modulation through the combination of ICI and antiangiogenic agents. Methods: This study is an open-label, phase 2 study to evaluate the efficacy of sitravatinib and tislelizumab combination treatment in advanced BTC patients who have failed to first-line chemotherapy. Eligible patients have histologically proven BTC (including intrahepatic cholangiocarcinoma, extrahepatic bile duct cancer, gallbladder cancer, and ampulla of Vater cancer) and have failed one prior systemic chemotherapy. Patients who have previously received ICI can be enrolled. However, patients who have experienced unacceptable toxicity during prior ICI treatment are excluded. All patients will receive sitravatinib 120mg orally once daily in combination with tislelizumab 200mg intravenously once every 3 weeks until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint is disease control rate, with key secondary endpoints including overall response rate, progression-free survival, overall survival, and safety. For evaluating metabolic response, 18F-FDG PET-CT scan will be performed before treatment and at the first response evaluation. Tissue biopsies will be conducted three times in total: screening, the first response evaluation, and disease progression. Blood samples are being collected every cycles for translational biomarker studies. Clinical trial information: NCT04727996.
Pivotal phase III COMPOSE trial will compare 177Lu-edotreotide with best standard of care for well-differentiated aggressive grade 2 and grade 3 gastroenteropancreatic neuroendocrine tumors.
Authors: Halfdanarson Thorvardur Ragnar , Reidy Diane Lauren , Vijayvergia Namrata , Halperin Daniel M. , Goldstein Grace , Kong Grace , Michael Michael , Leyden Simone , Grozinsky-Glasberg Simona , Sorbye Halfdan , Oberg Kjell E. , Sierras Cristina , Harris Philip 
Published: January 2022

TPS514 Background: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs), which represent approximately 70% of NETs, frequently develop metastatic disease with limited treatment options. Current standard therapies for well-differentiated high grade 2 and grade 3 GEP-NETs include cytoreductive procedures, somatostatin analogues, molecular targeted therapies (everolimus or sunitinib), chemotherapy and peptide receptor radionuclide therapy (PRRT), with no specified sequence of use. PRRT may stabilize disease and induce objective tumor responses. This treatment uses radiolabeled somatostatin analogues to selectively target somatostatin receptor expressing (SSTR+) tumor cells. 177Lu-edotreotide is an innovative radiolabeled somatostatin analogue with a favorable safety profile and promising efficacy. Retrospective data in metastatic GEP-NETs treated with two or more 177Lu-edotreotide cycles demonstrated a progression free survival (PFS) of at least 30 months. The currently recruiting Phase III COMPETE trial compares the efficacy and safety of 177Lu-edotreotide, versus everolimus, in grade 1 and grade 2 GEP-NETs. Methods: COMPOSE (NCT04919226) is a prospective, randomized, controlled, open-label, multi-center Phase III study, in patients with well-differentiated high grade 2 and grade 3 (Ki-67 index 15−55%), SSTR+, GEP-NETs. This trial is to evaluate the efficacy, safety and patient-reported outcomes of first- or second-line treatment with 177Lu-edotreotide PRRT compared to best standard of care. It aims to randomize 202 patients 1:1 to a defined number of cycles of 177Lu-edotreotide or an active comparator (either chemotherapy [CAPTEM or FOLFOX] or everolimus, according to investigator´s choice). The primary endpoint is PFS, assessed every 12 weeks until disease progression (RECIST v1.1), or death, whichever occurs earlier. Secondary outcomes include overall survival, assessed up to 2 years after disease progression. Study recruitment for COMPOSE commenced in September 2021. It is expected that COMPOSE will inform optimal treatment options for patients with well-differentiated high grade 2 and grade 3 SSTR+ GEP-NETs, including for first-line therapy. Clinical trial information: NCT04919226.
PANOVA-3: A phase 3 study of tumor treating fields (TTFields) with gemcitabine and nab-paclitaxel (GnP) for front-line treatment of locally advanced pancreatic adenocarcinoma.
Authors: Picozzi Vincent J. , Macarulla Teresa , Philip Philip A. , Becerra Carlos Roberto , Dragovich Tomislav 
Published: January 2022

TPS629 Background: Tumor Treating Fields (TTFields) are a non-invasive, loco-regional antimitotic therapy approved for the treatment of glioblastoma and malignant pleural mesothelioma. TTFields (150–200 kHz) are delivered via arrays placed on the skin surrounding the tumor site. In vitro, TTFields (150 kHz), with or without chemotherapy, had antiproliferative and anticlonogenic effects on pancreatic cancer cells. The Phase 2 PANOVA study (NCT01971281) demonstrated the safety and preliminary efficacy of TTFields combined with nab-paclitaxel and gemcitabine (GnP) in both metastatic and locally advanced pancreatic adenocarcinoma (LAPC). Methods: The Phase 3 PANOVA-3 trial (NCT03377491) will evaluate the efficacy and safety of adding TTFields to GnP in a larger group of patients with LAPC. This prospective, randomized trial is currently enrolling 556 patients with unresectable LAPC (per National Comprehensive Cancer Network guidelines), Eastern Cooperative Oncology Group performance status of 0-2, and no prior progression or treatment. Patients will be randomized 1:1 to receive TTFields plus GnP or to GnP alone, stratified by performance status and geographical region. A recent protocol amendment included the use of a smaller, more light-weight (reduced from 6 to 2.7 lbs.) TTFields device. Standard doses of nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2) will be administered on days 1, 8, and 15 of a 28-day cycle. TTFields (150 kHz) will be delivered ≥ 18 h/day until local disease progression per Response Evaluation Criteria In Solid Tumors Criteria V1.1. Follow-up visits will be conducted every 4 weeks; a computed tomography scan of the chest and abdomen will be performed every 8 weeks. After local disease progression, patients will be followed for survival on a monthly basis. The primary endpoint is overall survival (OS). Secondary endpoints include progression free survival (PFS), local PFS, objective response rate, 1 year survival rate, pain- and puncture-free survival rate, rate of resectability, quality of life, and toxicity. The sample size calculation used a log-rank test comparing time to event in patients treated with TTFields plus GnP with control patients on gemcitabine alone. PANOVA-3 is designed to detect a hazard ratio of 0.75 in OS. Type I error is set to 0.05 (2-sided) and power to 80%. Study locations in Austria, Belgium, Canada, Croatia, Czech Republic, France, Germany, Hong Kong, Hungary, Israel, Italy, Poland, Spain, Switzerland, and the US are currently recruiting. Clinical trial information: NCT03377491.
State Regulation and Hospital Community Benefit Spending in Medicaid Expansion States
Authors: Sun Qingqing , Spreen Thomas Luke 
Published: January 2022

Abstract
Context: Previous studies show that nonprofit hospital spending on charity care declined in Medicaid expansion states. We test whether state community benefit regulations mitigated the decline in charity care spending.
Methods: We use a fixed effects model to evaluate the association between state regulations and nonprofit hospital community benefit spending and its subcategories as a share of total expenses in Medicaid expansion states. We obtained community benefit spending data from the Internal Revenue Service Form 990 Schedule H filings of 1,738 hospitals in 44 states and the District of Columbia from 2010 to 2017. We determine the stringency of state regulations by comparing the provisions of state and federal requirements based on regulation information compiled by the Hilltop Institute.
Findings: State minimum community benefit requirements are associated with increased community benefit and charity care spending by nonprofit hospitals in Medicaid expansion states.
Conclusions: States that imposed minimum community benefit requirements on nonprofit hospitals did not experience a decline in charity care spending after Medicaid expansion. The results suggest state minimum community benefit rules may expand the provision of community benefit and charitable care spending.
Lipid-driven CFTR clustering is impaired in cystic fibrosis and restored by corrector drugs
Authors: Abu-Arish Asmahan , Pandžić Elvis , Luo Yishan , Sato Yukiko , Turner Mark J. , Wiseman Paul W. , Hanrahan John W. 
Published: January 2022

ABSTRACT
Membrane proteins often cluster in nanoscale membrane domains (lipid rafts) that coalesce into ceramide-rich platforms during cell stress, however the clustering mechanisms remain uncertain. The cystic fibrosis transmembrane conductance regulator (CFTR), which is mutated in cystic fibrosis (CF), forms clusters that are cholesterol dependent and become incorporated into long-lived platforms during hormonal stimulation. We report here that clustering does not involve known tethering interactions of CFTR with PDZ domain proteins, filamin A or the actin cytoskeleton. It also does not require CFTR palmitoylation but is critically dependent on membrane lipid order and is induced by detergents that increase the phase separation of membrane lipids. Clustering and integration of CFTR into ceramide-rich platforms are abolished by the disease mutations F508del and S13F and rescued by the CFTR modulators elexacaftor plus tezacaftor. These results indicate CF therapeutics that correct mutant protein folding restore both trafficking and normal lipid interactions in the plasma membrane.
This article has an associated First Person interview with the first author of the paper.
Enlightenment and Social Progress – Back to the Enlightenment
Authors: Stachoň Marek 
Published: January 2022

The world today operates in a highly fragmented manner and in constant motion. The question of social progress is tempered. Morality does not determine the direction of social development and social interest. Scientific schematizing of our social reality and education is done intentionally in order to achieve maximum profits and success in the sciences, whose justification is questionable under the influence of meeting the requirements of the time. It is therefore necessary to review the issue and return to the roots of reflection on the meaning of enlightenment and progress, hence the Enlightenment. Kant and Rousseau are very specific philosophers within the Enlightenment. In many issues they are different from the other philosophers of the Enlightenment. In many ways Kant overcomes the Enlightenment and both think about the question of social progress differently from their contemporaries.
Hepatitis B, Hepatitis C and Liver Disease: A Review for the Dental Practitioner
Authors: Macpherson Iain , Brennan Paul N , Dillon John F 
Published: January 2022

The prevalence of chronic liver disease continues to rise, and important causes include viral infections, such as hepatitis B and hepatitis C. Both of these viruses can be contracted by healthcare workers through an inoculation injury and can lead to liver cirrhosis and cancer. In addition, chronic liver disease can result in disorders of liver function, including coagulopathy and abnormal metabolism of drugs widely used in dentistry. This article reviews current prevalence, transmission rates and treatment of hepatitis B and hepatitis C, as well as particular considerations for dental patients with liver disease. CPD/Clinical Relevance: Viral hepatitis remains a risk to all healthcare workers, and patients with liver disease provide various challenges when providing dental treatment.
Hereditary Angioedema Type I Triggered by Dental Treatment: A Case Report and Review of the Literature
Authors: Jagatiya Yashoda , Yogarajah Sangeetha , Monteiro Luis , Carey Barbara , Albuquerque Rui 
Published: January 2022

Type 1 hereditary angioedema (HAE) is a rare genetic condition characterized by recurrent episodes of oedema caused by a deficiency of C1-esterase inhibitor (C1-INH). A 29-year-old male presented to the oral medicine department at Guy's Hospital, London, with lip swelling following crown preparation and impressions. Haematological investigations showed reduced levels of complement C4 (0.02 g/L; reference range 0.1–0.4 g/L) and C1-INH function was <31% (reference range 85–99%). Immunology confirmed the diagnosis of type 1 HAE, with a de novo mutation. This case highlights how a detailed medical history and multidisciplinary teamwork ensure the correct diagnosis and management. CPD/Clinical Relevance: To demonstrate the various dental triggers, relevant signs and symptoms, and management options for patients diagnosed with hereditary angioedema to allow for effective decision-making in a primary dental setting.
Authors submission guidelines, a survey of pediatric dentistry journals regarding ethical issues
Authors: Walia Tarun , Kalra Gauri , Mathur Vijay Prakash , Dhillon Jatinder Kaur 
Published: January 2022

Objective
To assess the pattern of instructions regarding the ethical requirements given to authors in various Pediatric Dental Journals.

Material & methods
A cross-sectional survey of ‘instructions for authors,’ for analysis of guidelines on ethical processes, was done. Instructions to authors in journals of pediatric dentistry across the globe were reviewed for guidelines with regards to fourteen key ethical issues. Descriptive statistics were used, and results were expressed in percentages as well as numbers.

Results
Of the 18journals of pediatric dentistry, all 14 ethical issues were covered by the instructions to authors in only three journals with only 50% of these providing clarity about authorship using ICMJE guidelines. Furthermore, COI declaration was found to be present as mandatory in about 44% of the journals. 38.9% of the sampled journals mentioned guidelines on research misconduct, publication issues such as plagiarism, overlapping/fragmented publications, and availability of raw research data from authors. Guidelines on handling of complaints about editorial team was provided to authors by slightly over 33% of the selected pediatric dentistry titles while handling of complaints about authors and reviewers were mentioned in 16.7%and 55.6% of the journals respectively.

Conclusion
A significant proportion of Journals of Pediatric Dentistry did not provide adequate instructions to authors regarding ethical issues.
Susceptibility to disease (tropical theileriosis) is associated with differential expression of host genes that possess motifs recognised by a pathogen DNA binding protein
Authors: Larcombe Stephen D. , Capewell Paul , Jensen Kirsty , Weir William , Kinnaird Jane , Glass Elizabeth J. , Shiels Brian R. 
Published: January 2022

Background
Knowledge of factors that influence the outcome of infection are crucial for determining the risk of severe disease and requires the characterisation of pathogen-host interactions that have evolved to confer variable susceptibility to infection. Cattle infected by Theileria annulata show a wide range in disease severity. Native (Bos indicus) Sahiwal cattle are tolerant to infection, whereas exotic (Bos taurus) Holstein cattle are susceptible to acute disease.

Methodology/Principal findings
We used RNA-seq to assess whether Theileria infected cell lines from Sahiwal cattle display a different transcriptome profile compared to Holstein and screened for altered expression of parasite factors that could generate differences in host cell gene expression.
Significant differences (<0.1 FDR) in the expression level of a large number (2211) of bovine genes were identified, with enrichment of genes associated with Type I IFN, cholesterol biosynthesis, oncogenesis and parasite infection. A screen for parasite factors found limited evidence for differential expression. However, the number and location of DNA motifs bound by the TashAT2 factor (TA20095) were found to differ between the genomes of B. indicus vs. B. taurus, and divergent motif patterns were identified in infection-associated genes differentially expressed between Sahiwal and Holstein infected cells.

Conclusions/Significance
We conclude that divergent pathogen-host molecular interactions that influence chromatin architecture of the infected cell are a major determinant in the generation of gene expression differences linked to disease susceptibility.