bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PR-011: Loss of compensatory feedback mechanism involving splicing factor SRSF1 accelerates KrasG12D-mediated pancreatic cancer initiation
Authors: Wan Ledong , Lin Kuan-Ting , Rahman Mohammad A. , Wang Zhikai , Park Youngkyu , Tuveson David A. , Krainer Adrian R. 
Published: November 2021

Abstract
KRAS is recurrently mutated in pancreatic ductal adenocarcinoma (PDAC), triggering the formation of acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN). However, the majority of pancreatic cells from KC (LSL-KrasG12D/+; Pdx-1-Cre) mice carrying the KrasG12D mutation remain morphologically normal for a long time, suggesting the existence of compensatory feedback mechanisms that buffer KrasG12D signaling, and that additional steps are required for disrupting cell homeostasis and promoting transformation. Here we found that splicing factor SRSF1, which is associated with cell transformation, is downregulated in the majority of morphologically normal pancreas cells with the KrasG12D mutation as a compensatory feedback mechanism. To assess the role of SRSF1 in PDAC, we generated a transgenic mouse strain (SC) with Dox-inducible pancreatic-specific expression of SRSF1 protein. Elevated SRSF1 alone is sufficient to induce pancreatitis and ADM transformation. By further crossing the SC strain with KrasG12D alone (KSC) or together with Trp53R172H (KPSC), we found that increasing SRSF1 accelerated KrasG12D-mediated tumor initiation and resulted in more aggressive PDAC. To address the underlying mechanisms of SRSF1’s involvement in the homeostatic response to KrasG12D mutation and in PDAC initiation, we generated organoid lines from the above mouse strains. Following Dox induction, elevated SRSF1 with Kras WT or KrasG12D consistently activated MAPK signaling, which is one of the top negatively enriched pathways in response to KrasG12D. Furthermore, SRSF1 promoted the expression of Il1r1—an IL1 receptor associated with the activation of MAPK signaling—by regulating an alternative-splicing event in the 5’UTR to generate a more stable mRNA isoform. We conclude that decreased SRSF1 is a compensatory feedback mechanism in pancreatic cells against the KrasG12D mutation, whose disruption facilitates PDAC initiation.
Citation Format: Ledong Wan, Kuan-Ting Lin, Mohammad A. Rahman, Zhikai Wang, Youngkyu Park, David A. Tuveson, Adrian R. Krainer. Loss of compensatory feedback mechanism involving splicing factor SRSF1 accelerates KrasG12D-mediated pancreatic cancer initiation [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PR-011.
BET Inhibition Enhances TNF-Mediated Antitumor Immunity
Authors: Wellinger Lisa C. , Hogg Simon J. , Newman Dane M. , Friess Thomas , Geiss Daniela , Michie Jessica , Ramsbottom Kelly M. , Bacac Marina , Fauti Tanja , Marbach Daniel , Jarassier Laura , Thienger Phillip , Paehler Axel , Cluse Leonie A. , Kearney Conor J. , Vervoort Stephin J. , Trapani Joseph A. , Oliaro Jane , Shortt Jake , Ruefli-Brasse Astrid , Rohle Daniel , Johnstone Ricky W. 
Published: November 2021

Abstract

Targeting chromatin binding proteins and modifying enzymes can concomitantly affect tumor cell proliferation and survival, as well as enhance antitumor immunity and augment cancer immunotherapies. By screening a small-molecule library of epigenetics-based therapeutics, BET (bromo- and extra-terminal domain) inhibitors (BETi) were identified as agents that sensitize tumor cells to the antitumor activity of CD8+ T cells. BETi modulated tumor cells to be sensitized to the cytotoxic effects of the proinflammatory cytokine TNF. By preventing the recruitment of BRD4 to p65-bound cis-regulatory elements, BETi suppressed the induction of inflammatory gene expression, including the key NF-κB target genes BIRC2 (cIAP1) and BIRC3 (cIAP2). Disruption of prosurvival NF-κB signaling by BETi led to unrestrained TNF-mediated activation of the extrinsic apoptotic cascade and tumor cell death. Administration of BETi in combination with T-cell bispecific antibodies (TCB) or immune-checkpoint blockade increased bystander killing of tumor cells and enhanced tumor growth inhibition in vivo in a TNF-dependent manner. This novel epigenetic mechanism of immunomodulation may guide future use of BETi as adjuvants for immune-oncology agents.
Processing Human Milk to Increase Nutrient Density for Preterm Infants
Authors: Ulus Hande Z. , Tekbudak Merve Yasemin , Allen Jonathan C. 
Published: November 2021

Background: Human milk is the optimal food for newborns. Choices to feed preterm infants in neonatal intensive care units are mother’s milk, donor milk, or formula. Preterm infants have better tolerance for human milk, but the lower caloric density of donor milk might not meet preterm infant growth needs. Preterm infants have higher protein and energy requirements with a limited stomach capacity. Therefore, there is a need for human milk with increased nutrient density. Research Aim: To concentrate donor milk to have a higher caloric and protein density while avoiding side effects of high osmolality by precipitating lactose at low temperatures. Methods: We investigated the results of volume reduction and lactose removal processes on the lactose, protein, osmolality, and viscosity of human milk. Donor milk was obtained from WakeMed Mothers’ Milk Bank. Homogenization and evaporative condensation were applied to samples ( N = 36) before they were stored frozen overnight, followed by refrigerated centrifugation for lactose removal at 0 °C. Supernatants were separated and compared to the composition of controls. Results: A significant reduction of lactose ( SW = -262, p < .0001) and osmolality ( SW = -211.5 p < .01) was achieved in the concentrated milk without a significant protein loss from centrifugation ( SW = -44.5, p = .49). A 30%–40% volume reduction is within the American Academy of Pediatrics recommended osmolality for infant feeding. Conclusion: Concentrating human milk in a milk bank setting for feeding preterm infants might be a simple and low-cost process to achieve a product with higher nutrient density and no non-human components.
Low-Input RNA-Sequencing in Patients with Cartilage Lesions, Osteoarthritis, and Healthy Cartilage
Authors: Wang Katherine , Esbensen Q.Y. , Karlsen T.A. , Eftang C.N. , Owesen C. , Aroen A. , Jakobsen R.B. 
Published: November 2021

Objective To analyze and compare cartilage samples from 3 groups of patients utilizing low-input RNA-sequencing. Design Cartilage biopsies were collected from patients in 3 groups ( n = 48): Cartilage lesion (CL) patients had at least ICRS grade 2, osteoarthritis (OA) samples were taken from patients undergoing knee replacement, and healthy cartilage (HC) was taken from ACL-reconstruction patients without CLs. RNA was isolated using an optimized protocol. RNA samples were assessed for quality and sequenced with a low-input SmartSeq2 protocol. Results RNA isolation yielded 48 samples with sufficient quality for sequencing. After quality control, 13 samples in the OA group, 9 in the HC group, and 9 in the CL group were included in the analysis. There was a high degree of co-clustering between the HC and CL groups with only 6 genes significantly up- or downregulated. OA and the combined HC/CL group clustered significantly separate from each other, yielding 659 significantly upregulated and 1,369 downregulated genes. GO-term analysis revealed that genes matched to cartilage and connective tissue development terms. Conclusion The gene expression profiles from the 3 groups suggest that there are no major differences in gene expression between cartilage from knees with a cartilage injury and knees without an apparent cartilage injury. OA cartilage, as expected, showed markedly different gene expression from the other 2 groups. The gene expression profiles resulting from this low-input RNA-sequencing study offer opportunities to discover new pathways not previously recognized that may be explored in future studies.
The association between sleep quality, preoperative risk factors for chronic postoperative pain and postoperative pain intensity 12 months after knee and hip arthroplasty
Authors: Boye Larsen Dennis , Laursen Mogens , Simonsen Ole , Arendt-Nielsen Lars , Petersen Kristian Kjaer 
Published: November 2021

Background: Chronic postoperative pain following total joint replacement (TJA) is a substantial clinical problem, and poor sleep may affect predictive factors for postoperative pain, such as pain catastrophizing. However, the magnitude of these associations is currently unknown. This exploratory study investigated (1) the relationship between preoperative sleep quality, clinical pain intensity, pain catastrophizing, anxiety, and depression and (2) their associations with chronic postoperative pain following TJA. Methods: This secondary analysis from a larger randomized controlled trial included rest pain intensity (preoperative and 12 months postoperative; visual analogue scale, VAS), preoperative Pittsburgh Sleep Quality Index (PSQI), Pain Catastrophizing Scale (PCS), Hospital Anxiety and Depression Scale (HADS) data from 74 knee and 89 hip osteoarthritis (OA) patients scheduled for TJA. Poor sleepers were identified based on preoperative PSQI scores higher than 5. Results: Poor sleepers demonstrated higher preoperative VAS, pain catastrophizing, anxiety, and depression compared with good sleepers (all p < 0.003). Preoperative PSQI (β = 0.23, p = 0.006), PCS (β = 0.44, p < 0.005), and anxiety (β = 0.18, p = 0.036) were independent factors for preoperative VAS. Preoperative VAS (β = 0.32, p < 0.005), but not preoperative sleep quality (β = −0.06, p = 0.5), was an independent factor for postoperative VAS. Conclusion: The OA patients reporting poor preoperative sleep quality show higher preoperative pain, pain catastrophizing, anxiety, and depression. High preoperative pain intensity, but not poor sleep quality, was associated with higher chronic postoperative pain intensity. Future studies are encouraged to explore associations between sleep and chronic postoperative pain.
Predicting Outcomes of Talar Osteochondritis Dissecans Lesions in Children
Authors: Johnson Mitchell A. , Park Kunbo , Talwar Divya , Maguire Kathleen J. , Lawrence J. Todd R. 
Published: November 2021

Background: Reports detailing the rates of radiographic healing after treatment of talar osteochondritis dissecans (TOCD) remain scarce. There is also a paucity of data characterizing treatment outcomes and the risk factors associated with poor outcomes in children with TOCD. Purpose: To identify factors associated with healing, assess treatment outcomes, and develop a clinically useful nomogram for predicting healing of TOCD in children. Study Design: Case-control study; Level of evidence, 3. Methods: This was a retrospective review of all patients ≤18 years of age with TOCD from a single pediatric institution over a 12-year period. Surgical treatment was left to the discretion of the treating surgeon based on standard treatment techniques. Medical records and radiographs were reviewed for patient and clinical data, lesion characteristics, and skeletal maturity. Radiographic healing was evaluated at the 1-year follow-up, and patients with complete versus incomplete healing were compared using multivariable logistic regression models to examine the predictive value of the variables. Results: The authors analyzed 92 lesions in 74 patients (mean age, 13.1 ± 2.7 years [range, 7.1-18.0 years]; 61% female). Of these, 58 (63%) lesions were treated surgically (drilling, debridement, microfracture, bone grafting, or loose body removal), and the rest were treated nonoperatively. Complete radiographic healing was seen in 43 (47%) lesions. In bivariate analysis, patients with complete healing were younger ( P = .006), were skeletally immature ( P = .013), and had a lower body mass index (BMI; P < .001) versus those with incomplete healing. In a multivariate regression model, the factors that correlated significantly with the rate of complete healing were age at diagnosis, BMI, and initial surgical treatment. The lesion dimensions were not significantly associated with the likelihood of healing. A nomogram was developed using the independent variables that correlated significantly with the likelihood of complete radiographic healing. Conclusion: Complete radiographic healing of TOCD lesions was more likely in younger patients with a lower BMI. The effect of initial surgical treatment on potential healing rate was greater in older patients with a higher BMI.
An evaluation of strategies to achieve greater than 90% coverage of maternal influenza and pertussis vaccines including an economic evaluation
Authors: Giles Michelle L. , Khai Kong , Krishnaswamy Sushena , Bellamy Karen , Angliss Margaret , Smith Christopher , Fay Olivia , Paddle Paul , Vollenhoven Beverley 
Published: November 2021

Abstract
Background
Maternal immunisation is an essential public health intervention aimed at improving the health outcomes for pregnant women and providing protection to the newborn. Despite international recommendations, safety and efficacy data for the intervention, and often a fully funded program, uptake of vaccines in pregnancy remain suboptimal. One possible explanation for this includes limited access to vaccination services at the point of antenatal care. The aim of this study is to evaluate the change in vaccine coverage among pregnant women following implementation of a modified model of delivery aimed at improving access at the point of antenatal care, including an economic evaluation.

Methods
This prospective multi-centre study, using action research design, across six maternity services in Victoria, Australia, evaluated the implementation of a co-designed vaccine delivery model (either a pharmacy led model, midwife led model or primary care led model) supported by provider education. The main outcome measure was influenza and pertussis vaccine uptake during pregnancy and the incremental cost of the new model (compared to existing models) and the cost-effectiveness of the new model at each participating health service.

Results
Influenza vaccine coverage in 2019 increased between 50 and 196% from baseline. All services reduced their average cost per immunisation under the new platforms due to efficiencies achieved in the delivery of maternal immunisations. This cost saving ranged from $9 to $71.

Conclusion
Our study demonstrated that there is no ‘one size fits all’ model of vaccine delivery. Future successful strategies to improve maternal vaccine coverage at other maternity services should be site specific, multifaceted, targeted at the existing barriers to maternal vaccine uptake, and heavily involve local stakeholders in the design and implementation of these strategies. The cost-effectiveness analysis indicates that an increase in maternal influenza immunisation uptake can be achieved at a relatively modest cost through amendment of maternal immunisation platforms.
METHODS - A randomised controlled trial of METhotrexate to treat Hand Osteoarthritis with Synovitis: study protocol for a randomised controlled trial
Authors: Wang Yuanyuan , Teichtahl Andrew J. , Jones Graeme , Keen Helen I. , Hill Catherine L. , Wluka Anita E. , Kasza Jessica , Cicuttini Flavia M. 
Published: November 2021

Abstract
Background
Hand osteoarthritis is a common and disabling problem without effective therapies. Accumulating evidence suggests the role of local inflammation in causing pain and structural progression in hand osteoarthritis, and hand osteoarthritis with synovitis is a commonly encountered clinical phenotype. Methotrexate is a well-established, low-cost, and effective treatment for inflammatory arthritis with a well-described safety profile. The aim of this multicentre, randomised, double-blind, placebo-controlled trial is to determine whether methotrexate reduces pain over 6 months in patients with hand osteoarthritis and synovitis.

Methods
Ninety-six participants with hand osteoarthritis and synovitis will be recruited through the Osteoarthritis Clinical Trial Network (Melbourne, Hobart, Adelaide, and Perth), and randomly allocated in a 1:1 ratio to receive either methotrexate 20 mg or identical placebo once weekly for 6 months. The primary outcome is pain reduction (assessed by 100 mm visual analogue scale) at 6 months. The secondary outcomes include changes in physical function and quality of life assessed using Functional Index for Hand Osteoarthritis, Australian Canadian Osteoarthritis Hand Index, Health Assessment Questionnaire, Michigan Hand Outcomes Questionnaire, Short-Form-36, tender and swollen joint count, and grip strength, and structural progression assessed using progression of synovitis and bone marrow lesions from magnetic resonance imaging and radiographic progression at 6 months. Adverse events will be recorded. The primary analysis will be by intention to treat, including all participants in their randomised groups.

Discussion
This study will provide high-quality evidence to address whether methotrexate has an effect on reducing pain over 6 months in patients with hand osteoarthritis and synovitis, with major clinical and public health importance. While a positive trial will inform international clinical practice guidelines for the management of hand osteoarthritis, a negative trial would be highly topical and change current trends in clinical practice.

Trial registration
Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12617000877381. Registered 15 June 2017, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=373124
Clinical risk factors and predictive score for the non-dipper profile in hypertensive patients: a case-control study
Authors: Chotruangnapa Chavalit , Tansakun Titima , Roubsanthisuk Weranuj 
Published: November 2021

Abstract
Background
Night-time BP, especially non-dipper, is a stronger predictor of adverse cardiovascular outcomes. Ambulatory blood pressure monitoring (ABPM) is a gold standard for the detection of non-dippers but it often is unavailable and expensive. This study aims to determine clinical risk factors that predict non-dipper.

Methods
An exploratory traditional case-control study, exclusive sampling of control was conducted from January 2013 to September 2018 to explore clinical risk factors associated with non-dippers in hypertensive patients. Subgroup analysis was performed in each treated and untreated hypertensive patient. The parsimonious predictive score for non-dippers was constructed.

Results
The study included 208 hypertensive patients receiving 24 h ABPM. There were 104 dippers and 104 non-dippers. Significant clinical risk factors associated with non-dippers were the age of > 65 years, average office diastolic blood pressure (DBP), and fasting plasma glucose of > 5.6 mmol/L. Results of subgroup analysis showed that dyslipidemia, history of coronary artery disease, use of angiotensin-converting enzyme inhibitors (ACEIs) and direct vasodilators, average office DBP, and serum uric acid were associated with non-dippers in treated hypertensive patients, however, there were no risk factors associated with non-dippers in the untreated group. The predictive score for non-dippers in treated group included average office DBP, dyslipidemia, serum uric acid, male, calcium channel blockers and ACEIs use. The area under Receiver Operating Characteristic (AuROC) was 0.723. A cut-off point which was > 0.0701 and prevalence of non-dippers of 46%, this score had a sensitivity of 77.4%, specificity of 65.6%, positive predictive value (PPV) of 66.1%, and negative predictive value (NPV) of 79.6%. For untreated group, age, hemoglobin and body mass index were included in the predictive model. AuROC was 0.74. There was a sensitivity of 51.9%, specificity of 91.2%, PPV of 82.4%, and NPV of 70.5% at the cut-off point of > 0.357, and prevalence of 44%.

Conclusion
There were several significant clinical risk factors associated with non-dippers in treated hypertensive patients. The predictive score might be useful for the detection of non-dippers; however, it cannot replace ABPM.
Role of multidetector ct in quantitative enhancement- washout analysis of solid renal masses
Authors: Abdelmegeed Shaimaa Alsayed , Farok Hesham Mohamed , Refaat Medhat Mohamed , Eldiasty Tarek Abd Elmeneim 
Published: November 2021

Abstract
Background
Enhancement washout technique in solid renal masses using multidetector computed tomography (MDCT) can differentiate different type of lesions. 99 Patients who are presenting with suspected renal masses or renal tumour for staging are included in this study. CT examination are carried out at urology and nephrology centre using MDCT. The attenuation values (Hounsfield Unit) will be assesed for each lesion on the pre enhanced, corticomedullary, nephrographic and delayed phases. Washout ratio will be calculated for each phase of enhancement in comparison to the unenhanced attenuation value. The characteristics of enhancement-washout will be correlated with the final histopathological diagnosis.

Results
Early enhancement and washout pattern was noted in 54 renal lesions (54.5%) representing 4 types of renal lesions; Oncocytoma (n = 13), clear cell renal cell carcinoma (n = 16), Chromophobe renal cell carcinoma (n = 15) and unclassified renal cell carcinoma (n = 10).Prolonged enhancement pattern was noted 45 lesions (45.4%); PRCC (n = 14), 10 case of lipid poor AML (n = 10), metanephric adenoma (n = 10) and Xp11 RCC (n = 11). High pre-contrast attenuation was noted in Xp 11RCC showing attenuation value 41.7 ± 6.823HU. The highest CMP values were noted in CCRCC (151.9 ± 20.4) followed by oncocytomas (137.6 ± 19.15HU) and then CHRCC (123.6 ± 16.6 HU)while the lowest values were noted in Metanephric adenoma)57.1 ± 17.4HU)and followed by PRCC (59.9 ± 4.8)and followed by lipid poor AML (79.17 ± 13.666) and RCC unclassified (89.06 ± 18.1).

Conclusions
Four-phase MDCT (the unenhanced, corticomedullary, nephrographic, and excretory phases) evaluate role of MDCT in differentiation of solid renal masses.