bluuebunny/crossref_metadata_2025_split huggingface dataset:
Restoration of p53 activity via intracellular protein delivery sensitizes triple negative breast cancer to anti-PD-1 immunotherapy
Authors: Yang Zaofeng , Sun Jacquelyne Ka-Li , Lee Marianne M , Chan Michael K 
Published: September 2022

BackgroundAlthough immune checkpoint inhibitors (ICIs) have been shown to yield promising therapeutic outcomes in a small subset of patients with triple negative breast cancer (TNBC), the majority of patients either do not respond or subsequently develop resistance. Recent studies have revealed the critical role ofTP53gene in cancer immunology. Loss or mutation of p53 in cancer cells has been found to promote their immune escape. Given the high mutation frequency ofTP53in TNBC cells, restoration of p53 function could be a potential strategy to overcome their resistance to anti-programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) therapy. Herein, we have assessed the use of Pos3Aa crystal-based platform to mediate the intracellular delivery of p53 protein to restore p53 activity in p53 null tumors and consequently augment anti-PD-1 activity.MethodsThe efficiency of Pos3Aa-p53 crystals in delivering p53 protein was evaluated using confocal imaging, immunofluorescence staining, flow cytometry and RNA-seq. The ability of Pos3Aa-p53 crystals to remodel tumor microenvironment was investigated by examining the markers of immunogenic cell death (ICD) and the expression of PD-L1, indoleamine 2,3-dioxygenase 1, tryptophan 2,3-dioxygenase 2 and type I interferon (IFN). Finally, both unilateral and bilateral 4T1 tumor mouse models were utilized to assess the efficacy of Pos3Aa-p53 crystal-mediated p53 restoration in enhancing the antitumor activity of ICIs. T cells in tumor tissues and spleens were analyzed, and the in vivo biosafety of the Pos3Aa-p53 crystal/anti-PD-1 antibody combination was also evaluated.ResultsDelivery of p53 protein into p53-null TNBC 4T1 cells via Pos3Aa-p53 crystals restored the p53 activity, and therefore led to the induction of ICD, activation of type I IFN signaling and upregulation of PD-L1 expression. Pos3Aa-p53 crystals significantly enhanced T cell infiltration and activation in 4T1 tumors, thereby sensitizing them to anti-PD-1 therapy. The combination of Pos3Aa-p53 crystals with anti-PD-1 antibody also induced a systemic antitumor immunity resulting in the inhibition of distal tumor growth with minimal toxicity.ConclusionThis study validates that p53 restoration can be an effective approach to overcome ICI resistance and demonstrates that intracellular delivery of p53 protein can be an efficient, safe and potentially universal strategy to restore p53 activity in tumors carryingTP53mutation.
Extensive plasma proteomic profiling revealed receptor activator of nuclear factor kappa-Β ligand (RANKL) as emerging biomarker of nivolumab clinical benefit in patients with metastatic renal cell carcinoma
Authors: Simonetti Sonia , Iuliani Michele , Stellato Marco , Cavaliere Silvia , Vincenzi Bruno , Tonini Giuseppe , Santini Daniele , Pantano Francesco 
Published: September 2022

BackgroundThe advent of immune checkpoint inhibitors (ICIs) have led to a paradigm change in the management of metastatic renal cell carcinoma (mRCC), nevertheless, the benefit of treatment is confined to a limited proportion of patients. Therefore, the identification of predictive biomarkers for response to ICIs represents an unmet clinical need. Here, we performed a large-scale plasma proteomic profile of patients with mRCC, treated with nivolumab, to identify soluble molecules potentially associated with clinical benefit.MethodsWe analyzed the levels of 507 soluble molecules in the pretreatment plasma of 16 patients with mRCC (discovery set) who received nivolumab therapy as a single agent. The ELISA assay was performed to confirm the protein level of candidate biomarkers associated to clinical benefit in 15 patients with mRCC (validation set). Survival curves of complete cohort were estimated by the Kaplan-Meier method and compared with the log-rank test.ResultsOut of 507 screened molecules, 135 factors were selected as expressed above background and 12 of them were significantly overexpressed in patients who did not benefit from treatment (non-responders (NR)) compared with responders (R) group. After multiplicity adjustment, receptor activator of nuclear factor kappa-Β ligand (RANKL) was the only molecule that retained the statistical significance (false discovery rate: 0.023). RANKL overexpression in NR patients was confirmed both in discovery (median NR: 528 pg/mL vs median R: 288 pg/mL, p=0.011) and validation set (median NR: 440 pg/mL vs median R: 253 pg/mL, p<0.001). Considering the complete cohort of patients (discovery+validation set), significantly higher RANKL levels were found in patients who primarily progressed from treatment compared with those who had a partial response (p=0.003) or stable disease (p=0.006). Moreover, patients with low RANKL levels had significant improvements in progression-free survival (median 14.0 months vs 3.4 months, p=0.004) and overall survival (median not reached vs 30.1 months, p=0.003).ConclusionsOur exploratory study suggests RANKL as a novel independent biomarker of response and survival in patients with mRCC treated with nivolumab.
Interleukin (IL) 16: a candidate urinary biomarker for proliferative lupus nephritis
Authors: Häyry Aliisa , Faustini Francesca , Zickert Agneta , Larsson Anders , Niewold Timothy B , Svenungsson Elisabet , Oke Vilija , Gunnarsson Iva 
Published: September 2022

ObjectiveLupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE). The pathogenesis is incompletely understood and diagnostic biomarkers are scarce. We investigated interleukin (IL) 16 as a potential biomarker for LN in a well-characterised cohort of patients with SLE.MethodsWe measured urinary (u-) and plasma (p-) levels of IL-16 in predefined patient groups using ELISA: LN (n=84), active non-renal SLE (n=63), inactive non-renal SLE (n=73) and matched population controls (n=48). The LN group included patients with recent biopsy-confirmed proliferative (PLN, n=47), mesangioproliferative (MES, n=11) and membranous (MLN, n=26) LN. Renal expression of IL-16 was investigated by immunohistochemistry. Associations between IL-16 measurements and clinical parameters and the diagnostic value for LN were explored.Resultsp-IL-16 was detected in all investigated cases and high p-IL-16 levels were observed in patients with active SLE. u-IL-16 was detected (dt-u-IL-16) in 47.6% of patients with LN, while only up to 17.8% had dt-u-IL-16 in other groups. In the LN group, 68% of patients with PLN had dt-u-IL-16, while the proportions in the MLN and MES groups were lower (11.5% and 45.5%, respectively). The highest u-IL-16 levels were detected in the PLN group. In the regression model, u-IL-16 levels differentiated PLN from other LN patient subgroups (area under the curve 0.775–0.896, p<0.0001). dt-u-IL-16 had superior specificity but slightly lower sensitivity than elevated anti-double-stranded DNA and low complement C3 or C4 in diagnosing PLN. A high proportion of LN kidney infiltrating cells expressed IL-16.ConclusionsWe demonstrate that detectable u-IL-16 can differentiate patients with PLN from those with less severe LN subtypes and active non-renal SLE. Our findings suggest that u-IL-16 could be used as a screening tool at suspicion of severe LN. Furthermore, the high IL-16 levels in plasma, urine and kidney tissue imply that IL-16 could be explored as a therapeutic target in SLE.
Valvular disease burden in the modern era of percutaneous and surgical interventions: the UK Biobank
Authors: Tung Monica , Nah Gregory , Tang Janet , Marcus Greg , Delling Francesca N 
Published: September 2022

BackgroundThe burden of valvular heart disease (VHD) has increased significantly among ageing populations, yet remains poorly understood in the present-day context of percutaneous and surgical interventions.ObjectiveTo define the incidence, clinical correlates and associated mortality of VHD in the UK Biobank cohort.MethodsWe interrogated data collected in the UK Biobank between 1 January 2000 and 30 June 2020. VHD incidence was determined using International Classification of Disease-10 codes for aortic stenosis (AS), aortic regurgitation (AR), mitral stenosis, mitral regurgitation (MR) and mitral valve prolapse. We calculated HRs for incident VHD and all-cause mortality. Clinical correlates of VHD included demographics, coronary artery disease, heart failure and atrial fibrillation. Surgical and percutaneous interventions for mitral and aortic VHD were considered time-dependent variables.ResultsAmong 486 187 participants, the incidence of any VHD was 16 per 10 000 person-years, with highest rates for MR (8.2), AS (7.2) and AR (5.0). Age, heart failure, coronary artery disease and atrial fibrillation were significantly associated with all types of VHD. In our adjusted model, aortic and mitral VHD had an increased risk of all-cause death compared with no VHD (HR 1.62, 95% CI 1.44 to 1.82, p<0.001 and HR 1.25, 95% CI 1.09 to 1.44, p=0.002 for aortic and mitral VHD, respectively).ConclusionVHD continues to constitute a significant public health burden, with MR and AS being the most common. Age and cardiac comorbidities remain strong risk factors for VHD. In the modern era of percutaneous and surgical interventions, mortality associated with VHD remains high.
How do multiple long-term conditions impact on the cost-of-illness in early rheumatoid arthritis?
Authors: Hsieh Ping-Hsuan , Geue Claudia , Wu Olivia , McIntosh Emma , Siebert Stefan 
Published: September 2022

ObjectiveMultiple long-term conditions (MLTCs) are prevalent in rheumatoid arthritis (RA) and associated with worse outcomes and greater economic burden. However, little is known about the impact of MLTCs on the cost-of-illness (COI) in early RA, including direct and indirect costs. The objective of this study was to quantify this impact on COI.MethodsThe Scottish Early Rheumatoid Arthritis study is a national cohort of adults with new-onset RA. Direct costs were estimated applying relevant unit costs to health resource utilisation; indirect costs were measured by productivity loss due to health conditions. Two-part models were used, adjusting for age, gender, baseline functional disability and health-related quality of life. The Charlson Comorbidity Index score was calculated using ICD-10 diagnoses. Individuals were defined as ‘RA alone’, ‘RA plus LTC’ and ‘RA plus MLTCs’ according to the number of coexisting LTCs.ResultsData were available for 818 participants. Average annualised direct costs incurred by people with early RA plus MLTCs (£4444; 95% CI £3100 to £6371) were twice as, and almost five times higher than, those with a single LTC (£2184; 95% CI £1596 to £2997) and those without LTC (£919; 95% CI £694 to £1218), respectively. Indirect costs incurred by RA plus MLTCs (£842; 95% CI £377to £1521) were 3.1 times higher than RA alone (£530; 95% CI £273to £854). The relative proportion of direct costs increased with LTC category, ranging from 77.2% to 84.1%. In addition to increased costs with LTCs, costs also increased with age and were higher for men regardless of LTC category.ConclusionsMLTCs impact on COI early in the course of RA. The presence of LTCs is associated with significant increases in both direct and indirect costs among people with early RA.
Prolonged COVID-19 symptom duration in people with systemic autoimmune rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance Vaccine Survey
Authors: DiIorio Michael , Kennedy Kevin , Liew Jean W , Putman Michael S , Sirotich Emily , Sattui Sebastian E , Foster Gary , Harrison Carly , Larché Maggie J , Levine Mitchell , Moni Tarin T , Thabane Lehana , Bhana Suleman , Costello Wendy , Grainger Rebecca , Machado Pedro M , Robinson Philip C , Sufka Paul , Wallace Zachary S , Yazdany Jinoos , Gore-Massy Monique , Howard Richard A , Kodhek More A , Lalonde Nadine , Tomasella Laura-Ann , Wallace John , Akpabio Akpabio , Alpízar-Rodríguez Deshiré , Beesley Richard P , Berenbaum Francis , Bulina Inita , Chock Eugenia Yupei , Conway Richard , Duarte-García Alí , Duff Eimear , Gheita Tamer A , Graef Elizabeth R , Hsieh Evelyn , El Kibbi Lina , Liew David FL , Lo Chieh , Nudel Michal , Singh Aman Dev , Singh Jasvinder A , Singh Namrata , Ugarte-Gil Manuel F , Hausmann Jonathan S , Simard Julia F , Sparks Jeffrey A 
Published: September 2022

ObjectiveWe investigated prolonged COVID-19 symptom duration, defined as lasting 28 days or longer, among people with systemic autoimmune rheumatic diseases (SARDs).MethodsWe analysed data from the COVID-19 Global Rheumatology Alliance Vaccine Survey (2 April 2021–15 October 2021) to identify people with SARDs reporting test-confirmed COVID-19. Participants reported COVID-19 severity and symptom duration, sociodemographics and clinical characteristics. We reported the proportion experiencing prolonged symptom duration and investigated associations with baseline characteristics using logistic regression.ResultsWe identified 441 respondents with SARDs and COVID-19 (mean age 48.2 years, 83.7% female, 39.5% rheumatoid arthritis). The median COVID-19 symptom duration was 15 days (IQR 7, 25). Overall, 107 (24.2%) respondents had prolonged symptom duration (≥28 days); 42/429 (9.8%) reported symptoms lasting ≥90 days. Factors associated with higher odds of prolonged symptom duration included: hospitalisation for COVID-19 vs not hospitalised and mild acute symptoms (age-adjusted OR (aOR) 6.49, 95% CI 3.03 to 14.1), comorbidity count (aOR 1.11 per comorbidity, 95% CI 1.02 to 1.21) and osteoarthritis (aOR 2.11, 95% CI 1.01 to 4.27). COVID-19 onset in 2021 vs June 2020 or earlier was associated with lower odds of prolonged symptom duration (aOR 0.42, 95% CI 0.21 to 0.81).ConclusionMost people with SARDs had complete symptom resolution by day 15 after COVID-19 onset. However, about 1 in 4 experienced COVID-19 symptom duration 28 days or longer; 1 in 10 experienced symptoms 90 days or longer. Future studies are needed to investigate the possible relationships between immunomodulating medications, SARD type/flare, vaccine doses and novel viral variants with prolonged COVID-19 symptoms and other postacute sequelae of COVID-19 among people with SARDs.
Risk stratification in symptomatic intracranial atherosclerotic disease with conventional vascular risk factors and cerebral haemodynamics
Authors: Tian Xuan , Fang Hui , Lan Linfang , Ip Hing Lung , Abrigo Jill , Liu Haipeng , Zheng Lina , Fan Florence S Y , Ma Sze Ho , Ip Bonaventure , Song Bo , Xu Yuming , Li Jingwei , Zhang Bing , Xu Yun , Soo Yannie O Y , Mok Vincent , Wong Ka Sing , Leung Thomas W , Leng Xinyi 
Published: September 2022

Background and purposeSymptomatic intracranial atherosclerotic stenosis (sICAS) is associated with a considerable risk of recurrent stroke despite contemporarily optimal medical treatment. Severity of luminal stenosis in sICAS and its haemodynamic significance quantified with computational fluid dynamics (CFD) models were associated with the risk of stroke recurrence. We aimed to develop and compare stroke risk prediction nomograms in sICAS, based on vascular risk factors and these metrics.MethodsPatients with 50%–99% sICAS confirmed in CT angiography (CTA) were enrolled. Conventional vascular risk factors were collected. Severity of luminal stenosis in sICAS was dichotomised as moderate (50%–69%) and severe (70%–99%). Translesional pressure ratio (PR) and wall shear stress ratio (WSSR) were quantified via CTA-based CFD modelling; the haemodynamic status of sICAS was classified as normal (normal PR&WSSR), intermediate (otherwise) and abnormal (abnormal PR&WSSR). All patients received guideline-recommended medical treatment. We developed and compared performance of nomograms composed of these variables and independent predictors identified in multivariate logistic regression, in predicting the primary outcome, recurrent ischaemic stroke in the same territory (SIT) within 1 year.ResultsAmong 245 sICAS patients, 20 (8.2%) had SIT. The D2H2A nomogram, incorporating diabetes, dyslipidaemia, haemodynamic status of sICAS, hypertension and age ≥50 years, showed good calibration (P for Hosmer-Lemeshow test=0.560) and discrimination (C-statistic 0.73, 95% CI 0.60 to 0.85). It also had better performance in risk reclassification and provided larger net benefits in decision curve analysis, compared with nomograms composed of conventional vascular risk factors only, and plus the severity of luminal stenosis in sICAS. Sensitivity analysis in patients with anterior-circulation sICAS showed similar results.ConclusionsThe D2H2A nomogram, incorporating conventional vascular risk factors and the haemodynamic significance of sICAS as assessed in CFD models, could be a useful tool to stratify sICAS patients for the risk of recurrent stroke under contemporarily optimal medical treatment.
Direct measurement of the ionization quenching factor of nuclear recoils in germanium in the keV energy range
Authors: Bonhomme A. , Bonet H. , Buck C. , Hakenmüller J. , Heusser G. , Hugle T. , Lindner M. , Maneschg W. , Nolte R. , Rink T. , Pirovano E. , Strecker H. 
Published: September 2022

AbstractThis article reports the measurement of the ionization quenching factor in germanium for nuclear recoil energies in the keV range. Precise knowledge of this factor in this energy range is highly relevant for coherent elastic neutrino-nucleus scattering and low mass dark matter searches with germanium-based detectors. Nuclear recoils were produced in a thin high-purity germanium target with a very low energy threshold via irradiation using monoenergetic neutron beams. The energy dependence of the ionization quenching factor was directly measured via kinematically constrained coincidences with surrounding liquid scintillator based neutron detectors. The systematic uncertainties of the measurements are discussed in detail. With measured quenching factors between 0.16 and 0.23 in the 0.4 keV$$_{nr}$$

nr

to 6.3 keV$$_{nr}$$

nr

energy range, the data are compatible with the Lindhard theory with a parameter k of 0.162 $$\pm \,0.004$$

±

0.004

(stat + sys).
Almost all 2-bridge knots are curly
Authors: Ernst C. , Gover S. 
Published: September 2022

A spiral knot or link diagram (introduced in [C. Adams, R. Hudson, Rachel, R. Morrison, W. George, L. Starkston, S. Taylor and O. Turanova, The spiral index of knots, Math. Proc. Cambridge Philos. Soc. 149(2) (2010) 297–315]) is an oriented knot or link diagram where, when traversing through the planar diagram, the curvature does not change sign. An oriented knot or link type is called curly if it admits a spiral diagram with fewer maxima than the braid index of that knot or link type. We prove that all 2-bridge knots and links with a braid index greater than three are curly. We also show that many alternating oriented Montesinos links are curly.
Instantaneous Wave-Free Ratio for the Assessment of Intermediate Left Main Coronary Artery Stenosis: Correlations With Fractional Flow Reserve/Intravascular Ultrasound and Prognostic Implications: The iLITRO-EPIC07 Study
Authors: Rodriguez-Leor Oriol , de la Torre Hernández José María , García-Camarero Tamara , García del Blanco Bruno , López-Palop Ramón , Fernández-Nofrerías Eduard , Cuellas Ramón Carlos , Jiménez-Kockar Marcelo , Jiménez-Mazuecos Jesús , Fernández Salinas Francisco , Gómez-Lara Josep , Brugaletta Salvatore , Alfonso Fernando , Palma Ricardo , Gómez-Menchero Antonio E. , Millán Raúl , Tejada Ponce David , Linares Vicente José Antonio , Ojeda Soledad , Pinar Eduardo , Fernández-Pelegrina Estefanía , Morales-Ponce Francisco J. , Cid-Álvarez Ana Belén , Rama-Merchan Juan Carlos , Molina Navarro Eduardo , Escaned Javier , Pérez de Prado Armando ,   on behalf of the iLITRO-EPIC07 Study Investigators
Published: September 2022

Background:
There is little information available on agreement between fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) in left main coronary artery (LMCA) intermediate stenosis. Besides, several meta-analyses support the use of FFR to guide LMCA revascularization, but limited information is available on iFR in this setting. Our aims were to establish the concordance between FFR and iFR in intermediate LMCA lesions, to evaluate with intravascular ultrasound (IVUS) in cases of FFR/iFR discordance, and to prospectively validate the safety of deferring revascularization based on a hybrid decision-making strategy combining iFR and IVUS.

Methods:
Prospective, observational, multicenter registry with 300 consecutive patients with intermediate LMCA stenosis who underwent FFR and iFR and, in case of discordance, IVUS and minimal lumen area measurements. Primary clinical end point was a composite of cardiovascular death, LMCA lesion-related nonfatal myocardial infarction, or unplanned LMCA revascularization.

Results:

FFR and iFR had an agreement of 80% (both positive in 67 and both negative in 167 patients); in case of disagreement (31 FFR+/iFR– and 29 FFR−/iFR+) minimal lumen area was ≥6 mm
2
in 8.7% of patients with FFR+ and 14.6% with iFR+. Among the 300 patients, 105 (35%) underwent revascularization and 181 (60%) were deferred according to iFR and IVUS. At a median follow-up of 20 months, major adverse cardiac events incidence was 8.3% in the defer group and 13.3% in the revascularization group (hazard ratio, 0.71 [95% CI 0.30–1.72];
P
=0.45).

Conclusions:
In patients with intermediate LMCA stenosis, a physiology-guided treatment decision is feasible either with FFR or iFR with moderate concordance between both indices. In case of disagreement, the use of IVUS may be useful to indicate revascularization. Deferral of revascularization based on iFR appears to be safe in terms of major adverse cardiac events.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT03767621.