bluuebunny/crossref_metadata_2025 huggingface dataset:
Nonlinear Energy Transfer of a Spar-Floater System Using the Inerter Pendulum Vibration Absorber
Authors: Gupta Aakash , Kiet Duong Van Tuan , Tai Wei-Che
Published: August 2023

The inerter pendulum vibration absorber (IPVA) is integrated between a spar and an annulus floater using a ball-screw mechanism to study its wave energy conversion potential. Hydrodynamic stiffness, added mass, and radiation damping effects on the spar-floater system are characterized using the boundary element method. It is found that a 1:2 internal resonance via a period-doubling bifurcation in the system is responsible for nonlinear energy transfer between the spar-floater system and the pendulum vibration absorber. This nonlinear energy transfer occurs when the primary harmonic solution of the system becomes unstable due to the 1:2 internal resonance phenomenon. The focus of this paper is to analyze this 1:2 internal resonance phenomenon near the first natural frequency of the system. The IPVA system when integrated with the spar-floater system is shown to outperform a linear coupling between the spar and the floater both in terms of the response amplitude operator (RAO) of the spar and one measure of the energy conversion potential of the system. Finally, experiments are performed on the IPVA system integrated with single-degree-of-freedom system (without any hydrodynamic effects) to observe the 1:2 internal resonance phenomenon and the nonlinear energy transfer between the primary mass and the pendulum vibration absorber. It is shown experimentally that the IPVA system outperforms a linear benchmark in terms of vibration suppression due to the energy transfer phenomenon.
Silicon dioxide by Ag Lα, hard x-ray photoelectron spectroscopy
Authors: Rincón-Ortiz Sergio A. , Quintero-Orozco Jorge H. , Ospina Rogelio
Published: August 2023

Silicon dioxide powder was characterized by hard x-ray photoelectron spectroscopy (HAXPES) with an Ag Lα (2984.2 eV) excitation source. The sample was fixed to a stainless-steel sample holder with copper double-sided adhesive tape. Survey spectrum, C 1s, O 1s, Si 1s, Si KLL, Si 2s, and Si 2p core levels spectra were acquired.
The Longitudinal Association of Cardiorespiratory Fitness and Adiposity With Clustered Cardiometabolic Risk: A Mediation Analysis
Authors: Silveira João Francisco de Castro , Brand Caroline , Welser Letícia , Gaya Anelise Reis , Burns Ryan Donald , Pfeiffer Karin Allor , Lima Rodrigo Antunes , Andersen Lars Bo , Reuter Cézane Priscila , Pohl Hildegard Hedwig
Published: August 2023

Purpose: Previous literature has demonstrated the mediating role of adiposity in the association between cardiorespiratory fitness (CRF) and cardiometabolic risk as well as the potential role of CRF in attenuating the adverse consequences associated with excess weight. This study aimed to evaluate the mediating role of CRF and adiposity in the possible association with cardiometabolic risk. Method: Observational 3-year longitudinal study that included 420 children and adolescents (10.50 [2.05] y of age at baseline; 56.2% girls). Body mass index (BMI) was calculated, and CRF was evaluated using field assessments. A clustered cardiometabolic risk score (cMetS) was calculated from glucose, systolic blood pressure, total cholesterol/high-density lipoprotein cholesterol ratio, and triglycerides z scores. Analyses evaluated the mediating role of BMI in the association between CRF and cMetS as well as whether CRF mediated the association between BMI and cMetS. Results: BMI at baseline was directly associated with the cMetS at follow-up (0.102; 95% confidence interval, 0.020 to 0.181), independently of CRF, whereas CRF was only indirectly associated with cMetS at follow-up through BMI (−0.036; 95% confidence interval, −0.070 to −0.009), meaning that the association between CRF and cMetS was explained via the mediation role of BMI. Conclusions: BMI presented direct association with cMetS, whereas CRF exhibited indirect association with cMetS mediated via BMI.
Fibroblasts generate topographical cues that steer cancer cell migration
Authors: Baschieri Francesco , Illand Abigail , Barbazan Jorge , Zajac Olivier , Henon Clémence , Loew Damarys , Dingli Florent , Vignjevic Danijela Matic , Lévêque-Fort Sandrine , Montagnac Guillaume
Published: August 2023

Fibroblasts play a fundamental role in tumor development. Among other functions, they regulate cancer cells’ migration through rearranging the extracellular matrix, secreting soluble factors, and establishing direct physical contacts with cancer cells. Here, we report that migrating fibroblasts deposit on the substrate a network of tubular structures that serves as a guidance cue for cancer cell migration. Such membranous tubular network, hereafter called tracks, is stably anchored to the substrate in a β5-integrin–dependent manner. We found that cancer cells specifically adhere to tracks by using clathrin-coated structures that pinch and engulf tracks. Tracks thus represent a spatial memory of fibroblast migration paths that is read and erased by cancer cells directionally migrating along them. We propose that fibroblast tracks represent a topography-based intercellular communication system capable of steering cancer cell migration.
Giant acceleration of polaron transport by ultrafast laser-induced coherent phonons
Authors: Wang Hui-Min , Liu Xin-Bao , Hu Shi-Qi , Chen Da-Qiang , Chen Qing , Zhang Cui , Guan Meng-Xue , Meng Sheng
Published: August 2023

Polaron formation is ubiquitous in polarized materials, but severely hampers carrier transport for which effective controlling methods are urgently needed. Here, we show that laser-controlled coherent phonon excitation enables orders of magnitude enhancement of carrier mobility via accelerating polaron transport in a prototypical material, lithium peroxide (Li
2
O
2
). The selective excitation of specific phonon modes, whose vibrational pattern directly overlap with the polaronic lattice deformation, can remarkably reduce the energy barrier for polaron hopping. The strong nonadiabatic couplings between the electronic and ionic subsystem play a key role in triggering the migration of polaron, via promoting phonon-phonon scattering in
q
space within sub-picoseconds. These results extend our understanding of polaron transport dynamics to the nonequilibrium regime and allow for optoelectronic devices with ultrahigh on-off ratio and ultrafast responsibility, competitive with those of state-of-the-art devices fabricated based on free electron transport.
Diversity of
bla
L1-like
genes in
Stenotrophomonas
species: insights from genome analysis of publicly available genome sequences
Authors: Yamada Kageto , Ishii Yoshikazu , Tateda Kazuhiro
Published: August 2023

L1 metallo-β-lactamases produced by
Stenotrophomonas maltophilia
exhibit high diversity. Here, we characterized the genomes of
Stenotrophomonas
species harboring
bla
L1-like
genes using publicly available genome sequences. Our findings provide evidence that
Stenotrophomonas
species with
bla
L1-like
genes constitute a complex comprising many species with high genetic diversity, and similarities between
bla
L1-like
genes are lower than those of the genome. This suggests that the diversity of
bla
L1-like
is attributable to species diversity in
Stenotrophomonas
species harboring
bla
L1-like
and the rapid evolutionary changes in
bla
L1-like
genes.
Diagnostic utility of oropharyngeal swabs as an alternative to lower respiratory tract samples for PCR-based syndromic testing in patients with community-acquired pneumonia
Authors: Serigstad Sondre , Knoop Siri T. , Markussen Dagfinn L. , Ulvestad Elling , Bjørneklett Rune O. , Ebbesen Marit H. , Kommedal Øyvind , Grewal Harleen M. S.
Published: August 2023

Syndromic PCR-based analysis of lower respiratory tract (LRT) samples in patients with community-acquired pneumonia (CAP) improves the bacterial yield and time-to-results compared to culture-based methods. However, obtaining adequate sputum samples can be challenging and is frequently not prioritized in the emergency department (ED). In this study, we assess the concordance of microbiological detections between oropharyngeal- (OP) and LRT samples from patients presenting to the ED with CAP using a syndromic PCR-based respiratory panel [Biofire FilmArray Pneumonia
plus
(FAP
plus
)]. Paired OP- and high-quality LRT samples were collected from 103 patients with confirmed CAP, who had been included in a randomized controlled trial (NCT04660084) or a subsequent observational study at Haukeland University Hospital, and analyzed using the FAP
plus
. The LRT samples were obtained mainly by sputum induction (88%). Using the LRT samples as a reference standard, the positive percent agreement (PPA), negative percent agreement (NPA), and overall percent agreement for the most common bacterial pathogens in CAP,
Streptococcus pneumoniae
and
Haemophilus influenzae
, were 85%, 99% and 95%, and 86%, 98% and 93%, respectively. For
Moraxella catarrhalis,
the PPA was lower (74%), while the NPA was 100%. For bacteria that are less likely causes of uncomplicated CAP (e.g.,
Staphylococcus aureus
and Enterobacterales) the results were more divergent. In conclusion, the FAP
plus
detects the most common CAP pathogens
S. pneumoniae
and
H. influenzae
from OP samples with high PPAs and excellent NPAs when compared with LRT samples. For these pathogens, the PPAs for OP samples were higher than previous reports for nasopharyngeal samples. This suggests that analysis of OP samples with syndromic PCR panels could represent an alternative approach for rapid microbiological testing in the ED, especially in patients where LRT samples are difficult to obtain. Divergent results for bacteria that are less likely to cause uncomplicated CAP do, however, emphasize the need for clinical evaluation of positive test results.
The SlyD metallochaperone targets iron-sulfur biogenesis pathways and the TCA cycle
Authors: Denic Milica , Turlin Evelyne , Zamble Deborah B. , Betton Jean-Michel , Vinella Daniel , De Reuse Hilde
Published: August 2023

Control of protein folding is a conserved function in all domains of life. The ubiquitous peptidyl-prolyl
cis-trans
isomerases (PPIases) catalyze the
cis
/
trans
-isomerization of peptidyl-prolyl bonds, often a rate-limiting step for protein folding. PPIases are involved in central processes in eucaryotes but their functions in bacteria are poorly understood. We applied a large-scale two-hybrid screen to identify novel targets of SlyD, a metallochaperone PPIase, from the model organism
Escherichia coli
, and the important gastric pathogen
Helicobacter pylori
. SlyD from both organisms interacts with metal-containing proteins including TCA cycle enzymes and with enzymes driving the biogenesis of iron-sulfur (Fe-S) clusters. In
H. pylori
, a ∆
slyD
mutant contains strongly diminished amounts of MisSU, its sole Fe-S biogenesis proteins as well as diminished activity of the Fe-S aconitase.
E. coli
and
H. pylori ∆slyD
mutants are less susceptible to ampicillin and gentamicin antibiotics and under microaerobic conditions to the ROS-producing molecule hypochlorite. In addition, the intracellular ATP content and proton motive force are reduced in the
H. pylori
∆
slyD
mutant, and its gentamicin and hypochlorite susceptibility phenotypes are rescued upon restoration of MisSU expression. Measurement of malate and fumarate in the
H. pylori ∆slyD
mutant suggests that the two enzymes before and after fumarase in the TCA cycle are affected. We conclude that SlyD regulates the activity of TCA cycle enzymes by controlling the efficiency of their Fe-S cluster formation. This is the first report of the role of a bacterial PPIase in central metabolism and susceptibility to stress and antibiotics.

IMPORTANCE

Correct folding of proteins represents a crucial step for their functions. Among the chaperones that control protein folding, the ubiquitous PPIases catalyze the
cis
/
trans
-isomerization of peptidyl-prolyl bonds. Only few protein targets of PPIases have been reported in bacteria. To fill this knowledge gap, we performed a large-scale two-hybrid screen to search for targets of the
Escherichia coli
and
Helicobacter pylori
SlyD PPIase-metallochaperone. SlyD from both organisms interacts with enzymes (i) containing metal cofactors, (ii) from the central metabolism tricarboxylic acid (TCA) cycle, and (iii) involved in the formation of the essential and ancestral Fe-S cluster cofactor.
E. coli
and
H. pylori ∆slyD
mutants present similar phenotypes of diminished susceptibility to antibiotics and to oxidative stress. In
H. pylori
, measurements of the intracellular ATP content, proton motive force, and activity of TCA cycle proteins suggest that SlyD regulates TCA cycle enzymes by controlling the formation of their indispensable Fe-S clusters.
Neoarchean synkinematic metamorphic peak in the Isua supracrustal belt (West Greenland)
Authors: Eskesen Benjamin , Fassmer Kathrin , Münker Carsten , Ulrich Thomas , Szilas Kristoffer , Wagner Simon , Hoffmann J. Elis , Nagel Thorsten J.
Published: August 2023

We present petrological data and seven Lu-Hf garnet–amphibole–whole rock ages obtained from a single garnet-hornblende-mica schist sample from the Isua supracrustal belt (West Greenland). Garnets grew during prograde metamorphism toward regional amphibolite-facies peak conditions, and a mylonitic foliation formed during and after garnet growth. Garnet crystals show typical prograde zoning with no visible traces of a relict garnet generation. They do show various degrees of retrogression. While some crystals are perfectly euhedral with only minor chemical alteration along cracks, others are elongated in the foliation and either grew in this shape or were deformed. Six garnet splits were separated from crushed single crystals and one from a crushed bulk sample. Individual three-point garnet–hornblende–whole rock ages scatter between 2.603 ± 0.018 Ga and 2.432 ± 0.059 Ga for single garnets. The garnet split from the bulk sample defines an age of 2.463 ± 0.031 Ga, the data point farthest from the regression line for all data points (2.551 ± 0.074 Ga, mean square of weighted deviates = 25). We interpret these data to indicate partial retrogression of a Neoarchean garnet population not significantly older than the oldest obtained three-point age. Well-preserved garnet zoning, regional peak temperatures well below the closing temperature of the Lu-Hf system, and the small scatter of Lu-Hf ages preclude an interpretation of the observed metamorphism and deformation as being Eoarchean in age.
Pulmonary homograft failure presents as abdominal ascites
Authors: Ding Kimberly Renae , Aboulhosn Jamil , Pillutla Priya
Published: August 2023

Ascites is a condition typically attributed to liver disease but can be cardiac in aetiology as well. We report of an atypical case of pulmonary homograft failure status—post the Ross-Yacoub procedure as an underlying cause of anasarca. A man in his mid-30s with a history of congenital heart disease presented with abdominal distension and exercise intolerance. His prior history was relevant for congenital bicuspid aortic valve with critical aortic stenosis. Abdomen and pelvis CT revealed a grossly dilated inferior vena cava while transthoracic echocardiogram showed severe homograft pulmonary stenosis and regurgitation. Further investigation with cardiac MRI demonstrated severe pulmonary valve stenosis and regurgitation with significant tricuspid regurgitation and right ventricular dilatation. The transcatheter stent in the right ventricular to pulmonary artery conduit followed by transcatheter valve replacement, which resulted in full resolution of his presenting symptoms.
Can quantifying the relative intensity of a person’s free-living physical activity predict how they respond to a physical activity intervention? Findings from the PACES RCT
Authors: Rowlands Alex V , Orme Mark W , Maylor Ben , Kingsnorth Andrew , Herring Louisa , Khunti Kamlesh , Davies Melanie , Yates Tom
Published: August 2023

Objectives

To determine whether quantifying both the absolute and relative intensity of accelerometer-assessed physical activity (PA) can inform PA interventions. We hypothesised that individuals whose free-living PA is at a low relative intensity are more likely to increase PA in response to an intervention, as they have spare physical capacity.

Method

We conducted a secondary data analysis of a 12-month randomised controlled trial, Physical Activity after Cardiac EventS, which was designed to increase PA but showed no improvement. Participants (N=239, 86% male; age 66.4 (9.7); control N=126, intervention N=113) wore accelerometers for 7 days and performed the incremental shuttle walk test (ISWT) at baseline and 12 months. PA intensity was expressed in absolute terms (intensity gradient) and relative to acceleration at maximal physical capacity (predicted from an individual’s maximal ISWT walking speed). PA outcomes were volume and absolute intensity gradient.

Results

At baseline, ISWT performance was positively correlated with PA volume (r=0.50, p<0.001) and absolute intensity (r=0.50, p<0.001), but negatively correlated with relative intensity (r=−0.13, p=0.025). Relative intensity of PA at baseline moderated the change in absolute intensity (p=0.017), but not volume, of PA postintervention. Low relative intensity at baseline was associated with increased absolute intensity gradient (+0.5 SD), while high relative intensity at baseline was associated with decreased absolute intensity gradient (−0.5 SD).

Conclusion

Those with low relative intensity of PA were more likely to increase their absolute PA intensity gradient in response to an intervention. Quantifying absolute and relative PA intensity of PA could improve enables personalisation of interventions.
Socioeconomic status, maternal risk factors, and gestational diabetes mellitus across reproductive years: a Finnish register-based study
Authors: Roustaei Zahra , Anttonen Sanna , Räisänen Sari , Gissler Mika , Heinonen Seppo
Published: August 2023

Introduction

To evaluate the degree to which socioeconomic differences in gestational diabetes mellitus (GDM) are accounted for by differences in maternal risk factors, to assess whether age-related risks of GDM differ across socioeconomic groups, and to identify priority populations for future interventions.

Research design and methods

We performed a register-based study using data from the Finnish Medical Birth Register and Statistics Finland on the 474 166 women who gave birth in Finland from 2008 to 2015. We collected information on GDM based on the International Classification of Diseases 10th Revision codes O24.4 and O24.9. We used multivariable models to examine the association between socioeconomic status, maternal risk factors, and GDM. We further tested interaction on multiplicative and additive scales.

Results

The incidence of GDM was 8.7% in 2008–2011 and 12.5% in 2012–2015. Lower socioeconomic levels than upper level employees were associated with an increased risk of GDM. Up to 64.0% of socioeconomic differences in GDM were attributed to body mass index and 5.5% to smoking. There was evidence for effect modification. Relative to women in the upper level category who were aged less than 19 years, GDM adjusted ORs (95% CIs) for women 35 years or older in upper level versus long-term unemployed groups were 3.28 (2.08–5.18) and 5.29 (3.35–8.35), respectively.

Conclusions

There is a paradox that socioeconomic advantage increases the incidence of GDM at the population level while reducing the incidence of GDM within the population. Nevertheless, socioeconomic differences in GDM persist and widen with increasing maternal age, even after accounting for maternal risk factors.
Biomodulating healing after arthroscopic rotator cuff repair: the protocol of a randomised proof of concept trial (BIOHACK)
Authors: Allaart Laurens Jan Houterman , Lech James , Macken Arno Alexander , Kling Agathe , Lafosse Laurent , Lafosse Thibault , van den Bekerom Michel P J , Buijze Geert Alexander
Published: August 2023

Purpose/introduction

Over the last decades, there has been increasing interest in biological stimulation or bioaugmentation after rotator cuff repair. So far, there is no consensus on the appropriate composition of biologicals or which patients would benefit most, and moreover, these biologicals are often expensive. However, there are other, non-pharmacological strategies that are also believed to achieve biological stimulation. This randomised controlled trial evaluates the possible cumulative effect of pragmatic application of cryobiomodulation, photobiomodulation and electrobiomodulation—collectively called biomodulation—on the bone-to-tendon healing process after rotator cuff repair.

Methods

In this randomised, controlled proof of concept study, 146 patients undergoing arthroscopic repair of a full thickness posterosuperior or anterosuperior rotator cuff tear will be 1:1 randomly assigned to either a control group or to the additional biomodulation protocol group. The adjuvant biomodulation protocol consists of seven self-applicable therapies and will be administered during the first 6 weeks after surgery. Primary outcome will be healing of the rotator cuff as evaluated by the Sugaya classification on MRI at 1-year postoperatively.

Ethics and dissemination

This study has been accepted by the National Ethical Review Board CPP Sud-Est IV in France and has been registered at Clinicaltrials.gov. The results of this study will be published in a peer-reviewed journal.

Trial registration number

NCT04618484.
Cost-effectiveness analysis of serplulimab combined with chemotherapy in the treatment of extensive-stage small-cell lung cancer from the perspective of the healthcare system in China
Authors: Long Yunchun , Xu Yuan , Liao Li , Zhou Yujie , Wang Hao
Published: August 2023

Objective

The ASTRUM-005 trial showed that serplulimab plus chemotherapy (SEP) significantly extended survival time compared with chemotherapy in the treatment of small cell lung cancer. But the survival benefits of SEP came at high costs, and its economy is not clear. Therefore, this study aimed to evaluate the cost-effectiveness of SEP from the perspective of the Chinese healthcare system.

Design

A partition survival model was built to simulate the outcomes. The clinical data came from the ASTRUM-005 trial, and only direct medical costs were included in the model. The utility values referred to the published literature. Scenario analyses 1 and 2 explored outcomes in the presence of a patient assistance plan (PAP) and different simulation periods, respectively. Scenario analysis 3 compared the cost-effectiveness of atezolizumab plus chemotherapy (AEP) with SEP by network meta-analysis. Sensitivity analyses were conducted to assess the robustness of the results.

Outcome measures

Total costs, incremental costs, life years, quality-adjusted life years (QALYs), incremental QALYs and incremental cost-effectiveness ratio (ICER).

Results

Compared with chemotherapy, SEP achieved an additional 0.34 QALYs at incremental costs of US$41 682.63, with an ICER of US$122 378.86/QALY. When PAP was available, ICER was US$58 316.46/QALY. In the simulation time of 5 years and 20 years, the ICER was US$132 637.97/QALY and US$118 054.59/QALY, respectively. When compared with AEP, SEP not only reduced the costs by US$47 244.87 but also gained 0.07 QALYs more. Sensitivity analyses showed that the price of serplulimab and the utility value of the progression-free survival stage were the main influencing parameters, and the results were stable.

Conclusions

Compared with chemotherapy, SEP was not cost-effective from the perspective of the Chinese healthcare system. However, SEP was absolutely dominant in comparison with AEP.
TCR-engaging scaffolds selectively expand antigen-specific T-cells with a favorable phenotype for adoptive cell therapy
Authors: Tvingsholm Siri Amanda , Frej Marcus Svensson , Rafa Vibeke Mindahl , Hansen Ulla Kring , Ormhøj Maria , Tyron Alexander , Jensen Agnete W P , Kadivar Mohammad , Bentzen Amalie Kai , Munk Kamilla K , Aasbjerg Gitte N , Ternander Jeppe S H , Heeke Christina , Tamhane Tripti , Schmess Christian , Funt Samuel A. , Kjeldsen Julie Westerlin , Kverneland Anders Handrup , Met Özcan , Draghi Arianna , Jakobsen Søren Nyboe , Donia Marco , Marie Svane Inge , Hadrup Sine Reker
Published: August 2023

Background

Adoptive cell therapy (ACT) has shown promising results for the treatment of cancer and viral infections. Successful ACT relies on ex vivo expansion of large numbers of desired T-cells with strong cytotoxic capacity and in vivo persistence, which constitutes the greatest challenge to current ACT strategies. Here, in this study, we present a novel technology for ex vivo expansion of antigen-specific T-cells; artificial antigen-presenting scaffolds (Ag-scaffolds) consisting of a dextran-polysaccharide backbone, decorated with combinations of peptide-Major Histocompatibility Complex (pMHC), cytokines and co-stimulatory molecules, enabling coordinated stimulation of antigen-specific T-cells.

Methods

The capacity of Ag-scaffolds to expand antigen-specific T-cells was explored in ex vivo cultures with peripheral blood mononuclear cells from healthy donors and patients with metastatic melanoma. The resulting T-cell products were assessed for phenotypic and functional characteristics.

Results

We identified an optimal Ag-scaffold for expansion of T-cells for ACT, carrying pMHC and interleukin-2 (IL-2) and IL-21, with which we efficiently expanded both virus-specific and tumor-specific CD8+ T cells from peripheral blood of healthy donors and patients, respectively. The resulting T-cell products were characterized by a high frequency of antigen-specific cells with high self-renewal capacity, low exhaustion, a multifunctional cytokine profile upon antigen-challenge and superior tumor killing capacity. This demonstrates that the coordinated stimuli provided by an optimized stoichiometry of TCR engaging (pMHC) and stimulatory (cytokine) moieties is essential to obtain desired T-cell characteristics. To generate an ‘off-the-shelf’ multitargeting Ag-scaffold product of relevance to patients with metastatic melanoma, we identified the 30 most frequently recognized shared HLA-A0201-restricted melanoma epitopes in a cohort of 87 patients. By combining these in an Ag-scaffold product, we were able to expand tumor-specific T-cells from 60–70% of patients with melanoma, yielding a multitargeted T-cell product with up to 25% specific and phenotypically and functionally improved T cells.

Conclusions

Taken together, the Ag-scaffold represents a promising new technology for selective expansion of antigen-specific CD8+ T cells directly from blood, yielding a highly specific and functionally enhanced T-cell product for ACT.
Reactivation of low avidity tumor-specific CD8+T cells associates with immunotherapeutic efficacy of anti-PD-1
Authors: Sugiyarto Gessa , Lau Doreen , Hill Samuel Luke , Arcia-Anaya David , Boulanger Denise S M , Parkes Eileen E , James Edward , Elliott Tim
Published: August 2023

Background

CD8+T cells are a highly diverse population of cells with distinct phenotypic functions that can influence immunotherapy outcomes. Further insights on the roles of CD8+specificities and TCR avidity of naturally arising tumor-specific T cells, where both high and low avidity T cells recognizing the same peptide-major histocompatibility complex (pMHC) coexist in the same tumor, are crucial for understanding T cell exhaustion and resistance to PD-1 immunotherapy.

Methods

CT26 models were treated with anti-PD-1 on days 3, 6 and 9 following subcutaneous tumor implantation generating variable responses during early tumor development. Tetramer staining was performed to determine the frequency and avidity of CD8+T cells targeting the tumor-specific epitope GSW11 and confirmed with tetramer competition assays. Functional characterization of high and low avidity GSW11-specific CD8+T cells was conducted using flow cytometry and bulk RNA-seq. In vitro cytotoxicity assays and in vivo adoptive transfer experiments were performed to determine the cytotoxicity of high and low avidity populations.

Results

Treatment success with anti-PD-1 was associated with the preferential expansion of low avidity (Tetlo) GSW11-specific CD8+T cells with Vβ TCR expressing clonotypes. High avidity T cells (Tethi), if present, were only found in progressing PD-1 refractory tumors. Tetlodemonstrated precursor exhausted or progenitor T cell phenotypes marked by higher expression of Tcf-1 and T-bet, and lower expression of the exhaustion markers CD39, PD-1 and Eomes compared with Tethi, whereas Tethicells were terminally exhausted. Transcriptomics analyses showed pathways related to TCR signaling, cytotoxicity and oxidative phosphorylation were significantly enriched in Tetlofound in both regressing and progressing tumors compared with Tethi, whereas genes related to DNA damage, apoptosis and autophagy were downregulated. In vitro studies showed that Tetloexhibits higher cytotoxicity than Tethi. Adoptive transfer of Tetloshowed more effective tumor control than Tethi, and curative responses were achieved when Tetlowas combined with two doses of anti-PD-1.

Conclusions

Targeting subdominant T cell responses with lower avidity against pMHC affinity neoepitopes showed potential for improving PD-1 immunotherapy. Future interventions may consider expanding low avidity populations via vaccination or adoptive transfer.
Immune dysfunction revealed by digital spatial profiling of immuno-oncology markers in progressive stages of renal cell carcinoma and in brain metastases
Authors: Schoenfeld David A , Moutafi Myrto , Martinez Sandra , Djureinovic Dijana , Merkin Ross D , Adeniran Adebowale , Braun David A , Signoretti Sabina , Choueiri Toni K , Parisi Fabio , Hurwitz Michael , Rimm David L , Wei Wei , Jilaveanu Lucia , Kluger Harriet M
Published: August 2023

Background

The tumor microenvironment (TME) contributes to cancer progression and treatment response to therapy, including in renal cell carcinoma (RCC). Prior profiling studies, including single-cell transcriptomics, often involve limited sample sizes and lack spatial orientation. The TME of RCC brain metastases, a major cause of morbidity, also remains largely uncharacterized.

Methods

We performed digital spatial profiling on the NanoString GeoMx platform using 52 validated immuno-oncology markers on RCC tissue microarrays representing progressive stages of RCC, including brain metastases. We profiled 76 primary tumors, 27 adjacent histologically normal kidney samples, and 86 metastases, including 24 brain metastases.

Results

We observed lower immune checkpoint (TIM-3 and CTLA-4), cytolytic (GZMA and GZMB), and T cell activation (CD25) protein expression in metastases compared with primary tumors in two separate cohorts. We also identified changes in macrophages in metastases, with brain metastases-susceptible patients showing less M1-like, inflammatory macrophage markers (HLA-DR and CD127) in metastatic samples. A comparison of brain metastases to extracranial metastases revealed higher expression of the anti-apoptotic, BCL-2-family protein BCL-XL and lower expression of the innate immune activator STING in brain metastases. Lower TIM-3 and CD40 in the TME of brain metastases appear to be associated with longer survival, a finding that requires further validation.

Conclusions

Compared with primary tumors, RCC metastases, including brain metastases, express lower levels of numerous markers of immune activation and current or investigational therapeutic targets. Our findings may have important implications for designing future biomarker and treatment studies and may aid in development of brain metastases-specific therapies.
ScRNA-seq defines dynamic T-cell subsets in longitudinal colon and peripheral blood samples in immune checkpoint inhibitor-induced colitis
Authors: Mann Jacqueline E , Lucca Liliana , Austin Matthew R , Merkin Ross D , Robert Marie E , Al Bawardy Badr , Raddassi Khadir , Aizenbud Lilach , Joshi Nikhil S , Hafler David A , Abraham Clara , Herold Kevan C , Kluger Harriet M
Published: August 2023

Immune checkpoint inhibitors (ICIs) are increasingly being used to manage multiple tumor types. Unfortunately, immune-related adverse events affect up to 60% of recipients, often leading to treatment discontinuation in settings where few alternative cancer therapies may be available. Checkpoint inhibitor induced colitis (ICI-colitis) is a common toxicity for which the underlying mechanisms are poorly defined. To better understand the changing colon-specific and peripheral immune environments over the course of progression and treatment of colitis, we collected blood and colon tissue from a patient with Merkel cell carcinoma who developed colitis on treatment with pembrolizumab. We performed single-cell RNA sequencing and T-cell receptor sequencing on samples collected before, during and after pembrolizumab and after various interventions to mitigate toxicity. We report T-cells populations defined by cytotoxicity, memory, and proliferation markers at various stages of colitis. We show preferential depletion of CD8+ T cells with biologic therapy and nominate both circulating and colon-resident T-cell subsets as potential drivers of inflammation and response to immune suppression. Our findings highlight the need for further exploration of the colon immune environment and rationalize future studies evaluating biologics for ICI-colitis, including in the context of ICI re-challenge.
Deep phenotyping of the neuroimaging and skeletal features in KBG syndrome: a study of 53 patients and review of the literature
Authors: Peluso Francesca , Caraffi Stefano G , Contrò Gianluca , Valeri Lara , Napoli Manuela , Carboni Giorgia , Seth Alka , Zuntini Roberta , Coccia Emanuele , Astrea Guja , Bisgaard Anne-Marie , Ivanovski Ivan , Maitz Silvia , Brischoux-Boucher Elise , Carter Melissa T , Dentici Maria Lisa , Devriendt Koenraad , Bellini Melissa , Digilio Maria Cristina , Doja Asif , Dyment David A , Farholt Stense , Ferreira Carlos R , Wolfe Lynne A , Gahl William A , Gnazzo Maria , Goel Himanshu , Grønborg Sabine Weller , Hammer Trine , Iughetti Lorenzo , Kleefstra Tjitske , Koolen David A , Lepri Francesca Romana , Lemire Gabrielle , Louro Pedro , McCullagh Gary , Madeo Simona F , Milone Annarita , Milone Roberta , Nielsen Jens Erik Klint , Novelli Antonio , Ockeloen Charlotte W. , Pascarella Rosario , Pippucci Tommaso , Ricca Ivana , Robertson Stephen P , Sawyer Sarah , Falkenberg Smeland Marie , Stegmann Sander , Stumpel Constanze T , Goel Amy , Taylor Juliet M , Barbuti Domenico , Soresina Annarosa , Bedeschi Maria Francesca , Battini Roberta , Cavalli Anna , Fusco Carlo , Iascone Maria , Van Maldergem Lionel , Venkateswaran Sunita , Zuffardi Orsetta , Vergano Samantha , Garavelli Livia , Bayat Allan
Published: August 2023

Background

KBG syndrome is caused by haploinsufficiency ofANKRD11and is characterised by macrodontia of upper central incisors, distinctive facial features, short stature, skeletal anomalies, developmental delay, brain malformations and seizures. The central nervous system (CNS) and skeletal features remain poorly defined.

Methods

CNS and/or skeletal imaging were collected from molecularly confirmed individuals with KBG syndrome through an international network. We evaluated the original imaging and compared our results with data in the literature.

Results

We identified 53 individuals, 44 with CNS and 40 with skeletal imaging. Common CNS findings included incomplete hippocampal inversion and posterior fossa malformations; these were significantly more common than previously reported (63.4% and 65.9% vs 1.1% and 24.7%, respectively). Additional features included patulous internal auditory canal, never described before in KBG syndrome, and the recurrence of ventriculomegaly, encephalic cysts, empty sella and low-lying conus medullaris. We found no correlation between these structural anomalies and epilepsy or intellectual disability. Prevalent skeletal findings comprised abnormalities of the spine including scoliosis, coccygeal anomalies and cervical ribs. Hand X-rays revealed frequent abnormalities of carpal bone morphology and maturation, including a greater delay in ossification compared with metacarpal/phalanx bones.

Conclusion

This cohort enabled us to describe the prevalence of very heterogeneous neuroradiological and skeletal anomalies in KBG syndrome. Knowledge of the spectrum of such anomalies will aid diagnostic accuracy, improve patient care and provide a reference for future research on the effects ofANKRD11variants in skeletal and brain development.
Reconstruction of the sphenoid sinus erosion or dehiscence after treatment of unruptured intracavernous aneurysms with flow diverter stents
Authors: Lorga Tiago , Pizzuto Silvia , Coskun Oguzhan , Sgreccia Alessandro , Cavazza Martino , Rahman Mohammad Habibur , Rodesch Georges , Di Maria Federico , Consoli Arturo
Published: August 2023

Background

Intracavernous carotid aneurysms (ICCAs) are rare, frequently asymptomatic, with a low rupture risk, which, however, can lead to life-threatening epistaxis. The aim of this study was to assess the effect of the treatment of asymptomatic ICCAs with flow diverters (FD) on sphenoid bone erosion or dehiscence in a selected cohort of patients.

Methods

We retrospectively reviewed all asymptomatic ICCAs with sphenoid bone erosion or dehiscence detected on cone beam CT (CBCT) and treated with FD between December 2018 and December 2022. Patients were followed-up with CBCT and bone reconstruction was blindly evaluated by two interventional neuroradiologists and classified as unchanged, partial, or complete.

Results

A total of 10 patients (women: 90%, mean age 58 years) treated with an FD for an asymptomatic ICCA with associated sphenoid bone erosion or dehiscence were included in this cohort. Sphenoid bone erosion was present in seven patients and dehiscence was observed in the remaining three. After treatment with FD, complete reconstruction of the sphenoid sinus wall occurred in seven cases, and partial reconstruction in two cases. Sphenoid bone erosion remained unchanged after treatment in only one patient.

Conclusions

The decision to treat asymptomatic and unruptured ICCAs remains challenging due to their benign natural history and low hemorrhagic risk. The presence of sphenoid sinus erosion or dehiscence should not be overlooked since it could be considered as an indication for prophylactic treatment of life-threatening epistaxis. The mechanisms of bone erosion by the aneurysm and of reconstruction after treatment are still to be fully elucidated.
Impact of diabetes on remodelling, microvascular function and exercise capacity in aortic stenosis
Authors: Dattani Abhishek , Brady Emer M , Alfuhied Aseel , Gulsin Gaurav S , Steadman Christopher D , Yeo Jian L , Aslam Saadia , Banovic Marko , Jerosch-Herold Michael , Xue Hui , Kellman Peter , Costet Philippe , Cvijic Mary Ellen , Zhao Lei , Ebert Christina , Liu Laura , Gunawardhana Kushan , Gordon David , Chang Ching-Pin , Arnold J Ranjit , Yates Thomas , Kelly Damian , Hogrefe Kai , Dawson Dana , Greenwood John , Ng Leong L , Singh Anvesha , McCann Gerry P
Published: August 2023

Objective

To characterise cardiac remodelling, exercise capacity and fibroinflammatory biomarkers in patients with aortic stenosis (AS) with and without diabetes, and assess the impact of diabetes on outcomes.

Methods

Patients with moderate or severe AS with and without diabetes underwent echocardiography, stress cardiovascular magnetic resonance (CMR), cardiopulmonary exercise testing and plasma biomarker analysis. Primary endpoint for survival analysis was a composite of cardiovascular mortality, myocardial infarction, hospitalisation with heart failure, syncope or arrhythmia. Secondary endpoint was all-cause death.

Results

Diabetes (n=56) and non-diabetes groups (n=198) were well matched for age, sex, ethnicity, blood pressure and severity of AS. The diabetes group had higher body mass index, lower estimated glomerular filtration rate and higher rates of hypertension, hyperlipidaemia and symptoms of AS. Biventricular volumes and systolic function were similar, but the diabetes group had higher extracellular volume fraction (25.9%±3.1% vs 24.8%±2.4%, p=0.020), lower myocardial perfusion reserve (2.02±0.75 vs 2.34±0.68, p=0.046) and lower percentage predicted peak oxygen consumption (68%±21% vs 77%±17%, p=0.002) compared with the non-diabetes group. Higher levels of renin (log10renin: 3.27±0.59 vs 2.82±0.69 pg/mL, p<0.001) were found in diabetes. Multivariable Cox regression analysis showed diabetes was not associated with cardiovascular outcomes, but was independently associated with all-cause mortality (HR 2.04, 95% CI 1.05 to 4.00; p=0.037).

Conclusions

In patients with moderate-to-severe AS, diabetes is associated with reduced exercise capacity, increased diffuse myocardial fibrosis and microvascular dysfunction, but not cardiovascular events despite a small increase in mortality.
Model based on single-nucleotide polymorphism to discriminate aspirin resistance patients
Authors: Liu Qingyuan , Guo Shuaiwei , Wang Nuochuan , Wang Kaiwen , Mo Shaohua , Li Xiong , Zhang Yanan , He Hongwei , Wang Shuo , Wu Jun
Published: August 2023

Background

Aspirin is widely used for preventing ischaemic events. About 20%–40% of patients have aspirin resistance (ASR), which prevents them from benefiting from aspirin medication. This study aimed to develop and validate a model based on single-nucleotide polymorphism (SNP) to distinguish ASR patients.

Methods

We included patients with spontaneous intracerebral haemorrhage and continuing antiplatelet therapy from a multicentre, prospective cohort study as the derivation cohort. Thromboelastography (inhibition of arachidonic acid channel<50%) was used to identify ASR. Genotyping was performed to identify the ASR-related SNP. Based on the result of the logistic analysis, the aspirin resistance in the Chinese population score (ASR-CN score) was established, and its accuracy was evaluated using the area under the curve (AUC). Patients receiving dual antiplatelet therapy for unruptured intracranial aneurysm embolism were prospectively included in the validation cohort. After embolism, 30-day ischaemic events, including ischaemic stroke, new or more frequent transient ischaemic attack, stent thrombosis and cerebrovascular death, were recorded.

Results

The derivation cohort included 212 patients (155 male patients and the median age as 59). 87 (41.0%) individuals were identified with ASR. The multivariate logistic analysis demonstrated six SNPs of
GP1BA, TBXA2R, PTGS2
and
NOS3
as risk factors related to ASR. The ASR-CN score integrating these SNPs performed well to discriminate ASR patients from non-ASR patients (AUC as 0.77). Based on the validation cohort of 372 patients receiving antiplatelet therapy after embolism (including 130 ASR patients), the ASR-CN score continued to distinguish ASR patients with good accuracy (AUC as 0.80). Patients with high a ASR-CN score were more likely to suffer from 30-day ischaemic events after embolism (OR, 1.28; 95% CI, 1.10 to 1.50; p=0.002).

Conclusion

GP1BA, TBXA2R, PTGS2
and
NOS3
were SNPs related to ASR. The ASR-CN score is an effective tool to discriminate ASR patients, which may guide antiplatelet therapy.

Clinical trial registration

Surgical Treatments of Antiplatelet Intracerebral Hemorrhage cohort (unique identifier: ChiCTR1900024406,
http://www.chictr.org.cn/edit.aspx?pid=40640&htm=4
).
Stereotactic radiosurgery for haemorrhagic cerebral cavernous malformation: a multi-institutional, retrospective study
Authors: Dumot Chloe , Mantziaris Georgios , Dayawansa Sam , Xu Zhiyuan , Pikis Stylianos , Peker Selcuk , Samanci Yavuz , Ardor Gokce D , Nabeel Ahmed M , Reda Wael A , Tawadros Sameh R , Abdelkarim Khaled , El-Shehaby Amr M N , Emad Eldin Reem M , Elazzazi Ahmed H , Moreno Nuria Martínez , Martínez Álvarez Roberto , Liscak Roman , May Jaromir , Mathieu David , Tourigny Jean-Nicolas , Tripathi Manjul , Rajput Akshay , Kumar Narendra , Kaur Rupinder , Picozzi Piero , Franzini Andrea , Speckter Herwin , Hernandez Wenceslao , Brito Anderson , Warnick Ronald E , Alzate Juan , Kondziolka Douglas , Bowden Greg N , Patel Samir , Sheehan Jason
Published: August 2023

Background

Cerebral cavernous malformations (CCMs) frequently manifest with haemorrhages. Stereotactic radiosurgery (SRS) has been employed for CCM not suitable for resection. Its effect on reducing haemorrhage risk is still controversial. The aim of this study was to expand on the safety and efficacy of SRS for haemorrhagic CCM.

Methods

This retrospective multicentric study included CCM with at least one haemorrhage treated with single-session SRS. The annual haemorrhagic rate (AHR) was calculated before and after SRS. Recurrent event analysis and Cox regression were used to evaluate factors associated with haemorrhage. Adverse radiation effects (AREs) and occurrence of new neurological deficits were recorded.

Results

The study included 381 patients (median age: 37.5 years (Q1–Q3: 25.8–51.9) with 414 CCMs. The AHR from diagnosis to SRS excluding the first haemorrhage was 11.08 per 100 CCM-years and was reduced to 2.7 per 100 CCM-years after treatment. In recurrent event analysis, SRS, HR 0.27 (95% CI 0.17 to 0.44), p<0.0001 was associated with a decreased risk of haemorrhage, and the presence of developmental venous anomaly (DVA) with an increased risk, HR 1.60 (95% CI 1.07 to 2.40), p=0.022. The cumulative risk of first haemorrhage after SRS was 9.4% (95% CI 6% to 12.6%) at 5 years and 15.6% (95% CI% 9 to 21.8%) at 10 years. Margin doses> 13 Gy, HR 2.27 (95% CI 1.20 to 4.32), p=0.012 and the presence of DVA, HR 2.08 (95% CI 1.00 to 4.31), p=0.049 were factors associated with higher probability of post-SRS haemorrhage. Post-SRS haemorrhage was symptomatic in 22 out of 381 (5.8%) patients, presenting with transient (15/381) or permanent (7/381) neurological deficit. ARE occurred in 11.1% (46/414) CCM and was responsible for transient neurological deficit in 3.9% (15/381) of the patients and permanent deficit in 1.1% (4/381) of the patients. Margin doses >13 Gy and CCM volume >0.7 cc were associated with increased risk of ARE.

Conclusion

Single-session SRS for haemorrhagic CCM is associated with a decrease in haemorrhage rate. Margin doses ≤13 Gy seem advisable.