bluuebunny/crossref_metadata_2025 huggingface dataset:
Presence of Permanent Pacemakers: Implications for Elderly Patients Presenting with Traumatic Injuries
Authors: Bhuiya Tanzim , Omeh Demian , Munshi Rezwan , Berookhim Brian , Roper Ashley , Vilcant Viliane , Syzdziak Elisa , Hai Ofek , Zeltser Roman , Digiacomo Jody , Makaryus Amgad N
Published: June 2023

Background

The presence of permanent pacemakers (PPM) is common among the elderly population. Trauma literature has shown that the inability to augment cardiac output by at least 30% after injury portends a higher mortality. The presence of a PPM may be a surrogate marker to identify patients who are unable to increase cardiac output. We aimed to evaluate the association between the presence of PPM and clinical outcomes in elderly patients presenting with traumatic injuries.

Methods

A total of 4505 patients aged ≥65 years admitted with acute trauma from 2009 to 2019 at our Level I Trauma center were evaluated and stratified into two groups using propensity matching on age, sex, injury severity score (ISS), and year of admission based on the presence of PPM. Logistic regression was performed to analyze the impact of the presence of PPM on mortality, surgical intensive care unit (SICU) admission, operative intervention, and length of stay. Prevalence of cardiovascular comorbidities was compared using χ2analysis.

Results

Data from 208 patients with PPM and 208 propensity-matched controls were evaluated. Charlson Comorbidity Index, mechanism of injury, intensive care unit admission, and rate of operative intervention were comparable in the two groups. PPM patients had more coronary artery disease (p=0.04), heart failure with reduced ejection fraction (p=0.003), atrial fibrillation (AF, p<0.0001), and antithrombotic use (p<0.0001). We found no association between mortality amongst the groups after controlling for influencing variables (OR=2.1 (0.97 to 4.74), p=0.061). Patient characteristics associated with survival included female sex (p=0.009), lower ISS (p<0.0001), lower revised trauma score (p<0.0001), and lower SICU admission (p=0.001).

Conclusion

Our study shows no association between mortality among patients with PPM admitted for treatment of trauma. Presence of a PPM may be an indicator of cardiovascular disease, but this does not translate into increased risk in the modern era of trauma management in our patient population.

Level of evidence

Level III.
Cases of pediatric intra-abdominal solid organ injury induced by blunt trauma experienced over a 15-year period at two centers in Japan
Authors: Matsui Mayu , Sugita Koshiro , Kawano Takafumi , Nishida Nanako , Nagano Ayaka , Murakami Masakazu , Yano Keisuke , Harumatsu Toshio , Onishi Shun , Yamada Koji , Yamada Waka , Muto Mitsuru , Kaji Tatsuru , Ieiri Satoshi
Published: June 2023

Objective

The present study attempts to clarify the clinical features of pediatric intra-abdominal solid organ injury at two institutions.

Methods

The injured organ, patient age, sex, injury grade, imaging findings, intervention, length of hospital stay, and complications were retrospectively reviewed using medical records at two centers from 2007 to 2021.

Results

There were 25 cases of liver injury, 9 of splenic injury, 8 of pancreatic injury, and 5 of renal injury. The mean age of all patients was 8.6±3.8 years old, with no difference between organ injury types. Radiological intervention was performed in four cases of liver injury (16.0%) and one case of splenic injury (11.1%), and surgery was performed in two cases of liver injury (8.0%) and three cases of pancreatic injury (37.5%). All other cases were treated conservatively. Complications included adhesive ileus in one case of liver injury (4.0%), splenic atrophy in one case of splenic injury (11.1%), pseudocysts in three cases of pancreatic injury (37.5%), atrophy of the pancreatic parenchyma in one case of pancreatic injury (12.5%), and urinoma in one case of renal injury (20.0%). No mortalities were observed.

Conclusion

Pediatric patients with blunt trauma had favorable outcomes at two pediatric trauma centers covering a broad medical area, including remote islands.
First-principle study of the optoelectronic properties of GaxIn1-xBiyP1-y quaternary alloys lattice-matched to InP for telecommunication applications
Authors: Tehami Malika , Benchehima Miloud , Ameur Djili , Abid Hamza
Published: June 2023

In this work, we present a theoretical investigation of the structural and optoelectronic properties of GaxIn1-xBiyP1-y quaternary alloys lattice-matched to InP using the full-potential linearized augmented plane wave approach based on the functional theory of density. The local density approximation (LDA) and the generalized gradient approximation of Wu–Cohen (WC-GGA) have been used for calculating the structural properties of GaxIn1-xBiyP1-y quaternaries. The lattice matching condition and the range of ( x, y) concentrations for which the quaternary alloys are lattice-matched to InP substrate were determined. It is found that the calculated lattice constants of GaxIn1-xBiyP1-y for all selected concentrations ( x, y) are about 5.9 Å, which are in good agreement with the experimental value of the lattice constant of InP (5.869 Å). The electronic property calculations are executed via EV-GGA and TB-mBJ approximations. The calculated band structures show that GaxIn1-xBiyP1-y quaternaries have semiconductor character and exhibit a direct band gap, for all selected concentrations ( x, y). In addition, the optical properties were calculated and discussed in detail. And also, the optical band gaps of quaternaries were determined using Tauc's method. We observed that the GaxIn1-xBiyP1-y quaternaries cover the wavelength ranging from 0.911 to 2.456 µm while maintaining a lattice match to the InP substrate. The obtained results reveal that these quaternaries are suitable candidates for telecommunication applications.
Operando Analysis of the Gassing and Swelling Behavior of Lithium-ion Pouch Cells during Formation
Authors: Stock Sandro , Diller Felix , Böhm Jonas , Hille Lucas , Hagemeister Jan , Sommer Alessandro , Daub Rüdiger
Published: June 2023

Improving the energy density of lithium-ion batteries advances the use of novel electrode materials having a high specific capacity, such as nickel-rich cathodes and silicon-containing anodes. These materials exhibit a high level of gas evolution during formation, which poses a safety hazard during operation. Analyzing the gas volume and the gassing duration is thus crucial to assess material properties and determining suitable formation procedures. This paper presents a novel method for evaluating both gassing and swelling simultaneously to determine the operando gas evolution of pouch cells with volume resolutions below 1 μl. Dual 1D dilatometry is performed using a cell expansion bracket which applies a quasi-constant force on the cell, thus providing reproducible formation conditions. The method was validated using the immersion bath measurement method and NCM/graphite pouch cells were compared to high-energy NCA/silicon-graphite pouch cells. Silicon-containing cells exhibited gas evolution higher by a factor of seven over ten successive cycles, thus demonstrating the challenges of high-silicon anodes. The concurrent dilation analysis further revealed a constant thickness increase over the formation, indicating continuous SEI growth and lithium loss. Consequently, the method can be used to select an ideal degassing time and to adjust the formation protocols with respect to gas evolution.
The oncogenic function of PLAGL2 is mediated via ASCL2 and IGF2 and a Wnt-independent mechanism in colorectal cancer
Authors: Fischer Anthony D. , Veronese Paniagua Daniel A. , Swaminathan Shriya , Kashima Hajime , Rubin Deborah C. , Madison Blair B.
Published: June 2023

A Let-7 target called PLAGL2 drives oncogenic transformation via Wnt-independent pathways. This work illustrates the robust effects of this zinc finger transcription factor in colorectal cancer (CRC) cell lines and nontransformed intestinal epithelium, with effects mediated, in part, via the direct target genes ASCL2 and IGF2. This has implications for the role of PLAGL2 in activation of onco-fetal and onco-stem cell pathways, contributing to immature and highly proliferative phenotypes in CRC.
Extracellular vesicles: effectors of transfusion-related acute lung injury
Authors: Kuebler Wolfgang M. , William Nishaka , Post Martin , Acker Jason P. , McVey Mark J.
Published: June 2023

Respiratory transfusion reactions represent some of the most severe adverse reactions related to receiving blood products. Of those, transfusion-related acute lung injury (TRALI) is associated with elevated morbidity and mortality. TRALI is characterized by severe lung injury associated with inflammation, pulmonary neutrophil infiltration, lung barrier leak, and increased interstitial and airspace edema that cause respiratory failure. Presently, there are few means of detecting TRALI beyond clinical definitions based on physical examination and vital signs or preventing/treating TRALI beyond supportive care with oxygen and positive pressure ventilation. Mechanistically, TRALI is thought to be mediated by the culmination of two successive proinflammatory hits, which typically comprise a recipient factor (1st hit—e.g., systemic inflammatory conditions) and a donor factor (2nd hit—e.g., blood products containing pathogenic antibodies or bioactive lipids). An emerging concept in TRALI research is the contribution of extracellular vesicles (EVs) in mediating the first and/or second hit in TRALI. EVs are small, subcellular, membrane-bound vesicles that circulate in donor and recipient blood. Injurious EVs may be released by immune or vascular cells during inflammation, by infectious bacteria, or in blood products during storage, and can target the lung upon systemic dissemination. This review assesses emerging concepts such as how EVs: 1) mediate TRALI, 2) represent targets for therapeutic intervention to prevent or treat TRALI, and 3) serve as biochemical biomarkers facilitating TRALI diagnosis and detection in at-risk patients.
Ultrasound-guided transfection of claudin-5 improves lung endothelial barrier function in lung injury without impairing innate immunity
Authors: Sanwal Rajiv , Mintsopoulos Victoria , Ditmans Mihails , Lang Alice , Latreille Elyse , Ghaffari Siavash , Khosraviani Negar , Karshafian Raffi , Leong-Poi Howard , Hwang David M. , Brochard Laurent , Goffi Alberto , Slutsky Arthur S. , Lee Warren L.
Published: June 2023

Acute respiratory distress syndrome is characterized by spatial heterogeneity, with severely injured lung regions adjacent to relatively normal areas. This makes targeting treatment to the injured regions difficult. Here we use thoracic ultrasound and intravenous microbubbles (USMBs) to direct gene transfection specifically to injured lung regions. Transfection of the tight junction protein claudin-5 improved oxygenation and decreased vascular leakage without impairing innate immunity. These findings suggest that USMB is a novel treatment for ARDS.
Low-dose vanadium pentoxide perturbed lung metabolism associated with inflammation and fibrosis signaling in male animal and in vitro models
Authors: He Xiaojia , Jarrell Zachery R. , Smith Matthew Ryan , Ly ViLinh Thi , Hu Xin , Sueblinvong Viranuj , Liang Yongliang , Orr Michael , Go Young-Mi , Jones Dean P.
Published: June 2023

We used relevant dietary and environmental doses of Vanadium pentoxide (V+5) to examine its metabolic impact in vitro and in vivo. Using liquid chromatography-high-resolution mass spectrometry (LC-HRMS), we found significant metabolic perturbations, with similar dose-dependent patterns observed in human lung fibroblasts and male mouse lungs. Alterations in lipid metabolism included inflammatory signaling, elevated hydroxyproline levels, and excessive collagen deposition were present in V+5-treated lungs. Our findings suggest that low levels of V+5 could trigger pulmonary fibrotic signaling.
Dynamic Numerical Simulation Model and Time-Domain Identification of Flexible AERORail Structure
Authors: Li Fang-yuan , Guo Zhen-wei , Cui Yun-xuan , Wei Si-hang
Published: June 2023

A simplified theoretical model of the AERORail vehicle-bridge coupling system and a corresponding numerical simulation system in Simulink are established. Based on several widely used methods for modelling and simplifying vehicle systems, the Simulink simulation system used in this study, including the vehicle system and the bridge (AERORail) system, is presented. Identification examples using a moving load model and a simplified 1/4-scale vehicle model are established. The simulation results agree with the data of the simplified dynamic model, with errors between 2.9% and 4.72%, and a satisfactory accuracy is achieved even for single-point signal identification, thereby verifying the correctness of the simplified dynamic model of the AERORail system and the improved time-domain method based on the method of moments.
Accuracy of UWB Path Loss‐Based Localization of Wireless Capsule Endoscopy
Authors: Hany Umma , Akter Lutfa
Published: June 2023

Wireless capsule endoscopy (WCE) is used to diagnose lesions in the gastrointestinal (GI) tract. The physicians require to know the exact position of the lesions which can be performed by localizing the WCE in the GI tract. In this paper, we propose ultra‐wideband (UWB) path loss‐based WCE localization and compute the Cramer–Rao lower bound (CRLB) to evaluate the accuracy bounds of localization in the small intestine. First, we propose the estimation of smoothed path loss by minimizing the path loss deviations caused by shadow fading effects of body tissues. Then, the estimated path loss is used to estimate the degree of path loss and to compute the weight of the sensor’s positions. Finally, we propose the smoothed path loss degree‐based weighted centroid localization (SPLD‐WCL) algorithm to estimate the location of the WCE. We simulate the proposed SPLD‐WCL algorithm and verify the accuracy by comparing it to the computed CRLB. The proposed SPLD‐WCL localization algorithm shows a significantly high accuracy of localization with a 6.83 mm root mean square error (RMSE) without any advanced knowledge of unknown parameters and bounds.
Comparative Diagnostic of Cervical Tuberculous Lymphadenitis: PCR is a Fast, Efficient, and Improved Diagnostic Approach
Authors: Jha Himanshu , Baveja Chandra Prakash , Kamal Vinay , Agarwal Prem Narayan , Saxena Sonal , Dhakad Megh Singh , Sharma Divakar
Published: June 2023

Background and Objectives. Tuberculosis has become a major health problem in India, and the incidence of tuberculous lymphadenitis (TBLN) has increased in parallel with the increase in the incidence of mycobacterial infection worldwide. Therefore, the main objective of this study was to correlate the diagnostic efficacy of polymerase chain reaction (PCR) with various diagnostic techniques in clinically suspected cases of TBLN. Methods. The study included 100 clinically suspected cases of TBLN. Fine needle aspirate (FNA) samples were processed for cytology staining and cultured on LJ & BACTEC 12B media. The biochemical tests were performed to identify the isolates at the species level. Additionally, for PCR, DNA was extracted and used for the diagnosis and identification of mycobacterial species. Results. Patients ranged from 2 to 45 years with a mean age of 24.96 ± 9.10 years. Out of 100 patients, 73% had clinical symptoms of weight loss, followed by fever (72%), anorexia (66%), and night sweats (58%). 24% of patients were found to be smear-positive after Ziehl–Neelsen (ZN) staining and statistically highly significant with PCR. On LJ medium 34% and on BACTEC radiometric 45% of samples were smearing positive. Overall, 48% of cases were PCR-positive for TBLN. When compared with culture, the sensitivity and specificity of PCR were 93.75% and 100%, respectively, which are higher than cytology. The true positive predictive value (PPV) and negative predictive value (NPV) were 83.3% and 61.5%, respectively. Conclusion. This study suggests that PCR is a rapid, sensitive, and specific tool for correct diagnosis of TBLN cases as compared to staining and culture which lead to the early and proper management of mycobacterial diseases.
Effect of Dissolved Oxygen and Chemical Scarification on Andrographis paniculata Seed Germination in Macrobubble Conditions
Authors: Promwee Athakorn , Islam Shams Shaila , Khomphet Thanet
Published: June 2023

Andrographis paniculata is used in Thai traditional medicine. This plant contains a bitter compound called andrographolide, which is highly effective in the prevention of many diseases. It is an effective treatment for infectious diseases and has a prophylactic effect owing to its powerful immunity-boosting benefits. Recently, it has been widely used to treat COVID-19. However, commercial planting of A. paniculata is performed by seeding, which leads to seed germination problems. The seed germination is relatively low and not efficient under normal conditions for various reasons, such as a combined dormancy of physical and innate nature, the diversity of the seeds in different lots, and the fact that the germination duration was not uniform in the same lot. An easily applied and inexpensive method for farmers to develop mass plantings to stimulate germination is by using macrobubble conditions by aerating seeds in sterile water in collaboration with chemical scarification, which is the idea of creating a hard seed coat that causes seed dormancy to break while root germination occurs at 25°C. Germination was completed after 16 days. The dissolved oxygen (DO) concentrations in this environment were 5, 6, 7, 8, and 9 mg·L−1. The oxygen intensity of 9 mg·L−1 showed the highest germination percentage (26.33%). It was found to be optimal for macrobubble conditions. Seedlings were treated with chemicals (PEG, NaCl, H2SO4, KCl, KNO3, NaHClO3, and GA3) after soaking in macrobubbles with optimum DO. The results showed that NaHClO3 conc. (30 min) showed a generation percentage reaching 92%, which could greatly promote up to 3.63 folds compared with the control in the macrobubble aeration system.
Homing Guidance Law Design against Maneuvering Targets Based on DDPG
Authors: Liang Yangang , Tang Jin , Bai Zhihui , Li Kebo
Published: June 2023

A novel homing guidance law against maneuvering targets based on the deep deterministic policy gradient (DDPG) is proposed. The proposed guidance law directly maps the engagement state information to the acceleration of the interceptor, which is an end-to-end guidance policy. Firstly, the kinematic model of the interception process is described as a Markov decision process (MDP) that is applied to the deep reinforcement learning (DRL) algorithm. Then, an environment of training, state, action, and network structure is reasonably designed. Only the measurements of line-of-sight (LOS) angles and LOS rotational rates are used as state inputs, which can greatly simplify the problem of state estimation. Then, considering the LOS rotational rate and zero-effort-miss (ZEM), the Gaussian reward and terminal reward are designed to build a complete training and testing simulation environment. DDPG is used to deal with the RL problem to obtain a guidance law. Finally, the proposed RL guidance law’s performance has been validated using numerical simulation examples. The proposed RL guidance law demonstrated improved performance compared to the classical true proportional navigation (TPN) method and the RL guidance policy using deep-Q-network (DQN).
The Spectra of Disease-Causing Mutations in the Ferroportin 1 (SLC40A1) Encoding Gene and Related Iron Overload Phenotypes (Hemochromatosis Type 4 and Ferroportin Disease)
Authors: Uguen Kevin , Ka Chandran , Collod-Béroud Gwenaelle , Le Tertre Marlène , Guellec Julie , Férec Claude , Béroud Christophe , Callebaut Isabelle , Le Gac Gérald
Published: June 2023

SLC40A1 is the sole iron export protein reported in mammals and is a key player in both cellular and systemic iron homeostasis. This unique iron exporter, which belongs to the major facilitator superfamily, is predominantly regulated by the hyposideremic hormone hepcidin. SLC40A1 dysfunction causes ferroportin disease, and autosomal dominant iron overload disorder characterized by cellular iron retention, principally in reticuloendothelial cells, correlating with high serum ferritin and low to normal transferrin saturation. Resistant to hepcidin, SLC40A1 mutations are rather associated with elevated plasma iron and parenchymal iron deposition, a condition that resembles HFE-related hemochromatosis and is associated with more clinical complications. With very few exceptions, only missense variations are reported at the SLC40A1 locus; this situation increasingly limits the establishment of pathogenicity. In this mutation update, we provide a comprehensive review of all the pathogenic or likely pathogenic variants, variants of unknown significance, and benign or likely benign SLC40A1 variants. The classification is essentially determined using functional, structural, segregation, and recurrence data. We furnish new information on genotype-phenotype correlations for loss-of-function, gain-of-function, and other SLC40A1 variants, confirming the existence of wide clinical heterogeneity and the potential for misdiagnosis. All information is recorded in a locus-specific online database.
A Genomic Snapshot of Antibiotic-ResistantEnterococcus faecalis within Public Hospital Environments in South Africa
Authors: Shobo Christiana O. , Amoako Daniel G. , Allam Mushal , Ismail Arshad , Essack Sabiha Y. , Bester Linda A.
Published: June 2023

Enterococci are among the most common opportunistic hospital pathogens. This study used whole-genome sequencing (WGS) and bioinformatics to determine the antibiotic resistome, mobile genetic elements, clone and phylogenetic relationship of Enterococcus faecalis isolated from hospital environments in South Africa. This study was carried out from September to November 2017. Isolates were recovered from 11 frequently touched sites by patients and healthcare workers in different wards at 4 levels of healthcare (A, B, C, and D) in Durban, South Africa. Out of the 245 identified E. faecalis isolates, 38 isolates underwent whole-genome sequencing (WGS) on the Illumina MiSeq platform, following microbial identification and antibiotic susceptibility tests. The tet(M) (31/38, 82%) and erm(C) (16/38, 42%) genes were the most common antibiotic-resistant genes found in isolates originating from different hospital environments which corroborated with their antibiotic resistance phenotypes. The isolates harboured mobile genetic elements consisting of plasmids (n = 11) and prophages (n = 14) that were mostly clone-specific. Of note, a large number of insertion sequence (IS) families were found on the IS3 (55%), IS5 (42%), IS1595 (40%), and Tn3 transposons the most predominant. Microbial typing using WGS data revealed 15 clones with 6 major sequence types (ST) belonging to ST16 (n = 7), ST40 (n = 6), ST21 (n = 5), ST126 (n = 3), ST23 (n = 3), and ST386 (n = 3). Phylogenomic analysis showed that the major clones were mostly conserved within specific hospital environments. However, further metadata insights revealed the complex intraclonal spread of these E. faecalis major clones between the sampling sites within each specific hospital setting. The results of these genomic analyses will offer insights into antibiotic-resistantE. faecalis in hospital environments relevant to the design of optimal infection prevention strategies in hospital settings.
Sleep Quality and Quantity in Caregivers of Children with Type 1 Diabetes Using Closed-Loop Insulin Delivery or a Sensor-Augmented Pump
Authors: Madrid-Valero Juan J. , Ware Julia , Allen Janet M. , Boughton Charlotte K. , Hartnell Sara , Wilinska Malgorzata E. , Thankamony Ajay , de Beaufort Carine , Schierloh Ulrike , Campbell Fiona M. , Sibayan Judy , Bocchino Laura E. , Kollman Craig , Hovorka Roman , Gregory Alice M. , Consortium KidsAP
Published: June 2023

Introduction. Parents of children living with type 1 diabetes (T1D) often report short and/or poor quality sleep. The development of closed-loop systems promises to transform the management of T1D. This study compared sleep quality and quantity in caregivers of children using a closed-loop system (CL) or sensor-augmented pump (SAP) therapy. Method. Data from sleep diaries, accelerometers, and questionnaires were provided by forty parents (classified as caregiver 1 (main analyses) or 2 (supplementary analyses) based on their contribution towards treatment management) of 21 very young children aged 1 to 7 years living with T1D (mean age: 4.7 (SD = 1.7)). Assessments were made at a single post-randomisation time point when the child was completing either the 16-week CL arm (n = 10) or the 16-week SAP arm (n = 11) of the main study. Results. Overall, there was a mixed pattern of results and group differences were not statistically significant at the

p
<
0.05

level. However, when we consider the direction of results and results from caregiver 1, sleep diary data showed that parents of the CL (as compared to the SAP) group reported a shorter sleep duration but better sleep quality, fewer awakenings, and less wake after sleep onset (WASO). Actiwatch data showed that caregiver 1 of the CL (as compared to the SAP) group had a shorter sleep latency; greater sleep efficiency; and less wake after sleep onset. Results from the Pittsburgh Sleep Quality Index also showed better sleep quality for caregiver 1 of the CL group as compared to the SAP group. Conclusions. Results from this study suggest that sleep quality and quantity in parents of children using CL were not significantly different to those using SAP. Considering effect sizes and the direction of the non-significant results, CL treatment could be associated with better sleep quality in the primary caregiver. However, further research is needed to confirm these findings. This trial is registered with NCT05158816.
A Method of Inverting Rock Grain Size Based on Nuclear Magnetic Resonance Logging Data and Application
Authors: Wu Jinbo , Hu Yitao , Zhang Hairong
Published: June 2023

Rock grain size parameter is the key parameter of reservoir rock physics analysis. The study found that the relationship between the NMR

T

2

spectrum and rock grain size distribution curve is directly related to NMR

T

2

distribution and grain size distribution of rock, so you can use

T

2

to retrieve the size distribution of rock NMR spectral data. Based on the calculation of the rock core experiment results of grain size distribution by NMR

T

2

distribution using the conversion method of piecewise nonlinear calibration for each core, adjusting the calibration parameters to make the grain size distribution calculated with the core analysis of grain size distribution approximation, the error is minimum to obtain each core scale parameter conversion. In the end, the core parameters are classified according to the parameters of pore and permeability. Finally, according to the actual NMR

T

2

distribution curve inversion of underground rock granularity, the inversion results contrast with the core analysis results, and the reliability of the method is verified to provide accurate, continuous rock size distribution profile analysis of geological reservoir rock physics.
Development of a Breast Cancer Risk Prediction Model Incorporating Polygenic Risk Scores and Nongenetic Risk Factors for Korean Women
Authors: Choi Jihye , Ha Tae-Woong , Choi Hye-Mi , Lee Han-Byoel , Shin Hee-Chul , Chung Woosung , Han Wonshik
Published: June 2023

Background:

To develop a breast cancer prediction model for Korean women using published polygenic risk scores (PRS) combined with nongenetic risk factors (NGRF).

Methods:

Thirteen PRS models generated from single or multiple combinations of the Asian and European PRSs were evaluated among 20,434 Korean women. The AUC and increase in OR per SD were compared for each PRS. The PRSs with the highest predictive power were combined with NGRFs; then, an integrated prediction model was established using the Individualized Coherent Absolute Risk Estimation (iCARE) tool. The absolute breast cancer risk was stratified for 18,142 women with available follow-up data.

Results:

PRS38_ASN+PRS190_EB, a combination of Asian and European PRSs, had the highest AUC (0.621) among PRSs, with an OR per SD increase of 1.45 (95% confidence interval: 1.31–1.61). Compared with the average risk group (35%–65%), women in the top 5% had a 2.5-fold higher risk of breast cancer. Incorporating NGRFs yielded a modest increase in the AUC of women ages >50 years. For PRS38_ASN+PRS190_EB+NGRF, the average absolute risk was 5.06%. The lifetime absolute risk at age 80 years for women in the top 5% was 9.93%, whereas that of women in the lowest 5% was 2.22%. Women at higher risks were more sensitive to NGRF incorporation.

Conclusions:

Combined Asian and European PRSs were predictive of breast cancer in Korean women. Our findings support the use of these models for personalized screening and prevention of breast cancer.

Impact:

Our study provides insights into genetic susceptibility and NGRFs for predicting breast cancer in Korean women.
Inclusion and Exclusion Criteria 1 from Eganelisib, a First-in-Class PI3Kγ Inhibitor, in Patients with Advanced Solid Tumors: Results of the Phase 1/1b MARIO-1 Trial
Authors: Hong David S. , Postow Michael , Chmielowski Bartosz , Sullivan Ryan , Patnaik Amita , Cohen Ezra E.W. , Shapiro Geoffrey , Steuer Conor , Gutierrez Martin , Yeckes-Rodin Heather , Ilaria Robert , O'Connell Brenda , Peng Joanna , Peng Guangbin , Zizlsperger Nora , Tolcher Anthony , Wolchok Jedd D.
Published: June 2023

Study IPI-549-01 full protocol inclusion and exclusion criteria
Supplementary Table S5 from SALVO: Single-Arm Trial of Ipilimumab and Nivolumab as Adjuvant Therapy for Resected Mucosal Melanoma
Authors: Kottschade Lisa A. , Pond Gregory Russell , Olszanski Anthony J. , Zakharia Yousef , Domingo-Musibay Evidio , Hauke Ralph J. , Curti Brendan D. , Schober Sarah , Milhem Mohammed M. , Block Matthew Stephen , Hieken Tina , McWilliams Robert R.
Published: June 2023

Representativeness of Study Participants
Supplementary Data S1 from Exploring the Immunogenicity of Noncanonical HLA-I Tumor Ligands Identified through Proteogenomics
Authors: Lozano-Rabella Maria , Garcia-Garijo Andrea , Palomero Jara , Yuste-Estevanez Anna , Erhard Florian , Farriol-Duran Roc , Martín-Liberal Juan , Ochoa-de-Olza Maria , Matos Ignacio , Gartner Jared J. , Ghosh Michael , Canals Francesc , Vidal August , Piulats Josep Maria , Matías-Guiu Xavier , Brana Irene , Muñoz-Couselo Eva , Garralda Elena , Schlosser Andreas , Gros Alena
Published: June 2023

Includes a large list of all the peptides and details of the HLA-I ligands identified at <=0.01 FDR and >=30 ALC score
Data from SALVO: Single-Arm Trial of Ipilimumab and Nivolumab as Adjuvant Therapy for Resected Mucosal Melanoma
Authors: Kottschade Lisa A. , Pond Gregory Russell , Olszanski Anthony J. , Zakharia Yousef , Domingo-Musibay Evidio , Hauke Ralph J. , Curti Brendan D. , Schober Sarah , Milhem Mohammed M. , Block Matthew Stephen , Hieken Tina , McWilliams Robert R.
Published: June 2023

AbstractPurpose:
Mucosal melanoma is a rare, aggressive form of melanoma with extremely high recurrence rates despite definitive surgical resection with curative intent. Currently there is no consensus on adjuvant therapy. Data on checkpoint inhibitors for adjuvant therapy are lacking.
Patients and Methods:
We performed a single-arm, multicenter clinical trial using “flip dose” ipilimumab (1 mg/kg q3w × 4 cycles), and nivolumab (3 mg/kg q3w × 4 cycles), then nivolumab 480 mg q4w × 11 cycles to complete a year of adjuvant therapy. Participants must have had R0/R1 resection ≤90 days before registration, no prior systemic therapy (adjuvant radiotherapy allowed), ECOG 0/1, and no uncontrolled autoimmune disease or other invasive cancer. Patients were recruited through the Midwest Melanoma Partnership/Hoosier Oncology Network.
Results:
From September 2017 to August 2021, 35 patients were enrolled. Of these, 29 (83%) had R0 resections, and 7 (20%) received adjuvant radiotherapy. Median age was 67 years, 21 (60.0%) female. Recurrence-free survival (RFS) rates at 1 and 2 years were 50% [95% confidence interval (CI), 31%–66%] and 37% (95% CI, 19%–55%), respectively. Overall survival rates at 1 and 2 years were 87% (95% CI, 68%–95%) and 68% (95% CI, 46%–83%), respectively. Median RFS was 10.3 months (95% CI, 5.7–25.8). Most common grade 3 toxicities were diarrhea (14%), hypertension (14%), and hyponatremia (11%), with no grade 4/5 toxicities.
Conclusions:
Flip-dose ipilimumab and nivolumab after resection of mucosal melanoma is associated with outcomes improved over that of surgical resection alone. Long-term follow-up, subgroup analyses and correlative studies are ongoing.
Data from Co-Clinical Study of [fam-] Trastuzumab Deruxtecan (DS8201a) in Patient-Derived Xenograft Models of Uterine Carcinosarcoma and Its Association with Clinical Efficacy
Authors: Yagishita Shigehiro , Nishikawa Tadaaki , Yoshida Hiroshi , Shintani Daisuke , Sato Sho , Miwa Maiko , Suzuki Mikiko , Yasuda Masanori , Ogitani Yusuke , Jikoh Takahiro , Yonemori Kan , Hasegawa Kosei , Hamada Akinobu
Published: June 2023

AbstractPurpose:
Uterine carcinosarcoma (UCS), a subtype of endometrial carcinoma, is a rare and aggressive cancer with a poor prognosis. High clinical efficacy of trastuzumab deruxtecan (T-DXd) in HER2-expressing UCS was recently reported in a phase II trial (STATICE trial). We performed a co-clinical study of T-DXd using patient-derived xenograft (PDX) models of participants in the STATICE trial.
Experimental Design:
Tumor specimens were resected during primary surgery or biopsied at recurrence from patients with UCS and transplanted into immunodeficient mice. Seven UCS-PDXs from six patients were established and HER2, estrogen receptor (ER), and p53 expression in PDX and the original tumor was assessed. Drug efficacy tests were performed using six of the seven PDXs. Of the six UCS-PDXs tested, two were derived from patients enrolled in the STATICE trial.
Results:
The histopathological characteristics of the six PDXs were well-conserved from the original tumors. HER2 expression was 1+ in all PDXs, and ER and p53 expression was almost similar to that in the original tumors. Remarkable tumor shrinkage after T-DXd administration was observed in four of the six PDXs (67%), comparable with the response rate (70%) of HER2 1+ patients in the STATICE trial. Two patients enrolled in the STATICE trial showed partial response as the best response, and the clinical effect was well-replicated with marked tumor shrinkage.
Conclusions:
We successfully performed a co-clinical study of T-DXd in HER2-expressing UCS, along with the STATICE trial. Our PDX models can predict clinical efficacy and serve as an effective preclinical evaluation platform.
Data from Antitumor Efficacy of Dual Blockade with Encorafenib + Cetuximab in Combination with Chemotherapy in Human BRAFV600E-Mutant Colorectal Cancer
Authors: Napolitano Stefania , Woods Melanie , Lee Hey Min , De Falco Vincenzo , Martini Giulia , Della Corte Carminia Maria , Martinelli Erika , Famiglietti Vincenzo , Ciardiello Davide , Anderson Amanda , Fowlkes Natalie Wall , Villareal Oscar Eduardo , Sorokin Alexey , Kanikarla Preeti , Coker Olu , Morris Van , Altucci Lucia , Tabernero Josep , Troiani Teresa , Ciardiello Fortunato , Kopetz Scott
Published: June 2023

AbstractPurpose:
Encorafenib + cetuximab (E+C) is an effective therapeutic option in chemorefractory BRAFV600E metastatic colorectal cancer (mCRC). However, there is a need to improve the efficacy of this molecular-targeted therapy and evaluate regimens suitable for untreated BRAFV600E in patients with mCRC.
Experimental Design:
We performed a series of in vivo studies using BRAFV600E mCRC tumor xenografts. Mice were randomized to receive 5-fluoruracil (5-FU), irinotecan, or oxaliplatin regimens (FOLFIRI or FOLFOX), (E+C) or the combination. Patients received long-term treatment until disease progression, with deescalation strategies used to mimic maintenance therapy. Transcriptomic changes after progression on cytotoxic chemotherapy or targeted therapy were assessed.
Results:
Antitumor activity of either FOLFIRI or E+C was better as first-line treatment as compared with second-line, with partial cross-resistance seen between a cytotoxic regimen and targeted therapy with an average 62% loss of efficacy for FOLFIRI after E+C and a 45% loss of efficacy of E+C after FOLFIRI (P < 0.001 for both). FOLFIRI-treated models had upregulation of epithelial–mesenchymal transition (EMT) and MAPK pathway activation, where E+C treated models had suppressed MAPK signaling. In contrast, with chemotherapy with E+C, EMT and MAPK signaling remained suppressed. FOLFOX or FOLFIRI, each in combination with E+C, were the most active first-line treatments as compared with E+C or to chemotherapy alone. Furthermore, FOLFOX in combination with E+C as first-line induction therapy, followed by E+C ± 5-FU as maintenance therapy, was the most effective strategy for long-term disease control.
Conclusions:
These results support the combination of cytotoxic chemotherapy and molecular-targeted therapy as a promising therapeutic approach in the first-line treatment of BRAFV600E mCRC.
Data from Expression and Therapeutic Targeting of TROP-2 in Treatment-Resistant Prostate Cancer
Authors: Sperger Jamie M. , Helzer Kyle T. , Stahlfeld Charlotte N. , Jiang Dawei , Singh Anupama , Kaufmann Katherine R. , Niles David J. , Heninger Erika , Rydzewski Nicholas R. , Wang Liguo , Wang Liewei , Yang Rendong , Ren Yanan , Engle Jonathan W. , Huang Peng , Kyriakopoulos Christos E. , Slovin Susan F. , Soule Howard R. , Zhao Shuang G. , Kohli Manish , Tagawa Scott T. , Cai Weibo , Dehm Scott M. , Lang Joshua M.
Published: June 2023

AbstractPurpose:
Men with metastatic castration-resistant prostate cancer (mCRPC) frequently develop resistance to androgen receptor signaling inhibitor (ARSI) treatment; therefore, new therapies are needed. Trophoblastic cell-surface antigen (TROP-2) is a transmembrane protein identified in prostate cancer and overexpressed in multiple malignancies. TROP-2 is a therapeutic target for antibody–drug conjugates (ADC).
Experimental Design:
TROP-2 gene (TACSTD2) expression and markers of treatment resistance from prostate biopsies were analyzed using data from four previously curated cohorts of mCRPC (n = 634) and the PROMOTE study (dbGaP accession phs001141.v1.p1, n = 88). EPCAM or TROP-2–positive circulating tumor cells (CTC) were captured from peripheral blood for comparison of protein (n = 15) and gene expression signatures of treatment resistance (n = 40). We assessed the efficacy of TROP-2–targeting agents in a mouse xenograft model generated from prostate cancer cell lines.
Results:
We demonstrated that TACSTD2 is expressed in mCRPC from luminal and basal tumors but at lower levels in patients with neuroendocrine prostate cancer. Patients previously treated with ARSI showed no significant difference in TACSTD2 expression, whereas patients with detectable AR-V7 expression showed increased expression. We observed that TROP-2 can serve as a cell surface target for isolating CTCs, which may serve as a predictive biomarker for ADCs. We also demonstrated that prostate cancer cell line xenografts can be targeted specifically by labeled anti–TROP-2 agents in vivo.
Conclusions:
These results support further studies on TROP-2 as a therapeutic and diagnostic target for mCRPC.
Data from Proinflammatory Macrophage Activation by the Polysialic Acid-Siglec-16 Axis Is Linked to Increased Survival of Patients with Glioblastoma
Authors: Thiesler Hauke , Gretenkort Lina , Hoffmeister Leonie , Albers Iris , Ohlmeier Luisa , Röckle Iris , Verhagen Andrea , Banan Rouzbeh , Köpcke Nora , Krönke Nicole , Feuerhake Friedrich , Behling Felix , Barrantes-Freer Alonso , Mielke Dorothee , Rohde Veit , Hong Bujung , Varki Ajit , Schwabe Kerstin , Krauss Joachim K. , Stadelmann Christine , Hartmann Christian , Hildebrandt Herbert
Published: June 2023

AbstractPurpose:
Interactions with tumor-associated microglia and macrophages (TAM) are critical for glioblastoma progression. Polysialic acid (polySia) is a tumor-associated glycan, but its frequency of occurrence and its prognostic value in glioblastoma are disputed. Through interactions with the opposing immune receptors Siglec-11 and Siglec-16, polySia is implicated in the regulation of microglia and macrophage activity. However, due to a nonfunctional SIGLEC16P allele, SIGLEC16 penetrance is less than 40%. Here, we explored possible consequences of SIGLEC16 status and tumor cell–associated polySia on glioblastoma outcome.
Experimental Design:
Formalin-fixed paraffin-embedded specimens of two independent cohorts with 70 and 100 patients with newly diagnosed glioblastoma were retrospectively analyzed for SIGLEC16 and polySia status in relation to overall survival. Inflammatory TAM activation was assessed in tumors, in heterotypic tumor spheroids consisting of polySia-positive glioblastoma cells and Siglec-16–positive or Siglec-16–negative macrophages, and by exposing Siglec-16–positive or Siglec-16–negative macrophages to glioblastoma cell–derived membrane fractions.
Results:
Overall survival of SIGLEC16 carriers with polySia-positive tumors was increased. Consistent with proinflammatory Siglec-16 signaling, levels of TAM positive for the M2 marker CD163 were reduced, whereas the M1 marker CD74 and TNF expression were increased, and CD8+ T cells enhanced in SIGLEC16/polySia double-positive tumors. Correspondingly, TNF production was elevated in heterotypic spheroid cultures with Siglec-16–expressing macrophages. Furthermore, a higher, mainly M1-like cytokine release and activating immune signaling was observed in SIGLEC16-positive as compared with SIGLEC16-negative macrophages confronted with glioblastoma cell–derived membranes.
Conclusions:
Collectively, these results strongly suggest that proinflammatory TAM activation causes the better outcome in patients with glioblastoma with a functional polySia-Siglec-16 axis.
Data from Clinical Importance of the lncRNA NEAT1 in Cancer Patients Treated with Immune Checkpoint Inhibitors
Authors: Toker Joseph , Iorgulescu J. Bryan , Ling Alexander L. , Villa Genaro R. , Gadet Josephina A.M.A. , Parida Laxmi , Getz Gad , Wu Catherine J. , Reardon David A. , Chiocca E. Antonio , Mineo Marco
Published: June 2023

AbstractPurpose:
mAbs targeting the PD-1/PD-L1 immune checkpoint are powerful tools to improve the survival of patients with cancer. Understanding the molecular basis of clinical response to these treatments is critical to identify patients who can benefit from this immunotherapy. In this study, we investigated long noncoding RNA (lncRNA) expression in patients with cancer treated with anti-PD-1/PD-L1 immunotherapy.
Experimental Design:
lncRNA expression profile was analyzed in one cohort of patients with melanoma and two independent cohorts of patients with glioblastoma (GBM) undergoing anti-PD-1/PD-L1 immunotherapy. Single-cell RNA-sequencing analyses were performed to evaluate lncRNA expression in tumor cells and tumor-infiltrating immune cells.
Results:
We identified the lncRNA NEAT1 as commonly upregulated between patients with melanoma with complete therapeutic response and patients with GBM with longer survival following anti-PD-1/PD-L1 treatment. Gene set enrichment analyses revealed that NEAT1 expression was strongly associated with the IFNγ pathways, along with downregulation of cell-cycle-related genes. Single-cell RNA-sequencing analyses revealed NEAT1 expression across multiple cell types within the GBM microenvironment, including tumor cells, macrophages, and T cells. High NEAT1 expression levels in tumor cells correlated with increased infiltrating macrophages and microglia. In these tumor-infiltrating myeloid cells, we found that NEAT1 expression was linked to enrichment in TNFα/NFκB signaling pathway genes. Silencing NEAT1 suppressed M1 macrophage polarization and reduced the expression of TNFα and other inflammatory cytokines.
Conclusions:
These findings suggest an association between NEAT1 expression and patient response to anti-PD-1/PD-L1 therapy in melanoma and GBM and have important implications for the role of lncRNAs in the tumor microenvironment.
Oncostatin-M and OSM-Receptor Feed-Forward Activation of MAPK Induces Separable Stem-like and Mesenchymal Programs
Authors: Polak Kelsey L. , Tamagno Ilaria , Parameswaran Neetha , Smigiel Jacob , Chan E. Ricky , Yuan Xueer , Rios Brenda , Jackson Mark W.
Published: June 2023

Patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) frequently present with advanced metastatic disease and exhibit a poor response to therapy, resulting in poor outcomes. The tumor microenvironment cytokine Oncostatin-M (OSM) initiates PDAC plasticity, inducing the reprogramming to a stem-like/mesenchymal state, which enhances metastasis and therapy resistance. Using a panel of PDAC cells driven through epithelial–mesenchymal transition (EMT) by OSM or the transcription factors ZEB1 or SNAI1, we find that OSM uniquely induces tumor initiation and gemcitabine resistance independently of its ability to induce a CD44HI/mesenchymal phenotype. In contrast, while ZEB1 and SNAI1 induce a CD44HI/mesenchymal phenotype and migration comparable with OSM, they are unable to promote tumor initiation or robust gemcitabine resistance. Transcriptomic analysis identified that OSM-mediated stemness requires MAPK activation and sustained, feed-forward transcription of OSMR. MEK and ERK inhibitors prevented OSM-driven transcription of select target genes and stem-like/mesenchymal reprogramming, resulting in reduced tumor growth and resensitization to gemcitabine. We propose that the unique properties of OSMR, which hyperactivates MAPK signaling when compared with other IL6 family receptors, make it an attractive therapeutic target, and that disrupting the OSM-OSMR-MAPK feed-forward loop may be a novel way to therapeutically target the stem-like behaviors common to aggressive PDAC.

Implications:

Small-molecule MAPK inhibitors may effectively target the OSM/OSMR-axis that leads to EMT and tumor initiating properties that promote aggressive PDAC.