bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety and efficacy of PD-1 inhibitor (sintilimab) combined with transarterial chemoembolization as the initial treatment in patients with intermediate-stage hepatocellular carcinoma beyond up-to-seven criteria
Authors: Li Lixing , Xu Xin , Wang Wentao , Huang Peiran , Yu Lei , Ren Zhenggang , Fan Jia , Zhou Jian , Zhang Lan , Wang Zheng
Published: January 2025

Background

Numerous studies have demonstrated limited survival benefits of transarterial chemoembolization (TACE) alone in the treatment of intermediate-stage hepatocellular carcinoma (HCC) beyond up-to-seven criteria. The advent of immunotherapy, particularly immune checkpoint inhibitors (ICIs), has opened new avenues for HCC treatment. However, TACE combined with ICIs has not been investigated for patients with intermediate-stage HCC beyond the up-to-seven criteria. The study aims to evaluate the efficacy and safety of this treatment strategy for such patients.

Methods

In this single-arm, prospective, phase II study, we enrolled eligible patients with HCC who were treated with TACE plus programmed cell death protein 1 (PD-1) inhibitors (sintilimab) from April 2021 to February 2023. The study’s primary objectives were to assess progression-free survival (PFS) and safety. Secondary objectives included measuring the objective response rate (ORR) and disease control rate (DCR) as per both Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1 and modified RECIST (mRECIST) criteria, as well as overall survival (OS). Additionally, we conducted correlation analyses to identify predictors influencing the efficacy of tumor treatment.

Result

20 patients participated in this study, with a median follow-up duration of 22.0 months. Median PFS was 8.4 months (95% CI: 4.7 to 19.7) according to both RECIST V.1.1 and mRECIST. The ORR was 30.0% (95% CI: 14.6% to 51.9%) per RECIST 1.1% and 60% (95% CI: 38.7% to 78.1%) per mRECIST. DCR was 95.0% (95% CI: 76.4% to 99.1%) according to both RECIST V.1.1 and mRECIST. Median OS was not yet reached. Notably, 20% (4/20) of patients underwent successful conversion to curative surgical resection. Treatment-related adverse events (TRAEs) mainly included elevated aspartate aminotransferase levels (19/20, 95.0%), elevated alanine aminotransferase levels (18/20, 90.0%), hypothyroidism (18/20, 90.0%), and reduced appetite (10/20, 50.0%). Among all participants, only one experienced grade 3 TRAE (myocarditis). We employed the Elastic Net regression model to analyze radiomic features from tumor and peritumoral areas to predict the efficacy of this treatment strategy.

Conclusion

TACE plus PD-1 inhibitors demonstrated promising efficacy and an acceptable safety profile, suggesting it as a potential treatment option for patients with intermediate-stage HCC beyond up-to-seven criteria. Furthermore, our study indicates that specific image-based features may serve as predictors for patients likely to benefit from this treatment approach.

Trial registration number

NCT04842565.
Pancreatic cancer cell-intrinsic transglutaminase-2 promotes T cell suppression through microtubule-dependent secretion of immunosuppressive cytokines
Authors: Lahusen Anton , Minhöfer Nora , Lohse Kim-André , Blechner Christine , Lindenmayer Jessica , Eiseler Tim , Wellstein Anton , Kleger Alexander , Seufferlein Thomas , Windhorst Sabine , Lin Yuan-Na
Published: January 2025

Background

Pancreatic ductal adenocarcinoma (PDAC) is mostly refractory to immunotherapy due to immunosuppression in the tumor microenvironment and cancer cell-intrinsic T cell tolerance mechanisms. PDAC is described as a “cold” tumor type with poor infiltration by T cells and factors leading to intratumoral T cell suppression have thus received less attention. Here, we identify a cancer cell-intrinsic mechanism that contributes to a T cell-resistant phenotype and describes potential combinatorial therapy.

Methods

We used an unbiased screening approach of T cell resistant and sensitive murine KPC (KrasLSL-G12D/+; Trp53fl/fl; Ptf1aCre/+) PDAC cells in a three-dimensional co-culture platform with syngeneic antigen-educated T cells to identify potential cell-intrinsic drivers of T cell suppression in PDAC. Comparative transcriptomic analysis was performed to reveal promising candidates that mediate resistance to T cells. We investigated their contribution by shRNA-mediated knockdown and pharmacological inhibition in murine in vitro and in vivo studies, as well as in patient-derived organoids (PDOs). A combination of transcriptomic analyses, cytometric and immunohistochemistry techniques allowed us to validate the underlying T cell response phenotypes of PDAC cells. The action of TGM2 via interaction with tubulin and the impact of microtubule dynamics and vesicle trafficking were evaluated by protein analyses and live-cell imaging. Correlation analyses via TCGA data complemented the functional studies.

Results

We identified transglutaminase 2 (TGM2) as a mediator of T cell suppression in PDAC. We report that high levels of TGM2 expression in patients’ tumors correlate with immunosuppressive signatures and poor overall survival. We found that TGM2 regulates vesicle trafficking by modulating microtubule network density and dynamics in pancreatic cancer cells, thus facilitating the secretion of immunosuppressive cytokines, which impair effector T cell functionality. In TGM2-expressing PDOs, pharmacological TGM2 inhibition or treatment with nocodazole increased T cell-mediated apoptosis. Also, pretreatment of TGM2highPDOs with sublethal doses of the spindle poisons paclitaxel or vincristine increased CD8+T cell activation and sensitized PDOs toward T cell-mediated cytotoxicity.

Conclusions

These findings indicate that targeting microtubular function therapeutically may enhance antitumor T cell responses by impacting activity of immunosuppressive cytokines in the PDAC microenvironment.
Cerebral blood volume index in the era of thrombectomy-treated large and medium vessel ischemic strokes
Authors: Koneru Manisha , Lakhani Dhairya A , Xu Risheng , Salim Hamza Adel , Urrutia Victor C , Marsh Elisabeth B , Dmytriw Adam A , Guenego Adrien , Llinas Rafael H , Hillis Argye E , Nael Kambiz , Wintermark Max , Albers Gregory W , Heit Jeremy J , Faizy Tobias D , Yedavalli Vivek
Published: January 2025

The cerebral blood volume index (CBV index) is a perfusion-based marker of collateral status. Several real-world data analyses from observational stroke cohorts have established relationships between this parameter and a range of favorable and unfavorable stroke outcomes. In this review, an overview is provided of the CBV index, within the context of thrombectomy-treated large vessel and medium vessel occlusion ischemic strokes. The current literature is summarized describing the CBV index and its association with a variety of efficacy, safety, and clinical outcome measures during the thrombectomy course and post-treatment recovery in both large vessel occlusion and medium vessel occlusion strokes. The range of CBV index value thresholds that have been identified and are able to differentiate between favorable and unfavorable outcomes across different clinical scenarios are summarized. This review underscores the need for additional analyses to further explore the CBV index in other clinical outcome contexts and for future prospective studies to validate the CBV index in thrombectomy-treated large vessel and medium vessel occlusion strokes, especially with increasing use of thrombectomy for treating medium vessel occlusions.
Angiographic signs during mechanical thrombectomy as predictors of post-stroke epilepsy: a multicenter retrospective study
Authors: Jiang Zongzhi , Sun Yining , Zheng Zhaoshi , Han Kai , Mo Zhanhao , Liu Songyan
Published: January 2025

Background

Post-stroke epilepsy (PSE) is a major complication of stroke. However, data about the predictors of PSE in patients with acute ischemic stroke (AIS) undergoing mechanical thrombectomy are limited.

Objective

To evaluate the relationship between intraoperative angiographic signs and PSE risk in patients with anterior circulation AIS who underwent mechanical thrombectomy.

Methods

We conducted a retrospective study. A total of 800 patients with AIS who underwent mechanical thrombectomy were classified into case and control groups based on the occurrence of PSE. Propensity score matching (PSM) (1:4) was applied using covariates such as age, sex, National Institutes of Health Stroke Scale score at admission, and baseline modified Rankin Scale score. Conditional logistic regression and mediation analysis were performed. Subgroup analyses were conducted to assess the effect of modification. A diagnostic model based on the angiographic signs and clinical characteristics was developed.

Results

After PSM, 67 and 234 patients with and without PSE, respectively, were selected. The PSE group had significantly higher incidences of hemorrhagic transformation, early seizures, early venous filling (EVF) sign, inferior frontal gyrus (IFG), hippocampus, basal ganglia blush sign, and larger infarct size. After adjusting for hypertension, diabetes, hemorrhagic transformation, infarct size, early seizure, IFG, and hippocampus involvement, EVF remained independently associated with PSE. Hemorrhagic transformation mediated 14.87% of the EVF–PSE associations. Comparison of the evaluation metrics of each model showed that model 3 exhibited the best overall performance.

Conclusion

Hemorrhagic transformation mediates the EVF–PSE association. EVF signs are key predictors of PSE following mechanical thrombectomy.
Infantry training outcomes: are they improved with an initial reduction in load carriage mass and additional sprint intensity exercise?
Authors: Groeller Herbert , Larsen P , Drain J R , Gibson N , Kitcher M , Alfiero L , Dascombe B J , Sampson J A
Published: January 2025

Introduction

Infantry is a physically demanding trade that is associated with elevated rates of musculoskeletal injury. A 17-week longitudinal intervention assessed the effect of a progressive increase in load carriage mass and sprint-intensity intervals on physical performance, physical complaints, medical encounters, physical activity and sleep in infantry trainees.

Methods

91 infantry trainees from 2 separate platoons, randomly assigned as control (CON) or experimental (EXP), provided written voluntary consent. Both completed a 17-week training syllabus that included physical training and military education lessons. Compared with CON, EXP completed a modified regimen that included; a 25%–30% reduction in load carriage mass (weeks 1–4), sprint (weeks 1–7) and 3 min running intervals. Endurance, strength, power and functional performance were assessed (weeks 1, 6–8), physical activity and sleep were recorded using actigraphy (each day of training, weeks 1–17), with daily physical complaints tabulated (weeks 1–7) and frequency of medical encounters retrospectively extracted from defence health records (weeks 1–17).

Results

On-time completion of training was attained in 93% and 79% of CON and EXP, respectively. Total load carriage mass (weeks 1–4) was 27% lower in EXP (10.1 kg/hour) than CON (13.9 kg/hour). Push-up repetitions in CON (5 reps) improved compared with EXP, with functional performance improving markedly in both groups (71 m, 23%). All other fitness assessments were similar between groups. No difference in sleep quality and quantity was observed between groups, with 77% and 16% of trainees sleeping <7 hours (suboptimal) and <6 hours (sleep restricted) per night, respectively. Physical complaints in CON were higher (62), despite no difference observed in medical encounters.

Conclusions

The reduction in load carriage mass and inclusion of sprint interval training did not modify the adaptative or maladaptive responses to infantry training. Most trainees experienced chronic suboptimal sleep quantity and quality with over 15% classified as sleep restricted.
High-grade liver injury: outcomes with a trauma surgery–liver surgery collaborative approach
Authors: Ramos-Jimenez Rafael G , Deeb Andrew-Paul , Truong Evelyn I , Newhouse David , Narayanan Sowmya , Alarcon Louis , Bauza Graciela M , Brown Joshua B , Forsythe Raquel , Leeper Christine , Mohan Deepika , Neal Matthew D , Puyana Juan Carlos , Rosengart Matthew R , Schuchert Vaishali Dixit , Sperry Jason L , Watson Gregory , Zuckerbraun Brian , Marsh J Wallis , Humar Abhinav , Geller David A , Billiar Timothy R , Peitzman Andrew B , Tevar Amit D
Published: January 2025

Background

Operative mortality for high-grade liver injury (HGLI) remains 42% to 66%, with near-universal mortality after retrohepatic caval injury. The objective of this study was to evaluate mortality and complications of operative and nonoperative management (OM and NOM) of HGLI at our institution, characterized by a trauma surgery–liver surgery collaborative approach to trauma care.

Methods

This was an observational cohort study of adult patients (age ≥16) with HGLI (The American Association for Surgery of Trauma (AAST) grades IV and V) admitted to an urban level I trauma center from January 2010 to November 2021. Data were obtained from the electronic medical record and state trauma registry. Patients were categorized by management strategy: immediate OM or planned NOM. The primary outcome was 30-day mortality.

Results

Our institution treated 179 patients with HGLI (78% blunt, 22% penetrating); 122 grade IV (68%) and 57 grade V (32%) injuries. All abdominal gunshot wounds and 49% of blunt injuries underwent initial OM; 51% of blunt injuries were managed initially by NOM. Procedures at the initial operation included hepatorrhaphy±packing (66.4%), nonanatomic resection (5.6%), segmentectomy (9.3%), and hepatic lobectomy (7.5%). Thirty-day mortality in the OM group was substantially lower than prior reports (23.4%). Operative mortality attributable to the liver injury was 15.7%. 19.4% of patients failed NOM with one death (1.4%).

Conclusion

We report an operative mortality of 23.4% for HGLI in a trauma care system characterized by a collaborative approach by trauma surgeons and liver surgeons.

Level of evidence

III
Universal cosmological solutions in Lovelock gravity
Authors: Nikolaev A. V.
Published: January 2025

This paper explores the Friedmann field equations within the framework of Lovelock gravity, a natural extension of Einstein’s gravity, focusing on both flat and open universes. Utilizing an approach based on independent Riemann tensor components, we derive generalized Friedmann equations for Lovelock gravity and categorize the solutions into Type I and Type II. We identify additional vacuum solutions in a flat universe and present a comprehensive solution for a pressure-free scenario in an open universe, both unique to Lovelock gravity. These findings provide new insights into the cosmological implications of Lovelock gravity and offer a foundation for further exploration into the universe’s evolutionary trajectory.
An identity involving co-commuting generalized skew derivations with nilpotent values on prime rings
Authors: Andaloro Milena , Scudo Giovanni
Published: January 2025

Let [Formula: see text] be a noncommutative prime ring, with [Formula: see text], [Formula: see text] its right Martindale quotient ring and [Formula: see text] its extended centroid.

Suppose that [Formula: see text] and [Formula: see text] are generalized skew derivations of [Formula: see text], associated with the same automorphism [Formula: see text] of R, and [Formula: see text] a fixed integer. If [Formula: see text] for all [Formula: see text], then either [Formula: see text], the ring of [Formula: see text] matrices over [Formula: see text] or there exist [Formula: see text] and [Formula: see text] such that [Formula: see text], [Formula: see text] for all [Formula: see text].
Automation in Model-Driven Engineering: A look back, and ahead
Authors: Burgueño Lola , Di Ruscio Davide , Sahraoui Houari , Wimmer Manuel
Published: January 2025

Model-Driven Engineering (MDE) provides a huge body of knowledge of automation for many different engineering tasks, especially those involving transitioning from design to implementation. With the huge progress made in Artificial Intelligence (AI), questions arise about the future of MDE, such as how existing MDE techniques and technologies can be improved or how other activities that currently lack dedicated support can also be automated. However, at the same time, it has to be revisited where and how models should be used to keep the engineers in the loop for creating, operating, and maintaining complex systems. To trigger dedicated research on these open points, we discuss the history of automation in MDE and present perspectives on how automation in MDE can be further improved and which obstacles have to be overcome in both the medium and long-term.
Uncovering IT Career Path Patterns with Job Embedding-based Sequence Clustering
Authors: Zhong Hao , Liu Chuanren , Wu Chaojiang
Published: January 2025

Extracting typical career paths from large-scale and unstructured talent profiles has recently attracted increasing research attention. However, various challenges arise in effectively analyzing self-reported career records. Inspired by recent advancements in neural networks and embedding models, we develop a novel career path clustering approach and apply it to uncover information technology (IT) career path patterns. Specifically, we construct employment profiles of over 60,000 IT professionals, and form their career path sequences by chaining the job records in each profile. Then we simultaneously learn cluster-wise job embeddings and construct career path clusters. The resultant cluster-wise likelihoods of career paths can quantify their soft bonding with different clusters, and the job embeddings can reveal connections among job titles within each cluster. With both real and simulated data, we conduct extensive experiments with our framework to establish the modeling performance and great improvement over the traditional optimal matching analysis methods. The empirical results from analyzing real data on career paths show that our approach can discover distinct IT career path patterns and reveal valuable insights.
Spirometry estimation of central airway dysanapsis on computed tomography in healthy subjects without active lung diseases
Authors: Shimada Takafumi , Tanabe Naoya , Mochizuki Fumi , Iijima Hiroaki , Shimizu Kaoruko , Chubachi Shotaro , Tanimura Kazuya , Sato Susumu , Hirai Toyohiro , Hizawa Nobuyuki
Published: January 2025

The airway-to-lung size discrepancy on computed tomography (CT-assessed dysanapsis) highlights a lifelong risk for developing lung diseases. This study demonstrated that the spirometric index of the dysanapsis ratio can be used for estimating CT-assessed dysanapsis of the entire central airway tree from the trachea to subsegmental airways, whereas a novel index, peak expiratory flow/forced vital capacity (PEF/FVC), can be used for estimating CT-assessed dysanapsis of the extrapulmonary airways (the trachea, main bronchus, and bronchus intermedius).
Neurovascular coupling: a review of spontaneous neocortical dynamics linking neuronal activity to hemodynamics and what we have learned from the rodent brain
Authors: Meyer-Baese Lisa , Jaeger Dieter , Keilholz Shella
Published: January 2025

The brain is a complex neural network whose functional dynamics offer valuable insights into behavioral performance and health. Advances in fMRI have provided a unique window into studying human brain networks, providing us with a powerful tool for clinical research. Yet many questions about the underlying correlates between spontaneous fMRI and neural activity remain poorly understood, limiting the impact of this research. Cross-species studies have proven essential in deepening our understanding of how neuronal activity is coupled to increases in local cerebral blood flow, changes in blood oxygenation, and the measured fMRI signal. In this article, we review some fundamental mechanisms implicated in neurovascular coupling. We then examine neurovascular coupling within the context of spontaneous cortical functional networks and their dynamics, summarizing key findings from mechanistic studies in rodents. In doing so, we highlight the nuances of the neurovascular coupling that ultimately influences the interpretation of derived hemodynamic functional networks, their dynamics, and the neural underpinnings they represent.
Innovative Hardware Accelerator Architecture for FPGA‐Based General‐Purpose RISC Microprocessors
Authors: Ali Ehsan
Published: January 2025

Reconfigurable computing (RC) theory aims to take advantage of the flexibility of general‐purpose processors (GPPs) alongside the performance of application specific integrated circuits (ASICs). Numerous RC architectures have been proposed since the 1960s, but all are struggling to become mainstream. The main factor that prevents RC to be used in general‐purpose CPUs, GPUs, and mobile devices is that it requires extensive knowledge of digital circuit design which is lacked in most software programmers. In an RC development, a processor cooperates with a reconfigurable hardware accelerator (HA) which is usually implemented on a field‐programmable gate arrays (FPGAs) chip and can be reconfigured dynamically. It implements crucial portions of software (kernels) in hardware to increase overall performance, and its design requires substantial knowledge of digital circuit design. In this paper, a novel RC architecture is proposed that provides the exact same instruction set that a standard general‐purpose RISC microprocessor (e.g., ARM Cortex‐M0) has while automating the generation of a tightly coupled RC component to improve system performance. This approach keeps the decades‐old assemblers, compilers, debuggers and library components, and programming practices intact while utilizing the advantages of RC. The proposed architecture employs the LLVM compiler infrastructure to translate an algorithm written in a high‐level language (e.g., C/C++) to machine code. It then finds the most frequent instruction pairs and generates an equivalent RC circuit that is called miniature accelerator (MA). Execution of the instruction pairs is performed by the MA in parallel with consecutive instructions. Several kernel algorithms alongside EEMBC CoreMark are used to assess the performance of the proposed architecture. Performance improvement from 4.09% to 14.17% is recorded when HA is turned on. There is a trade‐off between core performance and combination of compilation time, die area, and program startup load time which includes the time required to partially reconfigure an FPGA chip.
Supplementary Table S5 from A Phase III Randomized Trial of Integrated Genomics and Avatar Models for Personalized Treatment of Pancreatic Cancer: The AVATAR Trial
Authors: Sarno Francesca , Tenorio Jair , Perea Sofia , Medina Laura , Pazo-Cid Roberto , Juez Ignacio , Garcia-Carbonero Rocío , Feliu Jaime , Guillen-Ponce Carmen , Lopez-Casas Pedro P. , Guerra Carmen , Duran Yolanda , López-Acosta José Francisco , Alonso Carolina , Esquivel Estrella , Dopazo Ana , Akshinthala Dipikaa , Muthuswamy Senthil K. , Lapunzina Pablo , Bockorny Bruno , Hidalgo Manuel
Published: January 2025

Supplementary Table 5. Complete Efficacy Data
Supplementary Table S4 from A Phase III Randomized Trial of Integrated Genomics and Avatar Models for Personalized Treatment of Pancreatic Cancer: The AVATAR Trial
Authors: Sarno Francesca , Tenorio Jair , Perea Sofia , Medina Laura , Pazo-Cid Roberto , Juez Ignacio , Garcia-Carbonero Rocío , Feliu Jaime , Guillen-Ponce Carmen , Lopez-Casas Pedro P. , Guerra Carmen , Duran Yolanda , López-Acosta José Francisco , Alonso Carolina , Esquivel Estrella , Dopazo Ana , Akshinthala Dipikaa , Muthuswamy Senthil K. , Lapunzina Pablo , Bockorny Bruno , Hidalgo Manuel
Published: January 2025

Supplementary Table 4. Preclinical model recommendation
Supplementary Table S1 from Re-Irradiation Plus Pembrolizumab: A Phase II Study for Patients with Recurrent Glioblastoma
Authors: Iwamoto Fabio M. , Tanguturi Shyam K. , Nayak Lakshmi , Wang Tony J. , Desai Arati , Lustig Robert A. , Bagley Stephen , Wong Eric T. , Hertan Lauren M. , McCluskey Christine , Hayden Julia , Muzikansky Alona , Nakhawa Shreya , Japo Julia , Bossi Connor C. , Meylan Maxime , Tian Ye , Barlow Graham L. , Speliakos Paul , Ayoub Georges , Meredith David M. , Ligon Keith L. , Haas-Kogan Daphne , Huang Kun , Wucherpfennig Kai W. , Wen Patrick Y. , Reardon David A.
Published: January 2025

CODEX methods
Supplementary Figure S6 from Re-Irradiation Plus Pembrolizumab: A Phase II Study for Patients with Recurrent Glioblastoma
Authors: Iwamoto Fabio M. , Tanguturi Shyam K. , Nayak Lakshmi , Wang Tony J. , Desai Arati , Lustig Robert A. , Bagley Stephen , Wong Eric T. , Hertan Lauren M. , McCluskey Christine , Hayden Julia , Muzikansky Alona , Nakhawa Shreya , Japo Julia , Bossi Connor C. , Meylan Maxime , Tian Ye , Barlow Graham L. , Speliakos Paul , Ayoub Georges , Meredith David M. , Ligon Keith L. , Haas-Kogan Daphne , Huang Kun , Wucherpfennig Kai W. , Wen Patrick Y. , Reardon David A.
Published: January 2025

Supplementary Figure 6. Cell-cell interaction analyses. Cell-cell interaction comparison in pre- and post-treatment tumor samples using CODEX for patient #5. (A) All significant interacting cell types shown in the entire analyzed tumor region as annotated. (B) Example images of cell – cell interactions showing interaction of CD163+ macrophages with GZMB+ CD8 T cells, CD163+ macrophages with GZMB+ CD4 T cells, CD68+ macrophages with GZMB+ CD8 T cells. The plus sign indicates interactions that were in close proximity at a one-cell distance (20 pixels).
Supplementary Table S1 from Phase II Trial of Induction Chemotherapy for Advanced Sinonasal Squamous Cell Carcinoma
Authors: Contrera Kevin J. , Ferrarotto Renata , Gunn Brandon , Su Shirley Y. , Kies Merrill S. , Glisson Bonnie S. , Garden Adam S. , Roberts Dianna , Habna Curtis , Hoff Camilla O. , El-Naggar Adel , Williams Michelle D. , Raza Shaan M. , DeMonte Franco , Chen Melissa M. , Chambers Mark S. , Hanna Ehab Y.
Published: January 2025

Patient Clinical and Pathologic Characteristics
Supplementary Figure S8 from Aberrant Activation of Wound-Healing Programs within the Metastatic Niche Facilitates Lung Colonization by Osteosarcoma Cells
Authors: Reinecke James B. , Jimenez Garcia Leyre , Gross Amy C. , Cam Maren , Cannon Matthew V. , Gust Matthew J. , Sheridan Jeffrey P. , Gryder Berkley E. , Dries Ruben , Roberts Ryan D.
Published: January 2025

Niche-wide changes in target signaling pathway activity with immediate and delayed nintedanib
Supplementary Data S1 from Phase II Trial of Induction Chemotherapy for Advanced Sinonasal Squamous Cell Carcinoma
Authors: Contrera Kevin J. , Ferrarotto Renata , Gunn Brandon , Su Shirley Y. , Kies Merrill S. , Glisson Bonnie S. , Garden Adam S. , Roberts Dianna , Habna Curtis , Hoff Camilla O. , El-Naggar Adel , Williams Michelle D. , Raza Shaan M. , DeMonte Franco , Chen Melissa M. , Chambers Mark S. , Hanna Ehab Y.
Published: January 2025

Protocol
Supplementary Figure S4 from Aberrant Activation of Wound-Healing Programs within the Metastatic Niche Facilitates Lung Colonization by Osteosarcoma Cells
Authors: Reinecke James B. , Jimenez Garcia Leyre , Gross Amy C. , Cam Maren , Cannon Matthew V. , Gust Matthew J. , Sheridan Jeffrey P. , Gryder Berkley E. , Dries Ruben , Roberts Ryan D.
Published: January 2025

Tumor cell-intrinsic effects of nintedanib
Supplementary Figure S2 from Quantitative and Morphology-Based Deep Convolutional Neural Network Approaches for Osteosarcoma Survival Prediction in the Neoadjuvant and Metastatic Settings
Authors: Coudray Nicolas , Occidental Michael A. , Mantilla Jose G. , Claudio Quiros Adalberto , Yuan Ke , Balko Jan , Tsirigos Aristotelis , Jour George
Published: January 2025

Supervised learning of poor vs good outcome (defined as survival beyond 3 years) from morphological features of each segmented region. 3-fold cross validation training curves after supervised learning of poor vs good 3-year survival using exclusively tiles from the normal (column 1), necrosis (column 2) or tumor region (column 3). Error bars show the SEM of the 3 folds.
Supplementary Figure S1 from Quantitative and Morphology-Based Deep Convolutional Neural Network Approaches for Osteosarcoma Survival Prediction in the Neoadjuvant and Metastatic Settings
Authors: Coudray Nicolas , Occidental Michael A. , Mantilla Jose G. , Claudio Quiros Adalberto , Yuan Ke , Balko Jan , Tsirigos Aristotelis , Jour George
Published: January 2025

Training and cross-validation of the supervised segmentation of whole slide images. A. Evolution of the Area Under the receiver operating Curve (AUC) and area under the Precision/Recall (PR) curve during training of the self-supervised network for slide segmentation (n = 3). B. Performance of the validation cohort for each of the 3 folds.
Supplementary Table S2 from Clinical Pharmacology of Cytokine Release Syndrome with T-Cell–Engaging Bispecific Antibodies: Current Insights and Drug Development Strategies
Authors: Radtke Kendra K. , Bender Brendan C. , Li Zao , Turner David C. , Roy Sumedha , Belousov Anton , Li Chi-Chung
Published: January 2025

Overview of T-Cell Engaging Bispecific Antibodies (T-BiSp): Molecule Format, Dosing Schedule, Hospitalization, and Premedication
Supplementary Table S1 from Clinical Pharmacology of Cytokine Release Syndrome with T-Cell–Engaging Bispecific Antibodies: Current Insights and Drug Development Strategies
Authors: Radtke Kendra K. , Bender Brendan C. , Li Zao , Turner David C. , Roy Sumedha , Belousov Anton , Li Chi-Chung
Published: January 2025

Summary of CRS Occurrence by Step-Up Dose Fractions for Approved T-Cell Engaging Bispecific Antibodies (T-BiSp)
Supplementary Figure S2 from Clinical Pharmacology of Cytokine Release Syndrome with T-Cell–Engaging Bispecific Antibodies: Current Insights and Drug Development Strategies
Authors: Radtke Kendra K. , Bender Brendan C. , Li Zao , Turner David C. , Roy Sumedha , Belousov Anton , Li Chi-Chung
Published: January 2025

Overview of CRS Occurrence, Dosing Regimens, and Exposure Metrics for Exposure-Response Analyses of T-Cell Engaging Bispecific Antibodies (T-BiSp)
Supplementary Figure S5 from A Phase II Open-Label, Randomized Clinical Trial of Atezolizumab with or without Human Recombinant IL-7 (CYT107) in Advanced Urothelial Cancer
Authors: Sweis Randy F. , Chatta Gurkamal S. , Jain Rohit K. , Moon Helen , Delacroix Scott Edward , Fang Alana , D’Amico Leonard , Kask Angela Shaulov , Cheever Martin A. , Fling Steven , Sharon Elad , Lacroix Andreanne , Kaiser Judith C. , Pachynski Russell K. , Yu Evan Y.
Published: January 2025

Cytokine changes between C1D1 and C2D1 in the experimental arm.
Supplementary Table S1 from Phase Ib Clinical and Pharmacodynamic Study of the TIE2 Kinase Inhibitor Rebastinib with Paclitaxel or Eribulin in HER2-Negative Metastatic Breast Cancer
Authors: Anampa Jesus D. , Flynn Daniel L. , Leary Cynthia , Oh Sun , Xue Xiaonan , Oktay Maja H. , Condeelis John S. , Sparano Joseph A.
Published: January 2025

Supplementary Table S1 shows Representativeness of Study Participants
Supplementary Tables 1 - 8 from Utilizing Patient-Derived Xenografts to Model Precision Oncology for Biliary Tract Cancer
Authors: DiPeri Timothy P. , Evans Kurt W. , Scott Stephen , Zheng Xiaofeng , Varadarajan Kaushik , Kwong Lawrence N. , Kahle Michael , Tran Cao Hop S. , Tzeng Ching-Wei , Vu Thuy , Kim Sunhee , Su Fei , Raso Maria Gabriela , Rizvi Yasmeen , Zhao Ming , Wang Huamin , Lee Sunyoung S. , Yap Timothy A. , Rodon Jordi , Javle Milind , Meric-Bernstam Funda
Published: January 2025

Table S1, Table S2, Table S3, Table S4, Table S5, Table S6, Table S7, Table S8
Data from A First-in-Human Study of Cinrebafusp Alfa, a HER2/4-1BB Bispecific Molecule, in Patients with HER2-Positive Advanced Solid Malignancies
Authors: Piha-Paul Sarina , Olwill Shane A. , Hamilton Erika , Tolcher Anthony , Pohlmann Paula , Liu Stephen V. , Wurzenberger Cornelia , Hasenkamp Laura-Carolin , Hansbauer Eva-Maria , Shroff Rachna , Hurvitz Sara , Krishnamurthy Anuradha , Patnaik Amita , Hahn Noah , Kumar Raman , Duerr Manuela , Zettl Markus , Aviano Kayti , Matis Louis , Bruns Ingmar , Ku Geoffrey
Published: January 2025

AbstractPurpose:
4-1BB (CD137) is a costimulatory immune receptor expressed on activated T cells, activated B cells, NK cells, and tumor-infiltrating lymphocytes, making it a promising target for cancer immunotherapy. Cinrebafusp alfa, a monoclonal antibody-like bispecific protein targeting HER2 and 4-1BB, aims to localize 4-1BB activation to HER2-positive tumors. This study evaluated the safety, tolerability, and preliminary efficacy of cinrebafusp alfa in patients with previously treated HER2-positive malignancies.
Patients and Methods:
This was a multicenter dose-escalation study involving patients with HER2-positive malignancies who received prior treatment. The study assessed the safety and efficacy of cinrebafusp alfa across various dose levels. Patients were assigned to different cohorts, and antitumor responses were evaluated. The study aimed to determine the MTD and to observe any clinical activity at different dose levels.
Results:
Of 40 evaluable patients in the “active dose” efficacy cohorts, five showed an antitumor response, resulting in an overall response rate of 12.5% and a disease-control rate of 52.5%. Clinical activity was observed at the 8 and 18 mg/kg dose levels, with confirmed objective response rates of 28.6% and 25.0%, respectively. Cinrebafusp alfa was safe and tolerable, with grade ≤2 infusion-related reactions being the most frequent treatment-related adverse event. MTD was not reached during the study.
Conclusions:
Cinrebafusp alfa demonstrates promising activity in patients with HER2-positive malignancies who have progressed on prior HER2-targeting regimens. Its acceptable safety profile suggests it could be a treatment option for patients not responding to existing HER2-directed therapies.

See related commentary by Eguren-Santamaría et al., p. 231
Data from Phase Ib Clinical and Pharmacodynamic Study of the TIE2 Kinase Inhibitor Rebastinib with Paclitaxel or Eribulin in HER2-Negative Metastatic Breast Cancer
Authors: Anampa Jesus D. , Flynn Daniel L. , Leary Cynthia , Oh Sun , Xue Xiaonan , Oktay Maja H. , Condeelis John S. , Sparano Joseph A.
Published: January 2025

AbstractPurpose:
Breast cancer cells disseminate to distant sites via tumor microenvironment of metastasis (TMEM) doorways. The TIE2 inhibitor rebastinib blocks TMEM doorway function in the PyMT mouse model of breast cancer. We aimed to assess the safety and pharmacodynamics of rebastinib plus paclitaxel or eribulin in patients with HER2-negative metastatic breast cancer (MBC).
Patients and Methods:
This phase Ib trial enrolled 27 patients with MBC who received 50 mg or 100 mg of rebastinib orally twice daily in combination with weekly paclitaxel 80 mg/m2 (if ≤2 prior non-taxane regimens) or eribulin 1.4 mg/m2 on days 1 and 8 (if ≥1 prior regimen). Safety, tolerability, and pharmacodynamic parameters indicating TIE2 kinase inhibition and TMEM doorway function were evaluated.
Results:
No dose-limiting toxicities in cycle 1 or 2 were observed among the first 12 patients at either rebastinib dose level. The most common treatment-emergent adverse events were anemia (85%), fatigue (78%), anorexia (67%), leukopenia (67%), increased alanine aminotransferase (59%), hyperglycemia (56%), nausea (52%), and neutropenia (52%). Adverse events attributed to rebastinib include muscular weakness and myalgias. Intraocular pressure increased at the 100-mg rebastinib dose level, whereas angiopoietin-2 levels increased at both dose levels, providing pharmacodynamic evidence for TIE2 blockade. Circulating tumor cells decreased significantly with the combined treatment. Objective response occurred in 5/23 (22%) evaluable patients.
Conclusions:
In patients with MBC, the recommended phase II dose of rebastinib associated with pharmacodynamic evidence of TIE2 inhibition is either 50 or 100 mg orally twice daily in combination with paclitaxel or eribulin.
A Tale of Two Treatments: A Randomised Controlled Trial of Mindfulness or Cognitive Behaviour Therapy Delivered Online for People with Rheumatoid Arthritis
Authors: Sharpe Louise , Bisby Madelyne A. , Menzies Rachel E. , Boyse Jack Benjamin , Richmond Bethany , Todd Jemma , Sesel Amy-Lee , Dear Blake F.
Published: January 2025

Introduction: This study aimed to determine the relative efficacy of mindfulness-based stress reduction (MBSR) or cognitive behaviour therapy (CBT) in comparison to a waitlist control (WLC) for people with rheumatoid arthritis (RA). Participants completed assessments before and after treatment and at 6-month follow-up. Methods: Two hundred and sixty-nine participants with RA were recruited and randomised in a 2:2:1 ratio to MBSR:CBT:WLC. Participants completed a semi-structured clinical interview for depression and were stratified for history of recurrent depression. We measured the primary outcome of pain interference, as well as pain severity, depression, anxiety, functional ability, and fear of progression. We predicted that MBSR and CBT would result in improvements compared to WLC. We also predicted that those with a history of recurrent depression would benefit more from MBSR than CBT for depression. Results: MBSR and CBT were equally efficacious in reducing pain interference compared to WLC. Similar results were found for depression. MBSR demonstrated superior outcomes to CBT for fear of progression at post-treatment and functional ability at 6-month follow-up. CBT only was better than WLC for pain severity at 6-month follow-up. Depressive status did not moderate the efficacy of treatment. Conclusions: MBSR and CBT resulted in statistically and clinically significant changes in pain interference compared to WLC. MBSR was more efficacious than CBT for functional ability and fear of progression, while CBT showed superiority for pain severity. The effect sizes were comparable to those achieved with face-to-face interventions, confirming both online treatments are effective for people with RA.
The Superiority of European Kidney Function Consortium Cystatin C-Based Formula for Risk Stratification of All-Cause and Cardiovascular Deaths in US Adults
Authors: Ye Zixiang , Wang Haixu , Xie Enmin , Zhou Zeming , Dou Kefei
Published: January 2025

Introduction: We intended to compare the predictive value for all-cause and cardiovascular deaths between estimated glomerular filtration rate (eGFR) derived from the European Kidney Function Consortium (EKFC) cystatin C-based formula, the EKFC creatinine-based formula, and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) cystatin C- or creatinine-based formulas. Methods: Overall, 4,132 participants from the National Health and Nutrition Examination Survey between 1999 and 2002 were included, and death information was obtained through the National Death Index. To compare predictive accuracy between EKFC eGFRcys (EKFC cystatin C-based formula), CKD-EPI eGFRcys (CKD-EPI cystatin C-based formula), EKFC eGFRcr (EKFC creatinine-based formula), and CKD-EPI eGFRcr (CKD-EPI creatinine-based formula), we conducted time-dependent receiver operator characteristic (ROC) curves and reclassification analysis. Results: During a median follow-up of 17.4 years, a total of 1,987 all-cause and 530 cardiovascular deaths were confirmed. Restricted cubic splines analyses showed that reduced EKFC eGFRcys was linearly related to higher risks of all-cause and cardiovascular deaths (p for nonlinearity > 0.05). Time-dependent ROC curves suggested that EKFC eGFRcys exhibited higher predictive ability than CKD-EPI eGFRcys, EKFC eGFRcr, and CKD-EPI eGFRcr at 5-year and 10-year follow-ups. For 10-year all-cause deaths, EKFC eGFRcys yielded significant improvement over CKD-EPI eGFRcr (integrated discrimination improvement [IDI], 9.4%; net reclassification improvement [NRI], 39.7%). Similar improvement was observed in 10-year cardiovascular deaths when comparing EKFC eGFRcys to CKD-EPI eGFRcr (IDI, 6.7%; NRI, 45.1%). Conclusion: The EKFC eGFRcys outperformed CKD-EPI eGFRcys, EKFC eGFRcr, and CKD-EPI eGFRcr in predicting all-cause and cardiovascular deaths, providing the possibility to utilize EKFC eGFRcys in the stratification of death risk among the general US population.
Nourishment of nerves and innervation: A novel approach for the treatment of myocardial infarction
Authors: Yin Xiaorui , Cai Dan , Song Zhimin , Song Chunli
Published: January 2025

Background: Autonomic innervation of the heart plays a pivotal role not only in regulating the heart rate but also in modulating the cardiac cell microenvironment via cell-cell interactions and influencing the heart’s repair capabilities. Currently, the primary clinical approach for treating myocardial infarction (MI) is percutaneous coronary intervention. However, the myocardial salvage rate remains low for patients with advanced disease. MI is recognized as an autonomic nervous system disorder, marked by sympathetic hyperactivity and the loss of parasympathetic nerves. Following MI, ventricular sympathetic nerve sprouting occurs, leading to an increase in ventricular sympathetic innervation and, consequently, an increased risk of ventricular arrhythmia, which is the primary cause of sudden cardiac death in patients with a history of MI. The vagus nerve positively regulates cardiomyocyte proliferation and regeneration, enhancing ventricular remodeling and cardiac function post-MI. This process is highly significant in the treatment and rehabilitation of MI. Cardiac autonomic nerves are influenced by factors such as inflammation, immunity, intercellular communication, metabolism, genetics, epigenetics, and cytokine secretion related to cardiac mesenchymal nerves. In recent years, significant advancements have been made regarding treatment for MI, specifically in the fields of autonomic nervous system therapies, stem cell and extracellular vesicle treatments, traditional Chinese medicine acupuncture and moxibustion, and peripheral electrophysiological stimulation and bioengineering materials.

Summary: The balance of dominance between the sympathetic and parasympathetic nervous systems in the heart affects tissue regeneration and cardiac remodeling after MI. The secretion of neurons regulates the microenvironment of cardiac repair. The neural therapy of MI involves multiple fields such as traditional Chinese medicine, biomaterials, stem cell therapy, and drug research and development, and has broad development prospects

Key Messages: The regulation exerted by the cardiac autonomic nervous system on the heart significantly influences the prognosis of MI. This involves nervous system modulation of inflammation and heart rate and complex interactions between neurons and cardiomyocytes, immune cells, fibroblasts, adipocytes, stem cells, and other cellular components. Genetic and epigenetic modifications, as well as shifts in energy metabolism, also play crucial roles.
Fetal Extrahepatic Porto systemic Venous Shunts: prenatal diagnosis management and therapy: 21 years of evolving insights.
Authors: Achiron Reuven , Kivilevitch Zvi , Kassif Eran , Superina Riccardo A.
Published: January 2025

Introduction
Fetal extrahepatic portosystemic Venous Shunt (FEPSVS) are vascular malformations that divert placental and bowel blood from the liver into the systemic circulation. When uncorrected, it can lead to severe pathologic consequences after birth.
Objective
To report our method of prenatal diagnosis, the developing insight regarding prenatal counseling, and postnatal treatment.
Method
Retrospective review of fetuses diagnosed with FEPSVS, classified into Abernethy type I or II based on the absence or existence of intrahepatic portal venous system (IHPVS) flow. Two different counseling periods were compared regarding pregnancy management and postnatal outcome.
Results
In the first period (2000-2010), 5 cases were diagnosed; 4 were type I with an 80% termination rate.
In the second period (2011-2021), 6 cases were diagnosed; with only a 16% termination rate in type I cases.
Two type II cases were reclassified to type I postnatally and corrected successfully.
Of the six born alive, five had early surgical/endovascular corrections, and one experienced spontaneous closure. All the cases resulted in a successful rescue of the IHPVS with good outcomes.
Conclusions
During our developing insights we realized that: 1) the adult classification according to the IHPSVS is not relevant for prenatal prognostic counseling. 2) Prenatal diagnosis of FEPSVS is essential in promoting early postnatal investigation and corrective intervention, which might prevent the appearance of postnatal complications.
The Role of Climate and Residency in Storage Mite Sensitivity Among Children with Allergic Diseases in The Mediterranean Region
Authors: Kaya Mehmet Akif , Kocacik Uygun Dilara Fatma , Celik Enes , Bingol Aysen
Published: January 2025

Introduction: Mite allergy is the most common inhalant allergen sensitivity. In addition to house dust mites, which are indoor allergens, well-known storage mites also exist.
Methods: This study examines the frequency of storage mite sensitivity in children with allergic diseases, the rate of cross-sensitization with other mite species, and the relationship between mite sensitivities and various factors such as the type of region where patients reside and meteorological data from their locations.
Results: A total of 368 children with allergic diseases were included in the study. According to the results of the epidermal prick tests, 224 (60.9%) patients had sensitivity to at least one type of mite, while 171 (46.5%) patients had sensitivity to at least one house dust mite, and 135 (36.7%) had sensitivity to at least one storage mite. Among those with storage mite sensitivity, 82 patients (60.7%) also had sensitivity to house dust mites. In the group of patients living in rural areas, storage mite sensitivity was 57.9%, while in urban centers this rate was 16.8% (p < 0.001).
An increase in humidity level was found to increase the likelihood of developing house dust mite sensitivity and storage mite sensitivity (p <0.05, OR: 2.542 and p < 0.001, OR: 7.792). Additionally, increase in average wind speed was found to increase the likelihood of developing storage mite sensitivity (p < 0.001, OR: 9.582).
Conclusion: Storage mites, an often-overlooked factor in daily practice, are a respiratory allergen that is more common in children than often believed. Susceptibility to storage mites can be affected by the average wind speed and humidity in the region. When assessing the sensitization profiles of allergic children, storage mite sensitization should be considered in addition to house dust mites, and appropriate precautions should be taken.