bluuebunny/crossref_metadata_2025_split huggingface dataset:
Unveiling the Threat: Investigating Distributed and Centralized Backdoor Attacks in Federated Graph Neural Networks
Authors: Xu Jing , Koffas Stefanos , Picek Stjepan 
Published: November 2023

Graph neural networks (GNNs) have gained significant popularity as powerful deep learning methods for processing graph data. However, centralized GNNs face challenges in data-sensitive scenarios due to privacy concerns and regulatory restrictions. Federated learning has emerged as a promising technology that enables collaborative training of a shared global model while preserving privacy. Although federated learning has been applied to train GNNs, no research focuses on the robustness of Federated GNNs against backdoor attacks.
This article bridges this research gap by investigating two types of backdoor attacks in Federated GNNs: centralized backdoor attack (CBA) and distributed backdoor attack (DBA). Through extensive experiments, we demonstrate that DBA exhibits a higher success rate than CBA across various scenarios. To further explore the characteristics of these backdoor attacks in Federated GNNs, we evaluate their performance under different scenarios, including varying numbers of clients, trigger sizes, poisoning intensities, and trigger densities. Additionally, we explore the resilience of DBA and CBA against two defense mechanisms. Our findings reveal that both defenses cannot eliminate DBA and CBA without affecting the original task. This highlights the necessity of developing tailored defenses to mitigate the novel threat of backdoor attacks in Federated GNNs.
Avoiding Extinction: Cancer-Associated Fibroblasts Help Triple-Negative Breast Cancer Outrun Chemotherapy
Authors: Wall Steven W. , Echeverria Gloria V. 
Published: November 2023

AbstractNeoadjuvant chemotherapy is a staple of triple-negative breast cancer (TNBC) treatment. Predicated on the principle of fractional cell killing, chemotherapy regimens are typically cycles of short drug exposure followed by a period of recovery from the toxic side effects. However, many patients experience chemotherapy resistance for a variety of reasons, resulting in tumors that are not sufficiently reduced with treatment. Response to chemotherapy prior to surgical resection is a strong predictor of patient prognosis; therefore, finding ways to improve efficacy is a critical need. Tremendous effort has gone into understanding the relationship between the tumor microenvironment and treatment sensitivity in many tumor types. In this issue of Cancer Research, Miroshnychenko and colleagues investigate how the well-characterized phenomenon of cancer-associated fibroblast (CAF)–induced proliferation of tumor cells allows TNBC to evade extinction after multiple cycles of cytotoxic chemotherapies. Their findings imply CAF-promoted tumor cell proliferation allows tumor cells to push through stressful conditions caused by treatment and to avoid tumor elimination. This mechanism of ‘indirect’ chemoresistance contrasts with the dogma that tumor cell proliferation enhances chemosensitivity. This study opens the door for the discovery of mechanisms and therapeutic targets to limit the ability of CAFs to rescue tumor cells from the brink of extinction.See related article by Miroshnychenko et al., p. 3681
Detection of Recurrence through microRNA-371a-3p Serum Levels in a Follow-up of Stage I Testicular Germ Cell Tumors in the DRKS-00019223 Study
Authors: Belge Gazanfer , Dumlupinar Cansu , Nestler Tim , Klemke Markus , Törzsök Peter , Trenti Emanuela , Pichler Renate , Loidl Wolfgang , Che Yue , Hiester Andreas , Matthies Cord , Pichler Martin , Paffenholz Pia , Kluth Luis , Wenzel Mike , Sommer Jörg , Heinzelbecker Julia , Schriefer Philipp , Winter Alexander , Zengerling Friedemann , Kramer Mario Wolfgang , Lengert Marie , Frey Jana , Heidenreich Axel , Wülfing Christian , Radtke Arlo , Dieckmann Klaus-Peter 
Published: November 2023

Abstract

Purpose:
Surveillance of clinical stage I (CSI) testicular germ cell tumors (GCT) is hampered by low sensitivity and specificity of current biomarkers for detecting relapses. This study evaluated if serum levels of microRNA371a-3p (M371 test) can: (i) Accurately detect relapses, (ii) detect relapses earlier than conventional technology, and (iii) if elevated postoperative M371 levels may predict relapse.

Experimental Design:
In a multicentric setting, 258 patients with testicular CSI GCT were prospectively followed by surveillance for a median time of 18 months with serial measurements of serum M371 levels, in addition to standard diagnostic techniques. Diagnostic characteristics of M371 for detecting relapses were calculated using ROC curve analysis.

Results:
Thirty-nine patients recurred (15.1%), all with elevated M371 levels; eight without relapse had elevations, too. The test revealed the following characteristics: area under the ROC curve of 0.993, sensitivity 100%, specificity 96.3%, positive predictive value 83%, negative predictive value 100%. Earlier relapse detection with the test was found in 28%, with non-significant median time gain to diagnosis. Postoperative M371 levels did not predict future relapse.

Conclusions:
The sensitivity and specificity of the M371 test for detecting relapses in CSI GCTs are much superior to those of conventional diagnostics. However, post-orchiectomy M371 levels are not predictive of relapse, and there is no significant earlier relapse detection with the test. In all, there is clear evidence for the utility of the M371 test for relapse detection suggesting it may soon be ready for implementation into routine follow-up schedules for patients with testicular GCT.
Developing and Validating a Multivariable Prognostic-Predictive Classifier for Treatment Escalation of Oropharyngeal Squamous Cell Carcinoma: The PREDICTR-OPC Study
Authors: Mehanna Hisham , Rapozo Davy , von Zeidler Sandra V. , Harrington Kevin J. , Winter Stuart C. , Hartley Andrew , Nankivell Paul , Schache Andrew G. , Sloan Philip , Odell Edward W. , Thavaraj Selvam , Hunter Keith D. , Shah Ketan A. , Thomas Gareth J. , Long Anna , Amel-Kashipaz Rasoul , Brown Rachel M. , Conn Brendan , Hall Gillian L. , Matthews Paul , Weir Justin , Yeo Yen , Pring Miranda , West Catharine M.L. , McCaul James , Golusinski Pawel , Sitch Alice , Spruce Rachel , Batis Nikolaos , Bryant Jennifer L. , Brooks Jill M. , Jones Terence M. , Buffa Francesca , Haider Syed , Robinson Max 
Published: November 2023

Abstract

Purpose:
While there are several prognostic classifiers, to date, there are no validated predictive models that inform treatment selection for oropharyngeal squamous cell carcinoma (OPSCC).
Our aim was to develop clinical and/or biomarker predictive models for patient outcome and treatment escalation for OPSCC.

Experimental Design:
We retrospectively collated clinical data and samples from a consecutive cohort of OPSCC cases treated with curative intent at ten secondary care centers in United Kingdom and Poland between 1999 and 2012. We constructed tissue microarrays, which were stained and scored for 10 biomarkers. We then undertook multivariable regression of eight clinical parameters and 10 biomarkers on a development cohort of 600 patients. Models were validated on an independent, retrospectively collected, 385-patient cohort.

Results:
A total of 985 subjects (median follow-up 5.03 years, range: 4.73–5.21 years) were included. The final biomarker classifier, comprising p16 and survivin immunohistochemistry, high-risk human papillomavirus (HPV) DNA in situ hybridization, and tumor-infiltrating lymphocytes, predicted benefit from combined surgery + adjuvant chemo/radiotherapy over primary chemoradiotherapy in the high-risk group [3-year overall survival (OS) 63.1% vs. 41.1%, respectively, HR = 0.32; 95% confidence interval (CI), 0.16–0.65; P = 0.002], but not in the low-risk group (HR = 0.4; 95% CI, 0.14–1.24; P = 0.114). On further adjustment by propensity scores, the adjusted HR in the high-risk group was 0.34, 95% CI = 0.17–0.67, P = 0.002, and in the low-risk group HR was 0.5, 95% CI = 0.1–2.38, P = 0.384. The concordance index was 0.73.

Conclusions:
We have developed a prognostic classifier, which also appears to demonstrate moderate predictive ability. External validation in a prospective setting is now underway to confirm this and prepare for clinical adoption.
Longitudinal Natural History Study of Children and Adults with Rare Solid Tumors: Initial Results for First 200 Participants
Authors: Ahmed Shadin , Wedekind Mary Frances , Del Rivero Jaydira , Raygada Margarita , Lockridge Robin , Glod John W. , Flowers Crystal , Thomas BJ , Bernstein Donna B. , Kapustina Oxana B. , Jain Ashish , Miettinen Markku , Raffeld Mark , Xi Liqiang , Tyagi Manoj , Kim Jung , Aldape Kenneth , Malayeri Ashkan A. , Kaplan Rosandra N. , Allen Taryn , Vivelo Christina A. , Sandler Abby B. , Widemann Brigitte C. , Reilly Karlyne M. ,   for the MyPART network
Published: November 2023

Abstract

Understanding of tumor biology and identification of effective therapies is lacking for many rare tumors. My Pediatric and Adult Rare Tumor (MyPART) network was established to engage patients, advocates, and researchers and conduct a comprehensive longitudinal Natural History Study of Rare Solid Tumors. Through remote or in-person enrollment at the NIH Clinical Center, participants with rare solid tumors ≥4 weeks old complete standardized medical and family history forms, patient reported outcomes, and provide tumor, blood and/or saliva samples. Medical records are extracted for clinical status and treatment history, and tumors undergo genomic analysis. A total of 200 participants (65% female, 35% male, median age at diagnosis 43 years, range = 2–77) enrolled from 46 U.S. states and nine other countries (46% remote, 55% in-person). Frequent diagnoses were neuroendocrine neoplasms (NEN), adrenocortical carcinomas (ACC), medullary thyroid carcinomas (MTC), succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumors (sdGIST), and chordomas. At enrollment, median years since diagnosis was 3.5 (range = 0–36.6), 63% participants had metastatic disease and 20% had no evidence of disease. Pathogenic germline and tumor mutations included SDHA/B/C (sdGIST), RET (MTC), TP53 and CTNNB1 (ACC), MEN1 (NEN), and SMARCB1 (poorly-differentiated chordoma). Clinically significant anxiety was observed in 20%–35% of adults. Enrollment of participants and comprehensive data collection were feasible. Remote enrollment was critical during the COVID-19 pandemic. Over 30 patients were enrolled with ACC, NEN, and sdGIST, allowing for clinical/genomic analyses across tumors. Longitudinal follow-up and expansion of cohorts are ongoing to advance understanding of disease course and establish external controls for interventional trials.

Significance:
This study demonstrates that comprehensive, tumor-agnostic data and biospecimen collection is feasible to characterize different rare tumors, and speed progress in research. The findings will be foundational to developing external controls groups for single-arm interventional trials, where randomized control trials cannot be conducted because of small patient populations.
CAR T-cell Design-dependent Remodeling of the Brain Tumor Immune Microenvironment Modulates Tumor-associated Macrophages and Anti-glioma Activity
Authors: Haydar Dalia , Ibañez-Vega Jorge , Crawford Jeremy Chase , Chou Ching-Heng , Guy Clifford S. , Meehl Michaela , Yi Zhongzhen , Perry Scott , Laxton Jonathan , Cunningham Trevor , Langfitt Deanna , Vogel Peter , DeRenzo Christopher , Gottschalk Stephen , Roussel Martine F. , Thomas Paul G. , Krenciute Giedre 
Published: November 2023

Abstract

Understanding the intricate dynamics between adoptively transferred immune cells and the brain tumor immune microenvironment (TIME) is crucial for the development of effective T cell–based immunotherapies. In this study, we investigated the influence of the TIME and chimeric antigen receptor (CAR) design on the anti-glioma activity of B7-H3–specific CAR T-cells. Using an immunocompetent glioma model, we evaluated a panel of seven fully murine B7-H3 CARs with variations in transmembrane, costimulatory, and activation domains. We then investigated changes in the TIME following CAR T-cell therapy using high-dimensional flow cytometry and single-cell RNA sequencing. Our results show that five out of six B7-H3 CARs with single costimulatory domains demonstrated robust functionality in vitro. However, these CARs had significantly varied levels of antitumor activity in vivo. To enhance therapeutic effectiveness and persistence, we incorporated 41BB and CD28 costimulation through transgenic expression of 41BBL on CD28-based CAR T-cells. This CAR design was associated with significantly improved anti-glioma efficacy in vitro but did not result in similar improvements in vivo. Analysis of the TIME revealed that CAR T-cell therapy influenced the composition of the TIME, with the recruitment and activation of distinct macrophage and endogenous T-cell subsets crucial for successful antitumor responses. Indeed, complete brain macrophage depletion using a CSF1R inhibitor abrogated CAR T-cell antitumor activity. In sum, our study highlights the critical role of CAR design and its modulation of the TIME in mediating the efficacy of adoptive immunotherapy for high-grade glioma.

Significance:
CAR T-cell immunotherapies hold great potential for treating brain cancers; however, they are hindered by a challenging immune environment that dampens their effectiveness. In this study, we show that the CAR design influences the makeup of the immune environment in brain tumors, underscoring the need to target specific immune components to improve CAR T-cell performance, and highlighting the significance of using models with functional immune systems to optimize this therapy.
Factor XI Inhibition for the Prevention of Catheter-Associated Thrombosis in Patients With Cancer Undergoing Central Line Placement: A Phase 2 Clinical Trial
Authors: Pfeffer Michael A. , Kohs Tia C.L. , Vu Helen H. , Jordan Kelley R. , Wang Jenny Si Han , Lorentz Christina U. , Tucker Erik I. , Puy Cristina , Olson Sven R. , DeLoughery Thomas G. , Hinds Monica T. , Keshari Ravi S. , Gailani David , Lupu Florea , McCarty Owen J.T. , Shatzel Joseph J. 
Published: November 2023

BACKGROUND:
Despite the ubiquitous utilization of central venous catheters in clinical practice, their use commonly provokes thromboembolism. No prophylactic strategy has shown sufficient efficacy to justify routine use. Coagulation factors FXI (factor XI) and FXII (factor XII) represent novel targets for device-associated thrombosis, which may mitigate bleeding risk. Our objective was to evaluate the safety and efficacy of an anti-FXI mAb (monoclonal antibody), gruticibart (AB023), in a prospective, single-arm study of patients with cancer receiving central line placement.

METHODS:
We enrolled ambulatory cancer patients undergoing central line placement to receive a single dose of gruticibart (2 mg/kg) administered through the venous catheter within 24 hours of placement and a follow-up surveillance ultrasound at day 14 for evaluation of catheter thrombosis. A parallel, noninterventional study was used as a comparator.

RESULTS:

In total, 22 subjects (n=11 per study) were enrolled. The overall incidence of catheter-associated thrombosis was 12.5% in the interventional study and 40.0% in the control study. The anti-FXI mAb, gruticibart, significantly prolonged the activated partial thromboplastin time in all subjects on day 14 compared with baseline (
P
<0.001). Gruticibart was well tolerated and without infusion reactions, drug-related adverse events, or clinically relevant bleeding. Platelet flow cytometry demonstrated no difference in platelet activation following administration of gruticibart. T (thrombin)-AT (antithrombin) and activated FXI–AT complexes increased following central line placement in the control study, which was not demonstrated in our intervention study. CRP (C-reactive protein) did not significantly increase on day 14 in those who received gruticibart, but it did significantly increase in the noninterventional study.

CONCLUSIONS:
FXI inhibition with gruticibart was well tolerated without any significant adverse or bleeding-related events and resulted in a lower incidence of catheter-associated thrombosis on surveillance ultrasound compared with the published literature and our internal control study. These findings suggest that targeting FXI could represent a safe intervention to prevent catheter thrombosis.

REGISTRATION:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT04465760.
Birth Weight, Childhood and Young Adult Overweight, and the Risk of Coronary Heart Disease in Men
Authors: Bramsved Rebecka , Bygdell Maria , Martikainen Jari , Mårild Staffan , Lindh Ingela , Rosengren Annika , Ohlsson Claes , Kindblom Jenny M. 
Published: November 2023

BACKGROUND:
Low birth weight is a known risk factor for adult coronary heart disease (CHD), but the additional effect of weight development during childhood and early adult life has not been studied.

METHODS:
We included 35 659 men born 1945 to 1961 from the population-based BMI Epidemiology Study Gothenburg, with data available on birthweight, BMI in childhood (8 years), and BMI in young adulthood (20 years). Information on CHD diagnoses was retrieved from national registers. We used Cox proportional hazards regression to estimate hazard ratios and 95% CIs for the risk of early and late CHD (before and after 58.4 years of age, respectively).

RESULTS:
During follow-up, a total of 3380 cases of CHD (fatal and nonfatal) were registered. Birth weight was inversely associated with the risk of both early (hazard ratio, 0.88 per SD increase [95% CI, 0.84–0.92]) and late (hazard ratio, 0.94 per SD increase [95% CI, 0.90–0.98]) CHD, independently of BMI at 8 years and BMI change during puberty. In a model including birth weight (below or above the median) together with overweight at 8 and 20 years, only birth weight and young adult overweight, but not overweight in childhood, were significantly associated with the risk of CHD. A birth weight below the median, followed by overweight at 20 years of age was associated with a more than doubled risk of early CHD (hazard ratio, 2.29 [95% CI, 1.86–2.81]), compared with the reference (birth weight above the median and normal weight at 20 years of age). This excess risk was even more pronounced for a birthweight below 2.5 kg.

CONCLUSIONS:
We demonstrate that low birth weight and young adult overweight are important developmental markers of risk for adult CHD. These findings motivate a life course perspective for prevention and risk assessment of adult CHD.
Physics-Inspired Adaptions to Low-Parameter Neural Network Weather Forecast Systems
Authors: Scher Sebastian , Messori Gabriele 
Published: November 2023

Abstract
Recently, there has been a surge of research on data-driven weather forecasting systems, especially applications based on convolutional neural networks (CNNs). These are usually trained on atmospheric data represented on regular latitude–longitude grids, neglecting the curvature of Earth. We assess the benefit of replacing the standard convolution operations with an adapted convolution operation that takes into account the geometry of the underlying data (SphereNet convolution), specifically near the poles. Additionally, we assess the effect of including the information that the two hemispheres of Earth have “flipped” properties—for example, cyclones circulating in opposite directions—into the structure of the network. Both approaches are examples of physics-informed machine learning. The methods are tested on the WeatherBench dataset, at a resolution of ∼1.4°, which is higher than many previous studies on CNNs for weather forecasting. For most lead times up to day +10 for 500-hPa geopotential and 850-hPa temperature, we find that using SphereNet convolution or including hemisphere-specific information individually leads to improvement in forecast skill. Combining the two methods typically gives the highest forecast skill. Our version of SphereNet is implemented flexibly and scales well to high-resolution datasets but is still significantly more expensive than a standard convolution operation. Finally, we analyze cases with high forecast error. These occur mainly in winter and are relatively consistent across different training realizations of the networks, pointing to flow-dependent atmospheric predictability.
Uncertainty of the Simulated Mid-Pliocene Changes of Sahel Summer Rainfall in the PlioMIP2 Multimodel Ensemble
Authors: Han Zixuan , Li Gen 
Published: November 2023

Abstract
The mid-Pliocene (approximately 3.3–3.0 Ma) was one of the past geological warm periods. Since this past warmer climate was in many respects comparable to near future warming projections, how the regional monsoonal rainfall changed during the mid-Pliocene is an important scientific and socioeconomic concern. Based on phase 2 of the Pliocene Model Intercomparison Project (PlioMIP2), this work examines the simulated changes of Sahel summer rainfall during the mid-Pliocene. The results show the considerable intermodel uncertainty of the simulated mid-Pliocene Sahel rainfall changes in the PlioMIP2 multimodel ensemble, which is due to the uncertainties of both the simulated dynamic and thermodynamic responses to this past warmer climate. In particular, we find that the intermodel spread in the simulated northern North American warming is a major source of the uncertainty of the mid-Pliocene Sahel summer rainfall changes through two processes. One is a direct dynamic process: a stronger warming over northern North America could enhance the meridional temperature gradient between the extratropical and tropical regions, inducing an interhemisphere energy imbalance of the atmosphere. This could lead to a northward shift of the intertropical convergence zone, strengthening the Western African summer monsoon (WASM) circulation and Sahel summer rainfall. Another is an indirect thermodynamic process: the strengthened WASM circulation could further induce anomalous moisture convergence over the Sahel region, increasing local atmospheric moisture at the low-level troposphere, in favor of a wetter Sahel. Our results suggest that an improved warming simulation over northern North America is essential for the hydrological cycle simulation around the Sahel in the mid-Pliocene warmer climate.

Significance Statement
The Sahel summer rainfall change in a global warmer climate is a widespread scientific and socioeconomic issue because of its important impacts on regional agriculture, ecosystems, food security, water resources, and even cultural environment. However, the present study identifies a nonnegligible intermodel uncertainty of the simulated Sahel rainfall changes during the mid-Pliocene (one of the most recent geological warm periods in Earth’s history) in the Pliocene Model Intercomparison Project phase 2 (PlioMIP2) multimodel ensemble. In particular, such an intermodel uncertainty of the simulated Sahel rainfall changes during the mid-Pliocene is attributed to that of the simulated northern North America warming via both the direct dynamic process and the indirect thermodynamic process. This is quite different from the uncertainty source of near-future projections of Sahel summer rainfall changes. The present results improve our understanding of the underlying physics of the hydrological cycle change around the Sahel region in the mid-Pliocene warmer climate, with implications for the future projections of regional monsoonal rainfall.