bluuebunny/crossref_metadata_2025 huggingface dataset:
Falsely low glycosylated haemoglobin levels probably secondary to hypersplenism in a patient with diabetes mellitus
Authors: Hayakawa Guy , Leibowitz Maya M , Nagumantry Sateesh Kumar , Oyibo Samson Oghenetsovwe
Published: April 2024

A man in his 70s presented with a history of low glycated haemoglobin (HbA1c) values despite a diagnosis of type 2 diabetes. His blood glucose readings ranged between 8 and 15 mmol/L, but his HbA1c values were below 27 mmol/mol. Initial investigations demonstrated evidence of reduced red blood cell lifespan as a cause of misleadingly low HbA1c values. Further investigation revealed chronic liver disease and splenomegaly, with hypersplenism being the probable cause of increased red blood cell turnover. HbA1c estimation was no longer reliable, so ongoing diabetic care was guided by home capillary blood glucose monitoring. Healthcare providers and clinical laboratorians need to be aware of the possible clinical implications of very low HbA1c values in patients with type 2 diabetes.
Characterization of the zebrafish as a model of ATP-sensitive potassium channel hyperinsulinism
Authors: Juliana Christine A , Benjet Joshua , De Leon Diva D
Published: April 2024

Introduction

Congenital hyperinsulinism (HI) is the leading cause of persistent hypoglycemia in infants. Current models to study the most common and severe form of HI resulting from inactivating mutations in the ATP-sensitive potassium channel (KATP) are limited to primary islets from patients and theSur1-/-mouse model. Zebrafish exhibit potential as a novel KATPHI model since they express canonical insulin secretion pathway genes and those with identified causative HI mutations. Moreover, zebrafish larvae transparency provides a unique opportunity for in vivo visualization of pancreatic islets.

Research design and methods

We evaluated zebrafish as a model for KATPHI using a genetically encoded Ca2+sensor (ins:gCaMP6s) expressed under control of the insulin promoter in beta cells of anabcc8-/-zebrafish line.

Results

We observed significantly higher islet cytosolic Ca2+in vivo inabcc8-/-compared withabcc8+/+zebrafish larvae. Additionally,abcc8-/-larval zebrafish had significantly lower whole body glucose and higher whole body insulin levels compared withabcc8+/+controls. However, adultabcc8-/-zebrafish do not show differences in plasma glucose, plasma insulin, or glucose tolerance when compared withabcc8+/+zebrafish.

Conclusions

Our results identify that zebrafish larvae, but not adult fish, are a demonstrable novel model for advancement of HI research.
Influence of diabetes and other risk factors on in-hospital mortality following kidney transplantation: an analysis of the Spanish National Hospital Discharge Database from 2016 to 2020
Authors: Lopez-de-Andres Ana , Jimenez-Garcia Rodrigo , Lopez-Herranz Marta , Zamorano-Leon José Javier , Carabantes-Alarcon David , Hernandez-Barrera Valentin , de Miguel-Diez Javier , Carricondo Francisco , Romero-Gomez Barbara , Cuadrado-Corrales Natividad
Published: April 2024

Introduction

To assess time trends in incidence, clinical characteristics, complications, and hospital outcomes among patients with type 1 diabetes (T1D), with type 2 diabetes (T2D), and patients without diabetes who underwent kidney transplant (KT); to identify variables associated with in-hospital mortality (IHM); and to determine the impact of the COVID-19 pandemic.

Research design and methods

We used a nationwide discharge database to select KT recipients admitted to Spanish hospitals from 2016 to 2020. We stratified patients according to diabetes status. We used multivariable logistic regression to identify the variables associated with IHM.

Results

A total of 14 594 KTs were performed in Spain (T2D, 22.28%; T1D, 3.72%). The number of KTs rose between 2016 and 2019 and and decreased from 2019 to 2020 in all groups. In patients with T2D, the frequency of KT complications increased from 21.08% in 2016 to 34.17% in 2020 (p<0.001). Patients with T2D had significantly more comorbidity than patients with T1D and patients without diabetes (p<0.001). Patients with T1D experienced KT rejection significantly more frequently (8.09%) than patients with T2D (5.57%).

COVID-19 was recorded in 26 out of the 2444 KTs performed in 2020, being found in 6 of the 39 patients deceased that year (15.38%) and in 0.83% of the survivors.

The variables associated with IHM were comorbidity and complications of KT. The presence of T1D was associated with IHM (OR 2.6; 95% CI 1.36 to 5.16) when patients without diabetes were the reference category. However, T2D was not associated with a higher IHM (OR 0.86; 95% CI 0.61 to 1.2).

Conclusions

The COVID-19 pandemic led to a decrease in the number of transplants. Patients with T1D have more rejection of the transplanted organ than patients with T2D. Fewer women with T2D undergo KT. The presence of T1D is a risk factor for IHM.
Tale of two zones: investigating the clinical outcomes and research gaps in peripheral and transition zone prostate cancer through a systematic review and meta-analysis
Authors: Ali Amin , Elumalai Thiraviyam , Venkatesulu BhanuPrasad , Hekman Lauren , Mistry Hitesh , Sachdeva Ashwin , Oliveira Pedro , Clarke Noel , Baena Esther , Choudhury Ananya , Bristow Robert G
Published: April 2024

Objective

To assess pathological characteristics, clinical features and outcomes of patients diagnosed with peripheral zone (PZ) and transition zone (TZ) prostate cancer after prostatectomy.

Methods and analysis

We systematically reviewed PubMed, EMBASE and MEDLINE. Primary endpoints were biochemical relapse-free survival (bRFS) and distant metastases rate; secondary endpoints included clinical and pathological features.

Results

Ten retrospective cohort studies were identified, six reported HRs for bRFS between PZ and TZ tumours. Patients with TZ tumours had significantly better bRFS (pooled HR 0.57 (0.47, 0.68)) than those with PZ tumours. Two studies reported a lower proportion of distant metastasis in patients diagnosed with TZ tumours compared with PZ tumours (1.5% vs 4.9% (median follow-up 7.0 years) and 0% vs 5% (median follow-up 7.8 years)). PZ tumours presented higher Gleason group and T staging more frequently, while TZ tumours were associated with higher prostate specific antigen levels at diagnosis.

Conclusion

PZ tumours were associated with poorer prognostic clinical features and outcomes. Despite adjusting for poor prognostic clinical features, PZ tumours consistently showed worse clinical outcomes than TZ tumours. Our systematic review underscores the need for further research comparing PZ and TZ prostate cancer to understand the underlying differences and refine clinical practice.
History and its relevance to contemporary and future leadership
Authors: Bricknell Martin
Published: April 2024

Background/Aim

This paper argues that an inquisitiveness into the history of medicine and healthcare organisation is an important characteristic of a leader seeking to understand why facts are as they are, before embarking on leading change. I had the privilege of 34 years of service in the UK Defence Medical Services, culminating in the most senior role of Surgeon General. I, and many of my military medical colleagues, are members of the Faculty of Medical Leadership and Management. Through this, I hope that we have been able to add an interesting dimension to the practice of medical leadership in UK health organisations.

Methods

This paper is a reflection on my personal experience suggesting that studying the history of military medicine can provide insights into the collective knowledge of previous generations, the process of organisational development during war, and the clinical and system innovations needed for the next war.

Results

This paper summarises my personal experience of the relevance of the history of military medicine in clinical practice and policy development within the UK Defence Medical Services. It has five sections starting with history as a trajectory of knowledge, and how this links to my personal career. I then show how history informed my leadership influence on policy and practice in four topics: the prevention of heat illness, the organisation of medical services, partnerships in military medicine, and organisational learning. The paper is framed around my personal experience over a career that spanned clinical practice, policy development, leadership on military operations, and finally senior strategic roles.

Conclusion

While I have placed my argument in the context of military medical leadership, I suggest that understanding history is just as important in civilian medical leadership.
Precise QCD predictions for W-boson production in association with a charm jet
Authors: Ridder A. Gehrmann-De , Gehrmann T. , Glover E. W. N. , Huss A. , Garcia A. Rodriguez , Stagnitto G.
Published: April 2024

The production of a W-boson with a charm quark jet provides a highly sensitive probe of the strange quark distribution in the proton. Employing a novel flavour dressing procedure to define charm quark jets, we compute W+charm-jet production up to next-to-next-to-leading order (NNLO) in QCD. We study the perturbative stability of production cross sections with same-sign and opposite-sign charge combinations for the W boson and the charm jet. A detailed breakdown according to different partonic initial states allows us to identify particularly suitable observables for the study of the quark parton distributions of different flavours.
FAULT-TOLERANT CONTROL ALGORITHM FOR AUTOMOTIVE ELECTRONIC MECHANICAL BRAKING RAMP ASSIST
Authors: LIANG JIANWEI
Published: April 2024

The electronic mechanical braking system directly affects the driving safety of automobiles, but there are auxiliary control methods. Therefore, a fault-tolerant control algorithm for automotive electronic mechanical braking ramp assistance is proposed. The faults of the electronic mechanical braking ramp assistance system and select sensor faults are analyzed as the main research object. By introducing a BP neural network, the longitudinal speed of the vehicle, the wheel speed, the difference between the target slip rate and the current slip rate, and the rate of change of the difference are taken as the network input. Online learning is used to adjust and update the weight coefficients of each layer of the network, output fault diagnosis results and optimized PI controller parameters, and achieve fault-tolerant control. Three different types of sensor fault signals were artificially added in the experimental testing. After the proposed fault-tolerant control method, the controlled signals were used to replace the fault signals, ensuring the normal driving of the car.
2-Local derivations of Heisenberg–Virasoro type Lie algebras
Authors: Xia Chunguang , Dong Xiao , Ma Tianyu
Published: April 2024

Let [Formula: see text] with [Formula: see text] be the Heisenberg–Virasoro type Lie algebras, and [Formula: see text] be a thin Lie algebra with only one diamond. In this paper, we study [Formula: see text]-local derivations on [Formula: see text] and [Formula: see text]. For [Formula: see text], we show that every [Formula: see text]-local derivation is a derivation for almost all parameter pairs [Formula: see text], generalizing some previous results, while for [Formula: see text], we show that it admits infinite many [Formula: see text]-local derivations which are not derivations. Along the way, we also prove that the space of outer derivations of [Formula: see text] is infinite-dimensional.
Divisor graphs and symmetries of finite abelian groups
Authors: LaGrange John D.
Published: April 2024

The algebraic composition of an element [Formula: see text] of a commutative binary structure [Formula: see text] is modeled by its divisor (pseudo)graph [Formula: see text] (which can be regarded as a simple graph if [Formula: see text] is an abelian group), whose vertices are the elements of [Formula: see text] such that two vertices [Formula: see text] and [Formula: see text] are adjacent if and only if [Formula: see text]. With respect to the action of a group of symmetries on the set of divisor pseudographs of [Formula: see text], the numbers of orbits are considered, and these numbers are shown to yield groupoid-isotopy invariants when [Formula: see text] is a finite abelian group. The minimum number of orbits is computed for every abelian group of order at most 11, and it is also determined for all finite cyclic groups. Moreover, systems of pseudographs that can be realized as those of finite abelian groups are completely characterized. In fact, recurrence relations are given for constructing systems of divisor pseudographs of finite cyclic groups, and all commutative binary structures that are isotopic to a finite abelian group are established.
Reliability Performance Improvement of the Storage System by Using Weibull and Linear-Exponential Distributions
Authors: Mutar Emad Kareem
Published: April 2024

This research paper delves into the theory of reliability and its applications in various fields, particularly in engineering manufacturing. The study aims to address the problem of enhancing the reliability and performance of storage systems by incorporating two types of components with different distributions. These components are assumed to be identical, but their failure rates vary over time. Type (a) components follow a Weibull distribution, while type (b) components have a Linear-exponential distribution. The research examines different characteristics of the system, including the mean time to failure (MTTF), [Formula: see text]-fractiles, and equivalence factor of reliability (EFR). To improve the storage system’s performance, the reduction, warm duplication and cold duplication techniques are implemented. Further, the cold duplication approach outperforms warm duplication and reduction methods. Before the improvement, the original system generally showed the lowest level of reliability. The results indicate that these techniques are effective, and the study provides numerical data to support this finding.
Unlocking the Potential of Trans-Himalayan High-Altitude Seabuckthorn (Hippophae rhamnoides) Plants in the Green Synthesis of Silver Nanoparticles Against Drug-Resistant Foodborne Pathogens: A Step Towards Sustainable Food Safety Goals
Authors: Arora Richa , Bharti Vijay Kumar , Dey Shubhankhi
Published: April 2024

Controlling foodborne pathogens is challenging due to the new emergence of antimicrobial resistance to conventional antimicrobials. Therefore, new alternative antimicrobials need to be developed to control foodborne pathogens and avoid microbial resistance. Furthermore, the potential of trans-Himalayan high-altitude seabuckthorn (Hippophae rhamnoides ) plants has not been explored much for the synthesis of silver nanoparticles having antibacterial properties. Hence, this study investigated the development of long-term stable silver nanomaterials using the aqueous extract of seabuckthorn leaves through a green-synthesis approach and evaluated their antibacterial efficacy. These synthesized nanomaterials were characterized along with their stability using UV spectrometry for lambda max ([Formula: see text]) characteristics. Further, the nanoparticles were evaluated for zeta potential (mV), polydispersity index, particle size distribution (nm), electrophoretic mobility ([Formula: see text]mcm/Vs) and conductivity (mS/cm). The seabuckthorn silver nanoparticles are of 260[Formula: see text]nm size and stable (−15[Formula: see text]mV zeta potential) with good antioxidant and antibacterial properties against two typical food pathogens, e.g., Escherichia coli (MTCC 3222) and Salmonella typhimurium (MTCC 3224). Hence, this study developed an eco-friendly, rapid, low-cost green synthesis method for the development of seabuckthorn-coated, stable silver nanoparticles with good antibacterial activity against foodborne pathogens.
Locally identifying coloring of corona product of graphs
Authors: Pavithra R. , Reji T.
Published: April 2024

A proper vertex coloring of a graph [Formula: see text] is said to be locally identifying (lid-coloring) if for any pair [Formula: see text] of adjacent vertices with distinct closed neighborhoods, the sets of colors in the closed neighborhoods of [Formula: see text] and [Formula: see text] are different. The smallest integer [Formula: see text] for which [Formula: see text] admits a lid-coloring is called the lid-chromatic number of [Formula: see text]. The corona product [Formula: see text] of two graphs [Formula: see text] and [Formula: see text] is the graph obtained by taking one copy of [Formula: see text] and [Formula: see text] copies of [Formula: see text], and then joining the [Formula: see text]th vertex of [Formula: see text] to every vertex in the [Formula: see text]th copy of [Formula: see text] for every [Formula: see text], where [Formula: see text] denotes the number of elements in the set [Formula: see text]. In this paper, the lid-chromatic number of corona product of graphs has been studied.
Development of Raspberry Pi-based Processing Unit for UV Photon-Counting Detectors
Authors: Chandra P. Bharat , Nair B. G. , Ghatul Shubham Jankiram , Babu S Mahesh , Jain Shubhangi , Rai Richa , Mohan Rekhesh , Safonova Margarita , Murthy Jayant
Published: April 2024

In ultraviolet (UV) astronomical observations, photons from the sources are very few compared to the visible or infrared (IR) wavelength ranges. Detectors operating in the UV usually employ a photon-counting mode of operation. These detectors usually have an image intensifier sensitive to UV photons and a readout mechanism that employs photon counting. The development of readouts for these detectors is resource-intensive and expensive. In this paper, we describe the development of a low-cost UV photon-counting detector processing unit that employs a Raspberry Pi (RPi) with its built-in readout to perform the photon-counting operation. Our system can operate in both [Formula: see text] and [Formula: see text] window modes at 30 frames per second (fps). The system can be built quickly from readily available custom-off-the-shelf (COTS) components and is thus used in inexpensive CubeSats or small satellite missions.
Multi-Domain Image-to-Image Translation with Cross-Granularity Contrastive Learning
Authors: Fu Huiyuan , Liu Jin , Yu Ting , Wang Xin , Ma Huadong
Published: April 2024

The objective of multi-domain image-to-image translation is to learn the mapping from a source domain to a target domain in multiple image domains while preserving the content representation of the source domain. Despite the importance and recent efforts, most previous studies disregard the large style discrepancy between images and instances in various domains, or fail to capture instance details and boundaries properly, resulting in poor translation results for rich scenes. To address these problems, we present an effective architecture for multi-domain image-to-image translation that only requires one generator. Specifically, we provide detailed procedures for capturing the features of instances throughout the learning process, as well as learning the relationship between the style of the global image and that of a local instance in the image by enforcing the cross-granularity consistency. In order to capture local details within the content space, we employ a dual contrastive learning strategy that operates at both the instance and patch levels. Extensive studies on different multi-domain image-to-image translation datasets reveal that our proposed method outperforms state-of-the-art approaches.
Understanding the Potential of FPGA-based Spatial Acceleration for Large Language Model Inference
Authors: Chen Hongzheng , Zhang Jiahao , Du Yixiao , Xiang Shaojie , Yue Zichao , Zhang Niansong , Cai Yaohui , Zhang Zhiru
Published: April 2024

Recent advancements in large language models (LLMs) boasting billions of parameters have generated a significant demand for efficient deployment in inference workloads. While hardware accelerators for Transformer-based models have been extensively studied, the majority of existing approaches rely on temporal architectures that reuse hardware units for different network layers and operators. However, these methods often encounter challenges in achieving low latency due to considerable memory access overhead.

This article investigates the feasibility and potential of model-specific spatial acceleration for LLM inference on field-programmable gate arrays (FPGAs). Our approach involves the specialization of distinct hardware units for specific operators or layers, facilitating direct communication between them through a dataflow architecture while minimizing off-chip memory accesses. We introduce a comprehensive analytical model for estimating the performance of a spatial LLM accelerator, taking into account the on-chip compute and memory resources available on an FPGA. This model can be extended to multi-FPGA settings for distributed inference. Through our analysis, we can identify the most effective parallelization and buffering schemes for the accelerator and, crucially, determine the scenarios in which FPGA-based spatial acceleration can outperform its GPU-based counterpart.

To enable more productive implementations of an LLM model on FPGAs, we further provide a library of high-level synthesis (HLS) kernels that are composable and reusable. This library will be made available as open-source. To validate the effectiveness of both our analytical model and HLS library, we have implemented Bidirectional Encoder Representations from Transformers (BERT) and Generative Pre-trained Transformers (GPT2) on an AMD Xilinx Alveo U280 FPGA device. Experimental results demonstrate our approach can achieve up to 13.4× speedup when compared to previous FPGA-based accelerators for the BERT model. For GPT generative inference, we attain a 2.2× speedup compared to Design for Excellence, an FPGA overlay, in the prefill stage, while achieving a 1.9× speedup and a 5.7× improvement in energy efficiency compared to the NVIDIA A100 GPU in the decode stage.
A Two-Step Surface Modification Optimization for Performance Recovery of NaNi0.33Fe0.33Mn0.33O2
Authors: Rong Wenyi , He Kepiao , Xiong Yonglian , Yi Ting , Hou Quanhui , Li Chunsheng , Sun Yan
Published: April 2024

Due to its excellent electrochemical performance, O3-type NaNi0.33Fe0.33Mn0.33O2 (NFM) is one of the most promising cathode materials for sodium ion. However, its poor air stability has limited the industrialization process. In this work, a low-temperature two-step method which included carbon doping and acid treatment was used to improve the electrochemical property of the air-aged NaNi0.33Fe0.33Mn0.33O2. X-ray diffraction results indicated that the structure of modified NFM (NFM-M) has good crystal structure stability. NFM-M, NFM-48H (NFM after air ageing of 48 h) and fresh NFM possessed a discharge capacity of 95.25, 74.92, and 100.79 mAh·g−1 in the first cycle, respectively. The modified sample exhibits outstanding cycling stability, with a capacity retention of 90.15% after 100 cycles at 0.1 C rate. Moreover, the NFM-M sample delivers excellent rate capability with improved capacity retention of 66.9% at 2.0 C rate.
Identifying an Understudied Interface: Preliminary Evaluation of the Use of Retention Ponds on Commercial Poultry Farms by Wild Waterfowl
Authors: Sullivan Jeffery D. , McDonough Ayla M. , Lescure Lauren M. , Prosser Diann J.
Published: April 2024

While the recent incursion of highly pathogenic avian influenza into North America has resulted in notable losses to the commercial poultry industry, the mechanism by which virus enters commercial poultry houses is still not understood. One theorized mechanism is that waterfowl shed virus into the environment surrounding poultry farms, such as into retention ponds, and is then transmitted into poultry houses via bridge species. Little is known about if and when wild waterfowl use these retention ponds, leading to uncertainty regarding the potential significance of this interface. To quantify the use of retention ponds on commercial poultry farms by wild waterfowl, we surveyed 12 such ponds across Somerset and Dorchester counties, Maryland, USA. This region was chosen due to the high level of poultry production and its importance for migratory waterfowl. Surveys consisted of recording waterfowl visible on the retention ponds from public roadways at least once per week from 20 September 2022–31 March 2023. Throughout the course of this study, we observed a total of nine species of waterfowl using retention ponds on commercial poultry farms at nine of 12 sites. The number of waterfowl observed at retention ponds varied notably throughout the course of our survey period, with values generally following trends of fall migration within each species indicating that resident birds were not the only individuals to utilize these habitats. Additionally, waterfowl use was highest at sites with little vegetation immediately surrounding the pond, and lowest when ponds were surrounded by trees. Our data suggest that retention ponds on commercial poultry farms present a notable interface for waterfowl to introduce avian influenza viruses to farm sites. However, additional testing and surveys could provide further insight into whether it may be possible to reduce the use of these habitats by wild waterfowl through vegetative management as preliminarily reported here.
Lipase‐Catalyzed Synthesis of Cetyl Palmitate in the Presence of n‐Hexane and Ethyl Ether
Authors: Gealh Gustavo , Santos Maynara L. A. , Corazza Marcos L. , Bonilla-Petriciolet Adrián , Voll Fernando A. P.
Published: April 2024

Cetyl palmitate was produced by the esterification of palmitic acid with cetyl alcohol using n‐hexane and ethyl ether as solvents and a commercial lipase as a catalyst. The effect of solvents to reagents mass ratio (0.5 : 1–3 : 1), percentage of n‐hexane in the solvent mixture (0–100%), and reaction temperature (25–55°C) on the reaction rate were evaluated for a fixed amount of enzyme (1 wt% related to the total mass of substrates) in an equimolar mixture of palmitic acid and cetyl alcohol. Temperature and n‐hexane percentage in the solvent had positive effects on the reaction rate. The total solvent‐to‐reagent mass ratio showed a negative effect on the reaction rate when a solvent mixture rich in ethyl ether was used. The higher the concentration of n‐hexane, the lower the effect of the mass ratio of solvents to reagents on the reaction rate. Although the amount of ethyl ether in the solvent mixture had a negative effect on the reaction rate, it had a positive effect on the solubility of the system, that is, the more ethyl ether in the mixture, the lower the solvent to reagents mass ratio required to ensure a homogeneous mixture. A ping‐pong bi‐bi mechanism‐based model was proposed to represent the system kinetics and was well fitted to the experimental data.
Supplementary Figures 1-7 from Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRASG12C Inhibitor Efficacy
Authors: Mukhopadhyay Suman , Huang Hsin-Yi , Lin Ziyan , Ranieri Michela , Li Shuai , Sahu Soumyadip , Liu Yingzhuo , Ban Yi , Guidry Kayla , Hu Hai , Lopez Alfonso , Sherman Fiona , Tan Yi Jer , Lee Yeuan Ting , Armstrong Amanda P. , Dolgalev Igor , Sahu Priyanka , Zhang Tinghu , Lu Wenchao , Gray Nathanael S. , Christensen James G. , Tang Tracy T. , Velcheti Vamsidhar , Khodadadi-Jamayran Alireza , Wong Kwok-Kin , Neel Benjamin G.
Published: April 2024

Supplementary Figures 1-7 including Figure legends
Applications and Opportunities for Immune Cell CAR Engineering in Comparative Oncology
Authors: Rotolo Antonia , Atherton Matthew J.
Published: April 2024

Chimeric antigen receptor (CAR) T–adoptive cell therapy has transformed the treatment of human hematologic malignancies. However, its application for the treatment of solid tumors remains challenging. An exciting avenue for advancing this field lies in the use of pet dogs, in which cancers that recapitulate the biology, immunological features, and clinical course of human malignancies arise spontaneously. Moreover, their large size, outbred genetic background, shared environment with humans, and immunocompetency make dogs ideal for investigating and optimizing CAR therapies before human trials. Here, we will outline how challenges in early clinical trials in patients with canine lymphoma, including issues related to autologous CAR T-cell manufacturing, limited CAR T-cell persistence, and tumor antigen escape, mirrored challenges observed in human CAR T trials. We will then highlight emerging adoptive cell therapy strategies currently under investigation in dogs with hematological and solid cancers, which will provide crucial safety and efficacy data on novel CAR T regimens that can be used to support clinical trials. By drawing from ongoing studies, we will illustrate how canine patients with spontaneous cancer may serve as compelling screening platforms to establish innovative CAR therapy approaches and identify predictive biomarkers of response, with a specific emphasis on solid tumors. With increased funding for canine immunotherapy studies, multi-institutional investigations are poised to generate highly impactful clinical data that should translate into more effective human trials, ultimately benefiting both human and canine cancer patients.
A Proposed Framework and Lexicon for Cancer Prevention
Authors: Castle Philip E. , Faupel-Badger Jessica M. , Umar Asad , Rebbeck Timothy R.
Published: April 2024

Cancer prevention is central to efforts to control the burden of cancer. We propose a new terminology framework to help guide these efforts and promote a key equity principle: “equal care for equal risk.”
The 3D Revolution in Cancer Discovery
Authors: Wang Linghua , Li Mingyao , Hwang Tae Hyun
Published: April 2024

The transition from 2D to 3D spatial profiling marks a revolutionary era in cancer research, offering unprecedented potential to enhance cancer diagnosis and treatment. This commentary outlines the experimental and computational advancements and challenges in 3D spatial molecular profiling, underscoring the innovation needed in imaging tools, software, artificial intelligence, and machine learning to overcome implementation hurdles and harness the full potential of 3D analysis in the field.
Somatic Mutations in Normal Tissues: Calm before the Storm
Authors: Rahal Zahraa , Scheet Paul , Kadara Humam
Published: April 2024

We explore the phenomenon of somatic mutations, including those in cancer driver genes, that are present in healthy, normal-appearing tissues and their potential implications for cancer development. We also examine the landscape of these somatic mutations, discuss the role of clonal cell competition and external factors like inflammation in enhancing the fitness of mutant clones, and conclude by considering how understanding these mutations will aid in prevention and/or interception of cancer.
Cell States in Cancer: Drivers, Passengers, and Trailers
Authors: Gargiulo Gaetano , Serresi Michela , Marine Jean-Christophe
Published: April 2024

Cancer is traditionally perceived through a genetic lens, with therapeutic strategies targeting oncogenic driver mutations. We advocate an overarching framework recognizing tumors as comprising driver, passenger, and trailer cell states: Tailoring therapies to simultaneously target driver genetics and cell states may enhance effectiveness and durability.
Chemotherapy and the Extra-Tumor Immune Microenvironment: EXTRA-TIME
Authors: Phan Tri Giang , Weilbaecher Katherine N. , Aft Rebecca , Croucher Peter I. , Chaffer Christine L.
Published: April 2024

Understandably, conventional therapeutic strategies have focused on controlling primary tumors. We ask whether the cost of such strategies is actually an increased likelihood of metastatic relapse.
Phase-Separated Biomolecular Condensation in Cancer: New Horizons and Next Frontiers
Authors: Bivona Trever G.
Published: April 2024

Beyond lipid membrane compartments, cells including cancer cells utilize various membraneless compartments, often termed biomolecular condensates, to regulate or organize key cellular processes underlying physiologic or pathologic phenotypes. In this commentary, the emergence of biomolecular condensation in cancer biology is highlighted, with a focus on key unanswered questions and with implications for improving the understanding of cancer pathogenesis and developing innovative cancer management strategies.
From Base Pairs to City Squares: Comprehensive Precision Oncology for the Future
Authors: Leader Amy E. , McNair Christopher M. , Johnson Jennifer M.
Published: April 2024

An increased understanding of the role of the social determinants of health in cancer prevention, cancer care, and outcomes can lead to their integration into genetics and genomics as well as informing interventions and clinical trials, creating a comprehensive precision oncology framework.
Advancing Cancer Interception
Authors: Domchek Susan M. , Vonderheide Robert H.
Published: April 2024

Rapid advances in technology and therapeutics, along with better methods to discern who is at risk for cancer by genetic testing and other means, has enabled the development of cancer interception. Targeted therapies and “immuno-interception” may eliminate premalignant lesions and require clinical trial and treatment paradigms altogether distinct from current approaches.
Elucidating the Cell Surfaceome to Accelerate Cancer Drug Development
Authors: Geri Jacob B. , Pao William
Published: April 2024

Cell surface proteins represent ideal therapeutic targets because of their accessibility to antibodies, T cell–directed therapies, and radiotherapies, but there are only 25 therapeutically relevant cell surface targets for which cancer therapies are approved in the United States or European Union. This commentary calls for intensified research into mapping the universe of cell surface proteins – the cell surfaceome – in order to accelerate cancer drug development.
The Biden Cancer Moonshot: American Progress, Global Commitment
Authors: Young Catharine G. , Carnival Danielle M.
Published: April 2024

The Biden Cancer Moonshot is mobilizing efforts toward achieving two clear goals that President Joe Biden and First Lady Jill Biden set: prevent more than 4 million cancer deaths by 2047 and improve the experience of people who are touched by cancer. To achieve these ambitious but achievable goals, the Biden Cancer Moonshot is driving progress across the cancer journey utilizing all facets of the oncology community – federal agencies, and departments, private companies, healthcare providers, patient groups, and philanthropies - to end cancer as we know it here in the United States and all around the world.
The Neo-Open Reading Frame Peptides That Comprise the Tumor Framome Are a Rich Source of Neoantigens for Cancer Immunotherapy
Authors: Martin Michael V. , Aguilar-Rosas Salvador , Franke Katka , Pieterse Mark , Langelaar Jamie van , Schreurs Renée , Bijlsma Maarten F. , Besselink Marc G. , Koster Jan , Timens Wim , Khasraw Mustafa , Ashley David M. , Keir Stephen T. , Ottensmeier Christian H. , King Emma V. , Verheij Joanne , Waasdorp Cynthia , Valk Peter J.M. , Engels Sem A.G. , Oostenbach Ellen , van Dinter Jip T. , Hofman Damon A. , Mok Juk Yee , van Esch Wim J.E. , Wilmink Hanneke , Monkhorst Kim , Verheul Henk M.W. , Poel Dennis , Hiltermann T. Jeroen N. , Kempen Léon C.L.T. van , Groen Harry J.M. , Aerts Joachim G.J.V. , Heesch Sebastiaan van , Löwenberg Bob , Plasterk Ronald , Kloosterman Wigard P.
Published: April 2024

Identification of immunogenic cancer neoantigens as targets for therapy is challenging. Here, we integrate the whole-genome and long-read transcript sequencing of cancers to identify the collection of neo-open reading frame peptides (NOP) expressed in tumors. We termed this collection of NOPs the tumor framome. NOPs represent tumor-specific peptides that are different from wild-type proteins and may be strongly immunogenic. We describe a class of hidden NOPs that derive from structural genomic variants involving an upstream protein coding gene driving expression and translation of noncoding regions of the genome downstream of a rearrangement breakpoint, i.e., where no gene annotation or evidence for transcription exists. The entire collection of NOPs represents a vast number of possible neoantigens particularly in tumors with many structural genomic variants and a low number of missense mutations. We show that NOPs are immunogenic and epitopes derived from NOPs can bind to MHC class I molecules. Finally, we provide evidence for the presence of memory T cells specific for hidden NOPs in peripheral blood from a patient with lung cancer. This work highlights NOPs as a major source of possible neoantigens for personalized cancer immunotherapy and provides a rationale for analyzing the complete cancer genome and transcriptome as a basis for the detection of NOPs.
Preclinical Evaluation of Off-The-Shelf PD-L1+ Human Natural Killer Cells Secreting IL15 to Treat Non–Small Cell Lung Cancer
Authors: Lu Ting , Ma Rui , Mansour Anthony G. , Bustillos Christian , Li Zhiyao , Li Zhenlong , Ma Shoubao , Teng Kun-Yu , Chen Hanyu , Zhang Jianying , Villalona-Calero Miguel A. , Caligiuri Michael A. , Yu Jianhua
Published: April 2024

We described previously a human natural killer (NK) cell population that upregulates PD-L1 expression upon recognizing and reacting to tumor cells or exposure to a combination of IL12, IL18, and IL15. Here, to investigate the safety and efficacy of tumor-reactive and cytokine-activated (TRACK) NK cells, human NK cells from umbilical cord blood were expanded, transduced with a retroviral vector encoding soluble (s) IL15, and further cytokine activated to induce PD-L1 expression. Our results show cryopreserved and thawed sIL15_TRACK NK cells had significantly improved cytotoxicity against non–small cell lung cancer (NSCLC) in vitro when compared with non-transduced (NT) NK cells, PD-L1+ NK cells lacking sIL15 expression (NT_TRACK NK), or NK cells expressing sIL15 without further cytokine activation (sIL15 NK cells). Intravenous injection of sIL15_TRACK NK cells into immunodeficient mice with NSCLC significantly slowed tumor growth and improved survival when compared with NT NK and sIL15 NK cells. The addition of the anti-PD-L1 atezolizumab further improved control of NSCLC growth by sIL15_TRACK NK cells in vivo. Moreover, a dose-dependent efficacy was assessed for sIL15_TRACK NK cells without observed toxicity. These experiments indicate that the administration of frozen, off-the-shelf allogeneic sIL15_TRACK NK cells is safe in preclinical models of human NSCLC and has potent antitumor activity without and with the administration of atezolizumab. A phase I clinical trial modeled after this preclinical study using sIL15_TRACK NK cells alone or with atezolizumab for relapsed or refractory NSCLC is currently underway (NCT05334329).
FIGURE 6 from Induction of Viral Mimicry Upon Loss of DHX9 and ADAR1 in Breast Cancer Cells
Authors: Cottrell Kyle A. , Ryu Sua , Pierce Jackson R. , Soto Torres Luisangely , Bohlin Holly E. , Schab Angela M. , Weber Jason D.
Published: April 2024

Rescue of PKR activation by DHX9 mutants in SK-BR-3. A, Schematic showing the domain structure of ADAR1 isoforms, DHX9 and mutants of DHX9, dsRBD refers to the dsRNA binding domain. B, Representative immunoblot showing the phenotype of ADAR1 and DHX9 knockdown with DHX9, DHX9K417R or dsRBD-EGFP overexpression in SK-BR-3. Immunoblots for other replicates and uncropped blots can be found in Source Data Figures. C, Fold change of PKR phosphorylation at Thr-446 upon ADAR1 and DHX9 knockdown with DHX9, DHX9K417R or dsRBD-EGFP overexpression in SK-BR-3, quantified from immunoblots in B. Quantification of protein expression for other proteins of interest can be found in Supplementary Fig. S8B–S8F. D, Representative foci formation phenotype of ADAR1 and DHX9 knockdown with DHX9, DHX9K417R or dsRBD-EGFP overexpression in SK-BR-3. Quantification of relative foci area is shown in E. Timepoints for collecting protein lysates and foci formation are the same as described in Fig. 4 for SK-BR-3. Bars represent the average of at least three replicates, error bars are ± SD. *, P < 0.05; **, P < 0.01; ***, P < 0.001. P values determined by Dunnett test.
LINC00472 Regulates Ferroptosis of Neurons in Alzheimer’s Disease via FOXO1
Authors: Lin Ping , Wang Jiandong , Li Yuyan , Li Guofeng , Wang Ying
Published: April 2024

Introduction: The objective of the study was to explore the molecular mechanism of long noncoding RNA (lncRNA) LINC00472 in Alzheimer’s disease (AD) and identify potential novel targets for AD therapy. Method: Ferroptosis-related lncRNAs were screened by GEO database. AD mouse model was constructed for in vivo experiments. The content of Aβ protein and tau protein hyperphosphorylation were examined in hippocampal tissue samples of mice. Subsequently, HT22 cells were induced with Aβ25–35 to establish a neuronal injury model of AD in vitro. The expression of FOXO1, a key gene for ferroptosis, was verified by overexpressing/knocking down the LINC00472. The effects of LINC00472 on ROS and lipid peroxidation content, GPX4, and tau protein in AD model cells were examined by ROS assay, MDA assay, Western blot, and qRT-PCR. Subsequently, the expression of iron ion, FTH, TfRC, and Fpn protein were detected in AD cells. Results: The level of FOXO1 was positively correlated with the degree of AD. In vivo experiments showed that the expression of Aβ and tau hyperphosphorylated were significantly reduced in the inhibitor group and iron was significantly reduced relative to the AD group. In the AD cell model, the content of lipid peroxide was upregulated, GPX4 protein and mRNA were decreased, and phosphorylation of tau protein was enhanced in the AD cell model relative to the control group. Whereas knocking down LINC00472 inhibited the upregulation of lipid peroxide, decreased the level of GPX4, and enhanced tau protein phosphorylation, and reduced iron accumulation in AD cells. Conclusions: LINC00472 affects ferroptosis in AD by regulating iron accumulation in neuronal cells.
Infective Endocarditis and Antithrombotic Therapy
Authors: Morelli Cristina , Rocca Bianca , Gigante Bruna
Published: April 2024

Background: Incidence of infective endocarditis (IE) is progressively raising because of the increasing number of cardiovascular invasive procedures, support treatment and devices, awareness in the medical community, and improved diagnostic modalities. IE pathophysiology is a unique model of immunothrombosis, and the clinical course is often complicated by either embolic or hemorrhagic events. Managing antithrombotic treatment is challenging and the level of supporting evidence scant. The aim of this review was to discuss and present the embolic and bleeding complication associated with IE and review the available evidence on antithrombotic treatment in patients with IE with and without a previous indication to antithrombotic drugs. Summary: Embolic events occur in 20–40% of patients with IE and are associated with high morbidity and mortality. Acute ischemic stroke is the most common neurological complication. A beneficial effect of antithrombotic therapy in preventing ischemic stroke for patients with IE has never been formally tested in adequately powered randomized clinical trials. Atrial fibrillation is a common complication associated with severe infections, requiring anticoagulation. Furthermore, patients with IE have a high risk of unprovoked and anticoagulation treatment-related bleeding. In particular, intracerebral bleeding is the most severe complication in about 5% of patients with IE. Single antiplatelet therapy with low-dose aspirin after hospitalization for IE has been shown to reduce causes mortality within 90 days without an increase of hemorrhagic strokes. In the absence of bleeding complications, recent guidelines recommend to maintain low-dose aspirin. No data are available on the management of patients with IE while on dual antiplatelet therapy. Key Messages: Several gaps in knowledge remain about antithrombotic management in patients with IE and most of the evidence relies on observational studies. Individualized strategies based on clinical evaluation, comorbidities, patient engagement, and shared decisions strategies are encouraged.
Evaluating Pain Management from Peripheral Nerve Block for Geriatric Patients following Bipolar Hemiarthroplasty for Displaced Femoral-Neck Fracture
Authors: Lee Tae Sung , Kwon Hyuck Min , Park Jun Young , Park Min Cheol , Choi Yong Seon , Park Kwan Kyu
Published: April 2024

Introduction: The purpose of this study was to evaluate peripheral nerve block (PNB) effectiveness in postoperative pain management and surgical outcomes for displaced femoral-neck fracture in geriatric patients (>70 years) who underwent bipolar hemiarthroplasty (BHA). Methods: From January 2017 to December 2021, 231 geriatric patients with displaced femoral-neck fracture who consecutively underwent BHA were retrospectively reviewed. Patients were divided into two groups: the patient-controlled analgesia (PCA) group (n = 132) who received only intravenous (IV) PCA for postoperative pain management, and all others who received PNB with IV PCA (PNB+PCA) such as femoral nerve block or fascia iliaca compartment block after surgery (n = 99). Primary outcomes were postoperative visual analog scale (VAS) at rest and during activity at 6, 24, and 48 h postoperatively. Secondary outcomes were postoperative complications, changes in hemoglobin, length of hospital stay, and total morphine usage after surgery. Results: Postoperative resting VAS at 6 h and 48 h was significantly lower in the PNB+PCA group compared with the PCA group (p = 0.075, p = 0.0318, respectively). However, there was no significant difference in either resting VAS at 24 h or active VAS. Complications of pneumonia and delirium until 1 month postoperative were significantly lower in the PNB + PCA group than the PCA group (p = 0.0022, p = 0.0055, respectively). Conclusion: PNB with IV PCA seems to have a beneficial effect on geriatric femoral-neck patients who underwent BHA with postoperative analgesia for reducing postoperative resting pain and complications, especially pneumonia and delirium.
Association between Chronic Obstructive Pulmonary Disease and Hearing Loss with Impaired Speech Recognition: A Cross-Sectional Study
Authors: Belleze Leticia , Burch Monique Olivia , Soares Luciana Aparecida Teixeira , Pandini Viviane Cristina Martori , Prestes Raquel , Bertolino Jessica Regina , Mamoni Ronei Luciano , Ponte Eduardo Vieira
Published: April 2024

Introduction: Studies have identified a greater risk of sensory neural hearing loss in individuals with chronic obstructive pulmonary disease (COPD) compared to healthy individuals, but it is unclear whether they are at increased risk of hearing loss with impaired speech recognition. The aim of this study was to assess whether COPD is associated with hearing loss that affects speech recognition. Methods: This is a case-control study. We screened individuals from health facilities in the municipality of Jundiai. We enrolled a test group of individuals with COPD and an age-matched control group composed of individuals with asthma. The selected individuals attended an appointment with a chest physician, responded to questionnaires, and underwent tonal and speech audiometry. Adjusted binary logistic regression analysis evaluated whether COPD was associated with reduced speech recognition. Results: We enrolled 36 individuals with COPD and 72 with asthma. Individuals with COPD were more likely to have a reduced speech recognition compared to asthmatic individuals (reduced recognition of three-syllable words: adjusted OR 3.72, 95 CI [1.38–10.02]) (reduced recognition of monosyllable words: adjusted OR 4.74, 95 CI [1.52–14.76]). Conclusion: We conclude that individuals with COPD from primary and secondary healthcare facilities have at least 38% greater risk of hearing loss with reduced speech recognition compared to an age-matched control group of individuals with asthma recruited from the same facilities. We recommend that longitudinal studies evaluate whether regular screening could contribute to the prevention or early treatment of hearing loss in individuals with moderate-severe COPD.