bluuebunny/crossref_metadata_2025 huggingface dataset:
Shifting quality analysis of unmanned tractor equipped with series hydro-mechanical transmission
Authors: Chen Xiaohan , Zhao Yehui , Liu Kuan , Wang Guangming , Song Yue , Chakrabarti Prasun
Published: March 2024

The series hydro-mechanical transmission (HMT) can improve the power performance and fuel economy of unmanned tractors at a lower cost. However, its shifting impact problem needs to be solved before it can be applied in practice. In this study, the control parameters of the HMT power-shift system were optimized from the perspectives of energy loss and driving comfort to improve the shifting quality of the transmission. First, the powertrain of the HMT was introduced. Second, a shifting dynamics model of the HMT was established and experimentally validated. Third, based on the single-factor simulation results, the influence of each factor on the shifting quality of the tractor was analyzed. Finally, a matching strategy for shifting parameters was proposed, and related simulation analysis was conducted on the shifting quality under plowing conditions. Compared to the standard parameters, the results show that the optimized shift parameters reduce the sliding friction work of the clutch under 9 operating conditions as well as the peak acceleration of the tractor under 12 operating conditions. In summary, the parameter-matching method proposed in this study was effective and provided theoretical and methodological support for the development of HMT and its control system for unmanned tractors.
Optimal Re-Materialization Strategies for Heterogeneous Chains: How to Train Deep Neural Networks with Limited Memory
Authors: Beaumont Olivier , Eyraud-Dubois Lionel , Herrmann Julien , Joly Alexis , Shilova Alena
Published: March 2024

Training in Feed Forward Deep Neural Networks is a memory-intensive operation which is usually performed on GPUs with limited memory capacities. This may force data scientists to limit the depth of the models or the resolution of the input data if data does not fit in the GPU memory. The re-materialization technique, whose idea comes from the checkpointing strategies developed in the Automatic Differentiation literature, allows data scientists to limit the memory requirements related to the storage of intermediate data (activations), at the cost of an increase in the computational cost.

This paper introduces a new strategy of re-materialization of activations that significantly reduces memory usage. It consists in selecting which activations are saved and which activations are deleted during the forward phase and then recomputing the deleted activations when they are needed during the backward phase.

We propose an original computation model that combines two types of activation savings: either only storing the layer inputs or recording the complete history of operations that produced the outputs. This paper focuses on the fully heterogeneous case, where the computation time and the memory requirement of each layer is different. We prove that finding the optimal solution is NP-hard and that classical techniques from Automatic Differentiation literature do not apply. Moreover, the classical assumption of memory persistence of materialized activations, used to simplify the search of optimal solutions, does not hold anymore. Thus, we propose a weak memory persistence property and provide a dynamic program to compute the optimal sequence of computations.

This algorithm is made available through the
Rotor
software, a PyTorch plug-in dealing with any network consisting of a sequence of layers, each of them having an arbitrarily complex structure. Through extensive experiments, we show that our implementation consistently outperforms existing re-materialization approaches for a large class of networks, image sizes, and batch sizes.
Algorithm 1042: Sparse Precision Matrix Estimation with
SQUIC
Authors: Eftekhari Aryan , Gaedke-Merzhäuser Lisa , Pasadakis Dimosthenis , Bollhöfer Matthias , Scheidegger Simon , Schenk Olaf
Published: March 2024

We present
SQUIC
, a fast and scalable package for sparse precision matrix estimation. The algorithm employs a second-order method to solve the

\(\ell_{1}\)

-regularized maximum likelihood problem, utilizing highly optimized linear algebra subroutines. In comparative tests using synthetic datasets, we demonstrate that
SQUIC
not only scales to datasets of up to a million random variables but also consistently delivers runtimes that are significantly faster than other well-established sparse precision matrix estimation packages. Furthermore, we showcase the application of the introduced package in classifying microarray gene expressions. We demonstrate that by utilizing a matrix form of the tuning parameter (also known as the regularization parameter),
SQUIC
can effectively incorporate prior information into the estimation procedure, resulting in improved application results with minimal computational overhead.
IGF1 promotes human myotube differentiation toward a mature metabolic and contractile phenotype
Authors: Dreher Simon I. , Grubba Paul , von Toerne Christine , Moruzzi Alessia , Maurer Jennifer , Goj Thomas , Birkenfeld Andreas L. , Peter Andreas , Loskill Peter , Hauck Stefanie M. , Weigert Cora
Published: March 2024

Human skeletal muscle models are highly valuable to study how exercise prevents type 2 diabetes without invasive biopsies. Current models did not fully recapitulate the function of skeletal muscle especially during exercise. By supplementing insulin-like growth factor 1 (IGF1), the authors developed a functional human skeletal muscle model characterized by inducible contractility and increased oxidative and insulin-sensitive metabolism. The novel protocol overcomes the limitations of previous standards and enables investigation of exercise on a molecular level.
Bidirectional relation between dipeptidyl peptidase 4 and angiotensin II type I receptor signaling
Authors: Martins Flavia L. , Ribeiro-Silva Joao Carlos , Nistala Ravi , Girardi Adriana C. C.
Published: March 2024

Cardiometabolic diseases are often associated with heightened levels of angiotensin II (Ang II), which accounts for the observed oxidative stress, inflammation, and fibrosis. Accumulating evidence indicates a parallel upregulation of dipeptidyl dipeptidase 4 (DPP4) activity in cardiometabolic diseases, with its inhibition shown to mitigate oxidative stress, inflammation, and fibrosis. These findings highlight an overlap between the pathophysiological mechanisms used by Ang II and DPP4. Recent evidence demonstrates that targeted inhibition of DPP4 prevents the rise in Ang II and its associated molecules in experimental models of cardiometabolic diseases. Similarly, inhibitors of the angiotensin I-converting enzyme (ACE) or Ang II type 1 receptor (AT1R) blockers downregulate DPP4 activity, establishing a bidirectional relationship between DPP4 and Ang II. Here, we discuss the current evidence supporting the cross talk between Ang II and DPP4, along with the potential mechanisms promoting this cross regulation. A comprehensive analysis of this bidirectional relationship across tissues will advance our understanding of how DPP4 and Ang II collectively promote the development and progression of cardiometabolic diseases.
Activation of cardiac parasympathetic and sympathetic activity occurs at different skin temperatures during face cooling
Authors: Gorini Pereira Felipe , McBryde Muhamed , Reynolds Morgan , Sackett James R. , Chapman Christopher L. , Gideon Elizabeth A. , Schlader Zachary J. , Johnson Blair D.
Published: March 2024

Using a progressive face cooling challenge, we demonstrated that peak sympathetic activation occurs at a higher forehead skin temperature (forehead temperature: 19°C; stimulus temperature: 7°C) than peak cardiac parasympathetic activation (forehead temperature: 11°C; stimulus temperature: 0°C). Therefore, we suggest using a sufficiently cold stimulus (∼0°C ) when using face cooling to interrogate autonomic activation to stimulate both the sympathetic and cardiac parasympathetic nervous systems.
Healthcare Workers’ General Health and Its Relation with Anxiety, Anger, and Posttraumatic Stress Disorder during COVID‐19 Outbreak in Southeast Iran
Authors: Malakoutikhah Alireza , Ahmadi Lari Leila , Baharloo Pooya , Al-Amer Rasmieh , Alnaiem Mohamed , Khaluei Hossein , Dehghan Mahlagha
Published: March 2024

Background. Healthcare workers during the COVID‐19 pandemic played an effective role in providing preventive and curative measures. Scientific evidence confirmed that the outbreak of this disease has caused numerous psychological problems such as pre‐ and posttraumatic stress disorder (PTSD), anxiety, depression, and anger at a global level. This study is aimed at investigating the general health of healthcare workers and its relationship with anxiety, anger, and posttraumatic stress disorder during the outbreak of COVID‐19. Methods. This research was a cross‐sectional study conducted on 455 healthcare workers of four teaching hospitals in Kerman, southeast of Iran. The convenience sampling method was used. The research tools included the 12‐Item General Health Questionnaire (GHQ‐12), the Impact of Event Scale‐Revised (IES‐R), the trait anxiety section of State‐Trait Anxiety Inventory (STAI), and the trait anger section of Trait‐State Anger Expression Inventory 2 (STAXI‐2). Data analysis was done in IBM SPSS Statistics version 25 and using Pearson’s correlation tests, independent t‐test, ANOVA, and multivariate linear regression. Results. 28.1% (n = 128) of the participants had mental health disorders. The mean score of anxiety was 43.99 ± 9.24 which was at moderate to high level of anxiety. The mean score of anger was 18.65 ± 5.72 which was at the moderate level. The mean score of PTSD was 34.77 ± 15.24 which was less than the midpoint of the questionnaire, i.e., the score of 44. The results of the multiple linear regression model that showed anxiety, anger, gender, and hospital were predictors of mental health (P < 0.05). Conclusion. The results of the present study showed that about a quarter of the healthcare workers faced with the COVID‐19 pandemic had mental health disorders and suffered from moderate to high anxiety, moderate anger, and PTSD. It was also observed in this study that there was a weak to moderate significant correlation between general health and anxiety, anger, and PTSD in healthcare workers. So, healthcare workers need a lot of social and psychological support.
Clam Peptides Attenuated Adenine-Induced Chronic Kidney Disease by Improving Inflammation, Oxidative Stress, and Intestinal Flora Composition
Authors: Ren Wenping , You Qiaoni , Wang Shanglong , Liu Zimin , Zou Shengcan , Gao Xiang , Wei Yuxi
Published: March 2024

Previously, we have prepared clam peptides (RBPs) that exhibited potential antihypertension and kidney protective effects in SHR rats by fermentation of Ruditapes philippinarum with Bacillus natto. In this study, we established an adenine-induced chronic kidney disease (CKD) in SD rats and investigated the improvement effects of RBPs on CKD. The results showed that compared with the model group, 8 weeks gavage of RBPs restored the structure of the kidney and reduced serum levels of CKD-related biochemical indicators, including NGAL, CR, Ca, UA, TG, IP, L-FABP, BUN, CHO, and cystatin C (p<0.05). RBPs treatment also reduced serum levels of MDA, IL-1β, TGF-β1, and TNF-α and increased those of CAT and T-AOC (p<0.05). In addition, the results of intestinal microbiota analysis showed that RBPs improved the intestinal flora composition by downregulating the proportion of Firmicutes and Bacteroidetes, decreasing the relative abundance of Romboutsia, Ruminococcaceae_UCG-005, and Christensenellaceae_R-7_group and increasing that of Lactobacillus and Muribaculaceae (p<0.05). The results of this study indicated that RBPs can also be used as bioactive substances in marine drugs or functional foods to alleviate CKD.
Measuring the Nursing Work Environment during Public Health Emergencies: Scale Adaptation and Validation
Authors: Wang Xiyi , Shao Jing , Lian Jiaqi , Weng Aozhou , Chang Jianhong , Ji Mengting , Wang Caifeng , Fang Qiong , Ye Zhihong , Hu Yun
Published: March 2024

Aim. To develop a scale for measuring nurse’s perceived work environment during the public health emergencies (PHEs) and assess its reliability and validity. Background. Although there is extensive research on instruments for measuring nursing work environments in regular healthcare settings, there is a lack of specific scales tailored to address the unique work conditions experienced by nurses during PHEs. Design. This study employed a cross-sectional design for psychometric evaluation and adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement. Methods. A self-report scale, the Chinese Nursing Work Environment Scale for Public Health Emergencies (C-NWE-PHE), was developed, integrating situational characteristics. Data on demographics, adapted scale scores, and subjective evaluations of nursing management performance were collected from 1156 nurses through online surveys conducted between January 2023 and March 2023. Confirmatory factor analysis, Pearson correlations, and Cronbach’s alpha analyses were conducted to evaluate the psychometric properties of the scale. Results. The adapted C-NWE-PHE scale comprised 28 items organized into five subscales: Workforce and Deployment Support, Leadership and Emergency Management, Autonomy and Empowerment, Teamwork and Collaboration, and Logistics and Humanistic Care. Structural equation modelling showed satisfactory factor loadings for each subscale and a good model fit, confirming construct validity. The content validity and reliability of the total scale were confirmed. Conclusion. This study provides empirical evidence for understanding and assessing the nursing work environment during PHEs with a psychometrically sound scale. Implications for Nursing Management. The C-NWE-PHE scale, along with its five identified constructs, provides a nuanced comprehension of working conditions amid PHEs. Implementing this scale could foster specific enhancements, support nurse retention efforts, and enhance the effectiveness of responses during challenging emergency situations.
Table S4 from Pooled CRISPR Screening Identifies P-Bodies as Repressors of Cancer Epithelial–Mesenchymal Transition
Authors: Fang Liang , Zhang Li , Wang Mengran , He Yuhao , Yang Jiao , Huang Zengjin , Tan Ying , Fang Ke , Li Jun , Sun Zhiyuan , Li Yanping , Tang Yisen , Liang Weizheng , Cui Huanhuan , Zhu Qionghua , Wu Zhe , Li Yiming , Hu Yuhui , Chen Wei
Published: March 2024

Table S4. The list of differentially expressed genes upon DDX6 or EDC4 knockout
Table S2 from Pooled CRISPR Screening Identifies P-Bodies as Repressors of Cancer Epithelial–Mesenchymal Transition
Authors: Fang Liang , Zhang Li , Wang Mengran , He Yuhao , Yang Jiao , Huang Zengjin , Tan Ying , Fang Ke , Li Jun , Sun Zhiyuan , Li Yanping , Tang Yisen , Liang Weizheng , Cui Huanhuan , Zhu Qionghua , Wu Zhe , Li Yiming , Hu Yuhui , Chen Wei
Published: March 2024

Table S2. The list and sequences of gRNAs
Data from DNA-PK–Mediated Cytoplasmic DNA Sensing Stimulates Glycolysis to Promote Lung Squamous Cell Carcinoma Malignancy and Chemoresistance
Authors: Wang Hui , Zhang Yanyang , Tian Yu , Yang Wanlin , Wang Yan , Hou Hui , Pan Hanbo , Pei Siyu , Zhu Hongda , Gu Zenan , Zhang Yanyun , Dai Dongfang , Chen Wei , Zheng Mingyue , Luo Qingquan , Xiao Yichuan , Huang Jia
Published: March 2024

Abstract
Detection of cytoplasmic DNA is an essential biological mechanism that elicits IFN-dependent and immune-related responses. A better understanding of the mechanisms regulating cytoplasmic DNA sensing in tumor cells could help identify immunotherapeutic strategies to improve cancer treatment. Here we identified abundant cytoplasmic DNA accumulated in lung squamous cell carcinoma (LUSC) cells. DNA-PK, but not cGAS, functioned as a specific cytoplasmic DNA sensor to activate downstream ZAK/AKT/mTOR signaling, thereby enhancing the viability, motility, and chemoresistance of LUSC cells. DNA-PK–mediated cytoplasmic DNA sensing boosted glycolysis in LUSC cells, and blocking glycolysis abolished the tumor-promoting activity of cytoplasmic DNA. Elevated DNA-PK–mediated cytoplasmic DNA sensing was positively correlated with poor prognosis of human patients with LUSC. Targeting signaling activated by cytoplasmic DNA sensing with the ZAK inhibitor iZAK2 alone or in combination with STING agonist or anti-PD-1 antibody suppressed the tumor growth and improved the survival of mouse lung cancer models and human LUSC patient-derived xenografts model. Overall, these findings established DNA-PK–mediated cytoplasmic DNA sensing as a mechanism that supports LUSC malignancy and highlight the potential of targeting this pathway for treating LUSC.
Significance:
DNA-PK is a cytoplasmic DNA sensor that activates ZAK/AKT/mTOR signaling and boosts glycolysis to enhance malignancy and chemoresistance of lung squamous cell carcinoma.
Data from Lysine Deacetylation Is a Key Function of the Lysyl Oxidase Family of Proteins in Cancer
Authors: Wu Xingxing , Li Xue , Wang Luwei , Bi Xianxia , Zhong Weihong , Yue Jicheng , Chin Y. Eugene
Published: March 2024

Abstract
Mammalian members of the lysyl oxidase (LOX) family of proteins carry a copper-dependent monoamine oxidase domain exclusively within the C-terminal region, which catalyzes ε-amine oxidation of lysine residues of various proteins. However, recent studies have demonstrated that in LOX-like (LOXL) 2–4 the C-terminal canonical catalytic domain and N-terminal scavenger receptor cysteine-rich (SRCR) repeats domain exhibit lysine deacetylation and deacetylimination catalytic activities. Moreover, the N-terminal SRCR repeats domain is more catalytically active than the C-terminal oxidase domain. Thus, LOX is the third family of lysine deacetylases in addition to histone deacetylase and sirtuin families. In this review, we discuss how the LOX family targets different cellular proteins for deacetylation and deacetylimination to control the development and metastasis of cancer.
Figure S3 from PUMA/RIP3 Mediates Chemotherapy Response via Necroptosis and Local Immune Activation in Colorectal Cancer
Authors: Chen Dongshi , Ermine Kaylee , Wang Yi-Jun , Chen Xiaojun , Lu Xinyan , Wang Peng , Beer-Stolz Donna , Yu Jian , Zhang Lin
Published: March 2024

Figure S3. 5-FU and other antimetabolites induced necroptosis in p53-WT CRC cells expressing RIP3.
Figure S12 from ERBB4-Mediated Signaling Is a Mediator of Resistance to PI3K and BTK Inhibitors in B-cell Lymphoid Neoplasms
Authors: Arribas Alberto J. , Napoli Sara , Cascione Luciano , Barnabei Laura , Sartori Giulio , Cannas Eleonora , Gaudio Eugenio , Tarantelli Chiara , Mensah Afua A. , Spriano Filippo , Zucchetto Antonella , Rossi Francesca M. , Rinaldi Andrea , Castro de Moura Manuel , Jovic Sandra , Bordone Pittau Roberta , Stathis Anastasios , Stussi Georg , Gattei Valter , Brown Jennifer R. , Esteller Manel , Zucca Emanuele , Rossi Davide , Bertoni Francesco
Published: March 2024

(A) Cell viability for the combination of idelalisib and the ERBB inhibitor lapatinib in parental and resistant by MTT assay (72h). Bars correspond to the mean of two independent experiments. Error bars represent standard deviation of the mean. Table contains p-values from a moderated t-test comparing each combination to idelalisib as single agent. The benefit of the combination was assessed both as synergism according to the Chou-Talalay combination index (CI, synergistic: CI<0.9, additive: CI~1, antagonistic: CI>1) (B) (2) and as potency (x-axis, synergistic: potency>0.5, additive: 01, additive: 010, additive 0>ZIP>10, antagonistic: ZIP<0) and Highest Single Agent (HSA, right; synergistic HSA>10, additive: 0>HSA>10, antagonistic HSA<0), in additional lymphoma cell lines including the DLBCL lines TMD8, and OCILY10, and the MCL models SP53 and UPN1.
Supplementary Figure S4 from Palazestrant (OP-1250), A Complete Estrogen Receptor Antagonist, Inhibits Wild-type and Mutant ER-positive Breast Cancer Models as Monotherapy and in Combination
Authors: Parisian Alison D. , Barratt Susanna A. , Hodges-Gallagher Leslie , Ortega Fabian E. , Peña Guadalupe , Sapugay Judevin , Robello Brandon , Sun Richard , Kulp David , Palanisamy Gopinath S. , Myles David C. , Kushner Peter J. , Harmon Cyrus L.
Published: March 2024

OP-1250 demonstrates potent in vivo activity and outperforms competitor compounds in ESR1 mutant xenograft studies. A, Percent change in tumor volume of individual animals in listed treatment groups at day 29 of the ESR1Y537S HCI-013 PDX study, normalized to day 1 tumor volume. B, Mean and SEM tumor volume over time with listed treatments in the ESR1Y537S HCI-013EI PDX breast cancer model conducted in the absence of estrogen supplementation. The dotted line represents tumor stasis. C, Percent change in tumor volume of individual animals in listed treatment groups at day 29 of the ESR1Y537S PDX HCI-013EI xenograft study conducted in the absence of estrogen supplementation, normalized to day 1 tumor volume. D, Percent change in tumor volume of individual animals in listed treatment groups at day 29 of the ESR1Y537S ST941 PDX study, normalized to day 1 tumor volume. E, Representative ST941 PDX study immunostained tumor images of Ki67 and ER⍺ treated with vehicle, OP-1250 at 5 mg/kg, and OP-1250 at 10 mg/kg.
Supplementary Figure S2 from Palazestrant (OP-1250), A Complete Estrogen Receptor Antagonist, Inhibits Wild-type and Mutant ER-positive Breast Cancer Models as Monotherapy and in Combination
Authors: Parisian Alison D. , Barratt Susanna A. , Hodges-Gallagher Leslie , Ortega Fabian E. , Peña Guadalupe , Sapugay Judevin , Robello Brandon , Sun Richard , Kulp David , Palanisamy Gopinath S. , Myles David C. , Kushner Peter J. , Harmon Cyrus L.
Published: March 2024

Effects of E2 and antiestrogens on transcriptional activity and cellular proliferation in E2-depleted media. A, Volcano plot of genes differentially expressed by 15-min E2 treatment relative to vehicle in PRO-seq experiment. Each dot represents a gene in the annotation set. Adjusted p-value is plotted on the y-axis and fold-change relative to time-matched vehicle on the x-axis. The number in the top right-hand corner represents the number of genes changed, and red dots indicate genes with observed change in expression. B, PRO-seq read distribution at estrogen target genes CCND1 and MYC after 15 min of E2 treatment (red) compared to vehicle control (blue). The x-axis refers to the position along the genome, and the y-axis refers to the number of reads aligning to that position normalized for the depth of each sample. Replicates were averaged. Bars that are less than zero are reverse-strand reads; bars above zero are forward-strand reads. C, PRO-seq read distribution at estrogen target gene GREB1 after 6 h of OP-1250 treatment following E2 pretreatment (red) compared to 24-h E2 treatment (blue). The x-axis refers to the position along the genome, and the y-axis refers to the number of reads aligning to that position normalized for the depth of each sample. Replicates were averaged. Bars that are less than zero are reverse-strand reads; bars above zero are forward-strand reads. D, Heatmap of annotated G2/M checkpoint genes in CAMA-1 and MCF7 cells after 24 h of compound treatment in PRO-seq experiment. Red indicates high expression and blue low expression. Samples and genes with similar expression patterns are grouped together using hierarchical clustering, with sample relationships depicted by dendrograms at the top and left of graph. E, Chart showing number of differentially expressed genes compared to vehicle for each treatment group in CAMA-1 mRNA-seq experiment. Cells were treated with 100 pM E2 or 316 nM antiestrogen in E2-depleted media for 24 h.
Supplementary Figures and Tables from Bifunctional Inhibitor Reveals NEK2 as a Therapeutic Target and Regulator of Oncogenic Pathways in Lymphoma
Authors: McCrury Mason , Swafford Kennith , Shuttleworth Sydnye L. , Mehdi Syed Hassan , Acharya Baku , Saha Debasmita , Naceanceno Kevin , Byrum Stephanie D. , Storey Aaron J. , Xu Ying-Zhi , Doshier Claire , Patel Vijay , Post Ginell R. , De Loose Annick , Rodriguez Analiz , Shultz Leonard D. , Zhan Fenghuang , Yoon Donghoon , Frett Brendan , Kendrick Samantha
Published: March 2024

Supplemental Methods, Supplementary Figures S1-11, Supplementary tables S2, 3, and 5.
Figure S7 from Bifunctional Inhibitor Reveals NEK2 as a Therapeutic Target and Regulator of Oncogenic Pathways in Lymphoma
Authors: McCrury Mason , Swafford Kennith , Shuttleworth Sydnye L. , Mehdi Syed Hassan , Acharya Baku , Saha Debasmita , Naceanceno Kevin , Byrum Stephanie D. , Storey Aaron J. , Xu Ying-Zhi , Doshier Claire , Patel Vijay , Post Ginell R. , De Loose Annick , Rodriguez Analiz , Shultz Leonard D. , Zhan Fenghuang , Yoon Donghoon , Frett Brendan , Kendrick Samantha
Published: March 2024

NEK2 correlates with DLBCL patient survival but not with patient age or DLBCL subtype. A, Plot of the Cox proportional hazards model for UAMS cohort (n = 76) where expression of NEK2 and DLBCL subtype were used as covariates in relation to survival probability. B, Plot of percent NEK2 protein positive DLBCL cells in each tumor (n = 76) according to age of patient at diagnosis; Pearson correlation, P = 0.57. C, Volcano plots of percent NEK2 protein positive DLBCL cells in each tumor (n = 76) according to DLBCL cell-of-origin (COO) subtype; Two-tailed Student t test, P = 0.19. D, Kaplan-Meier overall survival curves of patients with DLBCL (n = 81) according to DLBCL COO; log-rank test.
Table S3. from Raludotatug Deruxtecan, a CDH6-Targeting Antibody–Drug Conjugate with a DNA Topoisomerase I Inhibitor DXd, Is Efficacious in Human Ovarian and Kidney Cancer Models
Authors: Suzuki Hirokazu , Nagase Shotaro , Saito Chiemi , Takatsuka Atsuko , Nagata Motoko , Honda Kokichi , Kaneda Yuki , Nishiya Yumi , Honda Tomoyo , Ishizaka Tomomichi , Nakamura Kensuke , Nakada Takashi , Abe Yuki , Agatsuma Toshinori
Published: March 2024

Concentration of sCDH6 in cell culture supernatant.
Figure S1 from Raludotatug Deruxtecan, a CDH6-Targeting Antibody–Drug Conjugate with a DNA Topoisomerase I Inhibitor DXd, Is Efficacious in Human Ovarian and Kidney Cancer Models
Authors: Suzuki Hirokazu , Nagase Shotaro , Saito Chiemi , Takatsuka Atsuko , Nagata Motoko , Honda Kokichi , Kaneda Yuki , Nishiya Yumi , Honda Tomoyo , Ishizaka Tomomichi , Nakamura Kensuke , Nakada Takashi , Abe Yuki , Agatsuma Toshinori
Published: March 2024

The binding activities of R-DXd.
Supplementary Methods from Improving Intracellular Delivery of an Antibody–Drug Conjugate Targeting Carcinoembryonic Antigen Increases Efficacy at Clinically Relevant Doses In Vivo
Authors: Nessler Ian , Rubahamya Baron , Kopp Anna , Hofsess Scott , Cardillo Thomas M. , Sathyanarayan Nalini , Donnell Jennifer , Govindan Serengulam V. , Thurber Greg M.
Published: March 2024

Synthesis of CEA ADC
Fig. S18 from Radiation Synergizes with IL2/IL15 Stimulation to Enhance Innate Immune Activation and Antitumor Immunity
Authors: Li Xuefeng , Huntoon Kristin , Wang Yifan , Lee DaeYong , Dong Shiyan , Antony Abin , Walkey Carl , Kim Betty Y.S. , Jiang Wen
Published: March 2024

Fig. S18
Fig. S13 from Radiation Synergizes with IL2/IL15 Stimulation to Enhance Innate Immune Activation and Antitumor Immunity
Authors: Li Xuefeng , Huntoon Kristin , Wang Yifan , Lee DaeYong , Dong Shiyan , Antony Abin , Walkey Carl , Kim Betty Y.S. , Jiang Wen
Published: March 2024

Fig. S13
Data from Bifunctional Inhibitor Reveals NEK2 as a Therapeutic Target and Regulator of Oncogenic Pathways in Lymphoma
Authors: McCrury Mason , Swafford Kennith , Shuttleworth Sydnye L. , Mehdi Syed Hassan , Acharya Baku , Saha Debasmita , Naceanceno Kevin , Byrum Stephanie D. , Storey Aaron J. , Xu Ying-Zhi , Doshier Claire , Patel Vijay , Post Ginell R. , De Loose Annick , Rodriguez Analiz , Shultz Leonard D. , Zhan Fenghuang , Yoon Donghoon , Frett Brendan , Kendrick Samantha
Published: March 2024

Abstract
Expression of the serine/threonine kinase never in mitosis gene A (NIMA)–related kinase 2 (NEK2) is essential for entry into mitosis via its role in facilitating centrosome separation. Its overactivity can lead to tumorigenesis and drug resistance through the activation of several oncogenic pathways, including AKT. Although the cancer-enabling activities of NEK2 are documented in many malignancies, including correlations with poor survival in myeloma, breast, and non–small cell lung cancer, little is known about the role of NEK2 in lymphoma. Here, in tumors from patients with diffuse large B-cell lymphoma (DLBCL), the most common, aggressive non-Hodgkin lymphoma, we found a high abundance of NEK2 mRNA and protein associated with an inferior overall survival. Using our recently developed NEK2 inhibitor, NBI-961, we discovered that DLBCL cell lines and patient-derived cells exhibit a dependency on NEK2 for their viability. This compromised cell fitness was directly attributable to efficient NEK2 inhibition and proteasomal degradation by NBI-961. In a subset of particularly sensitive DLBCL cells, NBI-961 induced G2/mitosis arrest and apoptosis. In contrast, an existing indirect NEK2 inhibitor, INH154, did not prevent NEK2 autophosphorylation, induce NEK2 proteasomal degradation, or affect cell viability. Global proteomics and phospho-proteomics revealed that NEK2 orchestrates cell-cycle and apoptotic pathways through regulation of both known and new signaling molecules. We show the loss of NEK2-sensitized DLBCL to the chemotherapy agents, doxorubicin and vincristine, and effectively suppressed tumor growth in mice. These studies establish the oncogenic activity of NEK2 in DLBCL and set the foundation for development of anti-NEK2 therapeutic strategies in this frequently refractory and relapse-prone cancer.
Abstract A111: Development and analytical validation of a multiplexed targeted mass spectrometry assay to detect ovarian cancer protein biomarkers in sera
Authors: Ryu Joohyun , Boylan Kristin L. M. , Twigg Carly A. I. , Evans Richard , Skubitz Amy P. N. , Thomas Stefani N.
Published: March 2024

Background: Ovarian cancer is the most lethal gynecologic malignancy in women, and high-grade serous ovarian cancer (HGSOC) is the most common subtype. Currently, no clinical test has been approved by the FDA for the detection of ovarian cancer in the general population. This underscores the critical need for the development of a robust methodology combined with novel technology to detect diagnostic biomarkers for HGSOC in the sera of women. Targeted mass spectrometry (MS) can be used to identify and quantify specific peptides/proteins in complex biological samples with high accuracy, sensitivity, and reproducibility. In this study, we developed and conducted analytical validation of a multiplexed Tier 2 targeted MS parallel reaction monitoring (PRM) assay for the relative quantification of 23 ovarian cancer protein biomarker candidates in sera. Methods: To develop a PRM method for our target peptides, we followed nationally recognized consensus guidelines for validating fit-for-purpose Tier 2 targeted mass spectrometry (MS) assays. The endogenous target peptide concentrations were calculated using the calibration curves for each target peptide. Receiver operating characteristic (ROC) curves were analyzed to evaluate the diagnostic performance of the biomarker candidates. Results: We describe the development and analytical validation of a multiplexed Tier 2 targeted MS PRM assay to quantify ovarian cancer protein biomarker candidates in sera. Among the 64 peptides corresponding to 23 proteins in our PRM assay, 24 peptides corresponding to 16 proteins passed the assay validation acceptability criteria. Six of these peptides from insulin-like growth factor-binding protein 2 (IBP2), sex hormone-binding globulin (SHBG), and TIMP metalloproteinase inhibitor 1 (TIMP1) were quantified in sera from a cohort of 69 patients with early-stage HGSOC, late-stage HGSOC, benign ovarian conditions, and healthy (non-cancer) controls. IBP2 was identified as a diagnostic biomarker candidate based on its significantly increased abundance in the late-stage HGSOC patient sera compared to the healthy controls and patients with benign ovarian conditions. Conclusions: This study developed and validated a multiplexed targeted MS PRM assay for diagnostic biomarker analysis in HGSOC. To evaluate the clinical utility of IBP2 for HGSOC detection, further studies need to be performed using a larger patient cohort.

Citation Format: Joohyun Ryu, Kristin L. M. Boylan, Carly A. I. Twigg, Richard Evans, Amy P. N. Skubitz, Stefani N. Thomas. Development and analytical validation of a multiplexed targeted mass spectrometry assay to detect ovarian cancer protein biomarkers in sera [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A111.
Supplementary Tables S1-S3 from Neutralizing Antibodies Impair the Oncolytic Efficacy of Reovirus but Permit Effective Combination with T cell–Based Immunotherapies
Authors: Groeneveldt Christianne , Kinderman Priscilla , Griffioen Lisa , Rensing Olivia , Labrie Camilla , van den Wollenberg Diana J.M. , Hoeben Rob C. , Coffey Matt , Loghmani Houra , Verdegaal Els M.E. , Welters Marij J.P. , van der Burg Sjoerd H. , van Hall Thorbald , van Montfoort Nadine
Published: March 2024

Table S1. List of antibodies used for flow cytometric analysis.
Table S2. Sequences of Reo-derived peptides tested using intracellular cytokine staining.
Table S3. List of primers used for RT-qPCR analysis.
Figure S1 from Intragenic Rearrangement Burden Associates with Immune Cell Infiltration and Response to Immune Checkpoint Blockade in Cancer
Authors: Zhang Han , Lee Sanghoon , Muthakana Renee R. , Lu Binfeng , Boone David N. , Lee Daniel , Wang Xiao-Song
Published: March 2024

Figure S1. Definition of intragenic rearrangements and the datasets and workflow used in this analysis (a) The datasets and workflow used in our analysis. The variant calling results were retrieved from the ICGC PCAWG cohort for the IGR calculation. Normalized gene expressions were used for the estimation of tumor infiltrating immune subsets and T-inflamed signatures. The results were validated in five clinical datasets. (b) Schematic showing the exon alterations resulting from intragenic rearrangements. (c) Scatter plot demonstrating that the number of missense variants correlate almost linearly with the number of all mutations (Pearson R=0.997, p<2.2e-16). Values on axes are normalized by square root.
Chronic Stress Exacerbates the Immunosuppressive Microenvironment and Progression of Gliomas by Reducing Secretion of CCL3
Authors: Wang Xu , Zhang Long , Zhou Yi , Wang Yan , Wang Xiang , Zhang Yining , Quan Ankang , Mao Yufei , Zhang Yu , Qi Ji , Ren Zhongyu , Gu Linbo , Yu Rutong , Zhou Xiuping
Published: March 2024

As understanding of cancer has deepened, increasing attention has been turned to the roles of psychological factors, especially chronic stress–induced depression, in the occurrence and development of tumors. However, whether and how depression affects the progression of gliomas are still unclear. In this study, we have revealed that chronic stress inhibited the recruitment of tumor-associated macrophages (TAM) and other immune cells, especially M1-type TAMs and CD8+ T cells, and decreased the level of proinflammatory cytokines in gliomas, leading to an immunosuppressive microenvironment and glioma progression. Mechanistically, by promoting the secretion of stress hormones, chronic stress inhibited the secretion of the chemokine CCL3 and the recruitment of M1-type TAMs in gliomas. Intratumoral administration of CCL3 reprogrammed the immune microenvironment of gliomas and abolished the progression of gliomas induced by chronic stress. Moreover, levels of CCL3 and M1-type TAMs were decreased in the tumor tissues of glioma patients with depression, and CCL3 administration enhanced the antitumor effect of anti–PD-1 therapy in orthotopic models of gliomas undergoing chronic stress. In conclusion, our study has revealed that chronic stress exacerbates the immunosuppressive microenvironment and progression of gliomas by reducing the secretion of CCL3. CCL3 alone or in combination with an anti–PD-1 may be an effective immunotherapy for the treatment of gliomas with depression.

See related Spotlight by Cui and Kang, p. 514.
Abstract P36: BIOLOGY IN ACUTE LYMPHOBLASTIC LEUKEMIA FROM DIAGNOSIS TO FOLLOW-UP: A STUDY OF 48CASES
Authors: Koundio Abou A , Ndour Moussa , Diouf Mame Ndella , Akonde Fatou Binetou , Toure Awa Oumar , Raphael Martine
Published: March 2024

OBJECTIVE: ALL is the most common cancer in children and the most common cause of cancer death before the age of 20. In low- and middle-income countries, ALL is associated with poor outcomes. Many constraints are at the root of management failures. Therefore, in view of the progressive improvements in the efficacy of chemotherapeutic regimens, we deemed it necessary to conduct this study, the objective of which is to evaluate the role of biology in the management of children with ALL in the Oncopediatric Unit of Dakar. METHODS: This is a prospective analytical study that started on November 15th, 2021 at the UOP in collaboration with the hematology and immunology laboratories. All newly diagnosed patients with ALL based-on cytology and/or immunophenotyping, treated according to the ALL-GFAOP protocol and registered in the REDcap database are included. RESULTS: From November, 15th 2021 to July, 31th 2023, 48 patients were diagnosed with de novo ALL. With an average age of 7.8 years, female represented the main group (52,08%). According to immunophenotyping, the B profile was found in 25.0 % and the T profile in 22.9 %. The ALL T group was older (9.2 vs 4.4 years) and have had higher platelet counts (122272.7 vs 46916.7) at diagnosis than the ALL B group. This latter had higher hemoglobin (7.4 vs 6.8), white blood cell (127296.2 vs 56511.2) and blast counts at diagnosis in peripheral blood (69.4% vs 55.1%) and also in bone marrow (84.2% vs 72.5%) and higher rate of residual blast counts at Day8 after induction (9198.4 vs 1301.4). Regarding corticosensitivity at D8 of induction, no difference was found according to the number of blasts, the hemoglobinlevel and the immunological profile at diagnosis. However, patients with hyperleukocytic ALL with a relatively higher platelet count were more sensitive to corticosteroid therapy. CONCLUSIONS: Understanding the biology of acute ALL is of major interest in the effectiveness of therapeutic approaches to this type of hematology malignancies.

Citation Format: Abou A Koundio, Moussa Ndour, Mame Ndella Diouf, Fatou Binetou Akonde, Awa Oumar Toure, Martine Raphael. BIOLOGY IN ACUTE LYMPHOBLASTIC LEUKEMIA FROM DIAGNOSIS TO FOLLOW-UP: A STUDY OF 48CASES [abstract]. In: Proceedings of the Blood Cancer Discovery Symposium; 2024 Mar 4-6; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(2_Suppl):Abstract nr P36.
Supplementary Table 7 from Establishment and Characterization of an Epstein-Barr Virus–positive Cell Line from a Non-keratinizing Differentiated Primary Nasopharyngeal Carcinoma
Authors: Chai Annie Wai Yeeng , Yee Shi Mun , Lee Hui Mei , Abdul Aziz Norazlin , Yee Pei San , Marzuki Marini , Wong Ka Wo , Chiang Alan K.S. , Chow Larry Ka-Yue , Dai Wei , Liu Teng Fei , Tan Lu Ping , Khoo Alan Soo Beng , Lo Kwok Wai , Lim Paul V.H. , Rajadurai Pathmanathan , Lightfoot Howard , Barthorpe Syd , Garnett Mathew J. , Cheong Sok Ching
Published: March 2024

List of SNVs found in mutational cancer driver genes in NPC268
Supplementary Table 4 from Establishment and Characterization of an Epstein-Barr Virus–positive Cell Line from a Non-keratinizing Differentiated Primary Nasopharyngeal Carcinoma
Authors: Chai Annie Wai Yeeng , Yee Shi Mun , Lee Hui Mei , Abdul Aziz Norazlin , Yee Pei San , Marzuki Marini , Wong Ka Wo , Chiang Alan K.S. , Chow Larry Ka-Yue , Dai Wei , Liu Teng Fei , Tan Lu Ping , Khoo Alan Soo Beng , Lo Kwok Wai , Lim Paul V.H. , Rajadurai Pathmanathan , Lightfoot Howard , Barthorpe Syd , Garnett Mathew J. , Cheong Sok Ching
Published: March 2024

Antibody and probe list for immunohistochemistry
Supplementary Table 1 from Establishment and Characterization of an Epstein-Barr Virus–positive Cell Line from a Non-keratinizing Differentiated Primary Nasopharyngeal Carcinoma
Authors: Chai Annie Wai Yeeng , Yee Shi Mun , Lee Hui Mei , Abdul Aziz Norazlin , Yee Pei San , Marzuki Marini , Wong Ka Wo , Chiang Alan K.S. , Chow Larry Ka-Yue , Dai Wei , Liu Teng Fei , Tan Lu Ping , Khoo Alan Soo Beng , Lo Kwok Wai , Lim Paul V.H. , Rajadurai Pathmanathan , Lightfoot Howard , Barthorpe Syd , Garnett Mathew J. , Cheong Sok Ching
Published: March 2024

Primer list and sequences
Deep Learning-Based Psoriasis Assessment: Harnessing Clinical Trial Imaging for Accurate Psoriasis Area Severity Index Prediction
Authors: Xing Yunzhao , Zhong Sheng , Aronson Samuel L. , Rausa Francisco M. , Webster Dan E. , Crouthamel Michelle H. , Wang Li
Published: March 2024

Introduction: Image-based machine learning holds great promise for facilitating clinical care; however, the datasets often used for model training differ from the interventional clinical trial-based findings frequently used to inform treatment guidelines. Here, we draw on longitudinal imaging of psoriasis patients undergoing treatment in the Ultima 2 clinical trial (NCT02684357), including 2,700 body images with psoriasis area severity index (PASI) annotations by uniformly trained dermatologists. Methods: An image-processing workflow integrating clinical photos of multiple body regions into one model pipeline was developed, which we refer to as the “One-Step PASI” framework due to its simultaneous body detection, lesion detection, and lesion severity classification. Group-stratified cross-validation was performed with 145 deep convolutional neural network models combined in an ensemble learning architecture. Results: The highest-performing model demonstrated a mean absolute error of 3.3, Lin’s concordance correlation coefficient of 0.86, and Pearson correlation coefficient of 0.90 across a wide range of PASI scores comprising disease classifications of clear skin, mild, and moderate-to-severe disease. Within-person, time-series analysis of model performance demonstrated that PASI predictions closely tracked the trajectory of physician scores from severe to clear skin without systematically over- or underestimating PASI scores or percent changes from baseline. Conclusion: This study demonstrates the potential of image processing and deep learning to translate otherwise inaccessible clinical trial data into accurate, extensible machine learning models to assess therapeutic efficacy.
Propylthiouracil-Induced Antineutrophil Cytoplasmic Antibody-Associated Vasculitis with Overlap IgA Nephropathy: A Case Report
Authors: Oakman Georgina , Ong Cindy
Published: March 2024

Background: The anti-thyroid medication propylthiouracil (PTU) is a recognised cause of drug-induced antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Pauci-immune crescentic glomerulonephritis is the characteristic feature of this condition on renal biopsy. We present a case of PTU-induced AAV with the unusual histological finding of overlap IgA nephropathy (IgAN) in a young female with treatment-resistant Graves’ disease. Case Report: A 26-year-old female presented with an acute kidney injury, macroscopic haematuria, and proteinuria 14 months after starting PTU for Graves’ disease. She had a history of established thyroid eye disease and a previous severe adverse reaction to carbimazole. Her autoantibodies were strongly positive for myeloperoxidase-ANCA (199 U/mL). Renal biopsy demonstrated both necrotising crescentic glomerulonephritis and prominent (3+) mesangial deposition of IgA. She was treated with glucocorticoids and rituximab with sustained improvement in her renal function but persisting mild proteinuria and microscopic haematuria. PTU was ceased following a dose of radioactive iodine (RAI). Twelve months post-RAI, her Graves’ orbitopathy remained stable, and her thyroid function was gradually normalising. Conclusion: This was a case of drug-induced AAV with histological features of overlap IgAN. We suggest that this patient had pre-existing subclinical IgAN and then developed AAV secondary to PTU. The management of her thyroid disease was complex given the PTU-induced vasculitis, previous reaction to carbimazole, the risks of a thyroidectomy on immunosuppression, and the possible worsening of her eye disease with RAI. The glucocorticoids and Rituximab prescribed for vasculitis may have prevented the progression of her Graves’ orbitopathy after RAI.
Tinea Unguium Yang Disebabkan Microsporum sp. : Sebuah Kasus Jarang
Authors: Saviestya Kaorie Bunga , Widasmara Dhelya
Published: March 2024

Onikomikosis merupakan suatu infeksi jamur pada kuku yang dapat disebabkan oleh dermatofita, non-dermatofita, dan yeast, sedangkan tinea unguium merupakan suatu infeksi oleh golongan dermatofita pada kuku. Onikomikosis diketahui terjadi pada 2-18,5% populasi di seluruh dunia dimana 4-20 kali lebih sering terdapat pada kuku jari kaki dibandingkan kuku jari tangan. Pada pasien sistemik lupus eritematosus dilaporkan 25% mengalami adanya perubahan kuku dimana abnormalitas yang paling sering ditemukan adalah onikolisis. Berikut dilaporkan pasien wanita berusia 27 tahun dengan keluhan kuku jari kaki kiri yang rusak dan rapuh disertai gatal. Dari pemeriksaan dermatologis digiti I-V pedis sinistra didapatkan discoloration dan onychodystrophy. Pemeriksaan KOH 20% pada potongan kuku menunjukkan gambaran hifa panjang bercabang. Hasil kultur jamur menunjukkan pertumbuhan Microsporum sp. Laporan kasus ini membahas tentang kasus jarang tinea unguium yang disebabkan Microsporum sp.
Retinal waves in adaptive rewiring networks orchestrate convergence and divergence in the visual system
Authors: Luna Raúl , Li Jia , Bauer Roman , van Leeuwen Cees
Published: March 2024

Spontaneous retinal wave activity shaping the visual system is a complex neurodevelopmental phenomenon. Retinal ganglion cells are the hubs through which activity diverges throughout the visual system. We consider how these divergent hubs emerge, using an adaptively rewiring neural network model. Adaptive rewiring models show in a principled way how brains could achieve their complex topologies. Modular small-world structures with rich-club effects and circuits of convergent-divergent units emerge as networks evolve, driven by their own spontaneous activity. Arbitrary nodes of an initially random model network were designated as retinal ganglion cells. They were intermittently exposed to the retinal waveform, as the network evolved through adaptive rewiring. A significant proportion of these nodes developed into divergent hubs within the characteristic complex network architecture. The proportion depends parametrically on the wave incidence rate. Higher rates increase the likelihood of hub formation, while increasing the potential of ganglion cell death. In addition, direct neighbors of designated ganglion cells differentiate like amacrine cells. The divergence observed in ganglion cells resulted in enhanced convergence downstream, suggesting that retinal waves control the formation of convergence in the lateral geniculate nuclei. We conclude that retinal waves stochastically control the distribution of converging and diverging activity in evolving complex networks.
SmallTAL: Real-Time Egocentric Online Temporal Action Localization for the Data-Impoverished
Authors: Joyce Eric C. , Chen Yao , Neeter Eduardo , Mordohai Philippos
Published: March 2024

We propose a real-time, online temporal action localization system that requires a small amount of annotated data. The main challenges we address are high intra-class variability and a large and diverse background class. We address these using a flexible frame descriptor, dynamic time warping, and a novel approach to database construction. Our solution receives egocentric RGB-D streams as input and makes predictions at regular temporal intervals. We validate our approach by localizing actions in a digital twin of an electrical substation, in which certain objects have been replaced by functional virtual replicas.