bluuebunny/crossref_metadata_2025 huggingface dataset:
Donepezil attenuates inflammation and apoptosis in ulcerative colitis via regulating LRP1/AMPK/NF‐κB signaling
Authors: Li Angqing , Zhang Junyi , Chen Ke , Wang Jian , Xu Aman , Wang Zhengguang
Published: October 2023

This article focuses on the specific effects and mechanisms of donepezil (DNPZ) hydrochloride on inflammation and apoptosis in ulcerative colitis (UC). In vivo and in vitro models of UC were established using dextran sodium sulfate (DSS)‐induced mice and NCM460 cells, respectively. Following oral administration of DNPZ, body weight, disease activity index (DAI) scores and colon lengths of mice were recorded. Histopathological damage was detected employing hematoxylin and eosin (H&E) staining. Inflammatory factors were tested using enzyme‐linked immunosorbent assay and quantitative reverse transcription polymerase chain reaction, respectively. Apoptosis was estimated utilizing terminal deoxynucleotidyl transferase dUTP nick‐end labeling and western blot. Low‐density lipoprotein receptor‐related protein 1 (LRP1)/AMP activated protein kinase (AMPK)/nuclear factor‐κB (NF‐ κB) signaling proteins were detected utilizing western blot. NCM460 cell viability was assessed by cell counting kit (CCK)‐8. We found that DNPZ partially restored body weight, reduced DAI scores and attenuated intestinal pathological damage in DSS‐induced mice. Additionally, inflammatory factors decreased significantly after DNPZ treatment, accompanied by reduced apoptosis level. Phosphorylation (p)‐AMPK increased and p‐p65 decreased after DNPZ treatment, whereas LRP1 knockdown showed the opposite effect. Moreover, DNPZ treatment greatly restored NCM460 cell viability after DSS stimulation. DNPZ attenuated DSS‐induced inflammation and apoptosis in NCM460 cells, which was reversed by LRP1 knockdown. In summary, DNPZ hydrochloride attenuates inflammation and apoptosis in UC via LRP1/AMPK/NF‐κB signaling.
Using a Mock Circulatory Loop as a Regulatory Science Tool to Simulate Different Heart Failure Conditions
Authors: D'Souza Gavin A. , Rinaldi Jean E. , Meki Moustafa , Crusan Annabelle , Richardson Eric , Shinnar Meir , Herbertson Luke H.
Published: October 2023

Mechanical circulatory support (MCS) device therapy is one of the primary treatment options for end-stage heart failure (HF), whereby a mechanical pump is integrated with the failing heart to maintain adequate tissue perfusion. The ISO 14708-5:2020 standard prescribes generic guidelines for nonclinical device evaluation and system performance testing of MCS devices using a mock circulatory loop (MCL). However, the utility of MCLs in premarket regulatory submissions of MCS devices is ambiguous, and the specific disease states that the device is intended to treat are not usually simulated. Hence, we aim to outline the potential of MCLs as a valuable regulatory science tool for characterizing MCS device systems by adequately representing target clinical-use HF conditions on the bench. Target pathophysiologic hemodynamics of HF conditions (i.e., cardiogenic shock (CS), left ventricular (LV) hypertrophy secondary to hypertension, and coronary artery disease), along with a healthy adult at rest and a healthy adult during exercise are provided as recommended test conditions. The conditions are characterized based on LV, aorta, and left atrium pressures using recommended cardiac hemodynamic indices such as systolic, diastolic, and mean arterial pressure, mean cardiac output (CO), cardiac cycle time, and systemic vascular resistance. This study is a first step toward standardizing MCLs to generate well-defined target HF conditions used to evaluate MCS devices.
Comparative metabolomics reveal key pathways associated with the synergistic activities of aztreonam and clavulanate combination against multidrug-resistant
Escherichia coli
Authors: Zhang Jiayuan , Yang Hai , Zhang Lei , Lv Zhihua , Yu Mingming , Sy Sherwin K. B. , Zhan Yuanchao
Published: October 2023

The use of combination antibiotics has been useful in the treatment of multidrug-resistant bacterial infections. The synergistic effect of amoxicillin/clavulanate and aztreonam combination against
Escherichia coli
carrying New Delhi metallo-β-lactamase (NDM) was primarily due to clavulanate inhibiting aztreonam degradation. In the present study, we employed metabolomic analysis to investigate the downstream changes in
E. coli
after treatment with aztreonam and clavulanate.
E. coli
metabolomes were compared at 1 and 24 h following treatments with clavulanate (4 µg/mL) and aztreonam (4 µg/mL) alone and in combination. Excluding false positives, 198 metabolites were identified to be affected by antibiotic treatment. Aztreonam/clavulanate combination inhibited cell wall synthesis more aggressively at 1 h and 24 h than aztreonam alone. The purine and pyrimidine metabolism, the central carbon metabolism, and the amino acid metabolism were also disrupted resulting in a prolonged bactericidal effect. This study reveals the synergistic killing mechanism of clavulanate and aztreonam combination against
E. coli
harboring NDM and provides a theoretical basis for the combined use of aztreonam/clavulanate in the treatment of multidrug-resistant
E. coli
infection.

IMPORTANCE

Multidrug-resistant
Escherichia coli
is a major threat to the health care system and is associated with poor outcomes in infected patients. The combined use of antibiotics has become an important treatment method for multidrug-resistant bacteria. However, the mechanism for their synergism has yet to be explored.
Different Clinical Relevance of Anti-Citrullinated Protein Antibodies in RA Patients
Authors: Avdeeva A. S. , Cherkasova M. V. , Nasonov E. L.
Published: October 2023

The objective of the study was to find a potential relationship between ACPAs and disease activity, bone destruction, and ACPA responses to various therapeutic regimens. The study included 232 patients with rheumatoid arthritis (RA); 90 patients had early RA, and 142 patients had an advanced stage of the disease. 77 (85.6%) patients with early RA were highly positive for anti-CCP, and 29 (70.7%) patients were highly positive for anti-MCV. A positive correlation was found between anti-MCV and DAS28 (r = 0.4; p = 0.04). As for advanced RA, 78 (80.4%) patients were high-positive for anti-CCP, and 70 (79.5%) were high-positive for anti-MCV. There was a positive correlation between anti-MCV concentration and SDAI (r = 0.4; p = 0.02), as well as CDAI (r = 0.4; p = 0.02). No significant correlations were found between the anti-CCP levels and activity indices, anti-CCP and acute-phase parameters in both early and advanced RA groups. Higher total Sharp scores (96.5 (65.0–122.0)) were found in pts highl-positive for anti-MCV (n = 79), compared to low-positive/negative (n = 27) patients (57.0 (31.0–88.0); p < 0.05). Anti-MCV levels dropped significantly in pts on rituximab and tocilizumab therapy at weeks 12 and 24 after initiation of treatment, while high anti-CCP concentration persisted throughout the treatment. Anti-MCV levels correlated with inflammatory activity and development of bone destruction and decreased in pts on treatment. Anti-CCP was less responsive and showed minor changes during treatment; therefore, its thorough monitoring was not feasible.
Interpretation and use of a decision support tool for multiple treatment options: a combined randomised controlled trial and survey of medical students
Authors: Stokke Hunskaar Birk , Løvsletten Per Olav , Muller Ashley , Vandvik Per Olav
Published: October 2023

Objectives

To investigate medical students’ ability to interpret evidence, as well as their self-assessed understandability, perceived usefulness and preferences for design alternatives in an interactive decision support tool, displaying GRADE evidence summaries for multiple treatment options (Making Alternative Treatment CHoices Intuitive and Trustworthy, MATCH-IT).

Design

A combined randomised controlled trial and survey. Participants were presented with a clinical scenario and randomised to one of two versions of the MATCH-IT tool (A/B), instructed to explore the evidence and decide on a recommendation. Participants answered a questionnaire assessing interpretation, treatment recommendation self-assessed understandability and perceived usefulness before exposure to the other MATCH-IT version and asked questions on design preferences.

Setting

Online lecture in an evidence-based medicine (EBM) introductory course.

Participants

149 third-year medical students. 52% (n=77) had 6 months of clinical training and 48% (n=72) had preclinical training only.

Interventions

The MATCH-IT tool version A uses colour coding to categorise interventions by magnitude and direction of effects and displays all outcomes in a table on entry. Version B has no colour coding, and the user must decide which outcomes to display in the table.

Main outcome measures

Interpretation of evidence, treatment recommendation, perceived usefulness and understandability, preference for format and design alternatives.

Results

82.5% (n=123) of medical students correctly answered ≥4 out of 5 multiple choice questions assessing interpretation of data. 75.8% (n=114) of students made a treatment recommendation in accordance with an expert panel for the same clinical scenario. 87.2% (n=130) found the tool understandable while 91.9% perceived the tool as useful in addressing the clinical scenario.

Conclusion

Medical students with no prior training in EBM can interpret and use the MATCH-IT tool. Certain design alternatives were preferred but had no bearing on interpretation of evidence or understandability of the tool.
Role of equation of state and clusterization algorithms on nuclear vaporization
Authors: Dhillon Navjot K. , Ahuja Sejal , Rana Rajat , Gautam Sakshi
Published: October 2023

By using the Quantum Molecular Dynamics (QMD) model, a study on the nuclear vaporization in [Formula: see text] collision is presented for different nuclear equations of state along with a systematic comparison of different clusterization methods based on simple spatial correlations, spatial-momentum correlations, mass dependent binding energy cuts and Simulated Annealing Clusterization Algorithm (SACA). The effect of different nuclear equations of state i.e., Soft, Hard and Soft with Momentum Dependent (SMD) interactions on the energy of onset of vaporization for [Formula: see text] collisions is predicted by investigating gas/liquid content and probability of vaporization versus incident energy behavior. These two observables probe the critical point of nuclear vaporization very well. Further outcome of different clusterization algorithms on the energy of onset of nuclear vaporization is also probed and a comparison of calculations with the experimental data for [Formula: see text] and [Formula: see text] collisions is carried out for different clusterization algorithms.
Weighted Guided Optional Fusion Network for RGB-T Salient Object Detection
Authors: Wang Jie , Li Guoqiang , Shi Jie , Xi Jinwen
Published: October 2023

There is no doubt that the rational and effective use of visible and thermal infrared image data information to achieve cross-modal complementary fusion is the key to improving the performance of RGB-T salient object detection (SOD). A meticulous analysis of the RGB-T SOD data reveals that it mainly consists of three scenarios in which both modalities (RGB and T) have a significant foreground and only a single modality (RGB or T) is disturbed. However, existing methods are obsessed with pursuing more effective cross-modal fusion based on treating both modalities equally. Obviously, the subjective use of equivalence has two significant limitations. Firstly, it does not allow for practical discrimination of which modality makes the dominant contribution to performance. While both modalities may have visually significant foregrounds, differences in their imaging properties will result in distinct performance contributions. Secondly, in a specific acquisition scenario, a pair of images with two modalities will contribute differently to the final detection performance due to their varying sensitivity to the same background interference. Intelligibly, for the RGB-T saliency detection task, it would be more reasonable to generate exclusive weights for the two modalities and select specific fusion mechanisms based on different weight configurations to perform cross-modal complementary integration. Consequently, we propose a weighted guided optional fusion network (WGOFNet) for RGB-T SOD. Specifically, a feature refinement module is first used to perform an initial refinement of the extracted multilevel features. Subsequently, a weight generation module (WGM) will generate exclusive network performance contribution weights for each of the two modalities, and an optional fusion module (OFM) will rely on this weight to perform particular integration of cross-modal information. Simple cross-level fusion is finally utilized to obtain the final saliency prediction map. Comprehensive experiments on three publicly available benchmark datasets demonstrate the proposed WGOFNet achieves superior performance compared with the state-of-the-art RGB-T SOD methods. The source code is available at:
https://github.com/WJ-CV/WGOFNet
.
Centering Race in Studies of Low-Wage Immigrant Labor
Authors: Dubuisson Darlène , Campos-Medina Patricia , Gleeson Shannon , Griffith Kati L.
Published: October 2023

This review examines the historical and contemporary factors driving immigrant worker precarity and the central role of race in achieving worker justice. We build from the framework of racial capitalism and historicize the legacies of African enslavement and Indigenous dispossession, which have cemented an exclusionary economic system in the United States and globally. We consider how racism and colonial legacies create migrant displacement and shape the experiences of immigrant workers. We also detail how racism permeates the immigration bureaucracy, driving migrant worker precarity. The traditional labor movement has played an important role in closing this gap, but increasingly so have worker centers and the immigrant rights movement as a whole. These partnerships have had to navigate coalitional tensions as they build new strategies for realizing immigrant worker rights.
The Effect of Ionomer to Carbon Ratio and Relative Humidity on Cathode Catalyst Degradation in PEM Fuel Cells
Authors: Schneider Patrick , Scherzer Anne-Christine , Storey Brian D. , Klingele Matthias , Zamel Nada , Gerteisen Dietmar
Published: October 2023

The effect of ionomer to carbon (I/C) weight ratio and relative humidity (RH) on cathode catalyst degradation was investigated by comprehensive in situ characterization. Membrane electrode assemblies (MEA) with I/C ratios of 0.5, 0.8 and 1.2 were subjected to an accelerated stress test performed at 40, 70 and 100% RH. The results show an increasing loss in electrochemical active surface area (ECSA) for both higher I/C ratios and RH during voltage cycling. To differentiate between ionomer and water connected ECSA, carbon monoxide stripping measurements were performed at varying RH. Before degradation, all MEAs show comparable total ECSA values, while higher I/C ratios lead to a larger fraction of ionomer connected ECSA. After degradation, ECSA measurements of the lowest I/C ratio showed a relatively higher loss of Pt in contact with ionomer than Pt in contact with water, while an opposite trend was observed for higher I/C ratios. H2/N2 impedance measurements showed drastically increasing protonic catalyst layer resistances for decreasing RH especially at low I/C ratios, which might hinder Pt2+ ion diffusion towards the membrane, hence decreasing the ECSA loss. Limiting current measurements show increasing molecular O2 diffusion resistances at end of test for samples with higher I/C ratios and higher ECSA loss.
Regional transcriptomic profiling reveals immune system enrichment in nonfailing atria and all chambers of the failing human heart
Authors: Sandstedt Mikael , Vukusic Kristina , Johansson Markus , Jonsson Marianne , Magnusson Rasmus , Mattsson Hultén Lillemor , Dellgren Göran , Jeppsson Anders , Lindahl Anders , Synnergren Jane , Sandstedt Joakim
Published: October 2023

The transcriptomic patterns of the four heart chambers were characterized in failing and nonfailing human hearts. Both nonfailing atria had distinct transcriptomic patterns characterized by cardiogenesis, the immune system and BMP/TGF-β, MAPK/JNK, and Wnt signaling. Failing atria and ventricles were enriched for gene sets associated with the innate and adaptive immune system. Key upstream regulators associated with heart failure were identified, including activated immune response elements, which may constitute novel therapeutic targets.
The effects of water-based circuit exercise training on vascular function in people with coronary heart disease
Authors: Scheer Anna S. , I. R. de Oliveira Beatriz , Shah Amit , Jacques Angela , Chasland Lauren C. , Green Daniel J. , Maiorana Andrew J.
Published: October 2023

This study found that 12 wk of water-based circuit exercise training was well tolerated and improved vascular endothelial function in people with stable coronary heart disease. However, there was no effect on endothelium-independent function. Water-based exercise appears to be an effective alternative to gym-based exercise for people with coronary heart disease, which has specific benefits to vascular health and function.
Facial Emotion Recognition and Classification Using the Convolutional Neural Network-10 (CNN-10)
Authors: Dada Emmanuel Gbenga , Oyewola David Opeoluwa , Joseph Stephen Bassi , Emebo Onyeka , Oluwagbemi Olugbenga Oluseun
Published: October 2023

The importance of facial expressions in nonverbal communication is significant because they help better represent the inner emotions of individuals. Emotions can depict the state of health and internal wellbeing of individuals. Facial expression detection has been a hot research topic in the last couple of years. The motivation for applying the convolutional neural network-10 (CNN-10) model for facial expression recognition stems from its ability to detect spatial features, manage translation invariance, understand expressive feature representations, gather global context, and achieve scalability, adaptability, and interoperability with transfer learning methods. This model offers a powerful instrument for reliably detecting and comprehending facial expressions, supporting usage in recognition of emotions, interaction between humans and computers, cognitive computing, and other areas. Earlier studies have developed different deep learning architectures to offer solutions to the challenge of facial expression recognition. Many of these studies have good performance on datasets of images taken under controlled conditions, but they fall short on more difficult datasets with more image diversity and incomplete faces. This paper applied CNN-10 and ViT models for facial emotion classification. The performance of the proposed models was compared with that of VGG19 and INCEPTIONV3. The CNN-10 outperformed the other models on the CK + dataset with a 99.9% accuracy score, FER-2013 with an accuracy of 84.3%, and JAFFE with an accuracy of 95.4%.
Instruments and Parameters for Evaluating Upper Limb Motor Fatigability in Individuals with Neuromuscular Diseases: Systematic Review
Authors: Petian-Alonso Danila Cristina , Franco Camila Scarpino Barboza , Martins Emanuela Juvenal , Cruz Karoliny Lisandra Teixeira , de Fátima Carreira Moreira Padovez Roberta , Mattiello-Sverzut Ana Claudia
Published: October 2023

Background. Neuromuscular diseases present a set of clinical and pathological disabilities that include muscle weakness and atrophy, perception of fatigue, fatigability, and contracture. Motor fatigability compromises the ability of the individual to generate muscle strength and perform their daily activities. Quantitative measures of strength and motor fatigability are important to determine the clinical progression of the disease and the response to the proposed treatments. Thus, the aim of this study was to identify the equipment and protocols frequently used to assess upper limb motor fatigability in patients with neuromuscular disease. Methods. Information such as equipment used to induce motor fatigability, body segment or joint studied, movement analyzed, type of contraction, and protocol utilized for the test was analyzed. Joanna Briggs Scale and Newcastle-Ottawa Scale assessed the methodological quality of the studies. In addition, a checklist was prepared by the research group to assess the protocols presented in the referred studies. Results. The isokinetic and handgrip dynamometers were the most utilized equipment to induce motor fatigability. 83% of the studies had a design with low methodological rigor and half of them with high risk of bias. In the analysis of the protocols utilized to induce motor fatigability, one study was classified as regular and the other ones as good. Conclusion. The methodological topics to assess motor fatigability were incompletely described considering the electrophysiological and biomechanical approach. Although the motor fatigability in the upper limb was evaluated using isokinetic and handgrip equipment, the absence of a gold standard protocol still compromises the understanding of clinical progression and responses to the treatments in the neuromuscular diseases. This trial is registered with CRD42021206934.
Laboratory Cultivation of Coregonus ussuriensis Berg: A Comprehensive Study on Rearing from Egg to Adult Stage
Authors: Liu Enhui , Huang Tianqing , Gu Wei , Wang Gaochao , Liu Bing , Wang Bingqian , Xu Gefeng
Published: October 2023

Conservation aquaculture aids in restoring and rebuilding populations of endangered species through artificial breeding. The Ussuri cisco (Coregonus ussuriensis Berg) is a valuable fish species in China, known for its high nutritional value. However, its current yield heavily relies on fishing, leading to a rapid decline in wild populations. This study documents the successful artificial breeding of C. ussuriensis and provides a comprehensive description of its life cycle. We performed in situ gamete stripping followed by manual fertilization. Fertilized eggs were incubated at the Bohai cold-water fish experimental station in Mudanjiang, China, where seed breeding and parental fish farming were conducted. Under controlled conditions, we obtained around 110,000 fertilized eggs. After a 2-month incubation period, we obtained around 50,000 oviparous eggs with an eyed rate of 45.5%. Additionally, we observed over 30,000 larvae with a hatching rate of 60%. We produced 20,000 juvenile fish weighing 30 g after 1 year. This procedure facilitates the successful completion of the C. ussuriensis life cycle in aquaculture, aiding in the species’ recovery.
Supplemental Figure S2 from Depth of Radiographic Response and Time to Tumor Regrowth Predicts Overall Survival Following Anti-VEGF Therapy in Recurrent Glioblastoma
Authors: Ellingson Benjamin M. , Hagiwara Akifumi , Morris Connor J. , Cho Nicholas S. , Oshima Sonoko , Sanvito Francesco , Oughourlian Talia C. , Telesca Donatello , Raymond Catalina , Abrey Lauren E. , Garcia Josep , Aftab Dana T. , Hessel Colin , Rachmilewitz Minei Tamar , Harats Dror , Nathanson David A. , Wen Patrick Y. , Cloughesy Timothy F.
Published: October 2023

Supplemental Figure S2
Supplemental Figure S1 from Depth of Radiographic Response and Time to Tumor Regrowth Predicts Overall Survival Following Anti-VEGF Therapy in Recurrent Glioblastoma
Authors: Ellingson Benjamin M. , Hagiwara Akifumi , Morris Connor J. , Cho Nicholas S. , Oshima Sonoko , Sanvito Francesco , Oughourlian Talia C. , Telesca Donatello , Raymond Catalina , Abrey Lauren E. , Garcia Josep , Aftab Dana T. , Hessel Colin , Rachmilewitz Minei Tamar , Harats Dror , Nathanson David A. , Wen Patrick Y. , Cloughesy Timothy F.
Published: October 2023

Supplemental Figure S1
Supplementary Table S2 from Targeting Hedgehog Signaling with Glasdegib in Patients with Refractory Sclerotic Chronic GVHD: A Report of Two Phase I/II Trials
Authors: Rodríguez-Arbolí Eduardo , Lee Catherine J. , Caballero-Velázquez Teresa , Martínez Carmen , García-Calderón Clara , Jiménez-León María Reyes , Bermúdez-Rodríguez María Aránzazu , López-Corral Lucía , Triguero Ana , Onstad Lynn , Horwitz Mitchell E. , Sarantopoulos Stefanie , Lee Stephanie J. , Pérez-Simón José Antonio
Published: October 2023

Monoclonal antibodies used in the T-cell co-stimulatory and co-inhibitory molecules expression assays
Supplementary Methods S1 from Safety, Immunologic, and Clinical Activity of Durvalumab in Combination with Olaparib or Cediranib in Advanced Leiomyosarcoma: Results of the DAPPER Clinical Trial.
Authors: Salawu Abdulazeez , Wang Ben X. , Han Ming , Geady Caryn , Heirali Alya , Berman Hal K. , Pfister Thomas D. , Hernando-Calvo Alberto , Al-Ezzi Esmail Mutahar , Stayner Lee-Anne , Gupta Abha A. , Ayodele Olubukola , Lam Bernard , Hansen Aaron R. , Spreafico Anna , Bedard Philippe L. , Butler Marcus O. , Avery Lisa , Coburn Bryan , Haibe-Kains Benjamin , Siu Lillian L. , Abdul Razak Albiruni R.
Published: October 2023

Supplementary Methods
Supplementary Figure S1 from Safety, Immunologic, and Clinical Activity of Durvalumab in Combination with Olaparib or Cediranib in Advanced Leiomyosarcoma: Results of the DAPPER Clinical Trial.
Authors: Salawu Abdulazeez , Wang Ben X. , Han Ming , Geady Caryn , Heirali Alya , Berman Hal K. , Pfister Thomas D. , Hernando-Calvo Alberto , Al-Ezzi Esmail Mutahar , Stayner Lee-Anne , Gupta Abha A. , Ayodele Olubukola , Lam Bernard , Hansen Aaron R. , Spreafico Anna , Bedard Philippe L. , Butler Marcus O. , Avery Lisa , Coburn Bryan , Haibe-Kains Benjamin , Siu Lillian L. , Abdul Razak Albiruni R.
Published: October 2023

Figure S1. Transcriptomic evaluation leiomyosarcoma patients in the TCGA dataset
Supplementary Figure S1 from Targeting Hedgehog Signaling with Glasdegib in Patients with Refractory Sclerotic Chronic GVHD: A Report of Two Phase I/II Trials
Authors: Rodríguez-Arbolí Eduardo , Lee Catherine J. , Caballero-Velázquez Teresa , Martínez Carmen , García-Calderón Clara , Jiménez-León María Reyes , Bermúdez-Rodríguez María Aránzazu , López-Corral Lucía , Triguero Ana , Onstad Lynn , Horwitz Mitchell E. , Sarantopoulos Stefanie , Lee Stephanie J. , Pérez-Simón José Antonio
Published: October 2023

Expression of T-cell co-stimulatory and co-inhibitory molecules. Expression of CTLA-4, TNFRSF18, PD-1, OX40 and 4-IBB in the CD4+ and CD8+ T-cell compartments was measured by flow cytometry under resting conditions and after 4-hour incubation with ionomycin (0.91 µg/mL) and PMA (20 µg/mL). Brefeldin A (10 μg/mL) was added in both conditions. Differences between serial evaluations on day 1 of cycles 1, 2 and 4 were examined in skin/joints scGVHD responder (C1D1: n=11; C2D1: n=13; C4D1: n=12) and non-responder patients (C1D1: n=7; C2D1: n=7; C4D1: n=5). n.s., non-statistically significant. *Omnibus Friedman test. In post-hoc tests, only a statistically significant difference between visits C2D1 and C4D1 was detected (p=0.011).
Data from Anlotinib in Locally Advanced or Metastatic Radioiodine-Refractory Differentiated Thyroid Carcinoma: A Randomized, Double-Blind, Multicenter Phase II Trial
Authors: Chi Yihebali , Zheng Xiangqian , Zhang Yuan , Shi Feng , Cheng Ying , Guo Zhuming , Ge Minghua , Qin Jianwu , Zhang Jiewu , Li Zhendong , Zhou Xiaohong , Huang Rui , Chen Xiaohong , Liu Hui , Cheng Ruochuan , Xu Zhengang , Li Dapeng , Tang Pingzhang , Gao Ming
Published: October 2023

AbstractPurpose:
Alhough antiangiogenic agents are the bedrock of treatment for radioiodine-refractory differentiated thyroid carcinoma (RAIR-DTC), novel antiangiogenic agents with optimized features like greater target-binding affinities and more favorable pharmacokinetics profile are needed. This phase II randomized, double-blind, placebo-controlled trial investigated the efficacy and safety of anlotinib, a multikinase inhibitor, for RAIR-DTC.
Patients and Methods:
Patients (ages between 18 and 70 years) with pathologically confirmed locally advanced or metastatic RAIR-DTC were enrolled and randomly received 12 mg anlotinib once daily or placebo on day 1 to 14 every 3 weeks. Patients on placebo were allowed to receive open-label anlotinib after disease progression. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS) and safety.
Results:
Between September 2015 and August 2018, 76 and 37 patients randomly received anlotinib and placebo, respectively. Patients receiving anlotinib had a significantly longer median PFS [40.5 months, 95% confidence interval (CI), 28.3–not estimable (NE) versus placebo 8.4 months, 95% CI, 5.6–13.8; HR = 0.21, 95% CI, 0.12–0.37, P < 0.001], meeting the primary endpoint. OS was still immature, with a trend of benefit with anlotinib (HR = 0.57, 95% CI, 0.29–1.12). All patients in the anlotinib group experienced adverse events (AE); 8 (10.5%) discontinued treatment due to AEs.
Conclusions:
Anlotinib demonstrated promising efficacy and favorable tolerance in the treatment of locally advanced or metastatic RAIR-DTC, supporting further research to establish its role in the treatment of this serious disease.
Data from Safety and Tolerability of Low-Dose Radiation and Stereotactic Body Radiotherapy + Sintilimab for Treatment-Naïve Stage IV PD-L1+ Non–Small Cell Lung Cancer Patients
Authors: Zhou Xiaojuan , Zhou Laiyan , Yao Zhuoran , Huang Meijuan , Gong Youling , Zou Bingwen , Zhu Jiang , Liu Yongmei , Peng Feng , Zhang Yan , Yu Min , Li Yanying , Na Feifei , Wu Yijun , Kang Kai , Xiu Weigang , Zhang Xuanwei , Zhou Lin , Xu Yong , Wang Jin , Wang Yan , Yang Xue , Wu Yuanjun , Li Rui , Zhang Yu , Yang Zhenzhou , Zhou Zhipeng , Bai Jing , Yi Xin , Tong Ruizhan , Yin Limei , Chen Chong , Niedermann Gabriele , Lu You , Xue Jianxin
Published: October 2023

AbstractPurpose:
Low-dose radiotherapy (LDRT) may enhance the synergistic antitumor effect of combined immunotherapy and stereotactic body radiotherapy (SBRT). The safety and efficacy of this novel triple-combination therapy were evaluated for the first time as first-line treatment for patients with metastatic non–small cell lung cancer (NSCLC).
Patients and Methods:
This prospective phase I study enrolled 29 patients and included a dose-escalation and dose-expansion phase. Patients received SBRT [30 Gray (Gy)/3f] to small lesions and LDRT (2 Gy/1f, 4 Gy/2f, or 10 Gy/5f) to a large lesion concurrently, followed by sintilimab (a programmed death-1 inhibitor). The primary endpoint was safety and tolerability; secondary endpoints included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).
Results:
No dose-limiting toxicities were observed during the dose-escalation phase; 4 Gy/2f was the recommended LDRT dose. Median follow-up was 15.6 months. Treatment-related adverse events (TRAE) occurred in 96.6% (28/29) of patients [grade ≥ 3; 20.7% (6/29)]; 2 patients (6.9%) discontinued due to TRAEs. Seven patients experienced pneumonitis (grade 2, n = 6; grade 3, n = 1). Immune-related adverse events were noted in 58.6% (17/29) of patients. In patients with tumor assessment (n = 28), ORR and confirmed ORR were 60.7% and 57.1%, respectively. Median PFS was 8.6 months (95% confidence interval, 3.7–16.5), and median OS was not reached. Exploratory analyses suggested both expanded and newly emerging T-cell receptor clonotypes were associated with better PFS.
Conclusions:
The findings indicate that the novel SBRT + LDRT + sintilimab therapy is safe and promising in patients with programmed death ligand-1–positive, driver gene–negative primary metastatic NSCLC.
Delivery versus Potency in Treating Brain Tumors: BI-907828, a MDM2-p53 Antagonist with Limited BBB Penetration but Significant In Vivo Efficacy in Glioblastoma
Authors: Zhang Wenjuan , Vaubel Rachael A. , Oh Ju-Hee , Mladek Ann C. , Talele Surabhi , Zhang Wenqiu , Waller Katie L. , Burgenske Danielle M. , Sarkaria Jann N. , Elmquist William F.
Published: October 2023

MDM2–p53 inhibition may be effective in glioblastoma (GBM). This study evaluates the pharmacokinetics/pharmacodynamics of BI-907828, a potent antagonist of MDM2, in GBM, and demonstrates a translational paradigm with a focus on a unified “Delivery – Potency – Efficacy” relationship in drug development for central nervous system(CNS) tumors. BI-907828 was tested for cytotoxicity and MDM2–p53 pathway inhibition. Systemic pharmacokinetics and transport mechanisms controlling CNS distribution were evaluated in mice. BI-907828 free fractions in cell media, mouse and human specimens were measured to determine “active” unbound concentrations. Efficacy measures, including overall survival and target expression were assessed in mouse orthotopic GBM xenografts. BI-907828 exhibited potent inhibition of MDM2–p53 pathway and promoted cell death in GBM TP53 wild-type cells. MDM2-amplified cells are highly sensitive to BI-907828, with an effective unbound concentration of 0.1 nmol/L. The CNS distribution of BI-907828 is limited by blood–brain barrier (BBB) efflux mediated by P-gp, resulting in a Kp,uu_brain of 0.002. Despite this seemingly “poor” BBB penetration, weekly administration of 10 mg/kg BI-907828 extended median survival of orthotopic GBM108 xenografts from 28 to 218 days (P < 0.0001). This excellent efficacy can be attributed to high potency, resulting in a limited, yet effective, exposure in the CNS. These studies show that efficacy of BI-907828 in orthotopic models is related to high potency even though its CNS distribution is limited by BBB efflux. Therefore, a comprehensive understanding of all aspects of the “Delivery – Potency – Efficacy” relationship is warranted in drug discovery and development, especially for treatment of CNS tumors.
Design and Evaluation of Phosphonamidate-Linked Exatecan Constructs for Highly Loaded, Stable, and Efficacious Antibody–Drug Conjugates
Authors: Schmitt Saskia , Machui Paul , Mai Isabelle , Herterich Sarah , Wunder Swetlana , Cyprys Philipp , Gerlach Marcus , Ochtrop Philipp , Hackenberger Christian P.R. , Schumacher Dominik , Helma Jonas , Vogl Annette M. , Kasper Marc-André
Published: October 2023

Topoisomerase I (TOP1) Inhibitors constitute an emerging payload class to engineer antibody–drug conjugates (ADC) as next-generation biopharmaceutical for cancer treatment. Existing ADCs are using camptothecin payloads with lower potency and suffer from limited stability in circulation. With this study, we introduce a novel camptothecin-based linker–payload platform based on the highly potent camptothecin derivative exatecan. First, we describe general challenges that arise from the hydrophobic combination of exatecan and established dipeptidyl p-aminobenzyl-carbamate (PAB) cleavage sites such as reduced antibody conjugation yields and ADC aggregation. After evaluating several linker–payload structures, we identified ethynyl-phosphonamidates in combination with a discrete PEG24 chain to compensate for the hydrophobic PAB–exatecan moiety. Furthermore, we demonstrate that the identified linker–payload structure enables the construction of highly loaded DAR8 ADCs with excellent solubility properties. Head-to-head comparison with Enhertu, an approved camptothecin-based ADC, revealed improved target-mediated killing of tumor cells, excellent bystander killing, drastically improved linker stability in vitro and in vivo and superior in vivo efficacy over four tested dose levels in a xenograft model. Moreover, we show that ADCs based on the novel exatecan linker–payload platform exhibit antibody-like pharmacokinetic properties, even when the ADCs are highly loaded with eight drug molecules per antibody. This ADC platform constitutes a new and general solution to deliver TOP1 inhibitors with highest efficiency to the site of the tumor, independent of the antibody and its target, and is thereby broadly applicable to various cancer indications.
RNF185 Control of COL3A1 Expression Limits Prostate Cancer Migration and Metastatic Potential
Authors: Van Espen Benjamin , Oo Htoo Zarni , Collins Colin , Fazli Ladan , Molinolo Alfredo , Yip Kevin , Murad Rabi , Gleave Martin , Ronai Ze'ev A.
Published: October 2023

RNF185 is a RING finger domain-containing ubiquitin ligase implicated in ER-associated degradation. Prostate tumor patient data analysis revealed a negative correlation between RNF185 expression and prostate cancer progression and metastasis. Likewise, several prostate cancer cell lines exhibited greater migration and invasion capabilities in culture upon RNF185 depletion. Subcutaneous inoculation of mouse prostate cancer MPC3 cells stably expressing short hairpin RNA against RNF185 into mice resulted in larger tumors and more frequent lung metastases. RNA-sequencing and Ingenuity Pathway Analysis identified wound-healing and cellular movement among the most significant pathways upregulated in RNF185-depleted lines, compared with control prostate cancer cells. Gene Set Enrichment Analyses performed in samples from patients harboring low RNF185 expression and in RNF185-depleted lines confirmed the deregulation of genes implicated in epithelial-to-mesenchymal transition. Among those, COL3A1 was identified as the primary mediator of RNF185’s ability to impact migration phenotypes. Correspondingly, enhanced migration and metastasis of RNF185 knockdown (KD) prostate cancer cells were attenuated upon co-inhibition of COL3A1. Our results identify RNF185 as a gatekeeper of prostate cancer metastasis, partly via its control of COL3A1 availability.

Implications:

RNF185 is identified as an important regulator of prostate cancer migration and metastasis, in part due to its regulation of COL3A1. Both RNF185 and COL3A1 may serve as novel markers for prostate tumors.
Statistical Assessment of Drug Synergy from In Vivo Combination Studies Using Mouse Tumor Models
Authors: Mao Binchen , Guo Sheng
Published: October 2023

Drug combination therapy is a promising strategy for treating cancer; however, its efficacy and synergy require rigorous evaluation in preclinical studies before going to clinical trials. Existing methods have limited power to detect synergy in animal studies. Here, we introduce a novel approach to assess in vivo drug synergy with high sensitivity and low false discovery rate. It can accurately estimate combination index and synergy score under the Bliss independence model and the highest single agent (HSA) model without any assumption on tumor growth kinetics, study duration, data completeness and balance for tumor volume measurement. We show that our method can effectively validate in vitro drug synergy discovered from cell line assays in in vivo xenograft experiments, and can help to elucidate the mechanism of action for immune checkpoint inhibitors in syngeneic mouse models by combining an anti-PD-1 antibody and several tumor-infiltrating leukocytes depletion treatments. We provide a unified view of in vitro and in vivo synergy by presenting a parallelism between the fixed-dose in vitro and the 4-group in vivo combination studies, so they can be better designed, analyzed, and compared. We emphasize that combination index, when defined here via relative survival of tumor cells, is both dose and time dependent, and give guidelines on designing informative in vivo combination studies. We explain how to interpret and apply Bliss and HSA synergies. Finally, we provide an open-source software package named invivoSyn that enables automated analysis of in vivo synergy using our method and several other existing methods.

Significance:

This work presents a general solution to reliably determine in vivo drug synergy in single-dose 4-group animal combination studies.
Thirty Years of Global Deep Brain Stimulation: “Plus ça change, plus c’est la même chose”?
Authors: Hariz Marwan , Cif Laura , Blomstedt Patric
Published: October 2023

Background: The advent of deep brain stimulation (DBS) of the subthalamic nucleus (STN) for Parkinson’s disease 30 years ago has ushered a global breakthrough of DBS as a universal method for therapy and research in wide areas of neurology and psychiatry. The literature of the last three decades has described numerous concepts and practices of DBS, often branded as novelties or discoveries. However, reading the contemporary publications often elicits a sense of déjà vu in relation to several methods, attributes, and practices of DBS. Here, we review various applications and techniques of the modern-era DBS and compare them with practices of the past. Summary: Compared with modern literature, publications of the old-era functional stereotactic neurosurgery, including old-era DBS, show that from the very beginning multidisciplinarity and teamwork were often prevalent and insisted upon, ethical concerns were recognized, brain circuitries and rational for brain targets were discussed, surgical indications were similar, closed-loop stimulation was attempted, evaluations of surgical results were debated, and controversies were common. Thus, it appears that virtually everything done today in the field of DBS bears resemblance to old-time practices, or has been done before, albeit with partly other tools and techniques. Movement disorders remain the main indications for modern DBS as was the case for lesional surgery and old-era DBS. The novelties today consist of the STN as the dominant target for DBS, the tremendous advances in computerized brain imaging, the sophistication and versatility of implantable DBS hardware, and the large potential for research. Key Messages: Many aspects of contemporary DBS bear strong resemblance to practices of the past. The dominant clinical indications remain movement disorders with virtually the same brain targets as in the past, with one exception: the STN. Other novel brain targets – that are so far subject to DBS trials – are the pedunculopontine nucleus for gait freezing, the anteromedial internal pallidum for Gilles de la Tourette and the fornix for Alzheimer’s disease. The major innovations and novelties compared to the past concern mainly the unmatched level of research activity, its high degree of sponsorship, and the outstanding advances in technology that have enabled multimodal brain imaging and the miniaturization, versatility, and sophistication of implantable hardware. The greatest benefit for patients today, compared to the past, is the higher level of precision and safety of DBS, and of all functional stereotactic neurosurgery.
Hospital Variation in Mortality and Failure to Rescue after Surgery for High-Risk Neonatal Diagnoses
Authors: Mehl Steven C. , Portuondo Jorge I. , Tian Yao , Raval Mehul V. , King Alice , Rialon Kristy L. , Vogel Adam M. , Wesson David E. , Shah Sohail R. , Massarweh Nader N.
Published: October 2023

Introduction: A large proportion of postoperative mortality after pediatric surgery occurs among neonates with specific high-risk diagnoses. The extent to which there is hospital-level mortality variation among patients with these diagnoses and whether this variation is associated with differences in failure to rescue (FTR) is unclear. Methods: The Pediatric Health Information System® database (2012–2020) was used to identify patients who underwent surgery for eight high-risk neonatal diagnoses: gastroschisis; volvulus; necrotizing enterocolitis; intestinal atresia; meconium peritonitis; tracheoesophageal fistula; congenital diaphragmatic hernia; and perinatal intestinal perforation. Hospitals were stratified into tertiles of reliability-adjusted inpatient mortality rates (lower than average mortality – tertile 1 [T1]; higher than average mortality – tertile 3 [T3]). Multivariable hierarchical regression was used to evaluate the association between hospital-level, reliability-adjusted mortality and FTR. Results: Overall, 20,838 infants were identified across 48 academic, pediatric hospitals. Adjusted hospital mortality rates ranged from 4.0% (95% CI, 0.0–8.2) to 16.3% (12.2–20.4). Median case volume (range, 80–1,238) and number of NICU beds (range, 24–126) were not significantly different across hospital tertiles. Compared to the hospitals with the lowest postoperative mortality (T1), the odds of FTR were significantly higher in hospitals with the highest (T3) postoperative mortality (odds ratio 1.97 [1.50–2.59]). Conclusions: Significant variation in neonatal hospital mortality for high-risk diagnoses does not appear to be explained by hospital structural characteristics. Rather, difference in FTR suggests quality improvement interventions targeting early recognition and management of postoperative complications could improve surgical quality and safety for high-risk neonatal care.
Stereotactic Staged Asymmetric Bilateral Radiofrequency Lesioning for Parkinson’s Disease
Authors: Kostiuk Kostiantyn
Published: October 2023

Introduction: Parkinson’s disease (PD) is one of the most common neurodegenerative progressive disorders. Despite the dominance of neurostimulation technology, stereotactic lesioning operations play a significant role in the treatment of PD. The aim of the study was to evaluate the effectiveness and safety of staged bilateral asymmetric radiofrequency (RF) stereotactic lesioning in a highly selected group of PD patients. Material and Methods: A retrospective review of 418 consecutive patients undergoing stereotactic ablation for advanced PD at our institution revealed 28 patients who underwent staged asymmetric bilateral ablation. In this subset, after initial RF thalamotomy, contralateral pallidotomy was performed in 16 (57.1%) patients (group Vim-GPi), and contralateral lesion of the subthalamic nucleus (STN) was performed in 12 (32.9%) patients (group Vim-STN). The mean duration of disease before the first surgery was 9.9 ± 0.8 years. The mean interval between the two operations was 3.5 ± 0.4 years (range, 1–10 years); in the Vim-GPi group, it was 3.1 ± 0.4 years; and in the Vim-STN group, it was 4.3 ± 0.1 years. After the second operation, the long-term follow-up lasted from 1 to 8 years (mean 4.8 ± 0.5 years). All patients were evaluated 1 year after the second operation. Results: One year after staged bilateral lesioning, the mean tremor score improved from baseline, prior to the first operation, from 19.8 to 3.8 (improvement of 81%), the overall mean rigidity score improved from 11.0 to 3.7 (improvement of 66%), and hypokinesia improved from 14.8 to 8.9 (improvement of 40%). One year after staged bilateral lesioning, the total UPDRS score improved in the Vim-GPi group by 47% in the OFF and 45.9% in the ON states. In the Vim-STN group, the total UPDRS score improved from baseline, prior to the first operation, by 44.8% in the OFF and 51.6% in the ON states. Overall, levodopa dose was reduced by 43.4%. Neurological complications were observed in 4 (14.3%) cases; among them, 1 (3.6%) patient had permanent events related to local ischemia after pallidotomy. Conclusion: Staged asymmetric bilateral stereotactic RF lesioning can be a safe and effective method in highly selected patients with advanced PD, particularly where deep brain stimulation is not available or desirable. Careful identification and selection of patients for ablative surgery allow achieving optimal results in the treatment of PD with bilateral symptoms.