bluuebunny/crossref_metadata_2025 huggingface dataset:
The Next-Generation Oral Selective Estrogen Receptor Degrader Camizestrant (AZD9833) Suppresses ER+ Breast Cancer Growth and Overcomes Endocrine and CDK4/6 Inhibitor Resistance
Authors: Lawson Mandy , Cureton Natalie , Ros Susana , Cheraghchi-Bashi Azadeh , Urosevic Jelena , D'Arcy Sophie , Delpuech Oona , DuPont Michelle , Fisher David I. , Gangl Eric T. , Lewis Hilary , Trueman Dawn , Wali Neha , Williamson Stuart C. , Moss Jennifer , Montaudon Elodie , Derrien Heloise , Marangoni Elisabetta , Miragaia Ricardo J. , Gagrica Sladjana , Morentin-Gutierrez Pablo , Moss Thomas A. , Maglennon Gareth , Sutton Daniel , Polanski Radoslaw , Rosen Alan , Cairns Jonathan , Zhang Pei , Sánchez-Guixé Mònica , Serra Violeta , Critchlow Susan E. , Scott James S. , Lindemann Justin P.O. , Barry Simon T. , Klinowska Teresa , Morrow Christopher J. , Carnevalli Larissa S.
Published: September 2023

Oral selective estrogen receptor degraders (SERD) could become the backbone of endocrine therapy (ET) for estrogen receptor–positive (ER+) breast cancer, as they achieve greater inhibition of ER-driven cancers than current ETs and overcome key resistance mechanisms. In this study, we evaluated the preclinical pharmacology and efficacy of the next-generation oral SERD camizestrant (AZD9833) and assessed ER–co-targeting strategies by combining camizestrant with CDK4/6 inhibitors (CDK4/6i) and PI3K/AKT/mTOR-targeted therapy in models of progression on CDK4/6i and/or ET. Camizestrant demonstrated robust and selective ER degradation, modulated ER-regulated gene expression, and induced complete ER antagonism and significant antiproliferation activity in ESR1 wild-type (ESR1wt) and mutant (ESR1m) breast cancer cell lines and patient-derived xenograft (PDX) models. Camizestrant also delivered strong antitumor activity in fulvestrant-resistant ESR1wt and ESR1m PDX models. Evaluation of camizestrant in combination with CDK4/6i (palbociclib or abemaciclib) in CDK4/6-naive and -resistant models, as well as in combination with PI3Kαi (alpelisib), mTORi (everolimus), or AKTi (capivasertib), indicated that camizestrant was active with CDK4/6i or PI3K/AKT/mTORi and that antitumor activity was further increased by the triple combination. The response was observed independently of PI3K pathway mutation status. Overall, camizestrant shows strong and broad antitumor activity in ER+ breast cancer as a monotherapy and when combined with CDK4/6i and PI3K/AKT/mTORi.

Significance:

Camizestrant, a next-generation oral SERD, shows promise in preclinical models of ER+ breast cancer alone and in combination with CDK4/6 and PI3K/AKT/mTOR inhibitors to address endocrine resistance, a current barrier to treatment.
Integration of Genomic Sequencing Drives Therapeutic Targeting of PDGFRA in T-Cell Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma
Authors: Paolino Jonathan , Dimitrov Boris , Apsel Winger Beth , Sandoval-Perez Angelica , Rangarajan Amith Vikram , Ocasio-Martinez Nicole , Tsai Harrison K. , Li Yuting , Robichaud Amanda L. , Khalid Delan , Hatton Charlie , Gillani Riaz , Polonen Petri , Dilig Anthony , Gotti Giacomo , Kavanagh Julia , Adhav Asmani A. , Gow Sean , Tsai Jonathan , Li Yen Der , Ebert Benjamin L. , Van Allen Eliezer M. , Bledsoe Jacob , Kim Annette S. , Tasian Sarah K. , Cooper Stacy L. , Cooper Todd M. , Hijiya Nobuko , Sulis Maria Luisa , Shukla Neerav N. , Magee Jeffrey A. , Mullighan Charles G. , Burke Michael J. , Luskin Marlise R. , Mar Brenton G. , Jacobson Matthew P. , Harris Marian H. , Stegmaier Kimberly , Place Andrew E. , Pikman Yana
Published: September 2023

Purpose:

Patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) or lymphoblastic lymphoma (T-LBL) have limited therapeutic options. Clinical use of genomic profiling provides an opportunity to identify targetable alterations to inform therapy.

Experimental Design:

We describe a cohort of 14 pediatric patients with relapsed or refractory T-ALL enrolled on the Leukemia Precision-based Therapy (LEAP) Consortium trial (NCT02670525) and a patient with T-LBL, discovering alterations in platelet-derived growth factor receptor-α (PDGFRA) in 3 of these patients. We identified a novel mutation in PDGFRA, p.D842N, and used an integrated structural modeling and molecular biology approach to characterize mutations at D842 to guide therapeutic targeting. We conducted a preclinical study of avapritinib in a mouse patient-derived xenograft (PDX) model of FIP1L1-PDGFRA and PDGFRA p.D842N leukemia.

Results:

Two patients with T-ALL in the LEAP cohort (14%) had targetable genomic alterations affecting PDGFRA, a FIP1-like 1 protein/PDGFRA (FIP1L1-PDGFRA) fusion and a novel mutation in PDGFRA, p.D842N. The D842N mutation resulted in PDGFRA activation and sensitivity to tested PDGFRA inhibitors. In a T-ALL PDX model, avapritinib treatment led to decreased leukemia burden, significantly prolonged survival, and even cured a subset of mice. Avapritinib treatment was well tolerated and yielded clinical benefit in a patient with refractory T-ALL.

Conclusions:

Refractory T-ALL has not been fully characterized. Alterations in PDGFRA or other targetable kinases may inform therapy for patients with refractory T-ALL who otherwise have limited treatment options. Clinical genomic profiling, in real time, is needed for fully informed therapeutic decision making.
Advanced Age in Humans and Mouse Models of Glioblastoma Show Decreased Survival from Extratumoral Influence
Authors: Johnson Margaret , Bell April , Lauing Kristen L. , Ladomersky Erik , Zhai Lijie , Penco-Campillo Manon , Shah Yajas , Mauer Elizabeth , Xiu Joanne , Nicolaides Theodore , Drumm Michael , McCortney Kathleen , Elemento Olivier , Kim Miri , Bommi Prashant , Low Justin T. , Memon Ruba , Wu Jennifer , Zhao Junfei , Mi Xinlei , Glantz Michael J. , Sengupta Soma , Castro Brandyn , Yamini Bakhtiar , Horbinski Craig , Baker Darren J. , Walunas Theresa L. , Schiltz Gary E. , Lukas Rimas V. , Wainwright Derek A.
Published: September 2023

Purpose:

Glioblastoma (GBM) is the most common aggressive primary malignant brain tumor in adults with a median age of onset of 68 to 70 years old. Although advanced age is often associated with poorer GBM patient survival, the predominant source(s) of maladaptive aging effects remains to be established. Here, we studied intratumoral and extratumoral relationships between adult patients with GBM and mice with brain tumors across the lifespan.

Experimental Design:

Electronic health records at Northwestern Medicine and the NCI SEER databases were evaluated for GBM patient age and overall survival. The commercial Tempus and Caris databases, as well as The Cancer Genome Atlas were profiled for gene expression, DNA methylation, and mutational changes with varying GBM patient age. In addition, gene expression analysis was performed on the extratumoral brain of younger and older adult mice with or without a brain tumor. The survival of young and old wild-type or transgenic (INK-ATTAC) mice with a brain tumor was evaluated after treatment with or without senolytics and/or immunotherapy.

Results:

Human patients with GBM ≥65 years of age had a significantly decreased survival compared with their younger counterparts. While the intra-GBM molecular profiles were similar between younger and older patients with GBM, non-tumor brain tissue had a significantly different gene expression profile between young and old mice with a brain tumor and the eradication of senescent cells improved immunotherapy-dependent survival of old but not young mice.

Conclusions:

This work suggests a potential benefit for combining senolytics with immunotherapy in older patients with GBM.
Novel Thienoduocarmycin–Trastuzumab ADC Demonstrates Strong Antitumor Efficacy with Favorable Safety Profile in Preclinical Studies
Authors: Valsasina Barbara , Orsini Paolo , Caruso Michele , Albanese Clara , Ciavolella Antonella , Cucchi Ulisse , Fraietta Ivan , Melillo Nicola , Fiorentini Francesco , Rizzi Simona , Salsa Matteo , Isacchi Antonella , Gasparri Fabio
Published: September 2023

New antibodies–drug conjugate (ADC) payloads overcoming chemoresistance and killing also poorly proliferating tumors at well-tolerated doses are much desired. Duocarmycins are a well-known class of highly potent cytotoxic agents, with DNA minor groove-binding and alkylation properties, active also in chemoresistant tumors. Although different duocarmycin derivatives have been used during the years as payloads for ADC production, unfavorable physicochemical properties impaired the production of ADCs with optimal features. Optimization of the toxin to balance reactivity and stability features and best linker selection allowed us to develop the novel duocarmycin-like payload–linker NMS-P945 suitable for conjugation to mAbs with reproducible drug–antibody ratio (DAR) >3.5. When conjugated to trastuzumab, it generated an ADC with good internalization properties, ability to induce bystander effect and immunogenic cell death. Moreover, it showed strong target-driven activity in cells and cytotoxic activity superior to trastuzumab deruxtecan tested, in parallel, in cell lines with HER2 expression. High in vivo efficacy with cured mice at well-tolerated doses in HER2-driven models was also observed. A developed pharmacokinetic/pharmacodynamic (PK/PD) model based on efficacy in mice and cynomolgus monkey PK data, predicted tumor regression in patients upon administration of 2 doses of trastuzumab–NMS-P945–ADC at 0.5 mg/kg. Thus, considering the superior physicochemical features for ADC production and preclinical results obtained with the model trastuzumab ADC, including bystander effect, immunogenic cell death and activity in chemoresistant tumors, NMS-P945 represents a highly effective, innovative payload for the creation of novel, next-generation ADCs.
Complementary Medicine in Acute Care Hospitals: Questionnaire Survey with Heads of Bavarian Hospitals
Authors: Kollikowski Anne , Gabriel Katharina M.A. , Schiffmann Lisa , Gágyor Ildiko , Güthlin Corina , Heuschmann Peter U. , Langhorst Jost , Keil Thomas , Löffler Claudia
Published: September 2023

Introduction: The demand for complementary medicine (CM) is well studied in the outpatient sector, but representative data on type and extent of inpatient care using CM are missing. Therefore, our aim was to examine the range of CM treatments offered and the types of indications for using CM in acute care hospitals in the German state of Bavaria. Methods: We conducted a cross-sectional questionnaire survey by contacting the medical heads of all 388 Bavarian acute care hospitals between November 2020 and April 2021. The questionnaire included a wide range of CM to assessed availability of CM supply, most frequent indications, and medical specialities. Furthermore, we assessed basic information about the hospital and the participating medical staff. Results: A total of 101 (26%) hospitals participated in the survey. At least one CM treatment was offered by 92% of the responding hospitals and 75% offered at least 5 therapy modalities (mean of 10 treatments, range: 0–25). These were most commonly massage therapies (68%), relaxation techniques (63%), phytotherapy (60%), mindfulness-based treatments (53%), art, diet, and exercise therapies (each 48%), aromatherapy (46%), acupuncture, and compresses/poultices (both 42%). The most reported medical conditions for CM treatments (in descending order) were chronic pain, mental disorders, degenerative affections, sleep disorders, fatigue syndrome, functional gastrointestinal disorders, and acute pain. Conclusion: According to the Bavarian acute care hospitals that participated in our postal survey, a considerable part offered CM. Further research should include personal interviews and more detailed assessments of indications and attitudes for the use of CM in acute care hospital settings.
Depression and Anxiety Trajectories in Chronic Disease: A Systematic Review and Meta-Analysis
Authors: Scott Amelia J. , Correa Ashleigh B. , Bisby Madelyne A. , Dear Blake F.
Published: September 2023

Introduction: People living with chronic diseases are at an increased risk of anxiety and depression, which are associated with poorer medical and psychosocial outcomes. Many studies have examined the trajectories of depression and anxiety in people with specific diseases, including the predictors of these trajectories. This is valuable for understanding the process of adjustment to diseases and informing treatment planning. However, no review has yet synthesised this information across chronic diseases. Methods: Electronic databases were searched for studies reporting trajectories of depression or anxiety in chronic disease samples. Data extracted included sample characteristics, results from trajectory analyses, and predictors of trajectories. Meta-analysis of the overall pooled prevalence of depression and anxiety trajectories was conducted, and qualitative synthesis of disease severity predictors was undertaken. Results: Following search and screening, 67 studies were included (N = 61,201 participants). Most participants followed a stable nonclinical trajectory for depression (69.0% [95% CI: 65.6, 72.2]) and anxiety (73.4% [95% CI: 66.3, 79.5]). Smaller but meaningful subsamples followed a trajectory of depression and anxiety symptoms consistently in the clinical range (11.8% [95% CI: 9.2, 14.8] and 13.7% [95% CI: 9.3, 19.7], respectively). Several clinical and methodological moderators emerged, and qualitative synthesis suggested that few aspects of disease severity were associated with participants’ trajectories. Conclusion: Most people with chronic disease follow a trajectory of distress that is low and stable, suggesting that most people psychologically adjust to living with chronic disease. Evidence also suggests that the nature and severity of the disease are not meaningful predictors of psychological distress.
Adoption and Diffusion of Transcarotid Artery Revascularization in Contemporary Practice
Authors: Columbo Jesse A. , Stone David H. , Martinez-Camblor Pablo , Goodney Philip P. , O’Malley A. James
Published: September 2023

BACKGROUND:

In 2015, the FDA approved transcarotid artery revascularization (TCAR) as an alternative to carotid endarterectomy (CEA) and transfemoral carotid artery stenting (TF-CAS) for high-risk patients with carotid stenosis. This was granted in the absence of level 1 evidence to support TCAR. We aimed to document trends in TCAR utilization, its diffusion over time, and the clinical phenotypes of patients undergoing TCAR, CEA, and TF-CAS.

METHODS:

We used the Vascular Quality Initiative to study patients who underwent TCAR. We calculated the number of TCARs performed and the percent of TCAR utilization versus CEA/TF-CAS. Using data from before TCAR was widespread, we calculated propensity scores for patients to receive CEA. We applied this model to patients undergoing carotid revascularization from 2016 to 2022 and grouped patients by the procedure they ultimately underwent, examining overlap in score distribution to measure patient similarity. We measured the trend of in-hospital stroke/death after TCAR.

RESULTS:

We studied 31 447 patients who underwent TCAR from January 1, 2016 to March 31, 2022. The number of centers performing TCAR increased from 29 to 606. In 2021, TCAR represented 22.5% of carotid revascularizations at centers offering all 3 procedures. The percentage of patients that underwent TCAR who met approved high-risk criteria decreased from 88.5% to 80.9% (
P
<0.001). Those with a prior ipsilateral carotid procedure decreased from 20.6% in 2016 to 12.0% in 2021 (
P
<0.001). Patients undergoing TCAR after stroke increased from 19.7% to 30.7% (
P
<0.001). Propensity-score overlap was 55.4% for TCAR/CEA, and 58.6% for TCAR/TF-CAS, demonstrating that TCAR patients have a clinical phenotype mixed between those who undergo CEA and TF-CAS. The average in-hospital stroke/death risk after TCAR was 2.3% in 2016 and 1.7% in 2022 (
P
trend: 0.954).

CONCLUSIONS:

TCAR now represents nearly 1-in-4 procedures at centers offering it. TCAR was increasingly performed among standard-risk patients and as a first-line procedural option after stroke. The absence of level 1 evidence underscores the importance of high-quality registry-based analyses to document TCAR’s real-world outcomes and durability.
Complete Revascularization Versus Culprit-Lesion-Only PCI in STEMI Patients With Diabetes and Multivessel Coronary Artery Disease: Results From the COMPLETE Trial
Authors: Oqab Zardasht , Kunadian Vijay , Wood David A. , Storey Robert F. , Rao Sunil V. , Mehran Roxana , Pinilla-Echeverri Natalia , Mani Thenmozhi , Boone Robert H. , Kassam Saleem , Bossard Matthias , Mansour Samer , Ball Warren , Sibbald Matthew , Valettas Nicholas , Moreno Raul , Steg Philippe Gabriel , Cairns John A. , Mehta Shamir R.
Published: September 2023

BACKGROUND:

In the COMPLETE trial (Complete Versus Culprit-Only Revascularization to Treat Multivessel Disease After Early PCI for STEMI), a strategy of complete revascularization reduced the risk of major cardiovascular events compared with culprit-lesion-only percutaneous coronary intervention in patients presenting with ST-segment–elevation myocardial infarction (STEMI) and multivessel coronary artery disease. Patients with diabetes have a worse prognosis following STEMI. We evaluated the consistency of the effects of complete revascularization in patients with and without diabetes.

METHODS:

The COMPLETE trial randomized a strategy of complete revascularization, consisting of angiography-guided percutaneous coronary intervention of all suitable nonculprit lesions, versus a strategy of culprit-lesion-only percutaneous coronary intervention (guideline-directed medical therapy alone). In prespecified analyses, treatment effects were determined in patients with and without diabetes on the first coprimary outcome of cardiovascular death or new myocardial infarction and the second coprimary outcome of cardiovascular death, new myocardial infarction, or ischemia-driven revascularization. Interaction
P
values were calculated to evaluate whether there was a differential treatment effect in patients with and without diabetes.

RESULTS:

Of the 4041 patients enrolled in the COMPLETE trial, 787 patients (19.5%) had diabetes. The median HbA1c (glycated hemoglobin) was 7.7% in the diabetes group and 5.7% in the nondiabetes group. Complete revascularization consistently reduced the first coprimary outcome in patients with diabetes (hazard ratio, 0.87 [95% CI, 0.59–1.29]) and without diabetes (hazard ratio, 0.70 [95% CI, 0.55–0.90]), with no evidence of a differential treatment effect (interaction
P
=0.36). Similarly, for the second coprimary outcome, no differential treatment effect (interaction
P
=0.27) of complete revascularization was found in patients with diabetes (hazard ratio, 0.61 [95% CI, 0.43–0.87]) and without diabetes (hazard ratio, 0.48 [95% CI, 0.39–0.60]).

CONCLUSIONS:

Among patients presenting with STEMI and multivessel disease, the benefit of complete revascularization over a culprit-lesion-only percutaneous coronary intervention strategy was consistent regardless of the presence or absence of diabetes.
Noisy Omens and Enslaved Gods
Authors: Réal Matthieu
Published: September 2023

I offer a reconsideration of Zoilus’ treatise Against Homer’s Poetry. Two fragments of this work, F9a and F14 Fogagnolo, especially showcase Zoilus’ significance in the context of ancient literary criticism. F9a is usually considered a sarcastic comment on Homer’s lack of realism. I propose instead that it is a critique of the way the poet crafted the bird omen of Il. 10.174-177: Zoilus regarded the omen as a symbolic device and focused on the details of the analogical relationship between interpretandum and the interpretamentum. I also suggest that Aristotle F369 Gigon may have originated as a defense of Homer against one of Zoilus’ criticisms. Through a new translation of F14, I show that Zoilus did not content himself with analyzing problematic lines of Homer in isolation, but also assessed passages of the poem in light of other relevant passages within the same poem. In short, he criticized Homer from Homer.
Ginsenoside Rg3 regulates sensitization effect of superoxide dismutase on thyroid cancer photodynamic therapy via antioxidant response element signaling pathway
Authors: Yin Yanhui , Li Qing , Zhang Yunlong
Published: September 2023

Clinical studies have shown that, ginsenoside Rg3 has strong antitumor and antioxidant effects. Therefore, this study used ginsenoside Rg3 to explore its role in the antioxidant response element (ARE) signaling pathway, to clarify the mechanism of regulating superoxide dismutase (SOD)
and enhancing sensitivity of cancer cells to photodynamic therapy, providing a basis for improving clinical treatment effect. A papillary thyroid carcinoma mouse model was constructed and divided into study groups, followed by Ki-67 and TUNEL (Terminal deoxynucleotidyl transferase dUTP nick
end labeling) staining, CCK-8 method and flow cytometry analysis. Level of reactive oxygen species, and ARE and SOD were assessed by qRT-PCR (quantificational rt-PCR) and Western blot. No mouse death occurred during model establishment and intervention, and the tumor formation rate was 100%.
Moreover, the Ki-67 positive cells in tumor tissues from the ginsenoside Rg3 group were lowest, indicating tumor growth was inhibited; while the TUNEL cells were increased, indicating that tumor cells underwent apoptosis. Meanwhile, BCPAP (Human Thyroid Cancer Papillary Cell) proliferation
and migration in the ginsenoside Rg3 group were lower than in the ARE inhibitor group, while apoptotic ability was increased. The levels of ARE and SOD in the ginsenoside Rg3 group were also increased. Ginsenoside Rg3 plays an anti-tumor effect through ARE signaling pathway and accelerates
cell apoptosis. At the same time, the Ginsenoside Rg3 can enhance ROS activity, upregulate ARE and SOD, and increase the sensitivity of cancer cells to photodynamic therapy.
Curcumin-Loaded nano-phospholipid complex maintains mitochondrial homeostasis through regulation of parkin in Parkinson’s disease
Authors: Xie Hejie , Zhou Dajin , Yan Tielun , Yan Xiumei , Wu Qiulin , Chen Weifeng
Published: September 2023

Curcumin (Cur) can modulate multiple signal transductions and play a protective role in Parkinson’s disease (PD). Nano-phospholipid composite carriers were prepared to observe the nano-phospholipid complex EM maps, and then evaluated the size and surface potential of the composites
using a Zetasizer IV analyzer. Microglial cells (BV2) were divided into control group, empty vector group, Cur group and drug-loaded group and administered treatment, respectively. The levels of Parkin, BAG5 and PINK1 were detected. With encapsulation efficiency of 26.0% and drug loading of
52.0%, respectively, the average particle size of the Cur-loaded nano-phospholipid was (197.15±4.42) nm, with a potential of (−18.2±2.0) mV. The difference between empty vector group and control group in the level of BAG5, Parkin and PINK1 was not significant (P
>0.05). BAG5 level increased significantly upon treatment with Cur or Cur-loaded nano-phospholipid complex, with highest level in the drug-loaded group (P <0.05). As such, Parkin and PINK1 expression increased greatly in the presence of Cur or Cur-loaded nano-phospholipid complex,
while the drug-loaded group had the highest level (P <0.05). Collectively, the curcumin/nano-phospholipid complexes upregulated Parkin, PINK1 and BAG5 expression, thereby maintaining mitochondria and potentiating the efficacy of Cur on PD. The Cur-loaded nano-phospholipid complexes
show promising potential for PD prevention and treatment.
Liensinine improves cognitive function of gastric cancer under dexmedetomidine anesthesia by inhibiting neuron apoptosis through synuclein
Authors: Ye Zhe , Long Lingling , Long Sizhu , Yang Min , Tan Ming
Published: September 2023

Surgical resection is the main treatment approach for gastric cancer (GC), but surgical anesthetics may have an impact on postoperative cognitive function. Therefore, this study investigated the effect of liensinine on neuronal apoptosis and cognitive function in mice with GC induced
by dexmedetomidine anesthesia. Firstly, a GC mouse model was established and divided into the following groups; blank control group, GC model group, low-dose (4 μmol/L) and high-dose (8 μmol/L) groups of liensinine (n = 6), to detect apoptosis of neurons. In addition,
the GC model group, Synuclein (SYN) mimic group, SYN inhibitor group, high-dose neusinine group, and high-dose liensinine+SYN inhibitor group were set up with 6 rats in each group. The cognitive function of mice after treatment was observed by Morris water maze experiment, and neuronal cell
apoptosis and expressions of SYN, brain-derived neurotrophic facto (BDNF) and Caspase-3 were explored. Liensinine significantly improved the cognitive function of GC mice after dexmedetomidine anesthesia, and this process is related to decreased SYN expression. Liensinine can inhibit increased
SYN expression, so apoptosis of neurons in the hippocampus of mice was controlled after the use of SYN inhibitors, especially in the high-dose liensinine+SYN inhibitor group. Liensinine down-regulated the expression of SYN and inhibited the Caspase-3 to reduce neuronal cell apoptosis, promoting
recovery of BDNF level, and then playing role in improving the cognitive function of GC mice after dexmedetomidine anesthesia.
Bujing yishi tablets inhibition of the expression of P53 and bax in the P53/Bax signal pathway protects the retina of DBA/2J mice with high intraocular pressure induced by anterior chamber injection of nanomagnetic beads
Authors: Yang Fengjiao , Li Xiang
Published: September 2023

The protective effect of Bujing Yishi tablets on the retina of DBA/2J mice with high intraocular pressure (IOP) induced by anterior chamber injection of nanomagnetic beads was observed on the basis of the modulation of the p53/Bax pathway. Thirty DBA/2J mice were randomly divided into
groups for control, model, and high, medium, and low dose of Bujing Yishi tablets. Excepting the control group, the other four groups received a nanomagnetic beads injection in the anterior chamber of the eye to establish a glaucoma model. Retinal structure was observed via hematoxylin and
eosin staining. p53 and Bax protein localization and mRNA and protein expression were respectively detected by immunofluorescence staining, q-PCR, and western blotting. Compared with before modeling, the IOP significantly increased in the model and the treatment group immediately after model
establishment; the IOP increased immediately in the model group compared with that in the control group (P <0.001). The control group had clear retinal structure, orderly structured retinal ganglion cells (RGCs), and clear cell nuclei, whereas the model group had RGCs with a disordered
arrangement and sparse nuclei. Compared with that in the model group, the retinal hierarchy of the treated group was apparent. p53 and Bax expression was higher in the model group than that in the control group (P <0.001) but was lower in treated groups than that in the model group
(P <0.05); the lowest level was observed in the high-dose group. For western blotting, the expression level of p53 and Bax protein in the model group was higher than that in the control group while the expression of both proteins in all treatment groups was lower than that in the
model group (P <0.001), with the lowest in the high-dose group. Thus, treatment with Bujing Yishi tablets can reduce the IOP, inhibit the decrease of RGCs, increase the retinal thickness, and improve the retinal pathological and morphological structure, which may be related to the
inhibition of expression the proapoptotic factors p53 and Bax in the p53/Bax pathway.
Civil War Settlements, Perceived Agreement Fairness, and Trust in Political Authorities: Investigating the Influence of Power Sharing on Public Opinion in Divided Societies
Authors: Hartzell Caroline A. , Hoddie Matthew , Page Douglas
Published: September 2023

Little is known about civil war settlements' effects on public opinion in countries emerging from conflict, cases in which beliefs in agreement fairness and trust in political authorities may influence acceptance of the peace process. We posit that settlements designed to redistribute power and resources will be perceived as fairer and produce larger improvements in trust in the national government for individuals from marginalized groups than for those from dominant groups. Employing original survey data collected in the Philippines, we test these propositions with reference to the country’s 2014 peace agreement. We find that marginalized Muslim groups perceive a fairer peace agreement and report improved trust in comparison to the dominant Christian community. Using a survey experiment to analyze the influence of power-redistributing settlement measures, we find that trust in the government is not significantly affected by information regarding power sharing, a result that holds for members of both communities.
Dynamic simulation of a motor longitudinally mounted on a centralized electric drive systems for pure electric vehicles under torque ripple and transmission error excitations
Authors: Liao Zhicheng , Hua Xia , Cheng Xiangle , Ning Xiaobin , Liu Zhengqing , Chen Gang
Published: September 2023

The dynamic characteristics of electric drive systems are crucial in electric vehicles. Based on the dynamic finite element method and previous studies, this study proposes and analyzes a new mathematical model for a motor longitudinally mounted on a centralized electric drive system of a pure electric vehicle. First, we analyze the largest torque ripple of a fractional slot concentrated winding inner-mounted permanent magnet synchronous motor designed for commercial electric vehicles. This torque ripple is identified as one of the excitations influencing the dynamic performance of the electric drive system. Second, a new dynamic mathematical model for the electric drive system is established. Third, we investigate the linear vibration responses of the system subject to torque ripple and transmission error. Finally, the relationships between critical motor parameters and dynamic mesh force are revealed. The results demonstrate that the proposed theoretical method can effectively determine the dynamic characteristics of the electric drive system, thereby providing valuable theoretical guidance for the design and optimization of the motor and electric drive system.
Trade-off between time and cost in project planning: a simulation-based optimization approach
Authors: Senses Sena , Kumral Mustafa
Published: September 2023

Mine development or construction projects should be carefully scheduled to meet the project objectives in terms of duration, budget, and scope since they include many highly time- and cost-sensitive activities. The inherent complexity in mining operations, coupled with material, equipment, and resource availabilities, commodity price cyclicality, and market trend uncertainties, can lead to a high risk to the project, resulting in schedule and cost overruns. Therefore, these projects must be planned and controlled efficiently to ensure that the required capital investment does not exceed the project budget and the project deadline is met. This paper proposes a simulation-based model to optimize the trade-off between time and cost of project planning problems under uncertainty. In doing so, equally probable realizations are generated considering different project duration crashing scenarios to quantify the impact of uncertainty on the total project cost and project completion time, and risks are assessed. A numerical example is provided to show the performance of the proposed approach through an underground mine development project. Statistical analysis of the results obtained from the developed simulation model identifies the risk of project completion time, the criticality of activities, and bottleneck activities of the project. In addition, the time–cost trade-off is achieved under the project deadline and budget constraints by implementing 20,736 different crashing scenarios. Finally, the results obtained from the developed formulation are compared with those obtained from the linear programming solution. The proposed approach has a strong potential to add value to project management of mining projects.
Joseph Agassi and the Various Guises of Magic
Authors: Fatić Aleksandar
Published: September 2023

Joseph Agassi’s last book, The Philosophy of Practical Affairs, offers a comprehensive look at key philosophical topics and doctrines with a common focus on the role of rationality, the evolution of rationality and the relationship between rationality and akin phenomena. A key topic he addresses is the relationship between rationality and magic. This dichotomy reverberates on a number of areas of applied philosophy, including philosophical practice and philosophically informed psychotherapy. Agassi’s views on magic offer a fundamentally rationalist view of the phenomenon of magic, however they open up significant inroads into nuanced insights of how magic can be seen as a cognitively significant complement to rationality in the strict sense.
KPCA-WPHM-SCNs-based remaining useful life prediction method for motor rolling bearings
Authors: Han Ying , Song Xinping , Shi Jinmei , Li Kun
Published: September 2023

Motor rolling bearings are the important supporting components of motors. It can ensure the stable operation of motor equipment in the power grid, and bearing life prediction of it is a key issue. To solve the problem of low accuracy of remaining useful life (RUL) prediction for motor rolling bearings, a neural network model based on Weibull proportional hazards model (WPHM) and stochastic configuration networks (SCNs) is proposed. To better extract and analyze features of the bearing vibration signal in both time and frequency domains, kernel principal component analysis (KPCA) is used to reduce the dimensionality of the data. Then, a WPHM model using the top three contributing feature parameters is built, which sets the start time based on the failure rate curve and reliability function. Finally, the validity of the model is verified with the rolling bearing full life cycle dataset from the IEEE PHM 2012 Data Challenge, and a comparison with other machine learning models shows that the accuracy of the proposed model in RUL prediction is higher.
Production prediction based on ASGA-XGBoost in shale gas reservoir
Authors: Zhou Xin , Ran Qiquan
Published: September 2023

The advancement of horizontal drilling and hydraulic fracturing technologies has led to an increased significance of shale gas as a vital energy source. In the realm of oilfield development decisions, production forecast analysis stands as an essential aspect. Despite numerical simulation being a prevalent method for production prediction, its time-consuming nature is ill-suited for expeditious decision-making in oilfield development. Consequently, we present a data-driven model, ASGA-XGBoost, designed for rapid and precise forecasting of shale gas production from horizontally fractured wells. The central premise of ASGA-XGBoost entails the implementation of ASGA to optimize the hyperparameters of the XGBoost model, thereby enhancing its prediction performance. To assess the feasibility of the ASGA-XGBoost model, we employed a dataset comprising 250 samples, acquired by simulating shale gas multistage fractured horizontal well development through the use of CMG commercial numerical simulation software. Furthermore, XGBoost, GA-XGBoost, and ASGA-XGBoost models were trained using the data from the training set and employed to predict the 30-day cumulative gas production utilizing the data from the testing set. The outcomes demonstrate that the ASGA-XGBoost model yields the lowest mean absolute error and offers optimal performance in predicting the 30-day cumulative gas production. Additionally, the mean absolute error of the unoptimized XGBoost model is markedly greater than that of the optimized XGBoost model, indicating that the latter, refined through the application of intelligent optimization algorithms, exhibits superior performance. The insights gleaned from this investigation have the potential to inform the development of strategic plans for shale gas oilfields, ultimately promoting the cost-effective exploitation of this energy resource.
Multifaceted neural and vascular pathologies after pediatric mild traumatic brain injury
Authors: Mayer Andrew R , Dodd Andrew B , Robertson-Benta Cidney R , Zotev Vadim , Ryman Sephira G , Meier Timothy B , Campbell Richard A , Phillips John P , van der Horn Harm J , Hogeveen Jeremy , Tarawneh Rawan , Sapien Robert E
Published: September 2023

Dynamic changes in neurodevelopment and cognitive functioning occur during adolescence, including a switch from reactive to more proactive forms of cognitive control, including response inhibition. Pediatric mild traumatic brain injury (pmTBI) affects these cognitions immediately post-injury, but the role of vascular versus neural injury in cognitive dysfunction remains debated. This study consecutively recruited 214 sub-acute pmTBI (8–18 years) and age/sex-matched healthy controls (HC; N = 186), with high retention rates (>80%) at four months post-injury. Multimodal imaging (functional MRI during response inhibition, cerebral blood flow and cerebrovascular reactivity) assessed for pathologies within the neurovascular unit. Patients exhibited increased errors of commission and hypoactivation of motor circuitry during processing of probes. Evidence of increased/delayed cerebrovascular reactivity within motor circuitry during hypercapnia was present along with normal perfusion. Neither age-at-injury nor post-concussive symptom load were strongly associated with imaging abnormalities. Collectively, mild cognitive impairments and clinical symptoms may continue up to four months post-injury. Prolonged dysfunction within the neurovascular unit was observed during proactive response inhibition, with preliminary evidence that neural and pure vascular trauma are statistically independent. These findings suggest pmTBI is characterized by multifaceted pathologies during the sub-acute injury stage that persist several months post-injury.
Valuing the Dental Caries Utility Index in Australia
Authors: Hettiarachchi Ruvini M. , Kularatna Sanjeewa , Byrnes Joshua , Mulhern Brendan , Chen Gang , Scuffham Paul A.
Published: September 2023

Introduction

The Dental Caries Utility Index (DCUI) is a new oral health–specific health state classification system for adolescents, consisting of 5 domains: pain/discomfort, difficulty eating food/drinking, worried, ability to participate in activities, and appearance. Each domain has 4 response levels. This study aims to generate an Australian-specific utility algorithm for the DCUI.

Methods

An online survey was conducted using a representative sample of the adult Australian general population. The discrete choice experiment (DCE) was used to elicit the preferences on 5 domains. Then, the latent utilities were anchored onto the full health-dead scale using the visual analogue scale (VAS). DCE data were modeled using conditional logit, and 2 anchoring procedures were considered: anchor based on the worst health state and a mapping approach. The optimal anchoring procedure was selected based on the model parsimony and the mean absolute error (MAE).

Results

A total of 995 adults from the Australian general population completed the survey. The conditional logit estimates on 5 dimensions and levels were monotonic and statistically significant, except for the second level of the “worried” and “appearance” domains. The mapping approach was selected based on a smaller MAE between the 2 anchoring procedures. The Australian-specific tariff of DCUI ranges from 0.1681 to 1.

Conclusion

This study developed a utility algorithm for the DCUI. This value set will facilitate utility value calculations from the participants’ responses for DCUI in economic evaluations of dental caries interventions targeted for adolescents.

Highlights

Preference-based quality-of-life measures (PBMs), which consist of a health state classification system and a set of utility values (a scoring algorithm), are used to generate utility weights for economic evaluations. This study is the first to develop an Australian utility value set for the Dental Caries Utility Index (DCUI), a new oral health–specific classification system for adolescents. The availability of a utility value set will enable using DCUI in economic evaluations of oral health interventions targeted for adolescents and may ultimately lead to more effective and efficient planning of oral health care services.
Amide proton transfer-weighted imaging of pediatric brainstem glioma and its predicted value for H3 K27 alteration
Authors: Cheng Dan , Zhuo Zhizheng , Zhang Peng , Qu Liying , Duan Yunyun , Xu Xiaolu , Xie Cong , Liu Xing , Haller Sven , Barkhof Frederik , Zhang Liwei , Liu Yaou
Published: September 2023

Background

Non-invasive determination of H3 K27 alteration of pediatric brainstem glioma (pedBSG) remains a clinical challenge.

Purpose

To predict H3 K27-altered pedBSG using amide proton transfer-weighted (APTw) imaging.

Material and Methods

This retrospective study included patients with pedBSG who underwent APTw imaging and had the H3 K27 alteration status determined by immunohistochemical staining. The presence or absence of foci of markedly increased APTw signal in the lesion was visually assessed. Quantitative APTw histogram parameters within the entire solid portion of tumors were extracted and compared between H3 K27-altered and wild-type groups using Student's t-test. The ability of APTw for differential diagnosis was evaluated using logistic regression.

Results

Sixty pedBSG patients included 48 patients with H3 K27-altered tumor (aged 2–48 years) and 12 patients with wild-type tumor (aged 3–53 years). Visual assessment showed that the foci of markedly increased APTw signal intensity were more common in the H3 K27-altered group than in wild-type group (60% vs. 16%, P = 0.007). Histogram parameters of APTw signal intensity in the H3 K27-altered group were significantly higher than those in the wild-type group (median, 2.74% vs. 2.22%, P = 0.02). The maximum (area under the receiver operating characteristic curve [AUC] = 0.72, P = 0.01) showed the highest diagnostic performance among histogram analysis. A combination of age, median and maximum APTw signal intensity could predict H3 K27 alteration with a sensitivity of 81%, specificity of 75% and AUC of 0.80.

Conclusion

APTw imaging may serve as an imaging biomarker for H3 K27 alteration of pedBSGs.
Reliability of tomographic 3D ultrasound in measuring internal carotid artery plaque volume
Authors: Alzahrani Adel , Sultan Salahaden R , Aslam Mohammed
Published: September 2023

Background

Tomographic 3D ultrasound (t3DUS) is a promise imaging technique for quantifying carotid plaque through measuring the degree of stenosis and plaque volume. Carotid plaque volume (CPV) could add benefit in predicting the potential risk of stroke.

Purpose

To assess the reproducibility and accuracy of t3DUS for measuring CPV within the internal carotid artery in patients undergoing carotid endarterectomy.

Material and Methods

t3DUS was used to obtain CPV in vivo from 25 symptomatic patients prior to surgery. Ex vivo CPV from the carotid endarterectomy specimen was then measured using a validated saline displacement method as a reference standard. CPV for each patient was measured twice using both methods (total n = 50 per technique). Intraclass correlation coefficient (ICC) and Bland–Altman plot were used to establish bias and limit of agreement between CPV measurements.

Results

There was an excellent agreement between t3DUS and reference test with respect to measuring CPV with an ICC value of 0.98 (95% confidence interval = 0.97–0.99, P < 0.001). Bias in measurements was 0.02 ± 0.11 cm3 (95% limit of agreement = −0.19 to 0.25). Intra-observer agreement of t3DUS CPV measurements was excellent with an ICC value of 0.95 (95% confidence interval = 0.92–0.97, P < 0.001). Bias in measurements was 0.004 ± 0.07 cm3 (95% limit of agreement = −0.14 to 0.15).

Conclusion

t3DUS is a reproducible imaging method and showed excellent agreement with the reference standard with respect to measuring CPV. These findings suggest that t3DUS has the potential to be a valuable non-invasive tool for assessing carotid plaque burden and predicting the risk of stroke.
Traffic Speed Deflectometer for Network-Level Pavement Management in Tennessee
Authors: Zhang Miaomiao , Jia Xiaoyang , Fu Guozhi , Polaczyk Pawel Andrzej , Ma Yuetan , Xiao Rui , Huang Baoshan
Published: September 2023

The traffic speed deflectometer (TSD) overcomes the limitations of the falling weight deflectometer (FWD) with respect to traffic interruption and test inefficiency and is considered the preferred method for network-level pavement structural evaluation. However, some challenges exist when applying the TSD to routine survey work. This study evaluated the long-term repeatability of TSDs and compared TSD measurements with FWD measurements to examine device-related errors in TSD measurements. In addition, a framework for incorporating TSD measurements into the pavement management system (PMS) was developed by introducing deflection bowl parameters (DBPs). All data analyses were based on TSD data collected in Tennessee. From the current study, the repeatability of the TSD has not been fully validated because of device-related errors. Since TSD measurements and FWD measurements are broadly similar, periodic validation of TSDs by FWDs is recommended for quality control. TSDs provide valuable information about pavement structural conditions that are not reliably or adequately reflected in the current PMS (which focuses mainly on pavement functional conditions). DBPs are a simple and fast method for making initial estimates of pavement structural conditions without the need for layer thickness. In the proposed DBP system, the surface curvature index (SCI_12) and D60 (TSD deflection at 60 in. before the load center) represent the structural strength of the asphalt layer and subgrade, respectively. The combination of pavement functional conditions and TSD-measured structural conditions (PMS+DBPs) may help to make more accurate predictions of pavement performance and to make more appropriate decisions on maintenance and rehabilitation strategies.