bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gradual C0: Symbolic Execution for Gradual Verification
Authors: DiVincenzo Jenna , McCormack Ian , Zimmerman Conrad , Gouni Hemant , Gorenburg Jacob , Ramos-Dávila Jan-Paul , Zhang Mona , Sunshine Joshua , Tanter Éric , Aldrich Jonathan 
Published: December 2024

Current static verification techniques such as separation logic support a wide range of programs. However, such techniques only support complete and detailed specifications, which places an undue burden on users. To solve this problem, prior work proposed gradual verification, which handles complete, partial, or missing specifications by soundly combining static and dynamic checking. Gradual verification has also been extended to programs that manipulate recursive, mutable data structures on the heap. Unfortunately, this extension does not reward users with decreased dynamic checking as more specifications are written and more static guarantees are made. In fact, all properties are checked dynamically regardless of any static guarantees. Additionally, no full-fledged implementation of gradual verification exists so far, which prevents studying its performance and applicability in practice.

We present Gradual C0, the first practicable gradual verifier for recursive heap data structures, which targets C0, a safe subset of C designed for education. Static verifiers supporting separation logic or implicit dynamic frames use symbolic execution for reasoning; so Gradual C0, which extends one such verifier, adopts symbolic execution at its core instead of the weakest liberal precondition approach used in prior work. Our approach addresses technical challenges related to symbolic execution with imprecise specifications, heap ownership, and branching in both program statements and specification formulas. We also deal with challenges related to minimizing insertion of dynamic checks and extensibility to other programming languages beyond C0. Finally, we provide the first empirical performance evaluation of a gradual verifier, and found that on average, Gradual C0 decreases run-time overhead between 7.1 and 40.2% compared to the fully dynamic approach used in prior work (for context, the worst cases for the approach by Wise et al. [
2020
] range from 0.1 to 4.5 seconds depending on the benchmark). Further, the worst-case scenarios for performance are predictable and avoidable. This work paves the way towards evaluating gradual verification at scale.
Cultural Adaptation and Psychometric Validation of the Simplified Chinese Version of the Fear Avoidance Component Scale (FACS)
Authors: Tu Zhongyi , Miao Junfang , Zhang Yanzhao , Yang Zhaohui , Xu Rui , Neblett Randy 
Published: December 2024

Background: Strong associations have been demonstrated between chronic musculoskeletal pain, pain‐related fear‐avoidance (FA) of activities of daily living, and functional disability. The Fear Avoidance Components Scale (FACS) is a patient‐reported outcome (PRO) measure, which was designed to evaluate cognitive, emotional, and behavioural dimensions of FA.Objective: The study aims were to translate the English version of the FACS into Simplified Chinese and then to examine its psychometric properties.Methods: The translation and cross‐cultural adaptation of the FACS from English to Chinese was performed with standard methodology. A group of 330 subjects with chronic musculoskeletal pain completed the FACS‐Chi and additional FA‐related PRO measures. The FACS‐Chi was then completed a second time, 1 week later.Results: The FACS‐Chi showed excellent internal consistency (Cronbach’s alpha = 0.920) and test‐retest reliability (ICC = 0.918). A confirmatory factor analysis of the 2‐factor model determined in the original English version of FACS revealed an acceptable fit. Strong correlations were found between FACS‐Chi scores and other PRO measures of perceived level of disability, pain catastrophizing, and pain‐related anxiety (p < 0.001 for all analyses).Conclusions: The FACS‐Chi demonstrated good psychometric properties, including excellent test‐retest reliability and internal consistency and satisfactory construct validity. The FACS‐Chi may be a useful measure of pain‐related FA in Chinese‐speaking patients with chronic musculoskeletal pain.
spatialGE Is a User-Friendly Web Application That Facilitates Spatial Transcriptomics Data Analysis
Authors: Ospina Oscar E. , Manjarres-Betancur Roberto , Gonzalez-Calderon Guillermo , Soupir Alex C. , Smalley Inna , Tsai Kenneth Y. , Markowitz Joseph , Khaled Mariam L. , Vallebuona Ethan , Berglund Anders E. , Eschrich Steven A. , Yu Xiaoqing , Fridley Brooke L. 
Published: December 2024

Abstract
Spatial transcriptomics (ST) is a powerful tool for understanding tissue biology and disease mechanisms. However, the advanced data analysis and programming skills required can hinder researchers from realizing the full potential of ST. To address this, we developed spatialGE, a web application that simplifies the analysis of ST data. The application spatialGE provided a user-friendly interface that guides users without programming expertise through various analysis pipelines, including quality control, normalization, domain detection, phenotyping, and multiple spatial analyses. It also enabled comparative analysis among samples and supported various ST technologies. The utility of spatialGE was demonstrated through its application in studying the tumor microenvironment of two data sets: 10× Visium samples from a cohort of melanoma metastasis and NanoString CosMx fields of vision from a cohort of Merkel cell carcinoma samples. These results support the ability of spatialGE to identify spatial gene expression patterns that provide valuable insights into the tumor microenvironment and highlight its utility in democratizing ST data analysis for the wider scientific community.
Significance: The spatialGE web application enables user-friendly exploratory analysis of spatial transcriptomics data by using a point-and-click interface to guide users from data input to discovery of spatial patterns, facilitating hypothesis generation.
First Results of Migoprotafib, a Potent and Highly Selective Src Homology-2 Domain–Containing Phosphatase 2 Inhibitor in Patients with Advanced Solid Tumors
Authors: Johnson Melissa L. , Wolf Beni B. , Wang Judy S. , Philipovskiy Alexander , Shapiro Geoffrey I. , Bockorny Bruno , Guo Wei , Shen Jinshan , Jen Kai Yu , LeRose MaryBeth , Hunter Tamieka Lauz , Padval Mahesh , Schmidt-Kittler Oleg , Bhatia Namrata , Dubey Sarita , Suchomel Julia , Bendell Johanna C. , Jauhari Shekeab , Eng-Wong Jennifer , Lin Jessica J. 
Published: December 2024

Abstract
Src homology-2 domain–containing phosphatase 2 promotes rat sarcoma viral oncogene homolog–MAPK signaling and tumorigenesis and is a promising therapeutic target for multiple solid tumors. Migoprotafib is a potent and highly selective Src homology-2 domain–containing phosphatase 2 inhibitor designed for the treatment of rat sarcoma viral oncogene homolog–MAPK–driven cancers, particularly in combination with other targeted agents. Here, we report first-in-human study results of single-agent migoprotafib in patients with advanced solid tumor. We conducted a phase Ia, open-label, multi-center, dose-escalation and expansion study in adult patients with locally advanced or metastatic solid tumors. The key objectives were to evaluate safety, pharmacokinetics (PK), pharmacodynamics (peripheral blood phosphorylated ERK), and preliminary antitumor activity. Fifty-six heavily pretreated patients were treated with migoprotafib (10–150 mg once daily). Migoprotafib had a rapid absorption rate (∼0.5–2 hours) with dose-dependent increases in exposure and pathway modulation (phosphorylated ERK changes). The maximum tolerated dose was 100 mg, and the recommended phase II dose was 60 mg daily (once daily) based on safety, PK, pharmacodynamics, and antitumor activity. Migoprotafib was generally well tolerated with the most frequent adverse events of diarrhea, peripheral edema, dyspnea, anemia, constipation, fatigue, aspartate aminotransferase increase, and platelet count decrease. Stable disease was observed in 10 patients (18%). Migoprotafib had predictable, dose-dependent PK with an effective half-life that supports once-daily dosing and demonstrated promising safety, tolerability, and clinical activity at the recommended phase II dose. Further clinical testing of migoprotafib in combination with other targeted agents is warranted.
Denfivontinib Activates Effector T Cells Through the NLRP3 Inflammasome, Yielding Potent Anticancer Effects by Combination with Pembrolizumab
Authors: Kim Dong Kwon , Synn Chun-Bong , Lee Wongeun , Jo Ha-Ni , Lee Chai Young , Lee Seul , Hwang Joon Yeon , Kim Youngtaek , Kang Seong-san , Baek Sujeong , Na Kwangmin , Yang Seung Min , Kim Mi Hyun , Han Heekyung , Han Yu Jin , Kim Jae Hwan , Park So Young , Park Young Joon , Lee Gang-Taik , Choi Su-Jin , Sohn Jie-Ohn , Ye Sang-Kyu , Lee Jii Bum , Lim Sun Min , Hong Min Hee , Pyo Kyoung-Ho , Cho Byoung Chul 
Published: December 2024

Abstract
Various combination therapies have been investigated to overcome the limitations of using immune checkpoint inhibitors. However, determining the optimal combination therapy remains challenging. To overcome the therapeutic limitation, we conducted a translational research to elucidate the mechanisms by which AXL inhibition enhances antitumor effects when combined with anti–PD-1 antibody therapy. Herein, we demonstrated improved antitumor effects through combination treatment with denfivontinib and pembrolizumab which resulted in enhanced differentiation into effector CD4+ and CD8+ memory T cells, accompanied by an increase in IFN-γexpression in the YHIM-2004 xenograft model derived from patients with non–small cell lung cancer. Concurrently, a reduction in the number of immunosuppressive M2 macrophages and myeloid-derived suppressor cells was observed. Mechanistically, denfivontinib potentiated the NOD-like receptor pathway, thereby facilitating NLRP3 inflammasome formation. This leads to macrophage activation via NF-κB signaling pathway activation. We have confirmed that the positive interaction between macrophages and T cells arises from the enhanced antigen-presenting machinery of activated macrophages. Furthermore, the observed tumor effects in AXL knockout mice confirmed that AXL inhibition by denfivontinib enhances the antitumor effects, thus opening new avenues for therapeutic interventions aimed at overcoming limitations in immunotherapy. To demonstrate the extent to which our findings reflect clinical results, we analyzed bulk RNA sequencing data from 21 patients with non–small cell lung cancer undergoing anti–PD-1 immunotherapy. The NLRP3 inflammasome score influenced enhanced immune responses in patient data undergoing anti–PD-1 immunotherapy, suggesting a role for the NLRP3 inflammasome in activating immune responses during treatment.
Circadian Dysfunction in the Skeletal Muscle Impairs Limb Perfusion and Muscle Regeneration in Peripheral Artery Disease
Authors: Zhu (朱培) Pei , Chao Calvin L. , Steffeck Adam W.T. , Dang Caitlyn , Hamlish Noah X. , Pfrender Eric M. , Jiang Bin , Peek Clara B. 
Published: December 2024

BACKGROUND:
Peripheral artery disease (PAD), caused by atherosclerosis, leads to limb ischemia, muscle damage, and impaired mobility in the lower extremities. Recent studies suggest that circadian rhythm disruptions can hinder vascular repair during ischemia, but the specific tissues involved and the impact on muscle health remain unclear. This study investigates the role of the skeletal muscle circadian clock in muscle adaptation to ischemic stress using a surgical mouse model of hindlimb ischemia.

METHODS:

We performed secondary analysis of publicly available RNA-sequencing data sets derived from patients with PAD to identify the differential expression of circadian-related genes in endothelial cells and ischemic limb skeletal muscles. We used mice with specific genetic loss of the circadian clock activator, BMAL1 (brain and muscle ARNT-like 1), in adult skeletal muscle tissues (
Bmal1

muscle

).
Bmal1

muscle

mice and controls underwent femoral artery ligation surgery to induce hindlimb ischemia. Laser Doppler imaging was used to assess limb perfusion at various time points after the surgery. Muscle tissues were analyzed with RNA sequencing and histological examination to investigate PAD-related muscle pathologies. Additionally, we studied the role of BMAL1 in muscle fiber adaptation to hypoxia using RNA and assay for transposase-accessible chromatin with sequencing analyses in primary myotube culture model.

RESULTS:

Disrupted expression of circadian rhythm–related genes was observed in existing RNA-sequencing data sets from endothelial cells and ischemic limb skeletal muscles derived from patients with PAD. Genetic loss of
Bmal1
specifically in adult mouse skeletal muscle tissues delayed reperfusion recovery following induction of hindlimb ischemia. Histological examination of muscle tissues showed reduced regenerated myofiber number and a decreased proportion of type IIB fast-twitch myofibers in
Bmal1

muscle

mouse muscles in the ischemic limbs but not in their contralateral nonischemic limbs. Transcriptomic analysis revealed abrogated metabolic, angiogenic, and myogenic pathways relevant to hypoxia adaptation in
Bmal1

muscle

mouse muscles. These changes were corroborated in
Bmal1
-deficient cultured primary myotubes cultured under hypoxic conditions.

CONCLUSIONS:
Circadian clock in skeletal muscle is crucial for the muscle’s response to hypoxia during hindlimb ischemia. Targeting the muscle circadian clock may have therapeutic potential for enhancing muscle response to reduced blood flow and promoting recovery in conditions such as PAD.
Human Genetic Evidence to Inform Clinical Development of IL-6 Signaling Inhibition for Abdominal Aortic Aneurysm
Authors: Burgess Stephen , Cronjé Héléne T. , deGoma Emil , Chyung Yung , Gill Dipender 
Published: December 2024

BACKGROUND:
Abdominal aortic aneurysm (AAA) represents a significant cause of mortality, yet no medical therapies have proven efficacious. The aim of the current study was to leverage human genetic evidence to inform clinical development of IL-6 (interleukin-6) signaling inhibition for the treatment of AAA.

METHODS:

Associations of rs2228145, a missense variant in the
IL6R
gene region, are expressed per additional copy of the C allele, corresponding to the genetically predicted effect of IL-6 signaling inhibition. We consider genetic associations with AAA risk in the AAAgen consortium (39 221 cases and 1 086 107 controls) and UK Biobank (1963 cases and 365 680 controls). To validate against known effects of IL-6 signaling inhibition, we present associations with rheumatoid arthritis, polymyalgia rheumatica, and severe COVID-19. To explore mechanism specificity, we present associations with thoracic aortic aneurysm, intracranial aneurysm, and coronary artery disease. We further explored genetic associations in clinically relevant subgroups of the population.

RESULTS:

We observed strong genetic associations with AAA risk in the AAAgen consortium, UK Biobank, and FinnGen (odds ratios: 0.91 [95% CI, 0.90–0.92],
P
=4×10
−30
; 0.90 [95% CI, 0.84–0.96],
P
=0.001; and 0.86 [95% CI, 0.82–0.91],
P
=7×10
−9
, respectively). The association was similar for fatal AAA but with greater uncertainty due to the lower number of events. The association with AAA was of greater magnitude than associations with coronary artery disease and even rheumatological disorders for which IL-6 inhibitors have been approved. No strong associations were observed with thoracic aortic aneurysm or intracranial aneurysm. Associations attenuated toward the null in populations with concomitant rheumatological or connective tissue disease.

CONCLUSIONS:
Inhibition of IL-6 signaling is a promising strategy for treating AAA but not other types of aneurysmal disease. These findings serve to help inform clinical development of IL-6 signaling inhibition for AAA treatment.
Cross-Sex Hormone Therapy Is Associated With Loss of Circadian Rhythm in the Male Rat
Authors: Mallette Jordan H. , Crudup Breland F. , Oudomrath Speyrer Adrian , Rawls Adam Z. , Cockrell Kathy , Willis Alex T. , Davenport Kacey , Yanes Cardozo Licy L. , Shawky Noha M. , Alexander Barbara T. 
Published: December 2024

BACKGROUND:
Transgender women are individuals born male but identify as female. Many transgender women undergo gender-affirming hormone therapy to alleviate the distress that can occur due to gender incongruence. For transgender women, gender-affirming hormone therapy includes 17β-estradiol (E2) combined with an antiandrogen therapy (AA) or surgical intervention. Numerous studies suggest that the risk of cardiovascular disease is elevated in transgender women; yet, the biological effects of gender-affirming hormone therapy on cardiovascular health are unknown. We hypothesize that a shift in the hormonal milieu versus natal sex in the male rat is associated with an increase in blood pressure at baseline and an enhanced responsiveness to a hypertensive challenge.

METHODS:
We developed clinically relevant models that mimic gender-affirming hormone therapy combination therapies utilized for the endocrine treatment of gender dysphoria in transgender women.

RESULTS:
Chronic E2 plus castration or the E2+antiandrogen spironolactone was associated with a significant reduction in lean mass and testosterone. At baseline, 24-hour mean arterial pressure did not differ in E2+castration or E2+antiandrogen therapy versus control, but circadian rhythm was disrupted. In response to chronic Ang II (angiotensin II; 200 ng/kg per minute), the Ang II-induced increase in blood pressure was attenuated in E2+castration compared with control, but the blood pressure response to Ang II was similar in E2+antiandrogen therapy versus control.

CONCLUSIONS:
Thus, these data indicate that the type of combination therapy utilized may exert differential effects on blood pressure and that disruption of circadian rhythm may be a contributory factor to the increased risk of adverse cardiovascular outcomes in transgender women exposed to high 17β-estradiol coupled to androgen suppression.
Decreased serum SLC7A11 and GPX4 levels may reflect disease severity of acute ischaemic stroke
Authors: Liu Chuan-Peng , Zheng Su , Zhang Ping , Chen Guang-Hui , Zhang Yuan-Yuan , Sun Hui-Lin , Peng Li 
Published: December 2024

Objective This study aimed to examine the levels of solute carrier family seven number 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) in the serum of patients with acute ischaemic stroke (AIS) and their relationship with disease severity. Methods A total of 148 patients with AIS together with 148 healthy controls (HCs) were enrolled. The expression levels of SLC7A11 and GPX4 in serum were detected immediately as early as possible. Radiographic severity was detected by Alberta Stroke Program Early CT Score (ASPECTS). Disease severity was evaluated using modified Rankin Scale (mRS). High-sensitivity C-reactive protein (hs-CRP) and matrix metalloproteinase-9 (MMP-9) expression levels were also measured. A correlation analysis was conducted to determine the relationship between the expression levels of SLC7A11 and GPX4 with the clinical severity of the disease and the levels of hs-CRP and MMP-9. Furthermore, receiver operating characteristic (ROC) curve analysis was utilized to assess the potential of SLC7A11 and GPX4 as diagnostic markers. Results Compared to the HC group, the serum expression levels of SLC7A11 and GPX4 were significantly lower in the AIS group. Serum SLC7A11 levels were positively associated with serum GPX4 levels. The AIS group included 50 patients with mild neurological impairment, 52 with moderate neurological impairment, and 46 with severe neurological impairment. AIS patients with mild neurological impairment had drastically higher serum SLC7A11 and GPX4 levels compared with those with moderate neurological impairment. AIS patients with moderate neurological impairment showed significantly higher serum SLC7A11 and GPX4 concentrations compared with those with severe neurological impairment. ROC curve analysis demonstrated that both serum SLC7A11 and GPX4 may both act as potential indicators for evaluating of AIS disease severity. In addition, both serum SLC7A11 and GPX4 levels were positively correlated with ASPECTS. Both serum SLC7A11 and GPX4 levels were negatively associated with hs-CRP as well as MMP-9 levels. Serum SLC7A11 and GPX4 levels were significantly increased following comprehensive therapy. Conclusions Decreased SLC7A11 and GPX4 levels may reflect disease severity of AIS.
The variability of measured and calculated low-density lipoprotein (LDL) cholesterol in statin-treated diabetes patients
Authors: Kilpatrick Eric S , Kallner Anders , Atkin Stephen L , Sathyapalan Thozhukat 
Published: December 2024

Background The Sampson-NIH and Martin-Hopkins low-density lipoprotein cholesterol (LDL-C) equations are advocated as being superior to the Friedewald calculation. However, their mathematical complexity means they may have different biological and analytical variation when tracking LDL-C in the same patient. This study has established the biological variation (BV) of calculated and directly measured LDL-C (dLDL-C) in patients taking equivalent doses of a long (atorvastatin) and short (simvastatin) half-life statin. It also modelled how analytical imprecision might add to these BVs. Methods In a crossover study of lipid BV involving 26 patients with type 2 diabetes (T2DM) initially taking either simvastatin 40 mg or atorvastatin 10 mg, fasting lipids were measured 10 times over 5 weeks after a 3 month run-in. The same procedure was then followed for the alternate statin. Outlier removal and CV-ANOVA established the BV of dLDL and each formula. Analytical measurement uncertainty was estimated from 6 months of real-world data. Results The intra-individual BV of dLDL-C measurement was considerably lower with atorvastatin than simvastatin (CV 1.3%(95% CI 1.1–1.5%) vs. 11.1%(10.2–12.2%), respectively). No equation could distinguish this difference (Friedewald 11.0%(95% CI 10.0–12.1%) vs. 12.9%(11.8–14.2%), Sampson-NIH 10.4%(9.5–11.5%) vs. 11.7% (10.7–12.8%) and Martin-Hopkins 9.3%(8.5–10.3%) vs. 11.3%(10.3–12.4%)). Real-world analytical CVs were 2.6% (Sampson-NIH), 2.6% (Martin-Hopkins) 2.8% (Friedewald) and 2.0% (dLDL-C). Conclusions Inherent biological LDL-C variability using these formulae is substantially greater than direct measurement in T2DM patients taking atorvastatin. Typical analytical imprecision was also greater. Together, this may fundamentally limit these equations’ ability to track true LDL-C changes in patients taking popular statin treatments.
What’s Your Damage? Assessing the Harms of Sexual Harassment From the Perspective of the Victim and the Accused
Authors: Taylor Alice , Taylor Joshua 
Published: December 2024

AbstractThis article begins with a simple question: why are the damages awarded to victims of sexual harassment so much lower than damages awarded for those defamed by false allegations of sexual harassment? This article undertakes a comparative analysis of the underlying rationales for awarding damages in the doctrines of sexual harassment and defamation, tracking the historical reasons why sexual harassment damages have traditionally been so low compared to other doctrines. Then, it directly analyses two cases which awarded some of the highest damages in their respective doctrines: Rush v Nationwide News Pty Ltd and Hughes v Hill. This analysis reveals how the ongoing effect that traditional factors inhibiting sexual harassment damages, such as gender stereotyping and the requirement to medicalise damages, results in ongoing discrepancies in the damages awarded between both doctrines. This article suggests a simple solution: applying similar rationales for assessing damages in defamation to sexual harassment decisions.