bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II Study of Docetaxel and Trametinib in Patients with KRAS Mutation Positive Recurrent Non–Small Cell Lung Cancer (NSCLC; SWOG S1507, NCT-02642042)
Authors: Gadgeel Shirish M. , Miao Jieling , Riess Jonathan W. , Moon James , Mack Philip C. , Gerstner Gregory J. , Burns Timothy F. , Taj Asma , Akerley Wallace L. , Dragnev Konstantin H. , Laudi Noel , Redman Mary W. , Gray Jhanelle E. , Gandara David R. , Kelly Karen 
Published: May 2023

Abstract

Purpose:
Efficacy of MEK inhibitors in KRAS+ NSCLC may differ based on specific KRAS mutations and comutations. Our hypothesis was that docetaxel and trametinib would improve activity in KRAS+ NSCLC and specifically in KRAS G12C NSCLC.

Patients and Methods:
S1507 is a single-arm phase II study assessing the response rate (RR) with docetaxel plus trametinib in recurrent KRAS+ NSCLC and secondarily in the G12C subset. The accrual goal was 45 eligible patients, with at least 25 with G12C mutation. The design was two-stage design to rule out a 17% RR, within the overall population at the one-sided 3% level and within the G12C subset at the 5% level.

Results:
Between July 18, 2016, and March 15, 2018, 60 patients were enrolled with 53 eligible and 18 eligible in the G12C cohort. The RR was 34% [95% confidence interval (CI), 22–48] overall and 28% (95% CI, 10–53) in G12C. Median PFS and OS were 4.1 and 3.3 months and 10.9 and 8.8 months, overall and in the subset, respectively. Common toxicities were fatigue, diarrhea, nausea, rash, anemia, mucositis, and neutropenia. Among 26 patients with known status for TP53 (10+ve) and STK11 (5+ve), OS (HR, 2.85; 95% CI, 1.16–7.01), and RR (0% vs. 56%, P = 0.004) were worse in patients with TP53 mutated versus wild-type cancers.

Conclusions:
RRs were significantly improved in the overall population. Contrary to preclinical studies, the combination showed no improvement in efficacy in G12C patients. Comutations may influence therapeutic efficacy of KRAS directed therapies and are worthy of further evaluation.
See related commentary by Cantor and Aggarwal, p. 3563
Sex-Associated Differences in the Clinical Outcomes of Left Ventricular Assist Device Recipients: Insights From Interagency Registry for Mechanically Assisted Circulatory Support
Authors: Shetty Naman S. , Parcha Vibhu , Abdelmessih Peter , Patel Nirav , Hasnie Ammar A. , Kalra Rajat , Pandey Ambarish , Breathett Khadijah , Morris Alanna A. , Arora Garima , Arora Pankaj 
Published: May 2023

Background:
Sex-associated differences in clinical outcomes among left ventricular assist device recipients in the United States have been recognized. However, an investigation of the social and clinical determinants of sex-associated differences is lacking.

Methods:
Left ventricular assist device receiving patients enrolled in Interagency Registry for Mechanically Assisted Circulatory Support between 2005 and 2017 were included. The primary outcome was all-cause mortality. Secondary outcomes included heart transplantation and postimplantation adverse event rates. The cohort was stratified by the social subgroup of race and ethnicity (non-Hispanic White, non-Hispanic Black, non-Hispanic Asian, and Hispanic), and clinical subgroups of device strategy (destination therapy, bridge to transplant, and bridge to candidacy), and implantation center volume (low [≤20 implants/y], medium [21–30 implants/y], and high [>30 implants/y]). A multivariable-adjusted Cox proportional hazard model was used to assess the risk of death and heart transplantation with prespecified interaction testing. Poisson regression was used to estimate adverse events by sex across the various subgroups.

Results:

Among 18 525 patients, there were 3968 (21.4%) females. Compared with their male counterparts, Hispanic (adjusted hazard ratio [HR
adj
], 1.75 [1.23–2.47]) females had the highest risk of death followed by non-Hispanic White females (HR
adj
, 1.15 [1.07–1.25];
P
interaction
=0.02). Hispanic (HR
adj
, 0.60 [0.40–0.89]) females had the lowest cumulative incidence of heart transplantation followed by non-Hispanic Black females (HR
adj
, 0.76 [0.67–0.86]), and non-Hispanic White females (HR
adj
, 0.88 [0.80–0.96]) compared with their male counterparts (
P
interaction
<0.001). Compared with their male counterparts, females on the bridge to candidacy strategy (HR
adj
, 1.32 [1.18–1.48]) had the highest risk of death (
P
interaction
=0.01). The risk of death (
P
interaction
=0.44) and cumulative incidence of heart transplantation (
P
interaction
=0.40) did not vary by sex in the center volume subgroup. A higher incidence rate of adverse events after left ventricular assist device implantation was also seen in females compared with the males, overall, and across all subgroups.

Conclusions:
Among left ventricular assist device recipients, the risk of death, the cumulative incidence of heart transplantation, and adverse events differ by sex across the social and clinical subgroups.
Heart Rate Variability Parameter Changes in Patients With Acute Ischemic Stroke Undergoing Intravenous Thrombolysis
Authors: Qu Yang , Sun Ying‐Ying , Abuduxukuer Reziya , Si Xiang‐Kun , Zhang Peng , Ren Jia‐Xin , Fu Yu‐Li , Zhang Ke‐Jia , Liu Jia , Zhang Pan‐Deng , Jin Hang , Yang Yi , Guo Zhen‐Ni 
Published: May 2023

Background
Autonomic dysfunction has been revealed in patients with acute ischemic stroke and is associated with poor prognosis. However, autonomic nervous system function assessed by heart rate variability (HRV) and its relationship with clinical outcomes in patients undergoing intravenous thrombolysis (IVT) remain unknown.

Methods and Results

Patients who did and did not undergo IVT between September 2016 and August 2021 were prospectively and consecutively recruited. HRV values were measured at 1 to 3 and 7 to 10 days after stroke to assess autonomic nervous system function. A modified Rankin scale score ≥2 at 90 days was defined as an unfavorable outcome. Finally, the analysis included 466 patients; 224 underwent IVT (48.1%), and 242 did not (51.9%). Linear regression showed a positive correlation of IVT with parasympathetic activation‐related HRV parameters at 1 to 3 days (high frequency:
β
=0.213,
P
=0.002) and with both sympathetic (low frequency:
β
=0.152,
P
=0.015) and parasympathetic activation‐related HRV parameters (high frequency:
β
=0.153,
P
=0.036) at 7 to 10 days after stroke. Logistic regression showed HRV values and autonomic function within 1 to 3 and 7 to 10 days after stroke were independently associated with 3‐month unfavorable outcomes after adjusting for confounders in patients who underwent IVT (all
P
<0.05). Furthermore, addition of HRV parameters to conventional risk factors significantly improved risk‐predictive ability of 3‐month outcome (the area under the receiver operating characteristic curve significantly improved from 0.784 [0.723–0.846] to 0.855 [0.805–0.906],
P
=0.002).

Conclusions
IVT positively affected HRV and autonomic nervous system activity, and autonomic function assessed by HRV in acute stroke phase was independently associated with unfavorable outcomes in patients undergoing IVT.
Agglomeration and Radiation: Central Cities and China's Spatial Economy
Authors: Li Jiewei , Zhao Wenyue , Liang Qianqian 
Published: May 2023

Abstract
This paper summarizes stylized facts of three dimensions of population agglomeration and the radiation effects of central cities relating to the evolutionary laws of China's population distribution. We test with decennial census data from 2000 to 2020 to identify determinants of population agglomeration and radiation effects. The results show that the distance to the major ports, central cities, and city centers of central cities determines China's population concentration. Moreover, central cities have apparent radiation effects. The closer to the central cities or the larger the population and economic scale of the central cities, the more the population is concentrated in peripheral cities or counties.
Becoming Marduk: A New Look at a Commentary on Marduk’s Address to the Demons from Assur
Authors: Gabbay Uri 
Published: May 2023

Abstract
The article deals with a commentary on the Akkadian composition Marduk’s Address to the Demons from the city of Assur. The first part of the article discusses the unique religious view found in Marduk’s Address and its commentary, in which the āšipu priest is identified with the god Marduk. The second part presents a new philological edition of the commentary.
Down-regulation of S1PR2 is correlated with poor prognosis and immune infiltrates in cervical squamous cell carcinoma and endocervical adenocarcinoma
Authors: Zhang Yu , Wang Haichuan , Lu Jie , Lv Qiang , Yun Bei , Ge Zhiru , Yan Li 
Published: May 2023

Objectives: Cervical squamous cell carcinoma and cervical adenocarcinoma (CESC) are the second leading cause of deaths from malignant tumors in women, while their therapeutic and diagnostic aims are still finited. A growing body of evidence indicated that sphingosine-1-phosphate receptor 2 (S1PR2) plays essential roles in the occurrence and development about several human cancers. Nevertheless, the key mechanism and role mechanism of S1PR2 in CESC are still unclear. Methods: We first used Tissue Expression (GTEx) and Genotypic Cancer Genome Atlas (TCGA) data to perform pan-cancer analysis on the expression and prognosis of S1PR2, and found that S1PR2 may have a potential impact on CESC. To generate a protein-protein interaction (PPI) network using the STRING database. The clusterProfiler package is used for feature-rich analysis. The Tumor IMmune Estimation Resource was used to determine the connection between S1PR2 mRNA expression and immune infiltrates. Results: S1PR2 expression in CESC tissues was down-regulated compared with adjacent normal tissues. Kaplan-Meier analysis indicated that compared with patients with high expression of S1PR2, CESC patients with low S1PR2 expression had a worse prognosis. Reduced S1PR2 expression is associated with patients with high clinical stage, more histological types of squamous cell carcinoma, and poor primary treatment outcomes. The receiver operating characteristic curve of S1PR2 was 0.870. Correlation analysis showed that the mRNA expression of S1PR2 was related to immune infiltrates and tumor purity. Conclusion: Down-regulated S1PR2 expression is related to poor survival and immune infiltration in CESC. S1PR2 is a potential biomarker for poor prognosis and as a potential target for CESC immune therapy.
Evaluation of Goal Phenytoin Levels After an Initial Intravenous Loading Dose at an Academic Medical Center
Authors: Kim Christine S. , Tran Lena K. , Goodberlet Melanie Z. , Szumita Paul M. , Marino Kaylee K. 
Published: May 2023

Background: Phenytoin intravenous loading doses are administered in status epilepticus to rapidly achieve therapeutic levels. Accurately assessing phenytoin levels after the initial load can be challenging because of its complex pharmacokinetic profile and nonstandardized weight-based loading doses. Objectives: The objectives of this analysis were to determine the incidence of patients achieving goal phenytoin levels after the initial loading dose and characterize factors that contribute to achieving the goal level. Methods: This single-center, retrospective cohort analysis was approved by our institutional review board and included adult patients who received a phenytoin load from May 2016 to March 2021. Patients were excluded if no total phenytoin level was drawn within 24 hours of the load, if the maintenance dose was given before the first level was drawn, or if the patient was on phenytoin before the load. The major endpoint was the percentage of patients achieving a corrected goal phenytoin level of ≥10 mcg/mL after the initial load. Multivariate regression was used to determine predictors of achieving the goal phenytoin level. Results: Of the 152 patients included, 139 patients (91.4%) achieved a corrected goal level after the first load. Patients at goal received a significantly higher median weight-based loading dose (19.1 mg/kg [15.0-20.0] vs 12.6 mg/kg [10.1-15.0], P < 0.01). The multivariate analysis identified weight-based dosing as a statistically significant predictor of achieving the corrected goal level (odds ratio, 1.30; 95% CI, 1.12-1.53; P < 0.01). Conclusion and Relevance: Most patients achieved a corrected goal phenytoin level after the initial load. A higher median weight-based loading dose was shown to be a predictor of achieving the goal level and should be encouraged for rapid seizure termination. Future studies are warranted to confirm patient-specific factors that affect rapid achievement of the goal phenytoin level.
Hsp70-Bim interaction facilitates mitophagy by recruiting parkin and TOMM20 into a complex
Authors: Song Ting , Yin Fangkui , Wang Ziqian , Zhang Hong , Liu Peng , Guo Yafei , Tang Yao , Zhang Zhichao 
Published: May 2023

Abstract
Background
For cancer therapy, the identification of both selective autophagy targets and small molecules that specifically regulate autophagy is greatly needed. Heat shock protein 70 (Hsp70) is a recently discovered BH3 receptor that forms a protein‒protein interaction (PPI) with Bcl-2-interacting mediator of cell death (Bim). Herein, a specific inhibitor of the Hsp70-Bim PPI, S1g-2, and its analog S1, which is a Bcl-2-Bim disruptor, were used as chemical tools to explore the role of Hsp70-Bim PPI in regulating mitophagy.

Methods
Co-immunoprecipitation and immunofluorescence assays were used to determine protein interactions and colocalization patterns. Organelle purification and immunodetection of LC3-II/LC3-I on mitochondria, endoplasmic reticulum (ER) and Golgi were applied to identify specific types of autophagy. Cell-based and in vitro ubiquitination studies were used to study the role of the Hsp70-Bim PPI in parkin-mediated ubiquitination of outer mitochondrial membrane 20 (TOMM20).

Results
We found that after the establishment of their PPI, Hsp70 and Bim form a complex with parkin and TOMM20, which in turn facilitates parkin translocation to mitochondria, TOMM20 ubiquitination and mitophagic flux independent of Bax/Bak. Moreover, S1g-2 selectively inhibits stress-induced mitophagy without interfering with basal autophagy.

Conclusions
The findings highlight the dual protective function of the Hsp70-Bim PPI in regulating both mitophagy and apoptosis. S1g-2 is thus a newly discovered antitumor drug candidate that drives both mitophagy and cell death via apoptosis.

Graphical Abstract
Membranous nephropathy caused by dimercaptosuccinic acid in a patient with Wilson’s disease: a case report and literature review
Authors: Li Xiang , Hu FengXin , Xu Gaosi 
Published: May 2023

Abstract
Background
Dimercaptosuccinic acid (DMSA) therapy is a kind of chelation therapy for patients with Wilson ‘s disease (WD). While there have been reports of side effects associated with DMSA, the development of membranous nephropathy as a result of this therapy is uncommon.

Case presentation
We present a case of a 19-year-old male patient with Wilson’s disease who experienced proteinuria while receiving long-term DMSA treatment. Further evaluation revealed abnormally low levels of serum ceruloplasmin and serum albumin, as well as a 24-hour urinary protein excretion of 4599.98 mg/24 h. A renal biopsy confirmed the presence of membranous nephropathy. After ruling out other potential causes, we determined that the patient’s membranous nephropathy was likely caused by DMSA. Following treatment with glucocorticoids, there was a significant reduction in proteinuria.

Conclusion
This case highlights the possibility of DMSA-induced membranous nephropathy and the importance of considering this diagnosis in patients receiving DMSA treatment. Given the widespread use of DMSA in the treatment of Wilson’s disease, further research is needed to fully understand the potential role of this drug in the development of membranous nephropathy.
Fatigue, depression, and product tolerability during long-term treatment with intravenous immunoglobulin (Gamunex® 10%) in patients with chronic inflammatory demyelinating polyneuropathy
Authors: Klehmet Juliane , Tackenberg Björn , Haas Judith , Kieseier Bernd C. 
Published: May 2023

Abstract

Introduction/Aims
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is characterized by progressive weakness and sensory loss, often affecting patient’s ability to walk and perform activities of daily living independently. Furthermore, patients often report fatigue and depression which can affect their quality of life. These symptoms were assessed in CIDP patients receiving long-term intravenous immunoglobulin (IVIG) treatment.

Methods
GAMEDIS was a multi-center, prospective, non-interventional study in adult CIDP patients treated with IVIG (10%) and followed for two years. Inflammatory Neuropathy Cause and Treatment (INCAT) disability score, Hughes Disability Scale (HDS), Fatigue Severity Scale (FSS), Beck Depression Inventory II (BDI), Short Form-36 health survey (SF-36) and Work Productivity and Activity Impairment Score Attributable to General Health (WPAI-GH) were assessed at baseline and quarterly. Dosing and treatment intervals, changes in outcome parameters, and adverse events (AEs) were analyzed.

Results
148 evaluable patients were followed for a mean of 83.3 weeks. The mean maintenance IVIG dose was 0.9 g/kg/cycle (mean cycle interval 38 days). Disability and fatigue remained stable throughout the study. Mean INCAT score: 2.4 ± 1.8 at baseline and 2.5 ± 1.9 at study end. HDS: 74.3% healthy/minor symptoms at baseline and 71.6% at study end. Mean FSS: 4.2 ± 1.6 at baseline and 4.1 ± 1.7 at study end. All patients reported minimal/no depression at baseline and throughout. SF-36 and WPAI-GH scores remained stable. Fifteen patients (9.5%) experienced potentially treatment-related AEs. There were no AEs in 99.3% of infusions.

Discussion
Long-term treatment of CIDP patients with IVIG 10% in real-world conditions maintained clinical stability on fatigue and depression over 96 weeks. This treatment was well-tolerated and safe.
CYD0281, a Bcl-2 BH4 domain antagonist, inhibits tumor angiogenesis and breast cancer tumor growth
Authors: Lin Yihua , Zhao Yiling , Chen Minggui , Li Zishuo , Liu Qiao , Chen Jian , Ding Yi , Ding Chunyong , Ding Ye , Qi Cuiling , Zheng Lingyun , Li Jiangchao , Zhang Rongxin , Zhou Jia , Wang Lijing , Zhang Qian-Qian 
Published: May 2023

Abstract
Background
B-cell lymphoma 2 (Bcl-2) family proteins are key regulators of apoptosis, which possess four conserved Bcl-2 homologies (BH) domains. Among the BH domains, the BH3 domain is considered as a potent ‘death domain’ while the BH4 domain is required for anti-apoptotic activity. Bcl-2 can be converted to a pro-apoptotic molecule through the removal or mutation of the BH4 domain. Bcl-2 is considered as an inducer of angiogenesis, which can promote tumor vascular network formation and further afford nutrients and oxygen to promote tumor progression. However, whether disrupting the function of the BH4 domain to convert Bcl-2 into a pro-apoptotic molecule could make Bcl-2 possess the potential for anti-angiogenic therapy remains to be defined.

Methods
CYD0281 was designed and synthesized according to the lead structure of BDA-366, and its function on inducing a conformational change of Bcl-2 was further evaluated via immunoprecipitation (IP) and immunofluorescence (IF) assays. Moreover, the function of CYD0281 on apoptosis of endothelial cells was analyzed via cell viability, flow cytometry, and western blotting assays. Additionally, the role of CYD0281 on angiogenesis in vitro was determined via endothelial cell migration and tube formation assays and rat aortic ring assay. Chick embryo chorioallantoic membrane (CAM) and yolk sac membrane (YSM) models, breast cancer cell xenograft tumor on CAM and in mouse models as well as the Matrigel plug angiogenesis assay were used to explore the effects of CYD0281 on angiogenesis in vivo.

Results
We identified a novel potent small-molecule Bcl-2-BH4 domain antagonist, CYD0281, which exhibited significant anti-angiogenic effects both in vitro and in vivo, and further inhibited breast cancer tumor growth. CYD0281 was found to induce conformational changes in Bcl-2 through the exposure of the BH3 domain and convert Bcl-2 from an anti-apoptotic molecule into a cell death inducer, thereby resulting in the apoptosis of vascular endothelial cells.

Conclusions
This study has revealed CYD0281 as a novel Bcl-2-BH4 antagonist that induces conformational changes of Bcl-2 to convert to a pro-apoptotic molecule. Our findings indicate that CYD0281 plays a crucial role in anti-angiogenesis and may be further developed as a potential anti-tumor drug candidate for breast cancer. This work also provides a potential anti-angiogenic strategy for breast cancer treatment.
Impact of digital economic development and environmental pollution on residents’ health: an empirical analysis based on 279 prefecture-level cities in China
Authors: He Yan-Ting , Zhang Yue-Chi , Huang Wen , Wang Ruo-Nan , He Luo-Xuan , Li Bei , Zhang Yi-Li 
Published: May 2023

Abstract
Background
The digital economy based on the internet and IT is developing rapidly in China, which makes a profound impact on urban environmental quality and residents’ health activities. Thus, this study introduces environmental pollution as a mediating variable based on Grossman’s health production function to explore the impact of digital economic development on the health of the population and its influence path.

Methods
Based on the panel data of 279 prefecture-level cities in China from 2011 to 2017, this paper investigates the acting mechanism of digital economic development on residents’ health by employing a combination of mediating effects model and spatial Durbin model.

Results
The development of digital economy makes direct improvement on residents’ health condition, which is also obtained indirectly by means of environmental pollution mitigation. Besides, from the perspective of spatial spillover effect, the development of digital economy also has a significant promoting effect on the health of adjacent urban residents, and further analysis reveals that the promoting effect in the central and western regions of China is more pronounced than that in the eastern region.

Conclusions
Digital economy can have a direct promoting effect on the health of residents, and environmental pollution has an intermediary effect between digital economy and residents’ health; At the same time, there is also a regional heterogeneity among the three relationships. Therefore, this paper believes that the government should continue to formulate and implement scientific digital economy development policies at the macro and micro levels to narrow the regional digital divide, improve environmental quality and enhance the health level of residents.