bluuebunny/crossref_metadata_2025 huggingface dataset:
Study of the Molecular Structure of Proteins in Eggs under Different Storage Conditions
Authors: Li Long , Ren Shujiang , Yang Hua , Liu Junhua , Zhang Jianbin
Published: April 2023

The aim of this study is to reveal the relationship between changes in the physical and chemical characterization of eggs during storage and to provide a new way to assess egg freshness at the molecular chemical level. In this study, the Fourier transform infrared (FTIR) spectra of egg albumin from 60 fresh eggs (ISA Brown layer) stored for 1, 10, 20, 30, and 40 days at 4°C and 10°C were measured (

n
=
6

), and the amide I band of the egg albumin spectra was quantified by Fourier deconvolution and curve fitting to obtain the composition of the protein molecular structure. The results showed that different storage temperatures and storage times led to protein denaturation, resulting in changes in the conformation of the protein secondary structure. With increasing storage temperature and storage time, the content of the ordered structures β-sheet and α-helix in the egg protein secondary structure decreased significantly (

p
<
0.05

), and the content of the disordered structure β-turn and random coil increased significantly (

p
<
0.05

). Based on the pattern of protein secondary structure changes during storage, it was found that fresh eggs were better stored at 4°C for up to 15 days. Spearman’s correlation analysis of egg protein height, Haugh unit, egg weight, and protein secondary structure in eggs stored at 4°C showed a significant positive correlation between β-sheet and α-helix and egg weight, protein height, and Haugh unit. And a significant negative correlation between random coil and egg weight, protein height, and Haugh unit. Therefore, a curve fitting method based on Fourier transform infrared spectroscopy of deconvoluted spectra is an effective method for evaluating egg quality and freshness.
Encapsulation of Origanum compactum Essential Oil in Beta-Cyclodextrin Metal Organic Frameworks: Characterization, Optimization, and Antioxidant Activity
Authors: Ez-zoubi Amine , Annemer Saoussan , El Amrani Soukaina , Ez zoubi Yassine , Farah Abdellah
Published: April 2023

The study is aimed at enhancing the physicochemical and antioxidant properties of encapsulated Origanum compactum essential oil (OCEO). In this context, a Clevenger apparatus was operated in the hydrodistillation process for O. compactum extraction, and the aroma profile of essential oil was investigated using GC/MS and GC/FID. The encapsulation process was based on beta-cyclodextrin (βCD) and metal organic frameworks (K-βCD-MOFs), analyzed by several techniques. Furthermore, the response surface design allows for improved encapsulation efficiency by optimizing OCEO/K-βCD-MOFs (

w
/
w

) and water/ethanol ratios (

v
/
v

). The antioxidant activity of the essential oil, both before and after the encapsulation, was evaluated through 1,1-diphenyl-2-picrylhydrazyl. As a result, the highest EE (

35.34
±
1.23
%

) was achieved in 1/12 and 4/5 for OCEO/K-βCD-MOFs and water/ethanol, respectively. The increase in thermal stability also occurred along with the encapsulation of O. compactum essential oil. Compared with the free form, the O. compactum essential oil encapsulated in K-βCD-MOFs gradually showed higher antioxidant activity.
Meta‐Analysis of Phacoemulsification and Laser Peripheral Iridotomy in the Treatment of Primary Angle‐Closure Glaucoma
Authors: Xie Jia , Li Pengcheng , Han Bo
Published: April 2023

Background. In this meta‐analysis, we aimed to systematically compare the efficacy and safety of phacoemulsification and laser peripheral iridotomy (LPI) in the treatment of primary angle‐closure glaucoma (PACG). Method. We searched PubMed, MEDLINE, EMBASE, the Cochrane Library, the Chinese Journal Full‐text Database (CNKI), the Wanfang database, and the China Science and Technology Journal Database for randomized controlled trials (RCTs) of phacoemulsification and LPI in the treatment of PACG published up to September 30, 2022. Postoperative intraocular pressure (IOP), anterior chamber depth (ACD), complications, corneal endothelial cell count, and best‐corrected visual acuity (BCVA) were compared. The effective quantity of measurement data was measured by the mean difference (MD) and 95% confidence interval (CI). The effect of counting data was measured by the odds ratio (OR). Result. A total of 1731 potential studies were identified, and after screening, 8 RCT studies were included. The results of the meta‐analysis showed that, compared to the LPI group, the patients in the phacoemulsification group showed lower IOP six and twelve months after operation (MD‐3.39, 95% CI −4.15∼−2.63, P < 0.00001; −2.29, −3.52∼−1.06, 0.0003). The ACD in the phacoemulsification group was significantly deeper than that in the LPI group (1.59, 1.10∼2.09, 0.00001). Meanwhile, the incidence of complications in the phacoemulsification group was lower than that in the LPI group (OR = 0.46, 0.29∼0.72, 0.0006). There was no statistically significant difference between the phacoemulsification group and the LPI group in corneal endothelial cell count and BCVA at 6 and 12 months after operation (P = 0.38; 0.11; 0.81). Conclusion. Compared with LPI, phacoemulsification is safer and more effective in the treatment of PACG, especially in controlling IOP and minimizing postoperative complications.
Dynamic Modelling and Continuous Trajectory Tracking Control of Space Robots Based on Lie Group SE(3)
Authors: Wang Yong , Gong Kejie , Duan Yurui , He Boyong , Ma Hong
Published: April 2023

For space robots, it is difficult to track continuous time-varying manifolds on SE(3) by using traditional closed-loop control strategies, which are designed to track the position and the attitude separately. Therefore, the dynamics model should be rebuilt, and the corresponding control strategy should be redesigned. Firstly, the dynamics equations for a space robot in the joint space and workspace are established separately in the framework of Lie group SE(3) and screw theory based on the Lagrange principle. Secondly, based on the proposed feedback form, a PD (proportional derivative) control law of output force on the end-effector is designed, and a closed-loop continuous tracking control strategy is proposed using the force Jacobian matrix and the kinematic model. The simulation results show that the control scheme has good performance when the system state changes gently. Furthermore, a robust sliding mode tracking control scheme is designed. The simulation results show that the proposed robust control law has better accuracy than the PD control law because the system state changes wildly. Finally, a robust fuzzy sliding mode tracking control scheme is designed to deal with the chattering phenomenon. The simulation results show that the proposed robust fuzzy control law can eliminate the chattering well and decrease the joint control torque significantly. The robustness of the proposed robust fuzzy control law is also verified by numerical simulation.
Epidemiological and Spatiotemporal Descriptive Analysis of Patients with Nonsyndromic Cleft Lip and/or Palate: A 12‐Year Retrospective Study in Southern Iran
Authors: Farshidfar Nima , Ajami Shabnam , Sahmeddini Sarina , Goli Ali , Foroutan Hamid Reza
Published: April 2023

Objectives. The current study is aimed at evaluating epidemiological characteristics and spatiotemporal distribution of cleft lip and/or palate (CL/P) in the south of Iran. Methods. Data were extracted from the 1840 medical records of patients who were referred to the Cleft Lip and Palate Center of Shiraz University of Medical Sciences, from January 1, 2011, to September 1, 2022. The collected variables included demographic data (gender, birth date and season, place, birth order, and weight), cleft types and the subtypes, parental information (health status, education level, marital status, and age during the pregnancy), and other basic parameters. The chi‐square test at a significance level of 0.05 was used to analyze collected data. The geographic information system (GIS) analysis was also used for analyzing the spatial distribution of CL/P patients. Results. Based on our inclusion criteria, 1281 nonsyndromic patients were included in this study. The most common type was cleft lip and palate (CLP) with 48.32%, whereas cleft palate (CP) and cleft lip (CL) accounted for 40.75% and 10.93% of the patients, respectively. There was a progressive increase in the frequency of all types of clefts, and most of them were male (P ≤ 0.001). The urban population outnumbered the rural ones in all provinces. Parents were mostly healthy (>80%) with low educational status (47.5%). Most born CL/P patients were from consanguineous marriages (58.9%), especially between first‐degree relatives. A majority of CL/P patients (73.1%) were born in the first two gestations with a birth weight of 2500‐4000 g (77.4%). Most infants with CL/P (84.3%) were born from mothers who had at least one of the predisposing factors. Conclusion. In this study, the frequency of cleft types and subtypes was similar to the existing literature. However, high rate of consanguineous marriage, especially between first‐degree relatives, was the most notable feature of this population.
Application of Treatment for Deep Hole Drilling Debris in Gas-Rich Soft Coal Seams
Authors: Niu Yihui , Xu Zuoming , Wang Wenhe , Jing Xiaofei , Mi Hongfu , Zhong Zhen
Published: April 2023

Hole accidents occurring in the drilling process and borehole collapse encountered in gas production are obstacles standing in the way of high efficiency of gas drainage through the outburst-prone soft coal seams in China. The fundamental testing data from existing suspending agents were combined to prepare a suspension in a specific density for testing debris disposal technology considering several adverse effects. Those effects include the sizeable residual volume of drilling debris, difficult debris disposal, the low effective utilization rate of drill holes, and the unideal extraction effect in drill holes with long-distance downward drill holes. The testing outcomes indicated that the suspension-aided debris disposal could contribute to the following aspects: discharging residual drilling debris out of the drill hole, rinsing the drill hole, preventing drilling debris from filling the coal seam, providing the adequate drill hole depth, and improving the effects of gas extraction. As a result, the gas production in shallow drill holes was increased by 40%, with gas concentration elevated by 21%. In addition, the scalar quantity and extraction concentration in the gas concentration of deep drill holes were increased by 84% and 260%, respectively. This study was undertaken to provide a specific reference for debris disposal work of deep drill holes for gas-rich soft coal seams.
Measuring the Impact of Social Media on Young People’s Mental Health: Development and Validation of the Social Media-Induced Tendency Scale
Authors: Ugwu Lawrence Ejike , Idemudia Erhabor Sunday , Chukwu Olive O. , Onyedibe Maria Chidi Christiana
Published: April 2023

Social media use has been linked to adverse health outcomes such as depression. To facilitate interventions, understanding the varied causes of depression is necessary. The authors developed a social media-induced depression tendency (SMIDT) scale for use with young people and aimed to validate it for young people in Nigeria. The study was conducted in three parts using an online survey (Google Forms) with purposive sampling targeting young people. Study 1 was an exploratory study that developed the SMIDT scale with 361 young people aged 16 to 26 years (

mean
 
age
=
22.81

). A concise measure of SMIDT was obtained. In study 2, confirmatory factor analysis was performed on the SMIDT with young people aged 17 to 25 years (

mean
 
age
=
23.61

). Construct, discriminant, and concurrent validities were established, and three factors were identified (sensitivity/attention seeking, worthlessness, and escapism/reality avoidance), which explained 55.87% of the variance. Study 3 tested the predictive validity of the scale. The results showed that the 15-item SMIDT scale had high internal consistency and satisfactory validity. The SMIDT scale can enable the assessment of factors associated with social media-induced depression tendency. The three factors identified in the scale provide insight into the factors contributing to depression associated with social media use. The SMIDT scale has the potential to help identify at-risk individuals and in-developing interventions to prevent or reduce social media-induced depression tendencies. However, this study only focused on young people in Nigeria. Additional studies using the SMIDT scale are required to assess its generalizability and applicability in evaluating other factors, such as quality of life among young people. Moreover, while social media use has been associated with adverse health outcomes, it is crucial to recognize that it can also positively affect mental health. Further research is necessary to explore the complex relationships between social media use and mental health outcomes.
Evaluation of Thermal Adsorption and Mechanical Behaviour of Intralaminar Jute/Sisal/E-Glass Fibre-Bonded Epoxy Hybrid Composite as an Insulator
Authors: Venkatesh R. , Raghuvaran S. , Vivekanandan M. , Kannan C. Ramesh , Thirugnanasambandham T. , Murugan Arundeep
Published: April 2023

A thermal gravimetric analyzer analyzed the thermal adsorption properties of developed composites with the temperature range of 28°C–650°C at a 20°C/min constant heat flow rate. The epoxy hybrid composites were synthesized using natural jute/sisal fibre hybridized with the addition of synthetic E-glass fibres at 0-degree, 0/90-degree, and intralaminar orientations through the wet filament-winding process. The effects of orientations on tensile, flexural, and impact strengths of epoxy hybrid composites were studied using ASTM D3039, D790, and D6110. The evaluated results were compared, and the epoxy hybrid composite containing intralaminar orientations found better thermal stability with reduced weight loss at 650°C. Similarly, the test result for mechanical studies of the hybrid composite showed superior tensile, flexural, and impact strengths. The epoxy hybrid composite with intralaminar orientation was found to have a maximum tensile, impact, and flexural strength of 61.91 MPa, 770.61 J/m, and 83.90 MPa, respectively.
GC-O-MS Analysis of Aroma-Active Compounds of Chinese Almonds Obtained by Different Pretreatment Methods
Authors: Gu Yuchen , Feng Tao , Song Shiqing , Yao Lingyun , Sun Min , Wang Huatian , Liu Qian , Yu Chuang
Published: April 2023

Almonds (Prunus dulcis) are an ancient and commercially valuable crop from Asia. In this experiment, solid-phase microextraction (SPME), solvent-assisted flavor evaporation (SAFE), and simultaneous distillation extraction (SDE) were used to pretreat the almonds from China. The almond extract was then analyzed by aroma extract dilution analysis (AEDA) with gas chromatography-olfactory-mass spectrometer (GC-O-MS). SPME and SAFE were identified as the better extraction methods, and 52 aroma-active compounds of almonds, such as 1-nonanal, eugenol, and linalool, were identified based on odor activity values (OAVs). Aroma recombination and omission experiments showed that “sweet,” “fruity,” and “fatty” are the main aroma attributes of Chinese almonds, with a strong relationship with hexanal, heptaldehyde, 1-nonanal, etc. This experiment provides new insights into the sensory contribution of Chinese almond volatiles and helps Chinese almond producers characterize and market the aroma profile of Chinese almond varieties.
BCA101 Is a Tumor-Targeted Bifunctional Fusion Antibody That Simultaneously Inhibits EGFR and TGFβ Signaling to Durably Suppress Tumor Growth
Authors: Boreddy Srinivas Reddy , Nair Reshmi , Pandey Prashant Kumar , Kuriakose Anshu , Marigowda Shivakumar Bhadravathi , Dey Chaitali , Banerjee Arindam , Kulkarni Hanumant , Sagar Milind , Krishn Shiv Ram , Rao Shruthi , AR Madhukara , Tiwari Vinita , Alke Bhavna , MV Prashantha Kumar , Shri Meena , Dhamne Chaitrali , Patel Sonal , Sharma Pinky , Periyasamy Sankar , Bhatnagar Jaya , Kuriakose Moni Abraham , Reddy Ram Bhupal , Suresh Amritha , Sreenivas Suma , Govindappa Nagaraja , Moole Praveen Reddy , Bughani Usha , Tan Seng-Lai , Nair Pradip
Published: April 2023

The EGFR and TGFβ signaling pathways are important mediators of tumorigenesis, and cross-talk between them contributes to cancer progression and drug resistance. Therapies capable of simultaneously targeting EGFR and TGFβ could help improve patient outcomes across various cancer types. Here, we developed BCA101, an anti-EGFR IgG1 mAb linked to an extracellular domain of human TGFβRII. The TGFβ “trap” fused to the light chain in BCA101 did not sterically interfere with its ability to bind EGFR, inhibit cell proliferation, or mediate antibody-dependent cellular cytotoxicity. Functional neutralization of TGFβ by BCA101 was demonstrated by several in vitro assays. BCA101 increased production of proinflammatory cytokines and key markers associated with T-cell and natural killer–cell activation, while suppressing VEGF secretion. In addition, BCA101 inhibited differentiation of naïve CD4+ T cells to inducible regulatory T cells (iTreg) more strongly than the anti-EGFR antibody cetuximab. BCA101 localized to tumor tissues in xenograft mouse models with comparable kinetics to cetuximab, both having better tumor tissue retention over TGFβ “trap.” TGFβ in tumors was neutralized by approximately 90% in animals dosed with 10 mg/kg of BCA101 compared with 54% in animals dosed with equimolar TGFβRII-Fc. In patient-derived xenograft mouse models of head and neck squamous cell carcinoma, BCA101 showed durable response after dose cessation. The combination of BCA101 and anti-PD1 antibody improved tumor inhibition in both B16-hEGFR–expressing syngeneic mouse models and in humanized HuNOG-EXL mice bearing human PC-3 xenografts. Together, these results support the clinical development of BCA101 as a monotherapy and in combination with immune checkpoint therapy.

Significance:

The bifunctional mAb fusion design of BCA101 targets it to the tumor microenvironment where it inhibits EGFR and neutralizes TGFβ to induce immune activation and to suppress tumor growth.
Supplementary Table 9 from Somatic Mosaic Chromosomal Alterations and Death of Cardiovascular Disease Causes among Cancer Survivors
Authors: Sun Maxine , Cyr Marie-Christyne , Sandoval Johanna , Lemieux Perreault Louis-Philippe , Busque Lambert , Tardif Jean-Claude , Dubé Marie-Pierre
Published: April 2023

Supplementary Table 9: The effect of mosaic loss of Y chromosome on death of cardiovascular disease causes, coronary artery disease causes, from cancer and any cause of death
Supplementary Table 13 from Somatic Mosaic Chromosomal Alterations and Death of Cardiovascular Disease Causes among Cancer Survivors
Authors: Sun Maxine , Cyr Marie-Christyne , Sandoval Johanna , Lemieux Perreault Louis-Philippe , Busque Lambert , Tardif Jean-Claude , Dubé Marie-Pierre
Published: April 2023

Supplementary Table 13: Cox regression analyses for the effect of mosaic chromosomal alterations on the risk of death of coronary artery disease causes by cancer type
Data from Somatic Mosaic Chromosomal Alterations and Death of Cardiovascular Disease Causes among Cancer Survivors
Authors: Sun Maxine , Cyr Marie-Christyne , Sandoval Johanna , Lemieux Perreault Louis-Philippe , Busque Lambert , Tardif Jean-Claude , Dubé Marie-Pierre
Published: April 2023

AbstractBackground:
Cancer survivors are at an increased risk of cardiovascular disease (CVD) compared with the general population. We sought to evaluate the impact of mosaic chromosomal alterations (mCA) on death of CVD causes, coronary artery disease (CAD) causes, and of any cause in patients with a cancer diagnosis.
Methods:
The study was a prospective cohort analysis of 48,919 UK Biobank participants with a cancer diagnosis. mCAs were characterized using DNA genotyping array intensity data and long-range chromosomal phase inference. Multivariable Cox regression models were used to ascertain the associations of mCAs. Exploratory endpoints included various incident cardiovascular phenotypes.
Results:
Overall, 10,070 individuals (20.6%) carried ≥ 1 mCA clone. In adjusted analyses, mCA was associated with an increased risk of death of CAD causes [HR, 1.37; 95% confidence interval (CI), 1.09–1.71; P = 0.006]. In sub-analyses, we found that carriers of mCAs diagnosed with kidney cancer had an increased risk of death of CVD causes (HR, 2.03; 95% CI, 1.11–3.72; P = 0.022) and CAD causes (HR, 3.57; 95% CI, 1.44–8.84; P = 0.006). Women diagnosed with breast cancer who carried a mCA also had a higher risk of death of CAD causes (HR, 2.46; 95% CI, 1.23–4.92; P = 0.011).
Conclusions:
Among cancer survivors, carriers of any mCA are at an increased risk of CAD death compared with noncarriers. Mechanistic studies should be considered to better ascertain the biological mechanisms underneath the observed associations between mCAs and cardiovascular events for specific cancer types.
Impact:
There may be clinical relevance in considering mCAs in patients diagnosed with cancer and undergoing treatment.
Data from Exploring the complex relationship between gut microbiota and risk of colorectal neoplasia using bidirectional Mendelian Randomization analysis
Authors: Li Wanxin , Zhou Xuan , Yuan Shuai , Wang Lijuan , Yu Lili , Sun Jing , Chen Jie , Xiao Qian , Wan Zhongxiao , Zheng Ju-Sheng , Zhang Cai-Xia , Larsson Susanna C. , Farrington Susan M. , Law Philip , Houlston Richard S. , Tomlinson Ian , Ding Ke-Feng , Dunlop Malcolm G. , Theodoratou Evropi , Li Xue
Published: April 2023

Abstract
Background: Human gut microbiome has complex relationships with the host, contributing to metabolism, immunity, and carcinogenesis.
Methods: Summary-level data for gut microbiota and metabolites were obtained from MiBioGen, FINRISK and human metabolome consortia. Summary-level data for CRC were derived from a genome-wide association study meta-analysis. In forward MR, we employed genetic instrumental variables (IVs) for 24 gut microbiota taxa and six bacterial metabolites to examine their causal relationship with CRC. We also utilized a lenient threshold for nine apriori gut microbiota taxa as secondary analyses. In reverse MR, we explored association between genetic liability to colorectal neoplasia and abundance of microbiota studied above using 95, 19, and 7 IVs for CRC, adenoma, and polyps, respectively.
Results: Forward MR didn’t find evidence indicating causal relationship between any of the gut microbiota taxa or six bacterial metabolites tested and CRC risk. However, reverse MR supported genetic liability to colorectal adenomas was causally related with increased abundance of two taxa: Gammaproteobacteria (β=0.027, which represents a 0.027 increase in log-transformed relative abundance values of Gammaproteobacteria for per one-unit increase in log odds ratio of adenoma risk; P=7.06×10-8), Enterobacteriaceae (β=0.023, P=1.29×10-5).
Conclusions: We find genetic liability to colorectal neoplasia may be associated with abundance of certain microbiota taxa. It is more likely that subset of CRC genetic liability variants changes gut biology by influencing both gut microbiota and CRC risk.
Impact: This study highlights the need of future complementary studies to explore causal mechanisms linking both host genetic variation with gut microbiome and CRC susceptibility.
Data from Exploring the Complex Relationship between Gut Microbiota and Risk of Colorectal Neoplasia Using Bidirectional Mendelian Randomization Analysis
Authors: Li Wanxin , Zhou Xuan , Yuan Shuai , Wang Lijuan , Yu Lili , Sun Jing , Chen Jie , Xiao Qian , Wan Zhongxiao , Zheng Ju-Sheng , Zhang Cai-Xia , Larsson Susanna C. , Farrington Susan M. , Law Philip , Houlston Richard S. , Tomlinson Ian , Ding Ke-Feng , Dunlop Malcolm G. , Theodoratou Evropi , Li Xue
Published: April 2023

AbstractBackground:
Human gut microbiome has complex relationships with the host, contributing to metabolism, immunity, and carcinogenesis.
Methods:
Summary-level data for gut microbiota and metabolites were obtained from MiBioGen, FINRISK and human metabolome consortia. Summary-level data for colorectal cancer were derived from a genome-wide association study meta-analysis. In forward Mendelian randomization (MR), we employed genetic instrumental variables (IV) for 24 gut microbiota taxa and six bacterial metabolites to examine their causal relationship with colorectal cancer. We also used a lenient threshold for nine apriori gut microbiota taxa as secondary analyses. In reverse MR, we explored association between genetic liability to colorectal neoplasia and abundance of microbiota studied above using 95, 19, and 7 IVs for colorectal cancer, adenoma, and polyps, respectively.
Results:
Forward MR did not find evidence indicating causal relationship between any of the gut microbiota taxa or six bacterial metabolites tested and colorectal cancer risk. However, reverse MR supported genetic liability to colorectal adenomas was causally related with increased abundance of two taxa: Gammaproteobacteria (β = 0.027, which represents a 0.027 increase in log-transformed relative abundance values of Gammaproteobacteria for per one-unit increase in log OR of adenoma risk; P = 7.06×10−8), Enterobacteriaceae (β = 0.023, P = 1.29×10−5).
Conclusions:
We find genetic liability to colorectal neoplasia may be associated with abundance of certain microbiota taxa. It is more likely that subset of colorectal cancer genetic liability variants changes gut biology by influencing both gut microbiota and colorectal cancer risk.
Impact:
This study highlights the need of future complementary studies to explore causal mechanisms linking both host genetic variation with gut microbiome and colorectal cancer susceptibility.
Data from KIT and PDGFRA Mutations and Survival of Gastrointestinal Stromal Tumor Patients Treated with Adjuvant Imatinib in a Randomized Trial
Authors: Joensuu Heikki , Wardelmann Eva , Eriksson Mikael , Reichardt Annette , Hall Kirsten Sundby , Schütte Jochen , Cameron Silke , Hohenberger Peter , Sihto Harri , Jost Philipp J. , Lindner Lars H. , Bauer Sebastian , Nilsson Bengt , Kallio Raija , Pesonen Tommi , Reichardt Peter
Published: April 2023

AbstractPurpose:
Limited data are available about the influence of KIT and PDGFRA mutations on overall survival (OS) of patients with gastrointestinal stromal tumor (GIST) treated with adjuvant imatinib.
Patients and Methods:
The Scandinavian Sarcoma Group XVIII/AIO multicenter trial accrued 400 patients with a high risk for GIST recurrence after macroscopically complete surgery between February 4, 2004, and September 29, 2008. The patients received adjuvant imatinib 400 mg/day for either 1 year or 3 years based on random allocation. We analyzed using conventional sequencing KIT and PDGFRA mutations centrally from 341 (85%) patients who had localized, centrally confirmed GIST, and correlated the results with recurrence-free survival (RFS) and OS in exploratory analyses.
Results:
During a median follow-up time of 10 years, 164 RFS events and 76 deaths occurred. Most patients were re-treated with imatinib when GIST recurred. Patients with KIT exon 11 deletion or indel mutation treated with 3 years of adjuvant imatinib survived longer than patients treated for 1 year [10-year OS 86% versus 64%, respectively; HR, 0.34; 95% confidence interval (CI), 0.15–0.72; P = 0.007], and also had longer RFS (10-year RFS 47% versus 29%; HR, 0.48; 95% CI, 0.31–0.74; P < 0.001). Patients with KIT exon 9 mutation had unfavorable OS regardless of the duration of adjuvant imatinib.
Conclusions:
Compared with 1 year of imatinib, 3 years of adjuvant imatinib led to 66% reduction in the estimated risk of death and a high 10-year OS rate in the subset of patients with a KIT exon 11 deletion/indel mutation.
Data from A Tumor-suppressive Molecular Axis EP300/circRERE/miR-6837-3p/MAVS Activates Type I IFN Pathway and Antitumor Immunity to Suppress Colorectal Cancer
Authors: Ding Nan , You A-Bin , Yang Hu , Hu Guo-Sheng , Lai Chun-Ping , Liu Wen , Ye Feng
Published: April 2023

AbstractPurpose:
The oncogenic role of circular RNAs (circRNA) has been well studied in cancers including colorectal cancer. However, tumor-suppressive circRNAs and the mechanism through which they exert their antitumor effects remain largely unknown. We aim to find out the critical tumor-suppressive circRNAs and their possibility to serve as gene therapy targets.
Experimental Design:
circRNA sequencing, gain-of-function and loss-of-function experiments, and transcriptomic analysis were performed to find tumor-suppressive and antitumor immunity effects of circRERE. Molecular biology experiments were conducted for mechanism exploration. Finally, we conducted adeno-associated virus (AAV) to deliver circRERE (circRERE-AAV) and evaluated circRERE-AAV alone and in combination with anti-PD-1 antibody in C57BL/6J mice bearing subcutaneous MC38 tumors.
Results:
circRERE is lowly expressed in colorectal cancer. Overexpression of circRERE inhibits the malignant behaviors of colorectal cancer in vitro and in vivo, while knockdown exhibits the opposite effects. The expression of circRERE is regulated by EP300, a histone acetyltransferase downregulated in colorectal cancer as well. Mechanistically, circRERE acts as a competitive endogenous RNA to sponge miR-6837-3p to upregulate MAVS expression, thereby activating type I IFN signaling and promoting antitumor immunity. Delivery of circRERE-AAV elicits significant antitumor effects, and combination treatment with circRERE-AAV and anti-PD-1 antibody exhibits synergistic effects on tumor growth in preclinical models of colorectal cancer.
Conclusions:
These results uncover modulatory axis constituting of EP300/circRERE/miR-6837-3p/MAVS and its essential roles in antitumor immunity, and demonstrate that circRERE-AAV might represent a new therapeutic avenue to prime immune responses and boost the effects of immunotherapy in clinic.
Novel BCL-2 Inhibitor Lisaftoclax in Relapsed or Refractory Chronic Lymphocytic Leukemia and Other Hematologic Malignancies: First-in-Human Open-Label Trial
Authors: Ailawadhi Sikander , Chen Zi , Huang Bo , Paulus Aneel , Collins Mary C. , Fu Lei (Tommy) , Li Mingyu , Ahmad Mohammad , Men Lichuang , Wang Hengbang , Davids Matthew S. , Liang Eric , Mekala Divya J. , He Zhicong , Lasica Masa , Yannakou Costas K. , Parrondo Ricardo , Glass Laura , Yang Dajun , Chanan-Khan Asher , Zhai Yifan
Published: April 2023

Purpose:

This global phase I trial investigated the safety, efficacy, pharmacokinetics, and pharmacodynamics of lisaftoclax (APG-2575), a novel, orally active, potent selective B-cell lymphoma 2 (BCL-2) inhibitor, in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (R/R CLL/SLL) and other hematologic malignancies (HMs).

Patients and Methods:

Maximum tolerated dose (MTD) and recommended phase II dose were evaluated. Outcome measures were safety and tolerability (primary) and pharmacokinetic variables and antitumor effects (secondary). Pharmacodynamics in patient tumor cells were explored.

Results:

Among 52 patients receiving lisaftoclax, MTD was not reached. Treatment-emergent adverse events (TEAEs) included diarrhea (48.1%), fatigue (34.6%), nausea (30.8%), anemia and thrombocytopenia (28.8% each), neutropenia (26.9%), constipation (25.0%), vomiting (23.1%), headache (21.2%), peripheral edema and hypokalemia (17.3% each), and arthralgia (15.4%). Grade ≥ 3 hematologic TEAEs included neutropenia (21.2%), thrombocytopenia (13.5%), and anemia (9.6%), none resulting in treatment discontinuation. Clinical pharmacokinetic and pharmacodynamic results demonstrated that lisaftoclax had a limited plasma residence and systemic exposure and elicited rapid clearance of malignant cells. With a median treatment of 15 (range, 6–43) cycles, 14 of 22 efficacy-evaluable patients with R/R CLL/SLL experienced partial responses, for an objective response rate of 63.6% and median time to response of 2 (range, 2–8) cycles.

Conclusions:

Lisaftoclax was well tolerated, with no evidence of tumor lysis syndrome. Dose-limiting toxicity was not reached at the highest dose level. Lisaftoclax has a unique pharmacokinetic profile compatible with a potentially more convenient daily (vs. weekly) dose ramp-up schedule and induced rapid clinical responses in patients with CLL/SLL, warranting continued clinical investigation.
KIT and PDGFRA Mutations and Survival of Gastrointestinal Stromal Tumor Patients Treated with Adjuvant Imatinib in a Randomized Trial
Authors: Joensuu Heikki , Wardelmann Eva , Eriksson Mikael , Reichardt Annette , Hall Kirsten Sundby , Schütte Jochen , Cameron Silke , Hohenberger Peter , Sihto Harri , Jost Philipp J. , Lindner Lars H. , Bauer Sebastian , Nilsson Bengt , Kallio Raija , Pesonen Tommi , Reichardt Peter
Published: April 2023

Purpose:

Limited data are available about the influence of KIT and PDGFRA mutations on overall survival (OS) of patients with gastrointestinal stromal tumor (GIST) treated with adjuvant imatinib.

Patients and Methods:

The Scandinavian Sarcoma Group XVIII/AIO multicenter trial accrued 400 patients with a high risk for GIST recurrence after macroscopically complete surgery between February 4, 2004, and September 29, 2008. The patients received adjuvant imatinib 400 mg/day for either 1 year or 3 years based on random allocation. We analyzed using conventional sequencing KIT and PDGFRA mutations centrally from 341 (85%) patients who had localized, centrally confirmed GIST, and correlated the results with recurrence-free survival (RFS) and OS in exploratory analyses.

Results:

During a median follow-up time of 10 years, 164 RFS events and 76 deaths occurred. Most patients were re-treated with imatinib when GIST recurred. Patients with KIT exon 11 deletion or indel mutation treated with 3 years of adjuvant imatinib survived longer than patients treated for 1 year [10-year OS 86% versus 64%, respectively; HR, 0.34; 95% confidence interval (CI), 0.15–0.72; P = 0.007], and also had longer RFS (10-year RFS 47% versus 29%; HR, 0.48; 95% CI, 0.31–0.74; P < 0.001). Patients with KIT exon 9 mutation had unfavorable OS regardless of the duration of adjuvant imatinib.

Conclusions:

Compared with 1 year of imatinib, 3 years of adjuvant imatinib led to 66% reduction in the estimated risk of death and a high 10-year OS rate in the subset of patients with a KIT exon 11 deletion/indel mutation.
A Phase II Redifferentiation Trial with Dabrafenib-Trametinib and 131I in Metastatic Radioactive Iodine Refractory BRAF p.V600E-Mutated Differentiated Thyroid Cancer
Authors: Leboulleux Sophie , Do Cao Christine , Zerdoud Slimane , Attard Marie , Bournaud Claire , Lacroix Ludovic , Benisvy Danielle , Taïeb David , Bardet Stéphane , Terroir-Cassou-Mounat Marie , Anizan Nadège , Bouvier-Morel Emilie , Lamartina Livia , Lion Georges , Betrian Sarah , Sajous Christophe , Schiazza Aurélie , Garcia Marie-Eve , Ciappuccini Renaud , Schlumberger Martin , Al Ghuzlan Abir , Godbert Yann , Borget Isabelle
Published: April 2023

Purpose:

To evaluate the efficacy and safety of dabrafenib-trametinib-131I for the treatment of radioactive iodine refractory metastatic differentiated thyroid cancer (DTC) with a BRAF p.V600E mutation.

Patients and Methods:

A prospective phase II trial including patients with RECIST progression within 18 months and no lesion > 3 cm. Following a baseline recombinant human (rh)TSH-stimulated diagnostic whole-body scan (dc1-WBS), dabrafenib and trametinib were given for 42 days. A second rhTSH-stimulated dc WBS (dc2-WBS) was done at day 28 and 131I (5.5 GBq–150 mCi after rhTSH) was administered at day 35. Primary endpoint was the 6-month RECIST objective response rate. In case of partial response (PR) at 6 or 12 months, a second treatment course could be given. Among 24 enrolled patients, 21 were evaluable at 6 months.

Results:

Abnormal 131I uptake was present on 5%, 65%, and 95% of the dc1-WBS, dc2-WBS, and post-therapy scans, respectively. At 6 months, PR was achieved in 38%, stable disease in 52%, and progressive disease (PD) in 10%. Ten patients received a second treatment course: one complete response and 6 PRs were observed at 6 months. The median progression-free survival (PFS) was not reached. The 12- and 24-month PFS were 82% and 68%, respectively. One death due to PD occurred at 24 months. Adverse events (AE) occurred in 96% of the patients, with 10 grade 3–4 AEs in 7 patients.

Conclusions:

Dabrafenib-trametinib is effective in BRAF p.V600E-mutated DTC patients for restoring 131I uptake with PR observed 6 months after 131I administration in 38% of the patients.
Supplementary Table 8 from Disruption of the MYC Superenhancer Complex by Dual Targeting of FLT3 and LSD1 in Acute Myeloid Leukemia
Authors: Yashar William M. , Curtiss Brittany M. , Coleman Daniel J. , VanCampen Jake , Kong Garth , Macaraeg Jommel , Estabrook Joseph , Demir Emek , Long Nicola , Bottomly Daniel , McWeeney Shannon K. , Tyner Jeffrey W. , Druker Brian J. , Maxson Julia E. , Braun Theodore P.
Published: April 2023

RNA PolII Pause Index Analysis from MOLM13 RBP1 CUT&Tag (6 Hours After Drug Treatment)
Supplementary Table 11 from Disruption of the MYC Superenhancer Complex by Dual Targeting of FLT3 and LSD1 in Acute Myeloid Leukemia
Authors: Yashar William M. , Curtiss Brittany M. , Coleman Daniel J. , VanCampen Jake , Kong Garth , Macaraeg Jommel , Estabrook Joseph , Demir Emek , Long Nicola , Bottomly Daniel , McWeeney Shannon K. , Tyner Jeffrey W. , Druker Brian J. , Maxson Julia E. , Braun Theodore P.
Published: April 2023

Super-Enhancer-Type Analysis of STAT5 ChIP-Seq Peaks (24 Hours After Drug Treatment).
Supplementary Fig. 4 from Disruption of the MYC Superenhancer Complex by Dual Targeting of FLT3 and LSD1 in Acute Myeloid Leukemia
Authors: Yashar William M. , Curtiss Brittany M. , Coleman Daniel J. , VanCampen Jake , Kong Garth , Macaraeg Jommel , Estabrook Joseph , Demir Emek , Long Nicola , Bottomly Daniel , McWeeney Shannon K. , Tyner Jeffrey W. , Druker Brian J. , Maxson Julia E. , Braun Theodore P.
Published: April 2023

Dual FLT3/LSD1 inhibition suppresses MYC expression and activity.
Supplementary Fig. 2 from Disruption of the MYC Superenhancer Complex by Dual Targeting of FLT3 and LSD1 in Acute Myeloid Leukemia
Authors: Yashar William M. , Curtiss Brittany M. , Coleman Daniel J. , VanCampen Jake , Kong Garth , Macaraeg Jommel , Estabrook Joseph , Demir Emek , Long Nicola , Bottomly Daniel , McWeeney Shannon K. , Tyner Jeffrey W. , Druker Brian J. , Maxson Julia E. , Braun Theodore P.
Published: April 2023

Efficacy of dual FLT3/LSD1 inhibition in MOLM13 cells.
Data from Disruption of the MYC Super-Enhancer Complex by Dual Targeting of FLT3 and LSD1 in Acute Myeloid Leukemia
Authors: Yashar William M. , Curtiss Brittany M. , Coleman Daniel J. , VanCampen Jake , Kong Garth , Macaraeg Jommel , Estabrook Joseph , Demir Emek , Long Nicola , Bottomly Daniel , McWeeney Shannon K. , Tyner Jeffrey W. , Druker Brian J. , Maxson Julia E. , Braun Theodore P.
Published: April 2023

Abstract
Mutations in Fms-like tyrosine kinase 3 (FLT3) are common drivers in acute myeloid leukemia (AML) yet FLT3 inhibitors only provide modest clinical benefit. Prior work has shown that inhibitors of lysine-specific demethylase 1 (LSD1) enhance kinase inhibitor activity in AML. Here we show that combined LSD1 and FLT3 inhibition induces synergistic cell death in FLT3-mutant AML. Multi-omic profiling revealed that the drug combination disrupts STAT5, LSD1, and GFI1 binding at the MYC blood super-enhancer, suppressing super-enhancer accessibility as well as MYC expression and activity. The drug combination simultaneously results in the accumulation of repressive H3K9me1 methylation, an LSD1 substrate, at MYC target genes. We validated these findings in 72 primary AML samples with the nearly every sample demonstrating synergistic responses to the drug combination. Collectively, these studies reveal how epigenetic therapies augment the activity of kinase inhibitors in FLT3-ITD AML.

Implications: This work establishes the synergistic efficacy of combined FLT3 and LSD1 inhibition in FLT3-ITD AML by disrupting STAT5 and GFI1 binding at the MYC blood-specific super-enhancer complex.
Data from Non-Essential Amino Acid Availability Influences Proteostasis and Breast Cancer Cell Survival During Proteotoxic Stress
Authors: Sannino Sara , Manuel Allison M. , Shang Chaowei , Wendell Stacy G. , Wipf Peter , Brodsky Jeffrey L.
Published: April 2023

Abstract
Protein homeostasis (proteostasis) regulates tumor growth and proliferation when cells are exposed to proteotoxic stress, such as during treatment with certain chemotherapeutics. Consequently, cancer cells depend to a greater extent on stress signaling, and require the integrated stress response (ISR), amino acid metabolism, and efficient protein folding and degradation pathways to survive. To define how these interconnected pathways are wired when cancer cells are challenged with proteotoxic stress, we investigated how amino acid abundance influences cell survival when Hsp70, a master proteostasis regulator, is inhibited. We previously demonstrated that cancer cells exposed to a specific Hsp70 inhibitor induce the ISR via the action of two sensors, GCN2 and PERK, in stress-resistant and sensitive cells, respectively. In resistant cells, the induction of GCN2 and autophagy supported resistant cell survival, yet the mechanism by which these events were induced remained unclear. We now report that amino acid availability reconfigures the proteostasis network. Amino acid supplementation, and in particular arginine addition, triggered cancer cell death by blocking autophagy. Consistent with the importance of amino acid availability, which when limited activates GCN2, resistant cancer cells succumbed when challenged with a potentiator for another amino acid sensor, mTORC1, in conjunction with Hsp70 inhibition.
Implications:
These data position amino acid abundance, GCN2, mTORC1, and autophagy as integrated therapeutic targets whose coordinated modulation regulates the survival of proteotoxic-resistant breast cancer cells.
Supplementary Figure S5 from Adaptive c-Met-PLXDC2 Signaling Axis Mediates Cancer Stem Cell Plasticity to Confer Radioresistance-associated Aggressiveness in Head and Neck Cancer
Authors: Lang Liwei , Chen Fanghui , Li Yamin , Shay Chloe , Yang Fan , Dan Hancai , Chen Zhuo G. , Saba Nabil F. , Teng Yong
Published: April 2023

c-Met-PLXDC2 signaling regulates EMT-associated invasion in HN6 cells.
Enhancing Immune Protection in Hemodialysis Patients: Role of the Polymethyl Methacrylate Membrane
Authors: Franzin Rossana , Stasi Alessandra , Caggiano Gianvito , Squiccimarro Elena , Losappio Vincenzo , Fiorentino Marco , Alfieri Carlo , Stallone Giovanni , Gesualdo Loreto , Castellano Giuseppe
Published: April 2023

End-stage renal disease (ESRD) is characterized by deep disorders in both innate and adaptive immune systems that imply unbalance deactivation and immunosuppression. The central, widely recognized factors responsible for this immune dysregulation are uremia, uremic toxin retention, hemodialysis membrane biocompatibility, and related cardiovascular complications. Recently, several studies strengthened the concept that dialysis membranes are not considered as a simple diffusive/adsorptive device but as a platform to personalize a dialysis approach to improve the quality of life of ESRD patients. Therefore, understanding of the molecules associated with altered immune response is crucial and could lead to therapeutically intervention or adaptation of the dialysis procedure itself for the management of immunological dysfunction of ESRD patients. The polymethyl methacrylate (PMMA)-based membrane is characterized by a symmetrical structure with large-sized pores, providing a better hydrophobic and cationic adsorption capacity compared to the other synthetic membranes. Together with hydrophobic interactions, the high adsorption rate of cytokines (i.e., IL-6) can also be enhanced by the size of nano-pores placed on the membrane surface. PMMA membranes exhibit adsorptive properties for a large amount of uremic toxins including p-cresol and indoxyl sulfate, as well as β2-microglobulin characterized by higher molecular weight, maintaining the diffusive clearance of small molecules like urea with a great biocompatibility. Besides exerting a strong anti-inflammatory effects in line with the improvement of immune responses in patients undergoing dialysis, PMMA also plays a role in modulating adaptive immune response, i.e., can clear blood from soluble CD40, a natural antagonist of the CD40/CD40L signaling that acts inhibiting immunoglobulin production by B cells. This review provides an overview of the main concepts and current understanding of immune dysfunction in hemodialysis and summarizes the recent findings regarding PMMA-based dialysis as potential strategy to restore immune balance in ESRD patients.
Physical Activity among Primary Health Care Physicians and Its Impact on Counseling Practices
Authors: Alyafei Mohammed , Alchawa Mohamad , Farooq Abdulaziz , Selim Nagah , Bougmiza Iheb
Published: April 2023

Introduction: Physical inactivity has been linked to various noncommunicable diseases and their related health problems. As primary health care physicians (PHCPs) play a crucial role in promoting health and preventing disease, this study aims to determine the extent of physical inactivity among PHCPs and its impact on their counseling practices. Methods: A cross-sectional study was conducted across all primary health care centers in Qatar, targeting 511 physicians. A modified self-administered WHO stepwise tool was used to measure physical activity (PA) with another questionnaire to assess the counseling practices among PHCPs. Results: Out of 511 physicians, 306 (59.9%) responded to the survey. The majority of the participants were male (58.1%) with an average age of 45.8 ± 7.9 years. The majority of PHCPs were from the UK (44.3%), while only 4.1% were Qatari. Family physician consultants made up 51% of the respondents, while 30.2% were general practitioners, and the average years of experience were 14 ± 8.3 years. Only 39.5% of the respondents met the WHO PA recommendations. 50.5% of the physicians were overweight, and 23.1% were obese. The median percentage of patients counseled about PA was only 60 [IQR: 40–80]%, and there was no link found between a physician’s PA level and the percentage of patients they counseled on the subject. Conclusion: Physicians reported a high prevalence of physical inactivity. Furthermore, the practice of counseling the public on PA was low. Interventions are needed inside and outside the workplace to improve the PA among PHCPs and their counseling practices.