bluuebunny/crossref_metadata_2025_split huggingface dataset:
IκBα kinase inhibitor BAY 11-7082 promotes anti-tumor effect in RAS-driven cancers
Authors: Guruvaiah Praveen , Gupta Romi 
Published: July 2024

AbstractBackgroundOncogenic mutations in the RAS gene are associated with uncontrolled cell growth, a hallmark feature contributing to tumorigenesis. While diverse therapeutic strategies have been diligently applied to treat RAS-mutant cancers, successful targeting of the RAS gene remains a persistent challenge in the field of cancer therapy. In our study, we discover a promising avenue for addressing this challenge.MethodsIn this study, we tested the viability of several cell lines carrying oncogenic NRAS, KRAS, and HRAS mutations upon treatment with IkappaBalpha (IκBα) inhibitor BAY 11-7082. We performed both cell culture-based viability assay and in vivo subcutaneous xenograft-based assay to confirm the growth inhibitory effect of BAY 11-7082. We also performed large RNA sequencing analysis to identify differentially regulated genes and pathways in the context of oncogenic NRAS, KRAS, and HRAS mutations upon treatment with BAY 11-7082.ResultsWe demonstrate that oncogenic NRAS, KRAS, and HRAS activate the expression of IκBα kinase. BAY 11-7082, an inhibitor of IκBα kinase, attenuates the growth of NRAS, KRAS, and HRAS mutant cancer cells in cell culture and in mouse model. Mechanistically, BAY 11-7082 inhibitor treatment leads to suppression of the PI3K-AKT signaling pathway and activation of apoptosis in all RAS mutant cell lines. Additionally, we find that BAY 11-7082 treatment results in the downregulation of different biological pathways depending upon the type of RAS protein that may also contribute to tumor growth inhibition.ConclusionOur study identifies BAY 11-7082 to be an efficacious inhibitor for treating RAS oncogene (HRAS, KRAS, and NRAS) mutant cancer cells. This finding provides new therapeutic opportunity for effective treatment of RAS-mutant cancers.
A novel CAF-cancer cell crosstalk-related gene prognostic index based on machine learning: prognostic significance and prediction of therapeutic response in head and neck squamous cell carcinoma
Authors: Xu Yuming , Li Junda , Wang Jinming , Deng Feilong 
Published: July 2024

Abstract
Background
Cancer-associated fibroblast (CAF)-cancer cell crosstalk (CCCT) plays an important role in tumor microenvironment shaping and immunotherapy response. Current prognostic indexes are insufficient to accurately assess immunotherapy response in patients with head and neck squamous cell carcinoma (HNSCC). This study aimed to develop a CCCT-related gene prognostic index (CCRGPI) for assessing the prognosis and response to immune checkpoint inhibitor (ICI) therapy of HNSCC patients.

Methods
Two cellular models, the fibroblast-cancer cell indirect coculture (FCICC) model, and the fibroblast-cancer cell organoid (FC-organoid) model, were constructed to visualize the crosstalk between fibroblasts and cancer cells. Based on a HNSCC scRNA-seq dataset, the R package CellChat was used to perform cell communication analysis to identify gene pairs involved in CCCT. Least absolute shrinkage and selection operator (LASSO) regression was then applied to further refine the selection of these gene pairs. The selected gene pairs were subsequently subjected to stepwise regression to develop CCRGPI. We further performed a comprehensive analysis to determine the molecular and immune characteristics, and prognosis associated with ICI therapy in different CCRGPI subgroups. Finally, the connectivity map (CMap) analysis and molecular docking were used to screen potential therapeutic drugs.

Results
FCICC and FC-organoid models showed that cancer cells promoted the activation of fibroblasts into CAFs, that CAFs enhanced the invasion of cancer cells, and that CCCT was somewhat heterogeneous. The CCRGPI was developed based on 4 gene pairs: IGF1-IGF1R, LGALS9-CD44, SEMA5A-PLXNA1, and TNXB-SDC1. Furthermore, a high CCRGPI score was identified as an adverse prognostic factor for overall survival (OS). Additionally, a high CCRGPI was positively correlated with the activation of the P53 pathway, a high TP53 mutation rate, and decreased benefit from ICI therapy but was inversely associated with the abundance of various immune cells, such as CD4+ T cells, CD8+ T cells, and B cells. Moreover, Ganetespib was identified as a potential drug for HNSCC combination therapy.

Conclusions
The CCRGPI is reliable for predicting the prognosis and immunotherapy response of HSNCC patients and may be useful for guiding the individualized treatment of HNSCC patients.
Dual targeting non-overlapping epitopes in HER2 domain IV substantially enhanced HER2/HER2 homodimers and HER2/EGFR heterodimers internalization leading to potent antitumor activity in HER2-positive human gastric cancer
Authors: Wei Ruicheng , Zhang Wenli , Yang Futang , Li Qianhao , Wang Qingyu , Liu Ningshu , Zhu Jun , Shan Yongqiang 
Published: July 2024

Abstract
Background
Trastuzumab and pertuzumab combination has been approved for the treatment of patients with HER2-positive metastatic breast cancer. However, trastuzumab and pertuzumab combination did not show improvement in overall survival in patients with HER2-positive metastatic gastric cancer.

Methods
We developed a new HER2-targeted monoclonal antibody, HLX22, targeting HER2 subdomain IV as trastuzumab but with non-overlapping epitopes. We examined the antitumor effects of this novel HER2-antibody in gastric cell lines and cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models.

Results
HLX22 in combination with HLX02 (trastuzumab biosimilar) induced enhancement of HER2/HER2 homodimers and HER2/EGFR heterodimers internalization, which ultimately led to the reduction in signal transductions involving STAT3, P70 S6, and AKT; gene expressions of FGF-FGFR-PI3K-MTOR, EGF-EGFR-RAS, TGF-β-SMAD, PLCG and cell cycle progression related pathways that favor tumor development, proliferation, progression, migration and survival in gastric cancer cell line NCI-N87 were also reduced. These differing but complementary actions contributed to the synergistic antitumor efficacy of the HLX22 and HLX02 combination in gastric cancer cell lines, CDX and PDX. In addition, HLX22 in combination with HLX02 demonstrated stronger antitumor efficacy than HLX02 and HLX11 (a potential pertuzumab biosimilar) combination treatment both in vitro and in vivo.

Conclusions
These results suggested that the application of non-competing antibodies HLX22 and HLX02 targeting HER2 subdomain IV together may be of substantial benefit to gastric cancer patients who currently respond suboptimal to trastuzumab therapy.
High positive predictive value of CNVs detected by clinical exome sequencing in suspected genetic diseases
Authors: Zeng Yimo , Ding Hongke , Wang Xingwang , Huang Yanlin , Liu Ling , Du Li , Lu Jian , Wu Jing , Zeng Yukun , Mai Mingqin , Zhu Juan , Yu Lihua , He Wei , Guo Fangfang , Peng Haishan , Yao Cuize , Qi Yiming , Liu Yuan , Li Fake , Yang Jiexia , Hu Rong , Liang Jie , Wang Jicheng , Wang Wei , Zhang Yan , Yin Aihua 
Published: July 2024

Abstract
Background
Genetic disorders often manifest as abnormal fetal or childhood development. Copy number variations (CNVs) represent a significant genetic mechanism underlying such disorders. Despite their importance, the effectiveness of clinical exome sequencing (CES) in detecting CNVs, particularly small ones, remains incompletely understood. We aimed to evaluate the detection of both large and small CNVs using CES in a substantial clinical cohort, including parent–offspring trios and proband only analysis.

Methods
We conducted a retrospective analysis of CES data from 2428 families, collected from 2018 to 2021. Detected CNV were categorized as large or small, and various validation techniques including chromosome microarray (CMA), Multiplex ligation-dependent probe amplification assay (MLPA), and/or PCR-based methods, were employed for cross-validation.

Results
Our CNV discovery pipeline identified 171 CNV events in 154 cases, resulting in an overall detection rate of 6.3%. Validation was performed on 113 CNVs from 103 cases to assess CES reliability. The overall concordance rate between CES and other validation methods was 88.49% (100/113). Specifically, CES demonstrated complete consistency in detecting large CNV. However, for small CNVs, consistency rates were 81.08% (30/37) for deletions and 73.91% (17/23) for duplications.

Conclusion
CES demonstrated high sensitivity and reliability in CNV detection. It emerges as an economical and dependable option for the clinical CNV detection in cases of developmental abnormalities, especially fetal structural abnormalities.
Microsecretory adenocarcinoma of the hard palate: a case report and literature review
Authors: Lu Yin , Wen Yanlin , Feng Sha , Huang Wenting 
Published: July 2024

AbstractMicrosecretory adenocarcinoma (MSA) is a new type of salivary gland neoplasm identified in the 2022 World Health Organization Classification of Head and Neck Tumour (Skalova et al., Head Neck Pathol 16:40-53, 2022) and is characterized by a unique set of histomorphologic and immunohistochemical features and a recurrent MEF2C::SS18 fusion. MSA was initially misdiagnosed as another salivary gland tumour due to its similar morphology; until recently, only fewer than 50 cases were reported. We present a case of MSA of the hard palate with diverse architectural growth patterns, bland cytological features, abundant basophilic intraluminal secretions and fibromyxoid stroma. The tumour cells were positive for the SOX10, S100, and p63 protein and negative for the p40 protein according to immunohistochemistry. SS18 gene rearrangement was demonstrated via break-apart fluorescence in situ hybridization. We also provided a comprehensive literature review and integrated the clinicopathological features, immunophenotype, and molecular alterations of the disease. A comprehensive understanding of MSA enables us to accurately distinguish and categorize MSA from other salivary gland tumours with analogous morphologies.
SP1 regulates BMSC osteogenic differentiation through the miR-133a-3p/MAPK3 axis
Authors: Zhong Liying , Sun Yehai , Wang Cong , Liu Runzhi , Ru Wenjuan , Dai Wei , Xiong Ting , Zhong Aimin , Li Shundong 
Published: July 2024

Abstract
Background
The progression of osteoporosis (OP) can dramatically increase the risk of fractures, which seriously disturb the life of elderly individuals. Specific protein 1 (SP1) is involved in OP progression. However, the mechanism by which SP1 regulates OP progression remains unclear.

Objective
This study investigated the mechanism underlying the function of SP1 in OP.

Methods
SAMP6 mice were used to establish an in vivo model of age-dependent OP, and BALB/c mice were used as controls. BMSCs were extracted from two subtypes of mice. Hematoxylin and eosin staining were performed to mark the intramedullary trabecular bone structure to evaluate histological changes. ChIP assay was used to assess the targeted regulation between SP1 and miR-133a-3p. The binding sites between MAPK3 and miR-133a-3p were verified using a dual-luciferase reporter assay. The mRNA levels of miR-133a-3p and MAPK3 were detected using quantitative reverse transcription polymerase chain reaction (RT-qPCR). The protein expression of SP1, MAPK3, Colla1, OCN, and Runx2 was examined using Western blotting. Alkaline phosphatase (ALP) kit and Alizarin Red S staining were used to investigate ALP activity and mineralized nodules, respectively.

Results
The levels of SP1 and miR-133a-3p were upregulated, whereas the expression of MAPK3 was downregulated in BMSCs from SAMP6 mice, and miR-133a-3p inhibitor accelerated osteogenic differentiation in BMSCs. SP1 directly targeted miR-133a-3p, and MAPK3 was the downstream mRNA of miR-133a-3p. Mechanically, SP1 accelerated osteogenic differentiation in BMSCs via transcriptional mediation of the miR-133a-3p/MAPK3 axis.

Conclusion
SP1 regulates osteogenic differentiation by mediating the miR-133a-3p/MAPK3 axis, which would shed new light on strategies for treating senile OP.
Efficacy and safety of D-penicillamine, trientine, and zinc in pediatric Wilson disease patients
Authors: Lee Eun Joo , Woo Min Hyung , Moon Jin Soo , Ko Jae Sung 
Published: July 2024

Abstract
Objectives
Wilson disease (WD) is a rare genetic disease affecting copper metabolism and the biliary tract’s copper excretion. Lifelong medication is necessary to prevent liver failure, neurological complications, and death. Although D-penicillamine (DPA), trientine, and zinc are used to treat WD, there is limited research on the long-term outcomes of these drugs, especially in children. This study aimed to evaluate the efficacy and safety of DPA, trientine, and zinc in patients diagnosed with WD during childhood.

Methods
Ninety out of 92 patients were included in the analysis, excluding two patients who underwent liver transplantation without drug treatment due to an acute liver failure diagnosis. Treatment outcomes and reasons for discontinuation of therapy in 148 treatment blocks (37 DPA, 50 trientine, and 61 zinc) were analyzed using Kaplan–Meier analysis.

Results
The median age at diagnosis was 8.3 years. There was a statistically significant difference in drug changes due to treatment ineffectiveness among the three drugs: trientine (22/50, 44%), zinc (15/61, 25%), and DPA (2/37, 5%) (all p < 0.05). Regarding drug changes due to adverse effects, the rate was the highest for DPA, followed by zinc and trientine. There were significant differences between DPA and zinc, zinc and trientine (all p < 0.05), but no significant difference was observed between DPA and zinc (p = 0.22).

Conclusions
In pediatric WD, DPA, zinc, and trientine have therapeutic effects in that order. However, DPA and zinc are associated with more adverse effects compared to trientine.
Ubiquitin recruiting chimera: more than just a PROTAC
Authors: Grigoreva Tatyana A. , Novikova Daria S. , Melino Gerry , Barlev Nick A. , Tribulovich Vyacheslav G. 
Published: July 2024

AbstractUbiquitinylation of protein substrates results in various but distinct biological consequences, among which ubiquitin-mediated degradation is most well studied for its therapeutic application. Accordingly, artificially targeted ubiquitin-dependent degradation of various proteins has evolved into the therapeutically relevant PROTAC technology. This tethered ubiquitinylation of various targets coupled with a broad assortment of modifying E3 ubiquitin ligases has been made possible by rational design of bi-specific chimeric molecules that bring these proteins in proximity. However, forced ubiquitinylation inflicted by the binary warheads of a chimeric PROTAC molecule should not necessarily result in protein degradation but can be used to modulate other cellular functions. In this respect it should be noted that the ubiquitinylation of a diverse set of proteins is known to control their transport, transcriptional activity, and protein-protein interactions. This review provides examples of potential PROTAC usage based on non-degradable ubiquitinylation.
Description of Babesia galileei sp. nov. A piroplasmid species causing severe disease in domestic cats
Authors: Baneth Gad , Nachum-Biala Yaarit , Dvorkin Ann , Arogeti Irit , Amiel Shlomo , Soueid Yamit , Shwartz Dor , Mumcuoglu Kosta Y. , Salant Harold 
Published: July 2024

AbstractBackgroundBabesiosis is a tick-borne infection caused by piroplasmid protozoa and associated with anemia and severe disease in humans, domestic animals and wildlife. Domestic cats are infected by at least sixBabesiaspp. that cause clinical disease.MethodsInfection with a piroplasmid species was detected by microscopy of stained blood smears in three sick cats from Israel. Genetic characterization of the piroplasmid was performed by PCR amplification of the18S rRNA, cytochorme B (CytB) and heat shock protein 70 (HSP70) genes and the internal transcribed spacer (ITS) locus, DNA sequencing and phylogenetic analysis. In addition,Haemaphysalis adleriticks collected from two cats were analyzed by PCR for piroplasmids.ResultsThe infected cats presented with anemia and thrombocytopenia (3/3), fever (2/3) and icterus (1/3). Comparison of gene and loci sequences found 99–100% identity between sequences amplified from different cats and ticks. Constructed phylogenetic trees and DNA sequence comparisons demonstrated a previously undescribedBabesiasp. belonging to theBabesiasensu stricto (clade X). The piroplasm forms detected included pear-shaped merozoite and round-to-oval trophozoite stages with average sizes larger than those ofBabesia felis,B. leoandB. lengauand smaller than canineBabesias.s. spp. Four of 11H. adleriadult ticks analyzed from cat # 3 were PCR positive forBabesiasp. with a DNA sequence identical to that found in the cats. Of these, two ticks were PCR positive in their salivary glands, suggesting that the parasite reached these glands and could possibly be transmitted byH. adleri.ConclusionsThis study describes genetic and morphological findings of a newBabesiasp. which we propose to nameBabesia galileeisp. nov. after the Galilee region in northern Israel where two of the infected cats originated from. The salivary gland PCR suggests that thisBabesiasp. may be transmitted byH. adleri. However, incriminating this tick sp. as the vector ofB. galileesp. nov. would require further studies.Graphical Abstract
Thyroid tuberculosis mimicking multinodular goiter: a case report
Authors: Kindie Endeshaw Asaye , Belachew Tigist Hailu , Habte Lidetu Temeche , Abera Samuel Addisu , Dejen Addisu Minaye , Abebe Sileshi Ayele , Molla Yohannis Derbew 
Published: July 2024

Abstract
Background
Mycobacterium tuberculosis is the second most common infectious cause of death in adults worldwide. The ability of this organism to efficiently establish latent infection has enabled it to spread to nearly one-third of individuals worldwide. Approximately 8 million new cases of active tuberculosis disease occur each year, leading to about 1.7 million deaths. The disease incidence is magnified by the concurrent epidemic of human immunodeficiency virus infection. A total of 1.3 million people died from tuberculosis in 2022. In 2022, an estimated 10.6 million people fell ill with tuberculosis worldwide, including 5.8 million men, 3.5 million women, and 1.3 million children. We report a case of thyroid tuberculosis presenting as multinodular goiter. Neck ultrasound was done and revealed abscess collection on the background of multinodular colloid goiter. The diagnosis of thyroid tuberculosis was confirmed by a positive GeneXpert of the pus sample and the presence of extensive caseous necrosis on cytopathology examination. Furthermore, anterior neck swelling may provide a diagnostic challenge by clinically mimicking multinodular goiter or thyroid neoplasms. Owing to its rarity and its tendency to pose a clinical diagnostic challenge, we decided to report it.

Case presentation
A 60-year-old retired female Ethiopian high-school teacher presented to University of Gondar Hospital, Gondar, Ethiopia with firm, nontender multinodular anterior neck swelling measuring at largest 2 × 3 cm that moves with swallowing. GeneXpert of the pus sample and cytopathology examination confirmed the diagnosis of thyroid tuberculosis, and the patient was started on 2 rifampicin−ethambutol−isoniazid−pyrazinamide/4 rifampicin−isoniazid 3 tablets by mouth/day, which is defined as the preferred first-line anti-tuberculosis regimen in Ethiopia, and pyridoxine 50 mg by mouth per day for 6 months. Since then, she has been followed with regular liver function tests. The patient has shown a smooth course with no significant adverse effects encountered. Currently, the patient has completed her anti-tuberculosis treatment and is doing well.

Conclusion
In the clinical evaluation of a patient with anterior neck swelling, tuberculosis must be considered as a differential diagnosis in subjects from endemic areas for early diagnostic workup and management.
Post-intensive care syndrome screening: a French multicentre survey
Authors: Agbakou Maïté , Combet Margot , Martin Maëlle , Blonz Gauthier , Desmedt Luc , Seguin Amélie , Lemarié Jérémie , Zambon Olivier , Reignier Jean , Lascarrou Jean-Baptiste , Ehrmann Stephan , Canet Emmanuel 
Published: July 2024

Abstract
Background
Post-intensive care syndrome (PICS), defined as physical, cognitive, and mental-health symptoms persisting long after intensive-care-unit (ICU) discharge, is increasingly recognised as a healthcare priority. Data on screening for PICS are sparse. Our objective here was to describe post-ICU screening in France, with special attention to visit availability and evaluations done during visits.

Methods
We conducted an online multicentre survey by emailing an anonymous 43-item questionnaire to French ICUs. For each ICU, a single survey was sent to either the head or the intensivist in charge of follow-up visits.

Results
Of 252 ICUs invited to participate, 161 (63.9%) returned the completed survey. Among them, 46 (28.6%) offered follow-up visits. Usually, a single visit led by an intensivist was scheduled 3 to 6 months after ICU discharge. Approximately 50 patients/year/ICU, that is, about 5% of admitted patients, attended post-ICU visits. The main criteria used to select patients for follow-up were ICU stay and/or invasive mechanical ventilation duration longer than 48 h, cardiac arrest, septic shock, and acute respiratory distress syndrome. Among ICUs offering visits, 80% used validated instruments to screen for PICS. Of the 115 ICUs not offering follow-up, 50 (43.5%) indicated an intention to start follow-up within the next year. The main barriers to offering follow-up were lack of available staff and equipment or not viewing PICS screening as a priority. Half the ICUs offering visits worked with an established network of post-ICU care professionals, and another 17% were setting up such a network. Obstacles to network creation were lack of interest among healthcare professionals and lack of specific training in PICS.

Conclusion
Only a small minority of ICU survivors received follow-up designed to detect PICS. Less than a third of ICUs offered follow-up visits but nearly another third planned to set up such visits within the next year. Recommendations issued by French health authorities in 2023 can be expected to improve the availability and standardisation of post-ICU follow-up.