bluuebunny/crossref_metadata_2025_split huggingface dataset:
Depleting the 19S proteasome regulatory PSMD1 subunit as a cancer therapy strategy
Authors: Adler Julia , Oren Roni , Shaul Yosef 
Published: March 2023

AbstractBackgroundProteasome inhibitors are in use in treating certain types of cancers. These drugs inhibit the catalytic activity of the 20S proteasome, shared by all the different proteasome complexes. Inhibitors of the 26S‐associated deubiquitinating activity explicitly inhibit the 26S proteasomal degradation of ubiquitinylated substrates. We have previously reported an alternative strategy that is based on reducing the 26S/20S ratio by depleting PSMD1, 6, and 11, the subunits of the 19S proteasome regulatory complex. Given the addiction of the many cancer types to a high 26S/20S ratio, the depletion strategy is highly effective in killing many aggressive cancer cell lines but not mouse and human immortalized and normal cells.MethodsWe used two aggressive cell lines, MDA‐MB‐231, a triple‐negative breast tumor cell line, and OVCAR8, a high‐grade ovary adenocarcinoma. Cell culture, mouse MDA‐MB‐231, OVCAR8 xenografts, and patient‐derived ovarian cancer xenograft (PDX) models were transduced with lentivectors expressing PSMD1 shRNA. Tumor size was measured to follow treatment efficacy.ResultsUsing different experimental strategies of expressing shRNA, we found that PSMD1 depletion, either by expressing PSMD1 shRNA in an inducible manner or in a constitutive manner, robustly inhibited MDA‐MB‐231, and OVCAR8 xenograft tumor growth. Furthermore, the PSMD1 depletion strategy compromised the growth of the PDX of primary ovarian cancer.ConclusionOur results suggest that reducing the 26S/20S ratio might be a valuable strategy for treating drug‐resistant aggressive types of cancers.
Prognostic risk factor of major salivary gland carcinomas and survival prediction model based on random survival forests
Authors: Chen Yufan , Li Guoli , Jiang Wenmei , Nie Rong Cheng , Deng Honghao , Chen Yingle , Li Hao , Chen Yanfeng 
Published: March 2023

AbstractSalivary gland malignancies are rare and are often acompanied by poor prognoses. So, identifying the populations with risk factors and timely intervention to avoid disease progression is significant. This study provides an effective prediction model to screen the target patients and is helpful to construct a cost‐effective follow‐up strategy. We enrolled 249 patients diagnosed with salivary gland tumors and analyzed prognostic risk factors using Cox proportional hazard univariable and multivariable regression models. The patients' data were split into training and validation sets on a 7:3 ratio, and the random survival forest (RSF) model was established using the training sets and validated using the validation sets. The maximally selected rank statistics method was used to determine a cut point value corresponding to the most significant relation with survival. Univariable Cox regression suggested age, smoking, alcohol consumption, untreated, neural invasion, capsular invasion, skin invasion, tumors larger than 4 cm, advanced T and N stage, distant metastasis, and non‐mucous cell carcinoma were risk factors for poor prognosis, and multivariable analysis suggested that female, aging, smoking, untreated, and non‐mucous cell carcinoma were risk factors. The time‐dependent ROC curve showed the AUC of the RSF prediction model on 1‐, 2‐, and 3‐year survival were 0.696, 0.779, and 0.765 respectively in the validation sets. Log‐rank tests suggested that the cut point 7.42 risk score calculated from the RSF was most effective in dividing patients with significantly different prognoses. The prediction model based on the RSF could effectively screen patients with poor prognoses.
A systematic review of neoadjuvant and definitive immunotherapy in locally advanced head and neck squamous cell carcinoma
Authors: Nindra Udit , Hurwitz Joshua , Forstner Dion , Chin Venessa , Gallagher Richard , Liu Jia 
Published: March 2023

AbstractBackgroundPatients with locally advanced head and neck squamous cell carcinoma (HNSCC) require multi‐modality treatment. Immune checkpoint inhibitors (ICIs) are now standard of care in management of recurrent/metastatic HNSCC. However, its role in the definitive and neoadjuvant setting remains unclear.MethodsA literature search was conducted that included all articles investigating ICI in untreated locally advanced (LA) HNSCC. Data was extracted and summarised and rated for quality using the Cochrane risk of bias tool.ResultsOf 1086 records, 29 met the final inclusion criteria. In both concurrent and neoadjuvant settings, the addition of ICI was safe and did not delay surgery or reduce chemoradiotherapy completion. In the concurrent setting, although ICI use demonstrates objective responses in all published trials, there has not yet been published data to with PFS or OS benefit. In the neoadjuvant setting, combination ICI resulted in superior major pathological response rates compared to ICI monotherapy without a significant increase adverse event profiles, but its value in improving survival is not clear. ICI efficacy appears to be affected by tumour characteristics, in particular PD‐L1 combined positive score, HPV status and the tumour microenvironment.ConclusionsThere is significant heterogeneity of ICI use in untreated LA HNSCC with multiple definitive concurrent and neoadjuvant protocols used. Resultantly, conclusions regarding the survival benefits of adding ICI to standard‐of‐care regimens cannot be made. Further trials and translational studies are required to elucidate optimal ICI sequencing in the definitive setting as well as better define populations more suited for neoadjuvant protocols.
Peripheral lymphocyte fluctuation as an indicator of severe immune‐related adverse events in patients treated with immune checkpoint inhibitors
Authors: Haraguchi Masafumi , Nakao Yasuhiko , Narita Syouhei , Matsumoto Kousuke , Fukushima Masanori , Sasaki Ryu , Honda Takuya , Miuma Satoshi , Miyaaki Hisamitsu , Nakao Kazuhiko 
Published: March 2023

AbstractAimImmune checkpoint inhibitors (ICIs) have proven to be effective treatments for various cancers, but can also elicit immune‐related adverse events (irAEs). Given that severe irAEs can be life‐threatening, biomarkers that can predict the occurrence of irAEs are of paramount importance. ICIs affect the dynamics of lymphocytes, and alterations in these dynamics may play a role in the development and severity of irAEs. The aim of this study was to investigate the correlation between irAEs and changes in lymphocyte counts.MethodsInformation on irAEs was collected from 226 ICI cases from 2014 to 2020. We compared lymphocyte counts before treatment and at the onset of irAE and investigated the association between lymphocyte count fluctuations and the presence and severity of irAE, the course after steroid treatment, and overall survival.ResultsOf the 226 cases, 27 patients developed grade 3 or higher irAE. Compared to the other groups, the lymphocyte count in this group was significantly decreased at the time of irAE (p < 0.01). There was a trend toward a rapid increase in lymphocyte count in the steroid responder group compared to the non‐responder group. Regarding overall survival, patients with irAE had significantly longer survival than those without irAE (p = 0.0025). However, there was no association between changes in lymphocyte count and survival in patients with irAE.ConclusionThe percentage change in lymphocyte count was found to correlate with the incidence of severe irAEs. Close monitoring of the patient's condition is crucial when the lymphocyte count decreases during ICI treatment.
MicroRNA‐17‐3p protects against excessive posthypoxic autophagy in H9C2 cardiomyocytes via PTEN–Akt–mTOR signaling pathway
Authors: He Yi , Zhang Dengwen , Zhang Qingqing , Cai Yin , Huang Chongfeng , Xia Zhengyuan , Wang Sheng 
Published: March 2023

AbstractThe activity of phosphatase and tensin homolog (PTEN) can be inhibited by miR‐17‐3p, which results in attenuating myocardial ischemia/reperfusion injury (IRI), however, the mechanism behind this phenomenon is still elusive. Suppression of PTEN leads to augmented protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling strength and constrained autophagy activation, which might be the one mechanism for the ameliorated myocardial IRI. Thus, we tested the hypothesis that miR‐17‐3p attenuated hypoxia/reoxygenation (H/R)‐mediated damage in cardiomyocytes by downregulating excessive autophagy via the PTEN–Akt–mTOR axis. The expression of miR‐17‐3p was remarkably increased after H/R treatment (6‐h hypoxia followed by 6‐h reoxygenation; H6/R6), which was concomitant with the increase of the release of lactic acid dehydrogenase (cell injury marker) and the enhancement LC3II/I ratio (autophagy markers) in H9C2 cardiomyocytes. Ectoexpression of miR‐17‐3p agomir led to remarkable augmentation of miR‐17‐3p expression and evidently attenuated H/R‐mediated cell damage and excessive autophagy. Furthermore, an increase in miR‐17‐3p expression elicited constrained phosphorylation of PTEN (Ser380) while enhanced the phosphorylation of Akt (Thr308, Ser473) and mTOR (Ser536) after H/R stimulation. In addition, pretreatment with LY‐294002 (an Akt selective inhibitor) and rapamycin (an mTOR selective inhibitor) significantly abrogated the protective function of miR‐17‐3p on H/R‐mediated cell damage and autophagy in H9C2 cardiomyocytes. Taken together, these observations indicated that the enhancement of the PTEN/Akt/mTOR axis and the consequent suppression of autophagy overactivation might represent an underlying mechanism by which miR‐17‐3p attenuated H/R‐mediated damage in H9C2 cells.
Exosomes in COVID‐19 infection: Focus on role in diagnosis, pathogenesis, immunity, and clinical trials
Authors: Aljuhani Alhanouf , Albalawi Omniah , Albalawi Rahaf , Alsalama Reem , Alatawi Safyah , Altemani Reem , Abdel‐Maksoud Mohamed S. , Elsherbiny Nehal 
Published: March 2023

AbstractSince the end of 2019, severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has spread as a new strain of coronavirus disease (COVID‐19) and progressed as a global pandemic. Exosomes are membrane‐bound vesicles released from almost all cells and are crucially involved in cell–cell communication. Interestingly, COVID‐19 viral particles produce exosomes that moderate communication between infected and uninfected cells. Hence, there is growing evidence highlighting the crucial implications of exosomes in COVID‐19 infection, transmission, intercellular spread, and reinfection. On the other hand, clinical trials have demonstrated mesenchymal stem cell‐derived exosomes as a promising therapeutic strategy for severely affected COVID‐19 patients. Also, convalescent plasma‐derived exosomes have been proposed for multiple efficacies in COVID‐19 patients. Furthermore, messenger RNAs (mRNA)‐loaded exosomes were superior to mRNA‐loaded lipid nanoparticles as a delivery system. Hence, exosomes can be used to safely induce SARS‐CoV‐2 immunity via their loading with mRNAs encoding immunogenic forms of SARS‐CoV‐2 spike and nucleocapsid proteins. Moreover, exosomes can be used as a nano‐delivery system for microRNA to alleviate cytokine storm and prevent the progression of organ failure in COVID‐19 patients. The present review summarizes state of the art concerning the role of exosomes in COVID‐19 infection and accompanying organ complications as well as the potential use of exosomes in COVID‐19 diagnosis, treatment, drug delivery, and vaccination. The review also sheds the light on the common biogenic pathway between the SARS‐CoV‐2 virus and exosomes. Additionally, the latest and current clinical trials using exosomes for COVID‐19 infection are summarized.
Unraveling the connection between calreticulin and myeloproliferative neoplasms via calcium signaling
Authors: Jaiswal Amit , Wang Zhiguo , Xudong Zhu , Ju Zhenyu 
Published: March 2023

AbstractMutations in the form of insertions and deletions (INDEL) in the calreticulin gene lead to essential thrombocythemia (ET) which is characterized by the formation of thrombosis. However, the connection between calreticulin INDEL and ET remains largely elusive. Through combined molecular dynamics simulation, clustered regularly interspaced short palindromic repeats (CRISPR) and calcium imaging studies on the wild type and mutated isoforms of calreticulin, the mechanism underlying the calreticulin INDEL induced ET was investigated at the molecular level. Our results demonstrate that mutations in exon‐9 could lead to significant conformational variations of calreticulin structure and thereby reducing its interaction with calcium ions due to decreased electrostatic contributions. The consequence of mutations on calreticulin's structural integrity was revealed by identifying the key residues and their roles in calcium binding. Furthermore, mutations implemented by CRISPR‐Cas9 in exon‐9 showed diminished calcium signaling in HEK‐293T cells, which agree well with our in‐silico findings. The current study might help in understanding the variations of molecular interactions between calreticulin's exon‐9 and calcium ions during physiological and pathological conditions. The results might also provide useful information for designing novel therapeutic approaches targeting ET.
The roles of ATP‐binding cassette transporter A1 and its substrate cholesterol in head and neck cancers
Authors: Sanli Fatma , Karatas Omer F. 
Published: March 2023

AbstractHead and neck cancer (HNC), which is among the deadliest malignancies, is the seventh most common cancer worldwide. How cholesterol homeostasis is linked to human cancers has long been a source of curiosity. One of the few proteins that are involved in cholesterol homeostasis is ATP‐binding cassette transporter A1 (ABCA1), which is broadly expressed in numerous tissues. ABCA1 increases cholesterol efflux, inhibits cholesterol deposition in cells, and modulates anticancer activities. Therefore, it is not surprising that decreased ABCA1 activity and altered cholesterol homeostasis are implicated in the patho‐physiology of HNCs. In this review, we focus on the role of cholesterol metabolism in the patho‐physiology and progression of HNCs, with an emphasis on biological effects of ABCA1 transporters. We also review therapeutic approaches targeting cholesterol metabolism, as well as how combining such approaches with existing anticancer treatments may have synergistic effects and therefore open up new therapeutic avenues.
Looking but not seeing the cap: The case for PROGRESS‐CTO
Authors: Tarantini Giuseppe , Cardaioli Francesco 
Published: March 2023

Key Points
Chronic total occlusion (CTO) procedures are a well‐established treatment strategy for selected patients with chronic coronary disease. Proximal cap ambiguity is one of the key aspects impacting procedural success and final results.
In this issue of CCI, data from a large multicenter prospective registry confirmed that proximal cap ambiguity is related to worse procedural outcomes, more aggressive procedural techniques, and higher rates of procedural complications.
Proximal cap ambiguity should be considered for patients' selection and procedural planning. Further analysis will be needed to test different imaging modalities for a clearer cap visualization.
Angiography‐derived functional assessment of left main coronary stenoses
Authors: Yuasa Sonoka , Lauri Francesco Maria , Mejia‐Renteria Hernan , Liontou Catherine , Lee Hyun‐Jong , Tanigaki Toru , Nakayama Masafumi , Warisawa Takayuki , Uchiyama Takashi , Matsuo Hitoshi , Davies Justin E. , Sato Takao , Escaned Javier 
Published: March 2023

AbstractObjectivesWe aimed to evaluate the diagnostic accuracy of quantitative flow ratio (QFR) in left main (LM) coronary stenoses, using Fractional Flow Reserve (FFR) as reference.BackgroundQFR has demonstrated a high accuracy in determining the functional relevance of coronary stenoses in non‐LM. However, there is an important paucity of data regarding its diagnostic value in the specific anatomical subset of LM disease.MethodsThis is a retrospective, observational, multicenter, international, and blinded study including patients with LM stenoses. Cases with significant ostial LM disease were excluded. QFR was calculated from conventional angiograms at blinded fashion with respect to FFR.ResultsSixty‐seven patients with LM stenoses were analyzed. Overall, LM had intermediate severity, both from angiographic (diameter stenosis [%DS] 43.8 ± 11.1%) and functional perspective (FFR 0.756 ± 0.105). Mean QFR was 0.733 ± 0.159. Correlation between QFR and FFR was moderate (r = 0.590). Positive and negative predictive value, sensitivity and specificity were 85.4%, 64%, 85.4%, and 69.6% respectively. Classification agreement of QFR and FFR in terms of functional stenosis severity was 78.1%. Area under the receiver operating characteristics of QFR using FFR as reference was 0.82 [95% confidence interval [CI], 0.71−0.93], and significantly better than angiographic evaluation including %DS (area under the receiver‐operating characteristic curve [AUC] 0.45 [95% CI, 0.32−0.58], p < 0.001) and minimum lumen diameter (AUC 0.60 [95% CI, 0.47−0.74], p < 0.001).ConclusionsCompared with FFR, QFR has acceptable diagnostic performance in determining the functional relevance of LM stenosis, being better than conventional angiographic assessment. Nonetheless, caution should be taken when applying functional angiography techniques for the assessment of LM stenosis given its particular anatomical characteristics.
In vivo evaluation of intravascular lithotripsy in a healthy porcine coronary model
Authors: Yin Jiasheng , Wang Rui , Chen Han , Lu Hao , Yang Zhuoran , Xu Fei , Zang Tongtong , Liu Chengpeng , Shen Li , Ge Junbo 
Published: March 2023

AbstractObjectivesIn this study, we aimed to investigate the vascular response to an intravascular lithotripsy (IVL) shockwave balloon in a healthy porcine coronary artery model.BackgroundIVL is a novel clinical technique for modifying heavily calcified atherosclerotic plaques.MethodsA total of 24 porcine coronary arteries were treated with IVL or plain old balloon angioplasty (POBA). Histology, histomorphometry, quantitative coronary angiography analysis (QCA), and optical coherence tomography (OCT) were performed postprocedure and at 1‐month follow‐up (1M‐FU).ResultsThere was no significant difference in the late lumen loss and diameter stenosis (determined by QCA) and the minimal lumen area (evaluated by OCT) of the IVL and POBA groups at 1M‐FU. Pathological analysis revealed that the lumen and neointima areas were similar between the two groups. However, the medial and adventitial layers were more prominent in the IVL than in the POBA group. The injury score and inflammation of the media and adventitia increased dramatically in the IVL group postprocedure and at 1M‐FU. At 1M‐FU, media fibrin deposition and adventitial fibrosis were also significantly increased in the IVL group. However, there was no significant difference in neointima fibrin deposition, endothelialization, and thrombosis between both groups. Layered separation of the media and adventitia was observed in the IVL group.ConclusionThe findings indicate that the IVL balloon did not cause serious intimal hyperplasia and endothelial damage compared with the effects of POBA in the healthy coronary artery. However, shock waves may cause unique damage to the vascular media and adventitia in the coronary artery, which was not observed in the peripheral artery.
Calcified coronary nodule: Tip of the iceberg on a road full of thorns
Authors: Grines Cindy L. , Tummala Pradyumna E. 
Published: March 2023

Key Points
Nodular coronary calcium (NC) is infrequent, is associated with advanced age and chronic kidney disease and may be responsible for acute coronary syndromes.
NC leads to a greater incidence of stent malapposition and target lesion revascularization, and intravascular imaging often shows recurrence of the calcified nodule within the stent.
Clinical outcomes are worse after stenting lesions with calcified nodules, but randomized studies are necessary to determine the best management strategy.
PROTOCOL: Evaluating the application and effectiveness of precision teaching: A systematic review and meta‐analysis
Authors: Vostanis Athanasios , Thompson Paul A. , Padden Ciara , Rizos Konstantinos , Langdon Peter E. 
Published: March 2023

AbstractPrecision Teaching is a behavior measurement system that emphasizes the development of behavioral repertoires and utilizes Standard Celeration Charts as its primary tool. This system has been applied across various areas, including mainstream and special education, and has successfully improved academic, motor, communication, and other skills. While previous systematic reviews have highlighted important aspects of Precision Teaching, a more comprehensive evaluation is needed to consider all its different applications and recent developments in conceptualizing it. Therefore, this systematic review and meta‐analysis will assess the effectiveness of Precision Teaching in accelerating human behavior, identify all the areas of its application, and review the technical aspects of its implementation. The review aims to provide a comprehensive understanding of the system and its potential benefits for individuals in different settings.
Malocclusions and oral dysfunctions: A comprehensive epidemiological study on 359 schoolchildren in France
Authors: Borsa Leslie , Estève Déborah , Charavet Carole , Lupi Laurence 
Published: March 2023

AbstractObjectivesThe purpose was to conduct a comprehensive study of malocclusions and oral dysfunctions on 11‐year‐old children and to study the risk factors associated with malocclusions.Material and MethodsA cross‐sectional descriptive epidemiological survey was conducted among 359 children in France. A clinical examination was conducted, and orthodontic and oral functional data were collected. In addition, the need for orthodontic treatment was evaluated using the criteria defined by of the French National Authority for Health (HAS). Finally, a univariate and multivariate analysis was performed to assess the risks associated with malocclusions.ResultsMost children (88%) exhibited a malocclusion, regardless of gender (p = .912). The examination of oral functions identified a large number of swallowing (87%) and respiration (42.7%) disorders. The presence of malocclusion was statistically linked to the low position of the tongue at rest (p < .001), abnormal swallowing (p = .03), and improper mouth breathing (p = .001). After a multivariate analysis, the type of respiration (odds ratio [OR] = 3.2 [1.4–7.3]) and the position of tongue at rest (OR = 3.43 [1.7–7.1]) were the two most prominent factors in the prediction of emerging malocclusion.ConclusionThis epidemiological survey reveals a high prevalence of dental malocclusions and functional disorders. Oral respiration and the low position of the tongue at rest are the most important factors in the prediction of a malocclusion.