bluuebunny/crossref_metadata_2025 huggingface dataset:
Knowledge, opinions, and practices related to oral cancer prevention and oral mucosal examination among dentists in Moldova, Belarus and Armenia: a multi-country cross-sectional study
Authors: Golburean Olga , Hagen Maria Helene , Uncuta Diana , Tighineanu Marcela , Manrikyan Gayane , Vardanian Izabella , Andresen Christoffer , Singh Bhavdeep , Porosencova Tatiana , Ivasiuc Irina , Cheptanaru Olga , Markaryan Marina , Shakavets Natalia , Sapkota Dipak , Søland Tine Merete , Costea Daniela-Elena , Özkaya Ferda
Published: December 2021

Introduction

Moldova, Belarus, and Armenia are post-Soviet countries with a high rate of heavy smokers and a relatively high age-standardized incidence of oral cancer. However, to our knowledge, there is lack of available information on dentists’ knowledge on prevention of oral cancer in the countries in question. Accordingly, this study aimed to assess the knowledge, opinions, and practices related to oral cancer prevention and oral mucosal examination among dentists in Moldova, Belarus, and Armenia.

Methods

This was a multi-country, cross-sectional study based on a self-administered questionnaire. A structured questionnaire was distributed to 3534 dentists (797 in Chisinau, Moldova, 1349 in Minsk, Belarus, and 1388 in Yerevan, Armenia). Dentists' knowledge about risk factors for oral cancer development and its clinical picture, current practices and opinions with regard to oral mucosal screening and oral cancer prevention, and their consistency to perform oral mucosal examination were assessed. A knowledge score ranging from 0 to 14 points was generated based on each dentist’s answer to the questionnaire.

Results

A total of 1316 dentists responded, achieving an overall response rate of 37.2% (34.5% in Moldova; 52.3% in Belarus; 24.2% in Armenia). Most dentists in the three countries correctly identified tobacco (83.8–98.2%) and prior oral cancer lesions (84.0–96.3%) as risk factors for oral cancer. Most dentists correctly identified leukoplakia as a lesion with malignant potential (68.7% in Moldova; 88.5% in Belarus; 69.9% in Armenia), while erythroplakia was identified by much fewer in all three countries. Less than 52% of dentists identified the tongue, rim of tongue, and floor of mouth as the most common sites for oral cancer. The mean knowledge score for all countries combined was 7.5 ± 2.7. The most commonly reported barriers to perform oral mucosal examination were lack of training, knowledge, and experience.

Conclusions

This study highlights the need for improved oral cancer-related education and training on oral mucosal examination for dentists in Moldova, Belarus, and Armenia. Such skills are essential to enhance oral cancer prevention and to improve the prognostic outcome by early detection.
Psychometric evaluation of the Lebanese Arabic version of the Dental Fear Survey: a cross-sectional study
Authors: Kassem El Hajj Hiba , Fares Youssef , Abou-Abbas Linda
Published: December 2021

Background

Dental fear is a prevalent problem that can lead to poor dental health. The Kleinknecht’s Dental Fear Survey (DFS) is one of the used scales to assess dental fear. The present study aims to evaluate the psychometric properties of the Lebanese Arabic version of the DFS (DFS-A) and to determine the optimal cut-off to identify dental fear as well as the correlates of dental fear in a group of Lebanese adults dental patients.

Methods

A cross-sectional study was conducted among a group of 442 dental patients (18–65 years) recruited at 29 dental clinics from March to June 2019. Patients completed a questionnaire including questions about demographic characteristics, previous bad dental experience, trauma’s experience period, the sensation of nausea during dental treatment, the DFS-A scale, the Lebanese Arabic version of the Modified Dental Anxiety Scale (MDAS-A), and a general question about dental fear.

Results

DFS-A revealed evidence of adequate psychometric properties. DFS-A scale demonstrated high internal consistency (cronbach’s alpha = 0.93). Test–retest reliability assessment demonstrated strong reproducibility of the DFS-A scale score (ICC = 0.92 with 95% CI (0.83–0.96), p value < 0.0001 (N = 30). Confirmatory factor analysis revealed a three-factor structure of the DFS-A reflecting fear associated with specific dental stimuli and procedures, patterns of dental avoidance and anticipatory anxiety, and physiologic arousal during dental treatment. A significant correlation was found between DFS-A and the MDAS-A indicating a good convergent validity. The optimal cut-off point to identify patients with and without dental fear is 41. Considering this cut-off score, the prevalence of dental fear in our sample was reported at 33.8%. Multivariable analysis showed that having previous scary and painful dental experiences, a sensation of nausea during treatment, and having dental anxiety were identified as predictors of dental fear.

Conclusion

The adapted Arabic version of the DFS (DFS-A) is a valid tool to evaluate dental fear among Lebanese adult patients.
Protective effects of exosomes derived from lyophilized porcine liver against acetaminophen damage on HepG2 cells
Authors: Tassinari Riccardo , Cavallini Claudia , Olivi Elena , Taglioli Valentina , Zannini Chiara , Ferroni Orlando , Ventura Carlo
Published: December 2021

Background

Recently, extracellular vesicles have come to the fore following their emerging role in cell communication, thanks to their ability to reach cells into the human body without dissipating their cargo, transferring biological active molecules, such as proteins, nucleic acids, lipids, etc. They appear as a promising tool in medicine, because of their capability to modulate cellular response in recipient cells. Moreover, a considerable number of publications suggests that exosome uptake is selective but not specific, and it can cross species and cell-type boundaries. This study aims to explore the potential role of porcine liver derived extracellular vesicles, exosomes in particular, to protect human cells from acute damage induced by acetaminophen.

Methods

Extracellular vesicles were isolated from porcine lyophilized liver using polymer-based precipitation and a further enrichment was performed using affinity beads. The effects of obtained fractions, total extracellular vesicles and enriched extracellular vesicles, were assessed on human liver derived HepG2 cells. Cell growth and survival were tested, with MTT and area coverage analysis designed by us, as well as protein expression, with immunofluorescence and Western blot. Oxidative stress in live cells was also measured with fluorogenic probes.

Results

After proving that porcine extracellular vesicles did not have a toxic effect on HepG2, quite the contrary total extracellular vesicle fraction improved cell growth, we investigated their protective capability with a preconditioning strategy in APAP-induced damage. EVs displayed not only the ability to strongly modulate cell survival responses, but they also were able to boost cell cycle progression.

Conclusions

Extracellular vesicles derived from farm animal food derivatives are able to modulate human hepatic cell metabolism, also improving cell survival in a damaged context.
Parental leave policy information during residency interviews
Authors: Kraus Molly B. , Reynolds Emily G. , Maloney Jillian A. , Buckner-Petty Skye A. , Files Julia A. , Hayes Sharonne N. , Stonnington Cynthia M. , Vallow Laura A. , Strand Natalie H.
Published: December 2021

Background

During interviews, medical students may feel uncomfortable asking questions that might be important to them, such as parental leave. Parental leave policies may be difficult for applicants to access without asking the program director or other interviewers. The goal of this study is to evaluate whether parental leave information is presented to prospective residents and whether medical students want this information.

Methods

Fifty-two program directors (PD’s) at 3 sites of a single institution received a survey in 2019 to identify whether parental leave information is presented at residency interviews. Medical students received a separate survey in 2020 to identify their preferences. Fisher exact tests, Pearson χ2 tests and Cochran-Armitage tests were used where appropriate to assess for differences in responses.

Results

Of the 52 PD’s, 27 responded (52%) and 19 (70%) indicated that information on parental leave was not provided to candidates. The most common reason cited was the belief that the information was not relevant (n = 7; 37%). Of the 373 medical students, 179 responded (48%). Most respondents (92%) wanted parental leave information formally presented, and many anticipated they would feel extremely or somewhat uncomfortable (68%) asking about parental leave. The majority (61%) felt that these policies would impact ranking of programs “somewhat” or “very much.”

Conclusions

Parental leave policies may not be readily available to interviewees despite strong interest and their impact on ranking of programs by prospective residents.
Navigating abortion law dilemmas: experiences and attitudes among Ethiopian health care professionals
Authors: Ewnetu Demelash Bezabih , Thorsen Viva Combs , Solbakk Jan Helge , Magelssen Morten
Published: December 2021

Background

Ethiopia’s 2005 abortion law improved access to legal abortion. In this study we examine the experiences of abortion providers with the revised abortion law, including how they view and resolve perceived moral challenges.

Methods

Thirty healthcare professionals involved in abortion provisions in Addis Ababa were interviewed. Transcripts were analyzed using systematic text condensation, a qualitative analysis framework.

Results

Most participants considered the 2005 abortion law a clear improvement—yet it does not solve all problems and has led to new dilemmas. As a main finding, the law appears to have opened a large space for professionals’ individual interpretation and discretion concerning whether criteria for abortion are met or not. Regarding abortion for fetal abnormalities, participants support the woman’s authority in deciding whether to choose abortion or not, although several saw these decisions as moral dilemmas. All thought that abortion was a justified choice when a diagnosis of fetal abnormality had been made.

Conclusion

Ethiopian practitioners experience moral dilemmas in connection with abortion. The law places significant authority, burden and responsibility on each practitioner.
Leveraging medical context to recommend semantically similar terms for chart reviews
Authors: Ye Cheng , Malin Bradley A. , Fabbri Daniel
Published: December 2021

Background

Information retrieval (IR) help clinicians answer questions posed to large collections of electronic medical records (EMRs), such as how best to identify a patient’s cancer stage. One of the more promising approaches to IR for EMRs is to expand a keyword query with similar terms (e.g., augmentingcancerwithmets). However, there is a large range of clinical chart review tasks, such that fixed sets of similar terms is insufficient. Current language models, such as Bidirectional Encoder Representations from Transformers (BERT) embeddings, do not capture the full non-textual context of a task. In this study, we present new methods that provide similar terms dynamically by adjusting with the context of the chart review task.

Methods

We introduce a vector space for medical-context in which each word is represented by a vector that captures the word’s usage in different medical contexts (e.g., how frequentlycanceris used when ordering a prescription versus describing family history) beyond the context learned from the surrounding text. These vectors are transformed into a vector space for customizing the set of similar terms selected for different chart review tasks. We evaluate the vector space model with multiple chart review tasks, in which supervised machine learning models learn to predict the preferred terms of clinically knowledgeable reviewers. To quantify the usefulness of the predicted similar terms to a baseline of standard word2vec embeddings, we measure (1) the prediction performance of the medical-context vector space model using the area under the receiver operating characteristic curve (AUROC) and (2) the labeling effort required to train the models.

Results

The vector space outperformed the baseline word2vec embeddings in all three chart review tasks with an average AUROC of 0.80 versus 0.66, respectively. Additionally, the medical-context vector space significantly reduced the number of labels required to learn and predict the preferred similar terms of reviewers. Specifically, the labeling effort was reduced to 10% of the entire dataset in all three tasks.

Conclusions

The set of preferred similar terms that are relevant to a chart review task can be learned by leveraging the medical context of the task.
Mapping the road to elimination: a 5-year evaluation of implementation strategies associated with hepatitis C treatment in the veterans health administration
Authors: Yakovchenko Vera , Morgan Timothy R. , Chinman Matthew J. , Powell Byron J. , Gonzalez Rachel , Park Angela , Malone Patrick S. , Chartier Maggie , Ross David , Rogal Shari S.
Published: December 2021

Background

While few countries and healthcare systems are on track to meet the World Health Organization’s hepatitis C virus (HCV) elimination goals, the US Veterans Health Administration (VHA) has been a leader in these efforts. We aimed to determine which implementation strategies were associated with successful national viral elimination implementation within the VHA.

Methods

We conducted a five-year, longitudinal cohort study of the VHA Hepatic Innovation Team (HIT) Collaborative between October 2015 and September 2019. Participants from 130 VHA medical centers treating HCV were sent annual electronic surveys about their use of 73 implementation strategies, organized into nine clusters as described by the Expert Recommendations for Implementing Change taxonomy. Descriptive and nonparametric analyses assessed strategy use over time, strategy attribution to the HIT, and strategy associations with site HCV treatment volume and rate of adoption, following the Theory of Diffusion of Innovations.

Results

Between 58 and 109 medical centers provided responses in each year, including 127 (98%) responding at least once, and 54 (42%) responding in all four implementation years. A median of 13–27 strategies were endorsed per year, and 8–36 individual strategies were significantly associated with treatment volume per year. Data warehousing, tailoring, and patient-facing strategies were most commonly endorsed. One strategy—“identify early adopters to learn from their experiences”—was significantly associated with HCV treatment volume in each year. Peak implementation year was associated with revising professional roles, providing local technical assistance, using data warehousing (i.e., dashboard population management), and identifying and preparing champions. Many of the strategies were driven by a national learning collaborative, which was instrumental in successful HCV elimination.

Conclusions

VHA’s tremendous success in rapidly treating nearly all Veterans with HCV can provide a roadmap for other HCV elimination initiatives.
The implementation potential of a method to monitor empirically-supported children’s mental health treatment through claims data
Authors: Walker Sarah Cusworth , Gubner Noah , Iztguttinov Aniyar , Rodriguez Felix , Davis Paul , Lyon Aaron , Kerns Suzanne , Bruns Eric , Qian Jiage , Sedlar Georganna
Published: December 2021

Background

The delivery of evidence-supported treatments (EST) in children’s mental health could be a valuable measure for monitoring mental healthcare quality; however, efforts to monitor the use of EST in real world systems are hindered by the lack of pragmatic methods. This mixed methods study examined the implementation and agency response rate of a pragmatic, claims-based measure of EST designed to be applied as a universal quality measure for child psychotherapy encounters in a state Medicaid system.

Methods

Implementation potential of the EST measure was assessed with healthcare leader rankings of the reporting method’s acceptability, appropriateness and feasibility (n = 53), and post-implementation ratings of EST rate accuracy. Ability of the healthcare system to monitor EST through claims was measured by examining the agency responsivity in using the claims-based measure across 98 Medicaid-contracted community mental health (CMH) agencies in Washington State.

Results

The analysis found the reporting method had high implementation potential. The method was able to measure the use of an EST for 83% of children covered by Medicaid with 58% CMH agencies reporting > 0 ESTs in one quarter. Qualitative analyses revealed that the most significant barrier to reporting ESTs was the operability of electronic health record systems and agencies’ mixed views regarding the accuracy and benefits of reporting.

Conclusions

Measurement of child mental health ESTs through Medicaid claims reporting has acceptable implementation potential and promising real world responsiveness from CMH agencies in one state. Variation in reporting by agency site and low to moderate perceived value by agency leaders suggests the need for additional implementation supports for wider uptake.
Defining a patient-centered approach to cancer survivorship care: development of the patient centered survivorship care index (PC-SCI)
Authors: Mead K. Holly , Wang Yan , Cleary Sean , Arem Hannah , Pratt-Chapman Mandi L.
Published: December 2021

Purpose

This study presents the validation of an index that defines and measures a patient-centered approach to quality survivorship care.

Methods

We conducted a national survey of 1,278 survivors of breast, prostate, and colorectal cancers to identify their priorities for cancer survivorship care. We identified 42 items that were “very important or absolutely essential” to study participants. We then conducted exploratory and confirmatory factor analyses (EFA/CFA) to develop and validate the Patient-Centered Survivorship Care Index (PC-SCI).

Results

A seven-factor structure was identified based on EFA on a randomly split half sample and then validated by CFA based on the other half sample. The seven factors include: (1) information and support in survivorship (7 items), (2) having a medical home (10 items) (3) patient engagement in care (3 items), (4) care coordination (5 items), (5) insurance navigation (3 items), (6) care transitions from oncologist to primary care (3 items), and (7) prevention and wellness services (5 items). All factors have excellent composite reliabilities (Cronbach’s alpha 0.84-0.94, Coefficient of Omega: 0.81-0.94).

Conclusions

Providing quality post-treatment care is critical for the long-term health and well-being of survivors. The PC-SCI defines a patient-centered approach to survivorship care to complement clinical practice guidelines. The PC-SCI has acceptable composite reliability, providing the field with a valid instrument of patient-centered survivorship care. The PC-SCI provides cancer centers with a means to guide, measure and monitor the development of their survivorship care to align with patient priorities of care.

Trial registration

ClinicalTrials.gov ID:NCT02362750, 13 February 2015
Direct phone communication to primary care physician to plan discharge from hospital: feasibility and benefits
Authors: Enzinger Lukas , Dumanoir Perrine , Boussat Bastien , Couturier Pascal , Francois Patrice
Published: December 2021

Background

The discharge summary is the main vector of communication at the time of hospital discharge, but it is known to be insufficient. Direct phone contact between hospitalist and primary care physician (PCP) at discharge could ensure rapid transmission of information, improve patient safety and promote interprofessional collaboration. The objective of this study was to evaluate the feasibility and benefit of a phone call from hospitalist to PCP to plan discharge.

Methods

This study was a prospective, single-center, cross-sectional observational study. It took place in an acute medicine unit of a French university hospital. The hospitalist had to contact the PCP by telephone within 72 h prior discharge, making a maximum of 3 call attempts. The primary endpoint was the proportion of patients whose primary care physician could be reached by telephone at the time of discharge. The other criteria were the physicians’ opinions on the benefits of this contact and its effect on readmission rates.

Results

275 patients were eligible. 8 hospitalists and 130 PCPs gave their opinion. Calls attempts were made for 71% of eligible patients. Call attempts resulted in successful contact with the PCP 157 times, representing 80% of call attempts and 57% of eligible patients. The average call completion rate was 47%. The telephone contact was perceived by hospitalist as useful and providing security. The PCPs were satisfied and wanted this intervention to become systematic. Telephone contact did not reduce the readmission rate.

Conclusions

Despite the implementation of a standardized process, the feasibility of the intervention was modest. The main obstacle was hospitalists lacking time and facing difficulties in reaching the PCPs. However, physicians showed desire to communicate directly by telephone at the time of discharge.

Trial registration

French C.N.I.L. registration number 2108852. Registration date October 12, 2017.
Integrative utility of long read sequencing-based whole genome analysis and phenotypic assay on differentiating isoniazid-resistant signature of Mycobacterium tuberculosis
Authors: Yu Ming-Chih , Hung Ching-Sheng , Huang Chun-Kai , Wang Cheng-Hui , Liang Yu-Chih , Lin Jung-Chun
Published: December 2021

Background

With the advancement of next generation sequencing technologies (NGS), whole-genome sequencing (WGS) has been deployed to a wide range of clinical scenarios. Rapid and accurate classification of drug-resistant Mycobacterium tuberculosis (MTB) would be advantageous in reducing the amplification of additional drug resistance and disease transmission.

Methods

In this study, a long-read sequencing approach was subjected to the whole-genome sequencing of clinical MTB clones with susceptibility test profiles, including isoniazid (INH) susceptible clones (n = 10) and INH resistant clones (n = 42) isolated from clinical specimens. Non-synonymous variants within the katG or inhA gene associated with INH resistance was identified using Nanopore sequencing coupled with a corresponding analytical workflow.

Results

In total, 54 nucleotide variants within the katG gene and 39 variants within the inhA gene associated with INH resistance were identified. Consistency among the results of genotypic profiles, susceptibility test, and minimal inhibitory concentration, the high-INH resistance signature was estimated using the area under the receiver operating characteristic curve with the existence of Ser315Thr (AUC = 0.822) or Thr579Asn (AUC = 0.875).

Conclusions

Taken together, we curated lists of coding variants associated with differential INH resistance using Nanopore sequencing, which may constitute an emerging platform for rapid and accurate identification of drug-resistant MTB clones.
Prognostic value and immune infiltration of novel signatures in colon cancer microenvironment
Authors: Lin Yilin , Pan Xiaoxian , Chen Zhihua , Lin Suyong , Shen Zhanlong , Chen Shaoqin
Published: December 2021

Background

Growing evidence has shown that the prognosis for colon cancer depends on changes in microenvironment. The purpose of this study was to elucidate the prognostic value of long noncoding RNAs (lncRNAs) related to immune microenvironment (IM) in colon cancer.

Methods

Single sample gene set enrichment analysis (ssGSEA) was used to identify the subtypes of colon cancer based on the immune genomes of 29 immune signatures. Cox regression analysis identified a lncRNA signatures associated with immune infiltration. The Tumor Immune Estimation Resource database was used to analyze immune cell content.

Results

Colon cancer samples were divided into three subtypes by unsupervised cluster analysis. Cox regression analysis identified an immune infiltration-related 5-lncRNA signature. This signature combined with clinical factors can effectively improve the predictive ability for the overall survival (OS) of colon cancer. At the same time, we found that the expression of H19 affects the content of B cells and macrophages in the microenvironment of colon cancer and affects the prognosis of colon cancer. Finally, we constructed the H19 regulatory network and further analyzed the possible mechanisms. We found that knocking down the expression of H19 can significantly inhibit the expression of CCND1 and VEGFA. At the same time, the immunohistochemical assay found that the expression of CCND1 and VEGFA protein was significantly positively correlated with the infiltration of M2 type macrophages.

Conclusion

The findings may help to formulate clinical strategies and understand the underlying mechanisms of H19 regulation. H19 may be a biomarker for targeted treatment of colon cancer.
Global, regional, and national quality of care of gallbladder and biliary tract cancer: a systematic analysis for the global burden of disease study 1990–2017
Authors: Khanali Javad , Malekpour Mohammad-Reza , Azangou-Khyavy Mohammadreza , Saeedi Moghaddam Sahar , Rezaei Negar , Kolahi Ali-Asghar , Abbasi-Kangevari Mohsen , Mohammadi Esmaeil , Rezaei Nazila , Yoosefi Moein , Keykhaei Mohammad , Farzi Yosef , Gorgani Fateme , Larijani Bagher , Farzadfar Farshad
Published: December 2021

Background

To improve health outcomes to their maximum level, defining indices to measure healthcare quality and accessibility is crucial. In this study, we implemented the novel Quality of Care Index (QCI) to estimate the quality and accessibility of care for patients with gallbladder and biliary tract cancer (GBBTC) in 195 countries, 21 Global Burden of Disease (GBD) regions, Socio-demographic Index (SDI) quintiles, and sex groups.

Method

This cross-sectional study extracted estimates on GBBTC burden from the GBD 2017, which presents population-based estimates on GBBTC burden for higher than 15-year-old patients from 1990 to 2017. Four secondary indices indicating quality of care were chosen, comprising Mortality to incidence, Disability-Adjusted Life Year (DALY) to prevalence, prevalence to incidence, and years of life lost (YLL) to years lived with disability (YLD) ratios. Then, the whole dataset was analyzed using Principal Component Analysis to combine the four indices and create a single all-inclusive measure named QCI. The QCI was scaled to the 0–100 range, with 100 indicating the best quality of care among countries. Gender Disparity Ratio (GDR) was defined as the female to male QCI ratio to show gender inequity throughout the regions and countries.

Results

Global QCI score for GBBTC was 33.5 in 2017, which has increased by 29% since 1990. There was a considerable gender disparity in favor of men (GDR = 0.74) in 2017, showing QCI has moved toward gender inequity since 1990 (GDR = 0.85). Quality of care followed a heterogeneous pattern among regions and countries and was positively correlated with the countries’ developmental status reflected in SDI (r = 0.7; CI 95%: 0.61–0.76; P value< 0.001). Accordingly, High-income North America (QCI = 72.4) had the highest QCI; whereas, Eastern Sub-Saharan Africa (QCI = 3) had the lowest QCI among regions. Patients aged 45 to 80 had lower QCI scores than younger and older adults. The highest QCI score was for the older than 95 age group (QCI = 54), and the lowest was for the 50–54 age group (QCI = 26.0).

Conclusions

QCI improved considerably from 1990 to 2017; however, it showed heterogeneous distribution and inequity between sex and age groups. In each regional context, plans from countries with the highest QCI and best gender equity should be disseminated and implemented in order to decrease the overall burden of GBBTC.
Effect of comorbidities and risk conditions on death from COVID-19 in migrants in Mexico
Authors: Martínez-Martínez Oscar A. , Valenzuela-Moreno Karla A. , Coutiño Brenda
Published: December 2021

Background

Comorbidities increase the risk of death for patients with COVID-19, however, little is known about how it affects the prognosis of migrants who contract the virus. Therefore, this article aims to determine which comorbidities and risk conditions are associated with the probability of death among migrants infected with COVID-19 in Mexico.

Methods

We use a sample of migrants with a positive diagnosis for COVID-19 (N = 2126) registered in the public database published in the National Epidemiological Surveillance System of the Mexican Ministry of Health; the technique used was a Probit regression.

Results

The findings show that most of the comorbidities commonly associated with death from COVID-19 in the native-born population were actually not significant when present in migrants infected with COVID-19. Additionally, migrants have lower comorbidities than locals. The results further indicate that the factors related to the death of migrants infected with COVID-19 are: age, intubation, nationality group, pneumonia and the Health Care Management of Patients.

Conclusions

In contrast to preceding studies with native-born populations with COVID-19, where pre-existing diseases aggravated the diagnosis of COVID-19 and sometimes led to death, in the case of migrants, only pneumonia was the significant comorbidity associated with mortality among migrants diagnosed with COVID-19.
circCHST15 is a novel prognostic biomarker that promotes clear cell renal cell carcinoma cell proliferation and metastasis through the miR-125a-5p/EIF4EBP1 axis
Authors: Gui Cheng-Peng , Liao Bing , Luo Cheng-Gong , Chen Yu-Hang , Tan Lei , Tang Yi-Ming , Li Jia-Ying , Hou Yi , Song Hong-De , Lin Hai-Shan , Xu Quan-Hui , Yao Gao-Sheng , Yao Hao-Hua , Xi-Liu  , Luo Jun-Hang , Cao Jia-Zheng , Wei Jin-Huan
Published: December 2021

Background

Circular RNAs (circRNAs) have been indicated as potentially critical mediators in various types of tumor progression, generally acting as microRNA (miRNA) sponges to regulate downstream gene expression. However, the aberrant expression profile and dysfunction of circRNAs in human clear cell renal cell carcinoma (ccRCC) need to be further investigated. This study mined key prognostic circRNAs and elucidates the potential role and molecular mechanism of circRNAs in regulating the proliferation and metastasis of ccRCC.

Methods

circCHST15 (hsa_circ_0020303) was identified by mining two circRNA microarrays from the Gene Expression Omnibus database and comparing matched tumor versus adjacent normal epithelial tissue pairs or matched primary versus metastatic tumor tissue pairs. These results were validated by quantitative real-time polymerase chain reaction and agarose gel electrophoresis. We demonstrated the biological effect of circCHST15 in ccRCC both in vitro and in vivo. To test the interaction between circCHST15 and miRNAs, we conducted a number of experiments, including RNA pull down assay, dual-luciferase reporter assay and fluorescence in situ hybridization.

Results

The expression of circCHST15 was higher in ccRCC tissues compared to healthy adjacent kidney tissue and higher in RCC cell lines compared to normal kidney cell lines. The level of circCHST15 was positively correlated with aggressive clinicopathological characteristics, and circCHST15 served as an independent prognostic indicator for overall survival and progression-free survival in patients with ccRCC after surgical resection. Our in vivo and in vitro data indicate that circCHST15 promotes the proliferation, migration, and invasion of ccRCC cells. Mechanistically, we found that circCHST15 directly interacts with miR-125a-5p and acts as a microRNA sponge to regulate EIF4EBP1 expression.

Conclusions

We found that sponging of miR-125a-5p to promote EIF4EBP1 expression is the underlying mechanism of hsa_circ_0020303-induced ccRCC progression. This prompts further investigation of circCHST15 as a potential prognostic biomarker and therapeutic target for ccRCC.
Characterization of novel CTNNB1 mutation in Craniopharyngioma by whole-genome sequencing
Authors: He Juan , Zeng Zhen , Wang Yuelong , Deng Jiaojiao , Tang Xin , Liu Fujun , Huang Jianhan , Chen Hongxu , Liang Ruichao , Zan Xin , Liu Zhiyong , Tong Aiping , Guo Gang , Xu Jianguo , Zhu Xiaofeng , Zhou Liangxue , Peng Yong
Published: December 2021

Background

Craniopharyngioma (CP) is rare histologically benign but clinically challenging tumor because of its intimate relationship with the critical structure in the central brain. CP can be divided into two major histologic subtypes: adamantinomatous-type CP (ACP) and papillary-type CP (PCP). Although some genetic aberrations for both categories have been revealed in previous studies, the complete spectrum of genetic changes of this tumor remains unknown.

Methods

In this study, we conducted whole genome sequencing (WGS) on twenty-six CPs including 16 ACPs and 10 PCPs together with their matched blood samples. Somatic variants (SNVs, InDels, SVs and CNVs) were identified and mutational signatures were characterized for each patient. We investigated the impact of a novel CTNNB1 mutant on its protein stability, ubiquitination and Wnt pathway activity. Cell proliferation ability of the CTNNB1 mutant in ACP primary cells was additionally analyzed by CCK8 and colony formation assays.

Results

We found that CPs had showed less complexity with fewer somatic mutations compared with malignant tumors. Moreover, mutations in CTNNB1 (68.75% of ACP) and BRAF V600E (70.00% of PCP) are mutually exclusive in ACP and PCP, consolidating that the driving roles of these two genes in ACP and PCP, respectively. A novel mutation in the exon 3 of CTNNB1 which compromised both a transversion and in-frame deletion was identified in ACP. This mutation was experimentally validated to confer β-catenin increased stability by inhibiting its ubiquitination, thus activating Wnt-signaling pathway and promoting cell proliferation.

Conclusions

Whole genome landscape for CP was revealed by WGS analysis, and a novel mutation in the exon 3 of CTNNB1 was identified. This novel mutation activates Wnt-signaling pathway through increasing the stability of β-catenin. Our findings provided us with more comprehensive insight into the spectrum of genetic alterations in CP.
CircIL4R activates the PI3K/AKT signaling pathway via the miR-761/TRIM29/PHLPP1 axis and promotes proliferation and metastasis in colorectal cancer
Authors: Jiang Tao , Wang Hongyu , Liu Lianyu , Song Hu , Zhang Yi , Wang Jiaqi , Liu Lei , Xu Teng , Fan Ruizhi , Xu Yixin , Wang Shuai , Shi Linsen , Zheng Li , Wang Renhao , Song Jun
Published: December 2021

Background

Accumulating studies have revealed that aberrant expression of circular RNAs (circRNAs) is widely involved in the tumorigenesis and progression of malignant cancers, including colorectal cancer (CRC). Nevertheless, the clinical significance, levels, features, biological function, and molecular mechanisms of novel circRNAs in CRC remain largely unexplored.

Methods

CRC-related circRNAs were identified through bioinformatics analysis and verified in clinical specimens by qRT–PCR and in situ hybridization (ISH). Then, in vitro and in vivo experiments were performed to determine the clinical significance of, functional roles of, and clinical characteristics associated with circIL4R in CRC specimens and cells. Mechanistically, RNA pull-down, fluorescence in situ hybridization (FISH), luciferase reporter, and ubiquitination assays were performed to confirm the underlying mechanism of circIL4R.

Results

CircIL4R was upregulated in CRC cell lines and in sera and tissues from CRC patients and was positively correlated with advanced clinicopathological features and poor prognosis. Functional experiments demonstrated that circIL4R promotes CRC cell proliferation, migration, and invasion via the PI3K/AKT signaling pathway. Mechanistically, circIL4R was regulated by TFAP2C and competitively interacted with miR-761 to enhance the expression of TRIM29, thereby targeting PHLPP1 for ubiquitin-mediated degradation to activate the PI3K/AKT signaling pathway and consequently facilitate CRC progression.

Conclusions

Our findings demonstrate that upregulation of circIL4R plays an oncogenic role in CRC progression and may serve as a promising diagnostic and prognostic biomarker for CRC detection and as a potential therapeutic target for CRC treatment.
Transgene expression in mice of the Opa1 mitochondrial transmembrane protein through bicontinuous cubic lipoplexes containing gemini imidazolium surfactants
Authors: Muñoz-Úbeda Mónica , Semenzato Martina , Franco-Romero Anais , Junquera Elena , Aicart Emilio , Scorrano Luca , López-Montero Iván
Published: December 2021

Background

Lipoplexes are non-viral vectors based on cationic lipids used to deliver DNA into cells, also known as lipofection. The positively charge of the hydrophilic head-group provides the cationic lipids the ability to condensate the negatively charged DNA into structured complexes. The polar head can carry a large variety of chemical groups including amines as well as guanidino or imidazole groups. In particular, gemini cationic lipids consist of two positive polar heads linked by a spacer with different length. As for the hydrophobic aliphatic chains, they can be unsaturated or saturated and are connected to the polar head-groups. Many other chemical components can be included in the formulation of lipoplexes to improve their transfection efficiency, which often relies on their structural features. Varying these components can drastically change the arrangement of DNA molecules within the lamellar, hexagonal or cubic phases that are provided by the lipid matrix. Lipofection is widely used to deliver genetic material in cell culture experiments but the simpler formulations exhibit major drawbacks related to low transfection, low specificity, low circulation half-life and toxicity when scaled up to in vivo experiments.

Results

So far, we have explored in cell cultures the transfection ability of lipoplexes based on gemini cationic lipids that consist of two C16 alkyl chains and two imidazolium polar head-groups linked with a polyoxyethylene spacer, (C16Im)2(C4O). Here, PEGylated lipids have been introduced to the lipoplex formulation and the transgene expression of the Opa1 mitochondrial transmembrane protein in mice was assessed. The addition of PEG on the surface of the lipid mixed resulted in the formation of Ia3d bicontinuous cubic phases as determined by small angle X-ray scattering. After a single intramuscular administration, the cubic lipoplexes were accumulated in tissues with tight endothelial barriers such as brain, heart, and lungs for at least 48 h. The transgene expression of Opa1 in those organs was identified by western blotting or RNA expression analysis through quantitative polymerase chain reaction.

Conclusions

The expression reported here is sufficient in magnitude, duration and toxicity to consolidate the bicontinuous cubic structures formed by (C16Im)2(C4O)-based lipoplexes as valuable therapeutic agents in the field of gene delivery.

Graphical Abstract
Nanofactory for metabolic and chemodynamic therapy: pro-tumor lactate trapping and anti-tumor ROS transition
Authors: He Ruiqing , Zang Jie , Zhao Yuge , Liu Ying , Ruan Shuangrong , Zheng Xiao , Chong Gaowei , Xu Dailin , Yang Yan , Yang Yushan , Zhang Tingting , Gu Jingjing , Dong Haiqing , Li Yongyong
Published: December 2021

Lactate plays a critical role in tumorigenesis, invasion and metastasis. Exhausting lactate in tumors holds great promise for the reversal of the immunosuppressive tumor microenvironment (TME). Herein, we report on a “lactate treatment plant” (i.e., nanofactory) that can dynamically trap pro-tumor lactate and in situ transformation into anti-tumor cytotoxic reactive oxygen species (ROS) for a synergistic chemodynamic and metabolic therapy. To this end, lactate oxidase (LOX) was nano-packaged by cationic polyethyleneimine (PEI), assisted by a necessary amount of copper ions (PLNPCu). As a reservoir of LOX, the tailored system can actively trap lactate through the cationic PEI component to promote lactate degradation by two-fold efficiency. More importantly, the byproducts of lactate degradation, hydrogen peroxide (H2O2), can be transformed into anti-tumor ROS catalyzing by copper ions, mediating an immunogenic cell death (ICD). With the remission of immunosuppressive TME, ICD process effectively initiated the positive immune response in 4T1 tumor model (88% tumor inhibition). This work provides a novel strategy that rationally integrates metabolic therapy and chemodynamic therapy (CDT) for combating tumors.

Graphical Abstract
D-dimer for risk stratification and antithrombotic treatment management in acute coronary syndrome patients: a systematic review and metanalysis
Authors: Biccirè Flavio Giuseppe , Farcomeni Alessio , Gaudio Carlo , Pignatelli Pasquale , Tanzilli Gaetano , Pastori Daniele
Published: December 2021

Background

Data on the prognostic role of D-dimer in patients with acute coronary syndrome (ACS) are controversial. Our aim was to summarize current evidence on the association between D-dimer levels and short/long-term poor prognosis of ACS patients. We also investigated the association between D-dimer and no-reflow phenomenon.

Methods

Systematic review and metanalysis of observational studies including ACS patients and reporting data on D-dimer levels. PubMed and SCOPUS databases were searched. Data were combined with hazard ratio (HR) and metanalysed. The principal endpoint was a composite of cardiovascular events (CVEs) including myocardial infarction, all-cause and cardiovascular mortality.

Results

Overall, 32 studies included in the systematic review with 28,869 patients. Of them, 6 studies investigated in-hospital and 26 studies long-term outcomes. Overall, 23 studies showed positive association of high D-dimer levels with CVEs. D-dimer levels predicted poor prognosis in all studies reporting in-hospital outcomes. Five studies satisfied inclusion criteria and were included in the metanalysis, with a total of 8616 patients. Median follow-up was 13.2 months with 626 CVEs. The pooled HR for D-dimer levels and CVEs was 1.264 (95% CI 1.134–1.409). Five out of 7 studies (4195 STEMI patients) investigating the association between D-dimer levels and no-reflow showed a positive correlation of D-dimer levels with no-reflow.

Conclusions

In patients with ACS, D-dimer was associated with higher in-hospital and short/long-term complications. D-dimer was also higher in patients with no-reflow phenomenon. The use of D-dimer may help to identify patients with residual thrombotic risk after ACS.

Trial registration

The review protocol was registered in PROSPERO International Prospective Register of Systematic Reviews: CRD42021267233.
PDIA3 inhibits mitochondrial respiratory function in brain endothelial cells and C. elegans through STAT3 signaling and decreases survival after OGD
Authors: Keasey Matt. P. , Razskazovskiy V. , Jia C. , Peterknecht E. D. , Bradshaw P. C. , Hagg T.
Published: December 2021

Background

Protein disulfide isomerase A3 (PDIA3, also named GRP58, ER-60, ERp57) is conserved across species and mediates protein folding in the endoplasmic reticulum. PDIA3 is, reportedly, a chaperone for STAT3. However, the role of PDIA3 in regulating mitochondrial bioenergetics and STAT3 phosphorylation at serine 727 (S727) has not been described.

Methods

Mitochondrial respiration was compared in immortalized human cerebral microvascular cells (CMEC) wild type or null for PDIA3 and in whole organism C. Elegans WT or null for pdi-3 (worm homologue). Mitochondrial morphology and cell signaling pathways in PDIA3-/- and WT cells were assessed. PDIA3-/- cells were subjected to oxygen–glucose deprivation (OGD) to determine the effects of PDIA3 on cell survival after injury.

Results

We show that PDIA3 gene deletion using CRISPR-Cas9 in cultured CMECs leads to an increase in mitochondrial bioenergetic function. In C. elegans, gene deletion or RNAi knockdown of pdi-3 also increased respiratory rates, confirming a conserved role for this gene in regulating mitochondrial bioenergetics. The PDIA3-/- bioenergetic phenotype was reversed by overexpression of WT PDIA3 in cultured PDIA3-/- CMECs. PDIA3-/- and siRNA knockdown caused an increase in phosphorylation of the S727 residue of STAT3, which is known to promote mitochondrial bioenergetic function. Increased respiration in PDIA3-/- CMECs was reversed by a STAT3 inhibitor. In PDIA3-/- CMECs, mitochondrial membrane potential and reactive oxygen species production, but not mitochondrial mass, was increased, suggesting an increased mitochondrial bioenergetic capacity. Finally, PDIA3-/- CMECs were more resistant to oxygen–glucose deprivation, while STAT3 inhibition reduced the protective effect.

Conclusions

We have discovered a novel role for PDIA3 in suppressing mitochondrial bioenergetic function by inhibiting STAT3 S727 phosphorylation.
Cytoplasmic eIF6 promotes OSCC malignant behavior through AKT pathway
Authors: Zhao Zechen , Chu Weiming , Zheng Yang , Wang Chao , Yang Yuemei , Xu Teng , Yang Xueming , Zhang Wei , Ding Xu , Li Gang , Zhang Hongchuang , Zhou Junbo , Ye Jinhai , Wu Heming , Song Xiaomeng , Wu Yunong
Published: December 2021

Background

Eukaryotic translation initiation factor 6 (eIF6), also known as integrin β4 binding protein, is involved in ribosome formation and mRNA translation, acting as an anti-association factor. It is also essential for the growth and reproduction of cells, including tumor cells. Yet, its role in oral squamous cell carcinoma (OSCC) remains unclear.

Methods

The expression characteristics of eIF6 in 233 samples were comprehensively analyzed by immunohistochemical staining (IHC). Effects of eIF6 over-expression and knockdown on cell proliferation, migration and invasion were determined by CCK-8, wound healing and Transwell assays. Western blot, immunofluorescence (IF) and co-immunoprecipitation (co-IP) were performed for mechanical verification.

Results

We found that cytoplasmic eIF6 was abnormally highly expressed in OSCC tissues, and its expression was associated with tumor size and the clinical grade. Amplification of eIF6 promoted the growth, migration and invasion capabilities of OSCC cell lines in vitro and tumor growth in vivo. Through Western blot analysis, we further discovered that eIF6 significantly promotes epithelial-mesenchymal transformation (EMT) in OSCC cells, while depletion of eIF6 can reverse this process. Mechanistically, eIF6 promoted tumor progression by activating the AKT signaling pathway. By performing co-immunoprecipitation, we discovered a direct interaction between endogenous eIF6 and AKT protein in the cytoplasm.

Conclusion

These results demonstrated that eIF6 could be a new therapeutic target in OSCC, thus providing a new basis for the prognosis of OSCC patients in the future.