bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel method to detect the early warning signal of COVID-19 transmission
Authors: Li Mingzhang , Ma Shuo , Liu Zhengrong
Published: July 2022

Background

Infectious illness outbreaks, particularly the corona-virus disease 2019 (COVID-19) pandemics in recent years, have wreaked havoc on human society, and the growing number of infected patients has put a strain on medical facilities. It’s necessary to forecast early warning signals of potential outbreaks of COVID-19, which would facilitate the health ministry to take some suitable control measures timely to prevent or slow the spread of COVID-19. However, since the intricacy of COVID-19 transmission, which connects biological and social systems, it is a difficult task to predict outbreaks of COVID-19 epidemics timely.

Results

In this work, we developed a new model-free approach, called, the landscape network entropy based on Auto-Reservoir Neural Network (ARNN-LNE), for quantitative analysis of COVID-19 propagation, by mining dynamic information from regional networks and short-term high-dimensional time-series data. Through this approach, we successfully identified the early warning signals in six nations or areas based on historical data of COVID-19 infections.

Conclusion

Based on the newly published data on new COVID-19 disease, the ARNN-LNE method can give early warning signals for the outbreak of COVID-19. It’s worth noting that ARNN-LNE only relies on small samples data. Thus, it has great application potential for monitoring outbreaks of infectious diseases.
The relationship between hematocrit and serum albumin levels difference and mortality in elderly sepsis patients in intensive care units—a retrospective study based on two large database
Authors: Wang Zichen , Zhang Luming , Li Shaojin , Xu Fengshuo , Han Didi , Wang Hao , Huang Tao , Yin Haiyan , Lyu Jun
Published: July 2022

Background

Sepsis still threatens the lives of more than 300 million patients annually and elderly patients with sepsis usually have a more complicated condition and a worse prognosis. Existing studies have shown that both Hematocrit (HCT) and albumin (ALB) can be used as potential predictors of sepsis, and their difference HCT-ALB has a significant capacity to diagnose infectious diseases. Currently, there is no relevant research on the relationship between HCT-ALB and the prognosis of elderly sepsis patients. Therefore, this study aims to explore the association between HCT-ALB and mortality in elderly patients with sepsis.

Methods

This study was a multi-center retrospective study based on the Medical Information Mart for Intensive Care (MIMIC-IV) database and the eICU Collaborative Research Database (eICU-CRD) in elderly patients with sepsis. The optimal HCT-ALB cut-off point for ICU mortality was calculated by the Youden Index based on the eICU-CRD dataset, and multivariate logistic regressions were conducted to explore the association between HCT-ALB and ICU/hospital mortality in the two databases. Subgroup analyses were performed for different parameters and comorbidity status.

Results

The number of 16,127 and 3043 elderly sepsis patients were selected from two large intensive care databases (eICU-CRD and MIMIC-IV, respectively) in this study. Depending on the optimal cut-off point, patients in both eICU-CRD and MIMIC-IV were independently divided into low HCT-ALB (< 6.7) and high HCT-ALB (≥ 6.7) groups. The odds ratio (95%confidence interval) [OR (95CI%)] of the high HCT-ALB group were 1.50 (1.36,1.65) and 1.71 (1.58,1.87) for ICU and hospital mortality in the eICU-CRD database after multivariable adjustment. Similar trends in the ICU and hospital mortality [OR (95%CI) 1.41 (1.15,1.72) and 1.27 (1.07,1.51)] were observed in MIMIC-IV database. Subgroup analysis showed an interaction effect with SOFA score in the eICU-CRD database however not in MIMIC-IV dataset.

Conclusions

High HCT-ALB (≥ 6.7) is associated with 1.41 and 1.27 times ICU and hospital mortality risk in elderly patients with sepsis. HCT-ALB is simple and easy to obtain and is a promising clinical predictor of early risk stratification for elderly sepsis patients in ICU.
The TAS Test project: a prospective longitudinal validation of new online motor-cognitive tests to detect preclinical Alzheimer’s disease and estimate 5-year risks of cognitive decline and dementia
Authors: Alty Jane , Bai Quan , Li Renjie , Lawler Katherine , St George Rebecca J. , Hill Edward , Bindoff Aidan , Garg Saurabh , Wang Xinyi , Huang Guan , Zhang Kaining , Rudd Kaylee D. , Bartlett Larissa , Goldberg Lynette R. , Collins Jessica M. , Hinder Mark R. , Naismith Sharon L. , Hogg David C. , King Anna E. , Vickers James C.
Published: July 2022

Background

The worldwide prevalence of dementia is rapidly rising. Alzheimer’s disease (AD), accounts for 70% of cases and has a 10–20-year preclinical period, when brain pathology covertly progresses before cognitive symptoms appear. The 2020 Lancet Commission estimates that 40% of dementia cases could be prevented by modifying lifestyle/medical risk factors. To optimise dementia prevention effectiveness, there is urgent need to identify individuals with preclinical AD for targeted risk reduction. Current preclinical AD tests are too invasive, specialist or costly for population-level assessments. We have developed a new online test, TAS Test, that assesses a range of motor-cognitive functions and has capacity to be delivered at significant scale. TAS Test combines two innovations: using hand movement analysis to detect preclinical AD, and computer-human interface technologies to enable robust ‘self-testing’ data collection. The aims are to validate TAS Test to [1] identify preclinical AD, and [2] predict risk of cognitive decline and AD dementia.

Methods

Aim 1 will be addressed through a cross-sectional study of 500 cognitively healthy older adults, who will complete TAS Test items comprising measures of motor control, processing speed, attention, visuospatial ability, memory and language. TAS Test measures will be compared to a blood-based AD biomarker, phosphorylated tau 181 (p-tau181). Aim 2 will be addressed through a 5-year prospective cohort study of 10,000 older adults. Participants will complete TAS Test annually and subtests of the Cambridge Neuropsychological Test Battery (CANTAB) biennially. 300 participants will undergo in-person clinical assessments. We will use machine learning of motor-cognitive performance on TAS Test to develop an algorithm that classifies preclinical AD risk (p-tau181-defined) and determine the precision to prospectively estimate 5-year risks of cognitive decline and AD.

Discussion

This study will establish the precision of TAS Test to identify preclinical AD and estimate risk of cognitive decline and AD. If accurate, TAS Test will provide a low-cost, accessible enrichment strategy to pre-screen individuals for their likelihood of AD pathology prior to more expensive tests such as blood or imaging biomarkers. This would have wide applications in public health initiatives and clinical trials.

Trial registration

ClinicalTrials.gov Identifier:NCT05194787, 18 January 2022. Retrospectively registered.
Stent-assisted coiling of acutely ruptured cerebral aneurysm: a multicenter prospective registry study (SAVE)
Authors: Li Gaozhi , Han Yongquan , Ding Shenghao , Pan Yaohua , Zhang Xiaohua , Zhao Bing
Published: July 2022

Background

Stent-assisted coiling (SAC) has been reported as a feasible and effective treatment of wide-neck cerebral aneurysms. However, the evidence of SAC of ruptured cerebral aneurysm is lacking. There are no prospective multicenter studies regarding SAC of acutely ruptured aneurysms within 72 hours after subarachnoid hemorrhage. The purpose of the study is to evaluate the safety and efficiency of SAC of acutely ruptured cerebral aneurysms.

Methods

This study is a prospective, multicenter, and observation registry of consecutive patients with acutely ruptured cerebral aneurysms treated with SAC. Acutely ruptured aneurysms were confirmed within 72 h after the onset of the syndrome. This study will enroll at least 300 patients in 7 high-volume tertiary hospitals (more than 150 cerebral aneurysms treated per year). The primary outcomes are treatment-related thromboembolic complications within 30 days of the treatment. The secondary outcomes are any hemorrhagic complications and aneurysm recurrence at 6 months of angiographic follow-up. The clinical outcomes are measured with the Modified Rankin Scale (mRS) at discharge and at the 6 months of follow-up. The favorable outcomes are defined as an mRS of grades 0 and 2.

Discussion

We will perform a prospective, multicenter, and observational registry study of consecutive patients with wide-neck acutely ruptured cerebral aneurysms to improve the safety strategy of SAC of acutely ruptured cerebral aneurysms.

Trial registration

Chinese Clinic Trial Registry: ChiCTR2000036972; Registration date: Aug 26, 2020
Obstetric outcomes following ovarian hyperstimulation syndrome in IVF – a comparison with uncomplicated fresh and frozen transfer cycles
Authors: Ganer Herman Hadas , Mizrachi Yossi , Horowitz Eran , Weissman Ariel , Sabban Ben , Gluck Ohad , Raziel Arieh , Kovo Michal
Published: July 2022

Background

We aimed to assess the correlation between ovarian hyperstimulation syndrome (OHSS) in the early course of in vitro fertilization (IVF) pregnancies and obstetric outcomes.

Methods

We identified records of patients admitted due to OHSS following IVF treatment at our institution between 2008 and 2020. Cases were included if pregnancy resulted in a live singleton delivery (OHSS group). OHSS cases were matched at a 1:5:5 ratio with live singleton deliveries following IVF with fresh embryo transfer (fresh transfer group) and frozen embryo transfer (FET group), according to maternal age and parity. Computerized files were reviewed, and maternal, obstetric and neonatal outcomes compared.

Results

Overall, 44 OHSS cases were matched with 220 fresh transfer and 220 FET pregnancies. Patient demographics were similar between the groups, including body mass index, smoking and comorbidities. Gestational age at delivery, the rate of preterm births, preeclampsia and cesarean delivery were similar between the groups. Placental abruption occurred in 6.8% of OHSS pregnancies, 1.4% of fresh transfer pregnancies and 0.9% of FET pregnancies (p=0.02). On post-hoc analysis, the rate of placental abruption was significantly higher in OHSS pregnancies, compared with the two other groups, and this maintained significance after adjustment for confounders. Birthweights were 3017 ± 483, 3057 ± 545 and 3213 ± 542 grams in the OHSS, fresh transfer and FET groups, respectively (p=0.004), although the rate of small for gestational age neonates was similar between the groups.

Conclusions

OHSS in the early course of IVF pregnancies is associated with an increased risk of placental abruption.
Geographical variations of cancer incidence in Guadeloupe, French West Indies
Authors: Bhakkan-Mambir Bernard , Deloumeaux Jacqueline , Luce Danièle
Published: July 2022

Background

Geographical disparities in cancer incidence are observed at different scales and may highlight areas of high risk that need special attention to improve health policies. In Guadeloupe, a French archipelago in the Caribbean, environmental and socioeconomic factors are potential factors associated with cancer incidence. Our objective was to describe geographical variations of cancer incidence in Guadeloupe at a small-area level, in order to identify potential clusters.

Methods

We conducted spatial analyses for the 18 most frequent cancer sites, using data collected by the population-based cancer registry of Guadeloupe over the period 2008–2017. For each cancer sites, we used the Besag, York and Mollié model to estimate smoothed standardized incidence ratios (SIRs) at a sub-municipality level. In addition, we performed ascendant hierarchical clustering of these smoothed SIRs to describe the relationship between the different cancer sites and to identify geographical clusters.

Results

We observed geographical disparities with a spatial pattern that varied across cancer sites. Clustering of the smoothed SIRs showed aggregations between breast cancer and multiple myeloma, thyroid and stomach cancer, cervical and head and neck cancers, lung and rectal cancers, ovarian and endometrial cancers. Cluster analysis also identified six geographical clusters. Features of these clusters suggest alcohol consumption, exposure to pesticides, pollution generated by open landfills, and ethnicity as possible explanatory factors.

Discussion/conclusion

Our study provided for the first time an extensive description of geographical disparities in cancer incidence in Guadeloupe, in a region where socioeconomic and environmental issues are major concerns. Although the identification of underlying factors was out of the scope of the present study, we highlighted areas of special interest and put forward some hypotheses that warrant to be further investigated in more in-depth analyses.
Prognostic impact of stromal periostin expression in upper urinary tract urothelial carcinoma
Authors: Miyai Kosuke , Kawamura Kazuki , Ito Keiichi , Matsukuma Susumu , Tsuda Hitoshi
Published: July 2022

Background

Periostin is an extracellular matrix protein that has been known to be implicated in fibrillogenesis and cell migration, including cancer metastasis. Periostin overexpression in cancer cells and/or intervening stroma is usually related to tumor progression and poor patient outcomes in various human cancers; however, its role in urothelial carcinoma, especially upper urinary tract urothelial carcinomas (UTUCs), remains inconclusive.

Methods

Samples from 126 consecutive cases of invasive UTUC (69 renal pelvic cancers and 57 ureteral cancers) were histologically reviewed and analyzed for periostin expression using immunohistochemistry. The intensities of immunoreactivity and the fraction of positive cancer cells and stroma (i.e., epithelial and stromal expression, respectively) were classified into four categories each (intensity, 0–3; fraction, 0–25% = 1; 26–50% = 2; 51–75% = 3; and > 75% = 4). The overall score was determined by multiplying both scores, and overall scores ≥ 6 were considered to indicate high periostin expression.

Results

Among 126 UTUCs, 55 (44%; 27 renal pelvic and 28 ureteral cancers) showed high stromal periostin expression. None of the cases were considered to have high epithelial periostin expression. High stromal periostin expression was associated with non-papillary gross findings, higher pathological T category, lymphovascular invasion, concomitant carcinoma in situ, subtype histology, lymph node metastasis, positive surgical margins, high tumor budding, and high tumor-associated immune cell status. Multivariate analysis revealed that high stromal periostin expression was an independent predictor of overall survival (p = 0.00072, hazard ratio = 3.62), and lymphovascular invasion and high stromal periostin expression were independent predictors of cancer-specific survival (p = 0.032 and 0.020, hazard ratio = 2.61 and 3.07, respectively).

Conclusions

Stromal periostin expression was often observed in invasive UTUCs with adverse clinicopathological factors and may be a useful predictor of patient outcomes.
TTK Protein Kinase promotes temozolomide resistance through inducing autophagy in glioblastoma
Authors: Yu Jian , Gao Ge , Wei Xiangpin , Wang Yang
Published: July 2022

Background

Temozolomide (TMZ) resistance remains the main therapy challenge in patients with glioblastoma multiforme (GBM). TTK Protein Kinase (TTK) contributes to the radioresistance and chemoresistance in many malignancies. However, the role of TTK in the TMZ resistance of GBM cells remains unknown.

Methods

The expression of TTK was measured by western blot. The proliferation of GBM cells was assessed through MTT assay and clonogenic assay. Cell apoptosis was evaluated using western blot. LC3B puncta were detected using immunohistochemistry staining. The mouse xenograft model was used to investigate the role of TTK in vivo.

Results

Knockdown of TTK increased the sensitivity of GBM cells to TMZ treatment, while overexpression of TTK induced TMZ resistance. Two specific TTK inhibitors, BAY-1217389 and CFI-402257, significantly inhibited GBM cell proliferation and improved the growth-suppressive effect of TMZ. In addition, the knockdown of TTK decreased the autophagy levels of GBM cells. Inhibition of TTK using specific inhibitors could also suppress the autophagy process. Blocking autophagy using chloroquine (CQ) abolished the TMZ resistance function of TTK in GBM cells and in the mouse model.

Conclusions

We demonstrated that TTK promotes the TMZ resistance of GBM cells by inducing autophagy in vitro and in vivo. The use of a TTK inhibitor in combination with TMZ might help to overcome TMZ resistance and improve therapy efficiency in GBM.
Assessing the accuracy of multiparametric MRI to predict clinically significant prostate cancer in biopsy naïve men across racial/ethnic groups
Authors: Meza Julio , Babajide Rilwan , Saoud Ragheed , Sweis Jamila , Abelleira Josephine , Helenowski Irene , Jovanovic Borko , Eggener Scott , Miller Frank H. , Horowitz Jeanne M. , Casalino David D. , Murphy Adam B.
Published: July 2022

Introduction

The Prostate Imaging Reporting and Data System (PIRADS) has shown promise in improving the detection of Gleason grade group (GG) 2–5 prostate cancer (PCa) and reducing the detection of indolent GG1 PCa. However, data on the performance of PIRADS in Black and Hispanic men is sparse. We evaluated the accuracy of PIRADS scores in detecting GG2-5 PCa in White, Black, and Hispanic men.

Methods

We performed a multicenter retrospective review of biopsy-naïve Black (n = 108), White (n = 108), and Hispanic (n = 64) men who underwent prostate biopsy (PB) following multiparametric MRI. Sensitivity and specificity of PIRADS for GG2-5 PCa were calculated. Race-stratified binary logistic regression models for GG2-5 PCa using standard clinical variables and PIRADS were used to calculate area under the receiver operating characteristics curves (AUC).

Results

Rates of GG2-5 PCa were statistically similar between Blacks, Whites, and Hispanics (52.8% vs 42.6% vs 37.5% respectively,p = 0.12). Sensitivity was lower in Hispanic men compared to White men (87.5% vs 97.8% respectively,p = 0.01). Specificity was similar in Black versus White men (21.6% vs 27.4%,p = 0.32) and White versus Hispanic men (27.4% vs 17.5%,p = 0.14).

The AUCs of the PIRADS added to standard clinical data (age, PSA and suspicious prostate exam) were similar when comparing Black versus White men (0.75 vs 0.73,p = 0.79) and White versus Hispanic men (0.73 vs 0.59,p = 0.11). The AUCs for the Base model and PIRADS model alone were statistically similar when comparing Black versus White men and White versus Hispanic men.

Conclusions

The accuracy of the PIRADS and clinical data for detecting GG2-5 PCa seems statistically similar across race. However, there is concern that PIRADS 2.0 has lower sensitivity in Hispanic men compared to White men. Prospective validation studies are needed.
Oral health professionals screening for undiagnosed type-2 diabetes and prediabetes: the iDENTify study
Authors: Mariño Rodrigo , Priede Andre , King Michelle , Adams Geoffrey G. , Sicari Maria , Morgan Mike
Published: July 2022

Background

As part of an evaluation of an oral healthcare practice-based model that identifies patients with prediabetes or type-2 diabetes, this study reports on the proportion of patients identified with clinically confirmed type-2 diabetes (T2D)/prediabetes and barriers of implementation of the model.

Methodology

Urban and rural oral healthcare practices were invited to participate. Participating practices invited eligible patients to participate in the screening program using the Australian Type-2 Diabetes Risk Assessment Tool (AUSDRISK). Participants were categorised as low, intermediate, or high-risk for prediabetes/T2D. Patients in the intermediate or high-risk category were referred to their General Medical Practitioner (GP) for further investigation.

Results

Fifty-one oral healthcare practices and 76 Oral Health Professionals (OHP) participated (60 Dentists, 8 Dental Hygienists, 8 Oral Health Therapists). 797 patients were screened; 102 were low-risk; 331 intermediate-risk; and 364 high-risk for T2D. Of the 695 participants in the intermediate or high-risk groups, 386 (55.5%) were referred to their GP for T2D assessment. Of them, 96 (25.0%) results were returned to OHPs. Of the returned results, six were (6.3%) diagnosed with pre-T2D.

Conclusion

Patients found to have undiagnosed T2D/prediabetes (6.3%) were within the expected range reported in the literature. Findings indicate that identifying individuals at an elevated risk of having or developing T2D is effective, feasible and could be incorporated into oral healthcare settings. However, this integration may require additional OHPs training and education to ensure that patients at elevated risk of T2D are referred for further assessment.
The mediating role of life satisfaction in the relationship between depression, anxiety, stress and burnout among Portuguese nurses during COVID-19 pandemic
Authors: Martins Vera , Serrão Carla , Teixeira Andreia , Castro Luísa , Duarte Ivone
Published: July 2022

Background

The COVID-19 pandemic had a large consequence on healthcare systems, increasing the risks of psychological issues in health professionals. Nurses, in particular, have been exposed to multiple psychosocial stressors and struggled with intensive work, insufficiency of resources and uncertainty in the face of an unknown disease. Life satisfaction might protect nurses from the consequences of chronic stress. The aim of this study was to explore the mediating role of satisfaction with life in the relationship between depression, stress, anxiety and burnout (personal, work-related, and client-related).

Methods

A cross-sectional, descriptive, correlational study design was performed, using an online questionnaire distributed via social networks. A total of 379 nurses completed the survey, comprising standardized measures of satisfaction with life, resilience (Resilience Scale), depression, anxiety, stress (Depression Anxiety Stress Scales), and burnout (Copenhagen Burnout Inventory Scale). A hierarchical regression model was estimated for each burnout dimension.

Results

Participants showed high levels of work, personal and client-related burnout, 57.3%, 57%, and 35.1%, respectively. More than 70% of the respondents had a normal level of depressive symptoms, 66.8% presented normal level of anxiety and 33.5% of the respondents reported mild, moderate, severe or extremely severe symptoms of stress. The results revealed that life satisfaction partially mediated the association between stress and personal burnout, depression and work-related burnout, and the association between anxiety and client-related burnout in nurses.

Conclusions

The COVID-19 pandemic brought added difficulties for nurses’ work conditions, whereby it became necessary to develop adaptative measures that reduce stressors in work environment and promote nurses’ life satisfaction.
Work schedule characteristics associated with sleep disturbance among healthcare professionals in Europe and South Korea: a report from two cross-sectional surveys
Authors: Min Ari , Hong Hye Chong
Published: July 2022

Background

Healthcare professionals worldwide are prone to sleep disturbance. Such sleep disturbance is associated with lower patient safety and quality of care. Therefore, this study aimed to identify the prevalence of sleep disturbance and determine the effect of work schedule characteristics on sleep disturbance among healthcare professionals in Europe and South Korea.

Methods

We used the sixth European Working Conditions Survey and the fifth Korean Working Conditions Survey for analyses. The study included 2285 healthcare professionals aged 18–65 years. Work schedule characteristics included shift work, night work, working hours per week, long work hours (i.e., more than 10 hours per shift), quick return to work, having to come to work on short notice, and changes in work schedules. A multiple logistic regression analysis was performed.

Results

The overall prevalence of sleep disturbance was 37.7%. The multivariate logistic regression model indicated that long work hours, quick return to, having to come to work on short notice, and changes in work schedules were significant factors associated with sleep disturbance among healthcare professionals.

Conclusion

The findings revealed that several work schedule-related factors were associated with sleep disturbances in healthcare professionals in Europe and Korea. Institutions and policymakers should implement strategies and policies to reduce the unpredictability of work schedules to ensure an adequate rest period between shifts and to reduce sleep disturbances.
An integrative perspective on interorganizational multilevel healthcare networks: a systematic literature review
Authors: van der Weert Galina , Burzynska Katarzyna , Knoben Joris
Published: July 2022

Background

Interorganizational networks in healthcare do not always attain their goals. Existing models outline the factors that could explain poor network performance: governance; structure; and the alignment of professional, organizational and network levels. However, these models are very generic and assume a functional approach. We investigate available empirical knowledge on how network structure and governance relate to each other and to network performance in a multilevel context, to get deeper insight, supported with empirics, of why networks (fail to) achieve their goals.

Method

A systematic literature review based on a search of Web of Science, Business Source Complete and PubMed was executed in May 2021 and repeated in January 2022. Full papers were included if they were written in English and reported empirical data in a healthcare interorganizational setting. Included papers were coded for the topics of governance, structure, performance and multilevel networks. Papers from the scientific fields of management, administration and healthcare were compared. Document citation and bibliographic coupling networks were visualized using Vosviewer, and network measures were calculated with UCINET.

Results

Overall, 184 papers were included in the review, most of which were from healthcare journals. Research in healthcare journals is primarily interested in the quality of care, while research in management and administration journals tend to focus on efficiency and financial aspects. Cross-citation is limited across different fields. Networks with a brokered form of governance are the most prevalent. Network performance is mostly measured at the community level. Only a few studies employed a multilevel perspective, and interaction effects were not usually measured between levels.

Conclusions

Research on healthcare networks is fragmented across different scientific fields. The current review revealed a range of positive, negative and mixed effects and points to the need for more empirical research to identify the underlying reasons for these outcomes. Hardly any empirical research is available on the effects of different network structures and governance modes on healthcare network performance at different levels. We find a need for more empirical research to study healthcare networks at multiple levels while acknowledging hybrid governance models that may apply across different levels.
DNA methylation subtypes guiding prognostic assessment and linking to responses the DNA methyltransferase inhibitor SGI-110 in urothelial carcinoma
Authors: Li Juan , Liang Yuan , Fan Jian , Xu Chunru , Guan Bao , Zhang Jianye , Guo Bin , Shi Yue , Wang Ping , Tan Yezhen , Zhang Qi , Yuan Changwei , Wu Yucai , Zhou Liqun , Ci Weimin , Li Xuesong
Published: July 2022

Background

At present, the extent and clinical relevance of epigenetic differences between upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB) remain largely unknown. Here, we conducted a study to describe the global DNA methylation landscape of UTUC and UCB and to address the prognostic value of DNA methylation subtype and responses to the DNA methyltransferase inhibitor SGI-110 in urothelial carcinoma (UC).

Methods

Using whole-genome bisulfite sequencing (n = 49 samples), we analyzed epigenomic features and profiles of UTUC (n = 36) and UCB (n = 9). Next, we characterized potential links between DNA methylation, gene expression (n = 9 samples), and clinical outcomes. Then, we integrated an independent UTUC cohort (Fujii et al., n = 86) and UCB cohort (TCGA, n = 411) to validate the prognostic significance. Furthermore, we performed an integrative analysis of genome-wide DNA methylation and gene expression in two UC cell lines following transient DNA methyltransferase inhibitor SGI-110 treatment to identify potential epigenetic driver events that contribute to drug efficacy.

Results

We showed that UTUC and UCB have very similar DNA methylation profiles. Unsupervised DNA methylation classification identified two epi-clusters, Methy-High and Methy-Low, associated with distinct muscle-invasive statuses and patient outcomes. Methy-High samples were hypermethylated, immune-infiltrated, and enriched for exhausted T cells, with poor clinical outcome. SGI-110 inhibited the migration and invasion of Methy-High UC cell lines (UMUC-3 and T24) by upregulating multiple antitumor immune pathways.

Conclusions

DNA methylation subtypes pave the way for predicting patient prognosis in UC. Our results provide mechanistic rationale for evaluating SGI-110 in treating UC patients in the clinic.
Optimization of the production process for the anticancer lead compound illudin M: process development in stirred tank bioreactors
Authors: Chaverra-Muñoz Lillibeth , Hüttel Stephan
Published: July 2022

Background

The fungal natural products illudin S and M have been investigated as precursors for the development of semisynthetic anticancer agents such as Irofulven (illudin S derivative) which is currently in phase II clinical trials. Recently, illudin M derivatives have shown improved in vitro selectivity towards cancer cells encouraging further investigation. This requires a stable supply of the precursor which is produced by Basidiomycota of the genus Omphalotus. We have recently reported a robust shake flask process for the production of gram quantities of illudin M from Omphalotus nidiformis aiming to transfer that process into stirred tank bioreactors, which can be used in a commercial production set-up. However, process transfer across different systems is not straightforward and particularly challenging when the producer is morphologically complex. There are only a few reports that address the development of bioprocesses for the production of compounds from Basidiomycota as these organisms have not been extensively studied because of their complex life cycles and often are difficult to cultivate under laboratory conditions.

Results

The recently developed shake flask process delivering stable titers of ~ 940 mg L−1 of illudin M was investigated using off-gas analysis to identify critical parameters which facilitated the transfer from shaken into stirred tank bioreactors. Comparable titers to the shake flask process were achieved in 2 L stirred tank bioreactors (1.5 L working volume) by controlling growth of biomass with a carefully timed pH-shift combined with an improved precursor-feeding strategy. A scale-up experiment in a 15 L bioreactor (10 L working volume), resembling the process at 1.5 L resulted in 523 mg L−1 and is the starting point for optimization of the identified parameters at that scale.

Conclusion

By identifying and controlling key process parameters, the production process for illudin M was transferred from shake flasks into 2 L stirred tank bioreactors reaching a comparable titer (> 900 mg L−1), which is significantly higher than any previously reported. The insights obtained from 10 L scale pave the way towards further scale-up studies that will enable a sustainable supply of illudin M to support preclinical and clinical development programs.
Mutual regulation between N6-methyladenosine (m6A) modification and circular RNAs in cancer: impacts on therapeutic resistance
Authors: Lin Hong , Wang Yuxi , Wang Pinghan , Long Fangyi , Wang Ting
Published: July 2022

The resistance of tumor cells to therapy severely impairs the efficacy of treatment, leading to recurrence and metastasis of various cancers. Clarifying the underlying mechanisms of therapeutic resistance may provide new strategies for overcoming cancer resistance. N6-methyladenosine (m6A) is the most prevalent RNA modification in eukaryotes, and is involved in the regulation of RNA splicing, translation, transport, degradation, stability and processing, thus affecting several physiological processes and cancer progression. As a novel type of multifunctional non-coding RNAs (ncRNAs), circular RNAs (circRNAs) have been demonstrated to play vital roles in anticancer therapy. Currently, accumulating studies have revealed the mutual regulation of m6A modification and circRNAs, and their interaction can further influence the sensitivity of cancer treatment. In this review, we mainly summarized the recent advances of m6A modification and circRNAs in the modulation of cancer therapeutic resistance, as well as their interplay and potential mechanisms, providing promising insights and future directions in reversal of therapeutic resistance in cancer.
High glucose and palmitic acid induces neuronal senescence by NRSF/REST elevation and the subsequent mTOR-related autophagy suppression
Authors: Xue Wen-Jiao , He Cheng-Feng , Zhou Ren-Yuan , Xu Xiao-Die , Xiang Lv-Xuan , Wang Jian-Tao , Wang Xin-Ru , Zhou Hou-Guang , Guo Jing-Chun
Published: July 2022

Cell senescence is a basic aging mechanism. Previous studies have found that the cellular senescence in adipose tissue and other tissues, such as the pancreas, muscle and liver, is associated with the pathogenesis and progression of type 2 diabetes; however, strong evidence of whether diabetes directly causes neuronal senescence in the brain is still lacking. In this study, we constructed a high glucose and palmitic acid (HGP) environment on PC12 neuronal cells and primary mouse cortical neurons to simulate diabetes. Our results showed that after HGP exposure, neurons exhibited obvious senescence-like phenotypes, including increased NRSF/REST level, mTOR activation and cell autophagy suppression. Downregulation of NRSF/REST could remarkably alleviate p16, p21 and γH2A.X upregulations induced by HGP treatment, and enhance mTOR-autophagy of neurons. Our results suggested that the diabetic condition could directly induce neuronal senescence, which is mediated by the upregulation of NRSF/REST and subsequent reduction of mTOR-autophagy.
Mitochondrial adaptation in cancer drug resistance: prevalence, mechanisms, and management
Authors: Jin Ping , Jiang Jingwen , Zhou Li , Huang Zhao , Nice Edouard C. , Huang Canhua , Fu Li
Published: July 2022

Drug resistance represents a major obstacle in cancer management, and the mechanisms underlying stress adaptation of cancer cells in response to therapy-induced hostile environment are largely unknown. As the central organelle for cellular energy supply, mitochondria can rapidly undergo dynamic changes and integrate cellular signaling pathways to provide bioenergetic and biosynthetic flexibility for cancer cells, which contributes to multiple aspects of tumor characteristics, including drug resistance. Therefore, targeting mitochondria for cancer therapy and overcoming drug resistance has attracted increasing attention for various types of cancer. Multiple mitochondrial adaptation processes, including mitochondrial dynamics, mitochondrial metabolism, and mitochondrial apoptotic regulatory machinery, have been demonstrated to be potential targets. However, recent increasing insights into mitochondria have revealed the complexity of mitochondrial structure and functions, the elusive functions of mitochondria in tumor biology, and the targeting inaccessibility of mitochondria, which have posed challenges for the clinical application of mitochondrial-based cancer therapeutic strategies. Therefore, discovery of both novel mitochondria-targeting agents and innovative mitochondria-targeting approaches is urgently required. Here, we review the most recent literature to summarize the molecular mechanisms underlying mitochondrial stress adaptation and their intricate connection with cancer drug resistance. In addition, an overview of the emerging strategies to target mitochondria for effectively overcoming chemoresistance is highlighted, with an emphasis on drug repositioning and mitochondrial drug delivery approaches, which may accelerate the application of mitochondria-targeting compounds for cancer therapy.
Improving the intensive care experience from the perspectives of different stakeholders
Authors: Latour Jos M. , Kentish-Barnes Nancy , Jacques Theresa , Wysocki Marc , Azoulay Elie , Metaxa Victoria
Published: July 2022

The intensive care unit (ICU) is a complex environment where patients, family members and healthcare professionals have their own personal experiences. Improving ICU experiences necessitates the involvement of all stakeholders. This holistic approach will invariably improve the care of ICU survivors, increase family satisfaction and staff wellbeing, and contribute to dignified end-of-life care. Inclusive and transparent participation of the industry can be a significant addition to develop tools and strategies for delivering this holistic care. We present a report, which follows a round table on ICU experience at the annual congress of the European Society of Intensive Care Medicine. The aim is to discuss the current evidence on patient, family and healthcare professional experience in ICU is provided, together with the panel’s suggestions on potential improvements. Combined with industry, the perspectives of all stakeholders suggest that ongoing improvement of ICU experience is warranted.
TN-GTN: fault diagnosis of aircraft wiring network over edge computing
Authors: Wang Tian , Fang Qiang , Liu Gongping , Chi Meng , Luo Yuanqi , Shen Jianming
Published: July 2022

Fault diagnosis of the aircraft wiring network plays an important role in the intelligent manufacture of the aircraft. Many studies focus on the feature-based machine learning methods. However, these methods are improper in handling the data on heterogeneous graphs. Due to the scatter of the valid feature information, the relevant information between the test nodes is ignored by these methods, which leads to the low accuracy fault diagnosis. Taking the advantage of the 5G technology that can remotely process large-scale graph data, this work proposes a fault diagnosis method named “topological network-graph transformer network (TN-GTN).” TN-GTN can improve the fault diagnosis accuracy through feature enhancement and classification, which is based on the topological information of heterogeneous graphs. The graph network is able to learn new graph structures by identifying useful meta-paths and multi-hop connections between unconnected nodes on original graphs. Feature-enhanced test nodes are used to classify the final labels by the artificial neural network. Results of the performed experiment showed that TN-GTN reduced the dependence on domain knowledge and achieved an accurate classification of the fault diagnosis on aircraft wiring network.
On fractional Simpson type integral inequalities for co-ordinated convex functions
Authors: Khan Sundas , Budak Hüseyin
Published: July 2022

In this study, we prove equality for twice partially differentiable mappings involving the double generalized fractional integral. Using the established identity, we offer some Simpson’s type inequalities for partially differentiable co-ordinated convex functions in a rectangle from the plane $\mathbb{R} ^{2}$

R
2

.
Enlarged integral inequalities through recent fractional generalized operators
Authors: Hyder Abd-Allah , Barakat M. A. , Fathallah Ashraf
Published: July 2022

This paper is devoted to proving some new fractional inequalities via recent generalized fractional operators. These inequalities are in the Hermite–Hadamard and Minkowski settings. Many previously documented inequalities may clearly be deduced as specific examples from our findings. Moreover, we give some comparative remarks to show the advantage and novelty of the obtained results.
Culture as an obstacle for entrepreneurship
Authors: Morales Gloria Leonor Ortiz , Aguilar Juan Carlos Ramos , Morales Katherin Yineth Lozada
Published: July 2022

This research was aimed to identify the main reasons why entrepreneurs in the city of Ibagué, who structure business ideas and participate in contests and/or calls, do not continue the entrepreneurial process until the creation of their companies. After applying the validated instrument (survey) to more than 100 students from the Universidad de Ibagué and expert advisers from the department of Tolima, made up of universities, entrepreneurs, and public–private institutions, with interests in entrepreneurship; it was possible to recognize that the main reason, why entrepreneurs generate ideas, but not companies, is the cultural factor. The foregoing is based on the fact that Tolima has been a quintessential agricultural department and this situation has contributed greatly to the fact that the entrepreneurial spirit has not been developed in people. Within the research results it was detected that in contrast with other cities of Colombia, like Manizales and Medellín, Ibagué has not been able to consolidate a solid entrepreneurial ecosystem due to the lack of coordination among private, public, and academic sectors, and on the other side, a majority of people from Ibagué do not have family support for the development of their initiatives, being fundamental components for the creation of enterprises. Among the recommendations proposed in the study is the construction of an entrepreneurial ecosystem, because it will allow the participation of the Triple Helix by providing opportunities to all entrepreneurs in the region; in addition, it is considered important that educational institutions, both schools and universities, promote the development of entrepreneurial skills and competencies in individuals involving their families.
Recent advances in chiral nanomaterials with unique electric and magnetic properties
Authors: Kwon Junyoung , Choi Won Jin , Jeong Uichang , Jung Wookjin , Hwang Inkook , Park Ki Hyun , Ko Seowoo Genevieve , Park Sung Min , Kotov Nicholas A. , Yeom Jihyeon
Published: July 2022

Research on chiral nanomaterials (NMs) has grown radically with a rapid increase in the number of publications over the past decade. It has attracted a large number of scientists in various fields predominantly because of the emergence of unprecedented electric, optical, and magnetic properties when chirality arises in NMs. For applications, it is particularly informative and fascinating to investigate how chiral NMs interact with electromagnetic waves and magnetic fields, depending on their intrinsic composition properties, atomic distortions, and assembled structures. This review provides an overview of recent advances in chiral NMs, such as semiconducting, metallic, and magnetic nanostructures.
Irvingia gabonensis leaf extract scavenges nitric oxide and hydrogen peroxide in vitro and modulates arsenic-induced hepatic oxidative stress in wistar rats
Authors: Ewere Efosa G. , Okolie Ngozi P. , Ndem Jessie I. , Eze Gerald I. , Oyebadejo Samson A.
Published: July 2022

Background

Arsenic is a carcinogenic heavy metal that contaminates the environment, predisposing the exposed populace to its detrimental health effects. This study investigated the liver protective effect of ethanol leaf extract of Irvingia gabonensis (ELEIG) in sodium arsenite (SA)-exposed Wistar rats and its nitric oxide (NO.) and hydrogen peroxide (H2O2)-scavenging properties in vitro.

Methods

Eleven experimental groups made up of five (5) rats each (weight range 100 - 161 g) were used in this study. Group 1 (normal control) had normal rat chow and water. Group 2 received 4.1 mg/kg body weight (kgbw) of SA. Groups 3–8 received SA and graded doses of ELEIG and groups 9-11 had varied doses of ELEIG. Treatment, which spanned 14 days, was by oral gavage. Concentrations of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), malondialdehyde (MDA) as well as activities of liver enzymes (AST, ALT, ALP, and GGT) and concentrations of total bilirubin (TBIL) and direct bilirubin (DBIL) were determined using standard procedures. Standard methods were also used to determine the in vitro NO. and H2O2-scavenging properties of the extract.

Results

Exposure to SA orchestrated significant (p ˂ 0.05) increases in CAT, MDA, AST, ALT, ALP and GGT and significant (p ˂ 0.05) decreases in SOD and GPx, relative to control. There were insignificant (p ˃ 0.05) differences in TBIL and DBIL concentrations, compared with control. Simultaneous and post-treatment with ELEIG at graded doses, alleviated the noxious effects of SA. In addition, ELEIG scavenged NO. and H2O2 in concentration-dependent manner.

Conclusion

The results suggest that ELEIG possesses potent antioxidant property and combats SA-induced hepatic oxidative stress/toxicity in Wistar rats.
3D printed integrated bolus/headrest for radiation therapy for malignancies involving the posterior scalp and neck
Authors: Hsu Eric J. , Parsons David , Chiu Tsuicheng , Godley Andrew R. , Sher David J. , Vo Dat T.
Published: July 2022

Background

Malignancies of the head and neck region, encompassing cutaneous, mucosal, and sarcomatous histologies, are complex entities to manage, comprising of coordination between surgery, radiation therapy, and systemic therapy. Malignancies of the posterior scalp are particular challenging to treat with radiation therapy, given its irregular contours and anatomy as well as the superficial location of the target volume. Bolus material is commonly used in radiation therapy to ensure that the dose to the skin and subcutaneous tissue is appropriate and adequate, accounting for the buildup effect of megavoltage photon treatment. The use of commercially available bolus material on the posterior scalp potentially creates air gaps between the bolus and posterior scalp.

Case presentations

In this report, we created and utilized a custom 3D-printed integrated bolus and headrest for 5 patients to irradiate malignancies involving the posterior scalp, including those with cutaneous squamous cell carcinoma, melanoma, malignant peripheral nerve sheath tumor, and dermal sarcoma. Treatment setup was consistently reproducible, and patients tolerated treatment well without any unexpected adverse effects.

Conclusions

We found that the use of this custom 3D-printed integrated bolus/headrest allowed for comfortable, consistent, and reproducible treatment set up while minimizing the risk of creating significant air gaps and should be considered in the radiotherapeutic management of patients with posterior scalp malignancies.