bluuebunny/crossref_metadata_2025 huggingface dataset:
Formin-like protein 2 promotes cell proliferation by a p27-related mechanism in human breast cancer cells
Authors: Jiao Xinyan , Wang Bo , Feng Chen , Song Shaoran , Tian Bixia , Zhou Can , Gao Xiaoqian , Sun Wei , Liu Peijun
Published: June 2021

Background

Breast cancer is the leading cause of cancer-related deaths in females worldwide. Formin-like protein 2 (FMNL2) is a member of formin family that governs cytokinesis, cell polarity, morphogenesis and cell division. To our knowledge, the function of FMNL2 in breast cancer proliferation still remains uncovered.

Methods

Tumor immune estimation resource (TIMER) analysis was used to detect the correlation between FMNL2 and Ki67 in breast cancer tissues. Quantitative real-time transcription polymerase chain reaction (qRT-PCR) and western blotting were performed to analyze the expression in human breast cancer cells. Moreover, RNA interference (RNAi) and plasmids were performed to silence and overexpress FMNL2 and p27. The CCK8, MTT, cell counting, colony formation, and 5-ethynyl-2-deoxyuridine (EdU) incorporation assays were used to detect cell proliferation, respectively. Flow cytometry analysis was used to detect cell cycle distribution. Further, the distribution of p27 was examined using immunofluorescence.

Results

We found that FMNL2 expression was positively associated with Ki67 among collected breast cancer tissues and in TCGA database. Compared to lower proliferative cells MCF7 and T47D, FMNL2 was overexpressed in highly proliferative breast cancer cells MDA-MB-231, BT549 and SUM159, accompanied by reduced levels of p27 and p21, and elevated CyclinD1 and Ki67 expression. FMNL2 silencing significantly inhibited the cell proliferation of MDA-MB-231 and BT549 cells. Meanwhile, FMNL2 overexpression distinctly promoted the cell proliferation of MCF7 cells. Furthermore, FMNL2 suppressed the nuclear levels of p27 and promoted p27 proteasomal degradation in human breast cancer cells. The ubiquitination of p27 was inhibited by FMNL2 silencing in BT549 cells. Besides, p27 silencing markedly elevated Ki67 expression and cell viability, which could be blocked by additionally FMNL2 silencing in MDA-MB-231 and BT549 cells. Furthermore, overexpression of p27WT significantly reversed the increased levels of FMNL2 and Ki67, cell viability and cell cycle progression induced by FMNL2 overexpression in MCF7 cells. More importantly, compared to p27WT group, those effects could be significantly reversed by p27△NLS overexpression.

Conclusions

These results demonstrated that FMNL2 promoted cell proliferation partially by reducing p27 nuclear localization and p27 protein stability in human breast cancer cells, suggesting the pivotal role of FMNL2 in breast cancer progression.
Report of two siblings with spondylodysplastic Ehlers-Danlos syndrome and B4GALT7 deficiency
Authors: Lorenz Delia , Kress Wolfram , Zaum Ann-Kathrin , Speer Christian P. , Hebestreit Helge
Published: June 2021

Background

The spondylodysplastic Ehlers-Danlos subtype (OMIM #130070) is a rare connective tissue disorder characterized by a combination of connective tissue symptoms, skeletal features and short stature. It is caused by variants in genes encoding for enzymes involved in the proteoglycan biosynthesis or for a zinc transporter.

Presentation of cases

We report two brothers with a similar phenotype of short stature, joint hypermobility, distinct craniofacial features, developmental delay and severe hypermetropia indicative for a spondylodysplastic Ehlers-Danlos subtype. One also suffered from a recurrent pneumothorax. Gene panel analysis identified two compound heterozygous variants in the B4GALT7 gene: c.641G > A and c.723 + 4A > G. B4GALT7 encodes for galactosyltransferase I, which is required for the initiation of glycosaminoglycan side chain synthesis of proteoglycans.

Conclusions

This is a first full report on two cases with spondylodysplastic Ehlers-Danlos syndrome and the c.723 + 4A > G variant of B4GALT7. The recurrent pneumothoraces observed in one case expand the variable phenotype of the syndrome.
Low intensity technology-delivered cognitive behavioral therapy for obsessive-compulsive disorder: a meta-analysis
Authors: Hoppen Laura Marie , Kuck Nora , Bürkner Paul-Christian , Karin Eyal , Wootton Bethany M. , Buhlmann Ulrike
Published: June 2021

Background

Cognitive behavioral therapy (CBT) is a well-established treatment for people suffering from obsessive-compulsive disorder (OCD) and technology-based CBT applications are an emerging treatment option for people with OCD. These applications involve treatment protocols with automated content delivery and relatively low clinical contact. Whilst such CBT applications are promising, however, further investigation is needed to establish the efficacy of this treatment approach for individuals with OCD. The aim of the present study was to review the efficacy of technology-delivered CBT with minimal clinician support for OCD using a meta-analytic approach.

Methods

Randomized controlled trials (RCT) were identified through PsycINFO, Medline and Scopus resulting in 18 eligible studies (n = 1707). Control conditions comprised both passive (namely no treatment, other treatments and waitlist controls) and active. Measurement of OCD symptoms improvement was the outcome in each study.

Results

Participants in the technology-delivered CBT group scored lower on Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) (g = − 0.59, 95% CI = [− 0.99, − 0.18], p = 0.01), Y-BOCS and Dimensional Obsessive-Compulsive Scale (DOCS) combined (g = − 0.55, 95% CI = [− 0.87, − 0.24], p = 0.003) and Obsessive-Compulsive-Inventory-Revised (OCI-R) (g = − 0.36, 95% CI = [− 0.62, − 0.09], p = 0.02) at post-treatment than passive control groups. There were no significant findings when compared to controls with other treatments.

Conclusions

This meta-analysis suggests that technology-delivered CBT with low personal contact intensity, relative to passive control groups, is an efficacious and promising treatment option for individuals with OCD. Further research is needed to allow for a comparison with control groups with other treatments.
A tale of two parts of Switzerland: regional differences in the impact of the COVID-19 pandemic on parents
Authors: Seiler Michelle , Staubli Georg , Hoeffe Julia , Gualco Gianluca , Manzano Sergio , Goldman Ran D.
Published: June 2021

Background

We aimed to document the impact of the coronavirus disease 2019 (COVID-19) pandemic on regions within a European country.

Methods

Parents arriving at two pediatric emergency departments (EDs) in North of Switzerland and two in South of Switzerland completed an online survey during the first peak of the pandemic (April–June 2020). They were asked to rate their concern about their children or themselves having COVID-19.

Results

A total of 662 respondents completed the survey. Parents in the South were significantly more exposed to someone tested positive for COVID-19 than in the North (13.9 and 4.7%, respectively;P <  0.001). Parents in the South were much more concerned than in the North that they (mean 4.61 and 3.32, respectively;P <  0.001) or their child (mean 4.79 and 3.17, respectively;P <  0.001) had COVID-19. Parents reported their children wore facemasks significantly more often in the South than in the North (71.5 and 23.5%, respectively;P <  0.001).

Conclusion

The COVID-19 pandemic resulted in significant regional differences among families arriving at EDs in Switzerland. Public health agencies should consider regional strategies, rather than country-wide guidelines, in future pandemics and for vaccination against COVID-19 for children.
Determinants of the quality of life amongst HIV clinic attendees in Malang, Indonesia
Authors: Wardojo Sri Sunaringsih Ika , Huang Ya-Li , Chuang Kun-Yang
Published: June 2021

Background

As the number of people living with human immunodeficiency virus (HIV; PLHIV) in Indonesia has increased in recent years, more efforts have been expended to improve their health status. However, in a country where PLHIV are very much stigmatized, there has been little research concerning their quality of life (QoL). Hence, this study aimed to assess the QoL among PLHIV and its associated factors. Findings of this research can contribute to improving the health and wellbeing of PLHIV in Indonesia.

Methods

A cross-sectional survey with convenience sampling was conducted from June to September 2018, at four healthcare centers in Malang, Indonesia. PLHIV, aged 18 years or over, were asked if they would like to participate in this study when they came to a health center to receive services. To protect confidentiality, the healthcare staff at the clinics assisted with recruitment and face-to-face interviews with structured questionnaires. Measurements included sociodemographic, medication-related, social support, HIV-stigma, and QoL variables.

Results

In total, 634 PLHIV agreed to participate in this study. A multivariate linear regression analysis showed that being older, having a job, living in an urban area, having better access to healthcare services, adhering to medication, being in an antiretroviral therapy (ART) program for more than 1 year, experiencing a lower level of stigma, and receiving more social support were associated with a better QoL. The regression model had an adjusted R2 of 0.21.

Conclusions

Findings from this research have significant policy implications. Policies focused on reducing social stigma and promoting medication adherence will likely have a positive impact on the QoL of PLHIV. Increasing public awareness and acceptance of PLHIV in Indonesia remains challenging, but would likely have significant impacts. Furthermore, interventions should also focus on reducing disparities in QoL between PLHIV living in rural areas and those in urban areas.
Health disparities of critically ill children according to poverty: the Korean population-based retrospective cohort study
Authors: Park Esther , Park Hyejeong , Kang Danbee , Chung Chi Ryang , Yang Jeong Hoon , Jeon Kyeongman , Guallar Eliseo , Cho Juhee , Suh Gee Young , Cho Joongbum
Published: June 2021

Background

There is a lack of nationwide studies on critically ill patients’ health disparity under the National Health Insurance (NHI) system. We evaluated health disparities in intensive care unit (ICU) admission, outcomes, and readmission in impoverished children.

Methods

We conducted a retrospective cohort study using a national database from the Korean NHI and Medical Aid Program (MAP). MAP supports the population whose household income is lower than 40% of the median Korean household income. We defined poverty as being a MAP beneficiary and compared the poverty and non-poverty groups. Patients between 28 days and 18 years old who were admitted to the ICU were included. Hospital mortality and readmission were analyzed with adjustment for patient characteristics, hospital type, and management procedures.

Results

Out of 17,893 patients, 1153 (6.4%) patients were in poverty. The age-standardized ICU admission rate was higher in the poverty group (126.9 vs. 80.2 per 100,000 person-years). There was more age-standardized mortality in the poverty group (11.8 vs. 4.3 per 100,000 person-years). Patients in the poverty group did not have a statistically different risk of adjusted in-hospital mortality to those in the non-poverty group (odds ratio: 1.15, confidence interval [CI]: 0.84–1.55) but had a higher readmission rate (hazard ratio 1.25, CI 1.09–1.42).

Conclusion

Under the NHI system, the disparity in pediatric critical care outcomes according to poverty is not definite, but the healthcare disparity in pre- and post-hospital care is a concern. Further studies are required to improve pre- and post-hospital healthcare quality of impoverished children.
Perspectives of education sector stakeholders on a teacher training module to reduce HIV/AIDS stigma in Western Kenya
Authors: Chory Ashley , Nyandiko Winstone , Beigon Whitney , Aluoch Josephine , Ashimosi Celestine , Munyoro Dennis , Scanlon Michael , Apondi Edith , Vreeman Rachel
Published: June 2021

Background

For adolescents living with HIV (ALWH), school may be the most important but understudied social sphere related to HIV stigma. Teachers are role models in the classroom and within the community, and their attitudes and behavior towards people living with HIV may have critical psychosocial and treatment ramifications. Altering teachers’ knowledge, attitudes and beliefs (K/A/B) about HIV could reduce the stigmatizing content within their teaching, classrooms and school, improving the environment for ALWH.

Methods

We developed a one-day teacher training module to enrich teacher K/A/B that included lecture presentations, HIV films and educational animation, structured instructions for teacher role play scenarios, and a question-and-answer session facilitated by a trained ALWH peer educator. We also conducted key informant interviews with education sector subject matter experts (SMEs), including education officers, county commissioners and head teachers to review and provide feedback on the teacher training module.

Results

We assembled an adolescent community advisory board and recruited 50 SMEs to review the training module and provide feedback. All SME participants stressed the importance and need for interventions to reduce stigma in the classroom, highlighting their own experiences observing stigmatizing behaviors in the community. The participants perceived the training as culturally relevant and easy to understand and had minor suggestions for improvement, including using image-based resources and brighter colors for ease of reading. All participants thought that the training should be expanded outside of the schools, as all people in a community have a role in the reduction of HIV stigma, and offered suggestions for other settings for implementation.

Conclusion

Data from interviews with education sector stakeholders demonstrate that our process for developing a culturally appropriate multi-media intervention to reduce HIV stigma in the schools was feasible.
Association of stress management skills and stressful life events with allergy risk: a case-control study in southern China
Authors: Cheng Jingru , Li Fei , Lai Yigui , Chen Jieyu , Sun Xiaomin , Xiang Lei , Jiang Pingping , Wu Shengwei , Xiao Ya , Zhou Lin , Luo Ren , Zhao Xiaoshan , Liu Yanyan
Published: June 2021

Background

Psychosocial stress and stressful life events are known to aggravate allergic diseases. Less is known about the impact of stress management skills on allergies. Here we sought to determine whether stress management skills are associated with the allergies and to assess the combined effects of stress management skills and stressful events on allergy risk.

Methods

A survey on risk factors for self-reported allergic diseases was carried out among 28,144 southern Chinese people; 14 stressful life events and 8 stress management skills were retrospectively recorded in a case-control setting with multivariate logistic regression analysis. Multiplicative and additive interactions between stressful events and stress management skills were evaluated.

Results

Stressful events significantly increased allergy risk. The odds ratio (OR) for allergies was 1.65 (95% confidence interval CI, 1.41–1.93) for those reporting one or two stressful events and 3.10 (95% CI, 2.55–3.79) for those reporting more than three stressful events compared to participants without stressful events. Stress management skills were adversely associated with allergic risk for people experiencing stressful events (OR, 0.71; 95% CI, 0.53–0.97) when adjusted demographically, particularly “concentrate on pleasant thoughts at bedtime” (OR, 0.67; 95% CI, 0.51–0.89), “pace myself to prevent tiredness” (OR, 0.67; 95% CI, 0.54–0.83), “get enough sleep” (OR, 0.48; 95% CI, 0.32–0.72) and “take some time for relaxation each day” (OR, 0.55; 95% CI, 0.37–0.80). But in people without stressful events, no association was observed. There was a significant linear trend for allergy risk from good stress management skills with no stressful events to poor stress management skills with stressful events (P < 0.001), with significant interaction in additive models (P = 0.006).

Conclusions

There are independent and antagonistic combined associations of stressful life events and stress management skills with allergy risk. The data supports the use of stress management skills in managing allergic disease among people with stressful life events.
Spatial clustering and genetic diversity of Mycobacterium tuberculosis isolate among pulmonary tuberculosis suspected patients, Arsi Zone, Ethiopia
Authors: Tafess Ketema , Beyen Teresa Kisi , Girma Sisay , Girma Asnakech , Siu Gilman
Published: June 2021

Background

Tuberculosis remains a serious public health concern globally. The enormous social, economic, and health impacts of the diseases are attributed to the lack of updated data on the prevalence, geospatial distribution, population structures, and genotypic variants of the circulating M. tuberculosis.

Methods

Structured questionnaire, mycobacterial culture, and standard 24-Mycobacterial Interspersed Repeated Units-Variable Number Tandem Repeats (MIRU-VNTR) were employed to collect sociodemographic characters, residence linked information, and genotype the isolates. The retrospective discrete Bernoulli model was used to identify the hot spot districts of sputum smear positivity, and Web-based Miru-VNTRPlus were used for the identification of lineages and sublineages.

Results

Out of 832 presumptive pulmonary tuberculosis (PTB) suspects, 119 (14.3%) were smear-positive. In the multivariate binary logistic model, PTB suspected patients in the age groups of 7–25 and 25–34 and those from rural residents were 4.53 (AOR = 4.53; 95% CI 2.25–9.13), 3.00 (AOR = 3.00; 95% CI 1.41–6.35) and 1.65 (AOR = 1.65; 95% CI 1.01–2.70) times at higher risk of turning smear-positive. Eleven (47.8%) districts of Arsi Zone were shown to have a high rate of clustering (RR = 2.27; 95% CI 1.62–3.2) of smear-positive PTB. Of 72 isolates queried for the lineage assignment, 59 (81.9%) were classified into the previously known lineages and 13 (18.1%) were not assigned to any known lineages. Overall, 42 (58.3%) belong to M. tuberculosis lineage 4 (Euro-American), 16 (22.2%) M. tuberculosis lineage 3 (Delhi/CAS), and 1 (1.4%) M. tuberculosis Lineage 1 (Indo-Oceanic/ East Africa Indian). Further classification to the sublineage indicates that the predominant lineage was Delhi/CAS comprising 16 (22.2%) isolates followed by 15 (20.8%) isolates belonging to Haarlem. The remaining isolates were distributed as 13 (18.1%) TUR, 6 (8.3%) LAM, 4 (5.5%) URAL, 4 (4.5%) NEW-1 and 1 (1.4%) EAI.

Conclusion

Our study showed higher smear-positive results among PTB suspected patients and remarkable spatial variation across districts of Arsi Zone in smear-positive PTB. This information together with the genotypic features could be used as input for the efforts of designing control strategies.
Mortality rate in rheumatoid arthritis-related interstitial lung disease: the role of radiographic patterns
Authors: Nieto Maria A. , Rodriguez-Nieto Maria J. , Sanchez-Pernaute Olga , Romero-Bueno Fredeswinda , Leon Leticia , Vadillo Cristina , Freites-Nuñez Dalifer D. , Jover Juan A. , Álvarez-Sala Jose L. , Abasolo Lydia
Published: June 2021

Background

To assess mortality rate (MR) and standardized mortality rate (SMR) of rheumatoid arthritis-related interstitial lung disease (RA-ILD) patients and to evaluate the role of radiographic patterns in mortality.

Methods

A longitudinal multicentric study was conducted in RA-ILD patients from 2005 to 2015 and followed-up until October 2018 in Madrid. Patients were included in the Neumologia-Reumatología y Enfermedades Autoinmunes Registry, from diagnosis of ILD. The main outcome was all-cause mortality. The radiographic pattern at baseline [usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), or others] was the independent variable. Covariables included sociodemographic and clinical data. Survival techniques were used to estimate MR, expressed per 1000 persons-year with their 95% confidence intervals [CI]. Cox multiple regression model was run to examine the influence of radiographic patterns on survival. SMR [CI] was calculated comparing MR obtained with MR expected in the general population of Madrid by indirect age-gender standardization.

Results

47 patients were included with a follow-up 242 patients-year. There were 16 (34%) deaths, and most frequent causes were acute ILD exacerbation and pneumonia. MR was 64.3 [39.4–104.9], and 50% of the patients died at 8.3 years from ILD diagnosis. After adjusting for confounders, (UIP compared to NSIP was associated with higher mortality risk. The overall SMR was 2.57 [1.4–4.17]. Women of 60–75 years of age were the group with the highest SMR.

Conclusions

RA-ILD is associated with an excess of mortality compared to general population. Our results support that UIP increases the risk of mortality in RA-ILD, regardless other factors.
Anti-TIF1 gamma-positive IPAF patient developed stage IVB lung squamous carcinoma in 1 year: a case report
Authors: Xie Jiao-jiao , Li Bin , Xu Rui , Du Xian-zhi , He Jin-zhi
Published: June 2021

Background

Patients with connective tissue disease, such as dermatomyositis (DM), and positive anti-TIF1γ self-antibodies are commonly diagnosed with malignant tumors as a comorbidity. The relationship between anti-TIF1γ self-antibodies and existing malignant tumors has been confirmed by several reports. However, interstitial pneumonia with autoimmune features (IPAF) cases with a positive anti-TIF1γ self-antibody developing to solid malignant tumors are rarely reported now.

Case presentation

Herein, we presented an IPAF patient with anti-TIF1γ self-antibodies. No evidence of malignant tumors was found at the initial visit. However, the patient had developed stage IVB lung squamous cell carcinoma at the 1-year follow-up review.

Conclusions

Altogether, this report described a rare case of IPAF patient with anti-TIF1γ self-antibodies developed to advanced lung squamous cell carcinoma in 1 year. The present case highlights more frequent imaging examinations to identify the occurrence of malignant tumors as early as possible in IPAF patients with positive anti-TIF1γ self-antibodies.
Identification of potential hub genes associated with skin wound healing based on time course bioinformatic analyses
Authors: Zhu Hai-jun , Fan Meng , Gao Wei
Published: June 2021

Background

The skin is the largest organ of the body and has multiple functions. Wounds remain a significant healthcare problem due to the large number of traumatic and pathophysiological conditions patients suffer.

Methods

Gene expression profiles of 37 biopsies collected from patients undergoing split-thickness skin grafts at five different time points were downloaded from two datasets (GSE28914 and GSE50425) in the Gene Expression Omnibus (GEO) database. Principal component analysis (PCA) was applied to classify samples into different phases. Subsequently, differentially expressed genes (DEGs) analysis, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway functional enrichment analyses were performed, and protein–protein interaction (PPI) networks created for each phase. Furthermore, based on the results of the PPI, hub genes in each phase were identified by molecular complex detection combined with the ClueGO algorithm.

Results

Using principal component analysis, the collected samples were divided into four phases, namely intact phase, acute wound phase, inflammatory and proliferation phase, and remodeling phase. Intact samples were used as control group. In the acute wound phase, a total of 1 upregulated and 100 downregulated DEGs were identified. Tyrosinase (TYR), tyrosinase Related Protein 1 (TYRP1) and dopachrome tautomerase (DCT) were considered as hub genes and enriched in tyrosine metabolism which dominate the process of melanogenesis. In the inflammatory and proliferation phase, a total of 85 upregulated and 164 downregulated DEGs were identified. CHEK1, CCNB1 and CDK1 were considered as hub genes and enriched in cell cycle and P53 signaling pathway. In the remodeling phase, a total of 121 upregulated and 49 downregulated DEGs were identified. COL4A1, COL4A2, and COL6A1 were considered as hub genes and enriched in protein digestion and absorption, and ECM-receptor interaction.

Conclusion

This comprehensive bioinformatic re-analysis of GEO data provides new insights into the molecular pathogenesis of wound healing and the potential identification of therapeutic targets for the treatment of wounds.
Documentation of ethically relevant information in out-of-hospital resuscitation is rare: a Danish nationwide observational study of 16,495 out-of-hospital cardiac arrests
Authors: Milling Louise , Binderup Lars Grassmé , de Muckadell Caroline Schaffalitzky , Christensen Erika Frischknecht , Lassen Annmarie , Christensen Helle Collatz , Nielsen Dorthe Susanne , Mikkelsen Søren ,   The Danish Cardiac Arrest Registry Group, Bergmann René Arne , Blomberg Stig Nikolaj Fasmer , Borup Lars , Holgersen Mathias Geldermann , Jensen Theo Walther , Kjærgaard-Andersen Gunhild , Kjerulff Julie Linding Bogh , Larsen Heinrich Dedenroth , Lübcke Kenneth , Ringgren Kristian Bundgaard
Published: June 2021

Background

Decision-making in out-of-hospital cardiac arrest should ideally include clinical and ethical factors. Little is known about the extent of ethical considerations and their influence on prehospital resuscitation. We aimed to determine the transparency in medical records regarding decision-making in prehospital resuscitation with a specific focus on ethically relevant information and consideration in resuscitation providers’ documentation.

Methods

This was a Danish nationwide retrospective observational study of out-of-hospital cardiac arrests from 2016 through 2018. After an initial screening using broadly defined inclusion criteria, two experienced philosophers performed a qualitative content analysis of the included medical records according to a preliminary codebook. We identified ethically relevant content in free-text fields and categorised the information according to Beauchamp and Childress’ four basic bioethical principles: autonomy, non-maleficence, beneficence, and justice.

Results

Of 16,495 medical records, we identified 759 (4.6%) with potentially relevant information; 710 records (4.3%) contained ethically relevant information, whereas 49 did not. In general, the documentation was vague and unclear. We identified four kinds of ethically relevant information: patients’ wishes and perspectives on life; relatives’ wishes and perspectives on patients’ life; healthcare professionals’ opinions and perspectives on resuscitation; and do-not-resuscitate orders. We identified some “best practice” examples that included all perspectives of decision-making.

Conclusions

There is sparse and unclear evidence on ethically relevant information in the medical records documenting resuscitation after out-of-hospital cardiac arrests. However, the “best practice” examples show that providing sufficient documentation of decision-making is, in fact, feasible. To ensure transparency surrounding prehospital decisions in cardiac arrests, we believe that it is necessary to ensure more systematic documentation of decision-making in prehospital resuscitation.
Electronic health record–integrated approach for collection of patient-reported outcome measures: a retrospective evaluation
Authors: Horn Maggie E. , Reinke Emily K. , Mather Richard C. , O’Donnell Jonathan D. , George Steven Z.
Published: June 2021

Background

The integration of Patient Reported Outcome Measures (PROMs) into clinical care presents many challenges for health systems. PROMs provide quantitative data regarding patient-reported health status. However, the most effective model for collecting PROMs has not been established. Therefore the purpose of this study is to report the development and preliminary evaluation of the standardized collection of PROMs within a department of orthopedic surgery at a large academic health center.

Methods

We utilized the Users’ Guide to Integrating Patient-Reported Outcomes in Electronic Health Records by Gensheimer et al., 2018 as a framework to describe the development of PROMs collection initiative. We framed our initiative by operationalizing the three aspects of PROM collection development: Planning, Selection, and Engagement. Next, we performed a preliminary evaluation of our initiative by assessing the response rate of patients completing PROMs (no. of PROMs completed/no. of PROMs administered) across the entire department (18 clinics), ambulatory clinics only (14 clinics), and hospital-based clinics only (4 clinics). Lastly, we reported on the mean response rates for the top 5 and bottom 5 orthopaedic providers to describe the variability across providers.

Results

We described the development of a fully-integrated, population health based implementation strategy leveraging the existing resources of our local EHR to maximize clinical utility of PROMs and routine collection. We collected a large volume of PROMs over a 13 month period (n = 10,951) across 18 clinical sites, 7 clinical specialties and over 100 providers. The response rates varied across the department, ranging from 29 to 42%, depending on active status for the portal to the electronic health record (MyChart). The highest single provider mean response rate was 52%, and the lowest provider rate was 13%. Rates were similar between hospital-based (26%) and ambulatory clinics (29%).

Conclusions

We found that our standardized PROMs collection initiative, informed by Gensheimer et al., achieved scope and scale, but faced challenges in achieving a high response rate commensurate with existing literature. However, most studies reported a targeted recruitment strategy within a narrow clinical population. Further research is needed to elucidate the trade-off between scalability and response rates in PROM collection initiatives.
Integration of enzyme constraints in a genome-scale metabolic model of Aspergillus niger improves phenotype predictions
Authors: Zhou Jingru , Zhuang Yingping , Xia Jianye
Published: June 2021

Background

Genome-scale metabolic model (GSMM) is a powerful tool for the study of cellular metabolic characteristics. With the development of multi-omics measurement techniques in recent years, new methods that integrating multi-omics data into the GSMM show promising effects on the predicted results. It does not only improve the accuracy of phenotype prediction but also enhances the reliability of the model for simulating complex biochemical phenomena, which can promote theoretical breakthroughs for specific gene target identification or better understanding the cell metabolism on the system level.

Results

Based on the basic GSMM model iHL1210 of Aspergillus niger, we integrated large-scale enzyme kinetics and proteomics data to establish a GSMM based on enzyme constraints, termed a GEM with Enzymatic Constraints using Kinetic and Omics data (GECKO). The results show that enzyme constraints effectively improve the model’s phenotype prediction ability, and extended the model’s potential to guide target gene identification through predicting metabolic phenotype changes of A. niger by simulating gene knockout. In addition, enzyme constraints significantly reduced the solution space of the model, i.e., flux variability over 40.10% metabolic reactions were significantly reduced. The new model showed also versatility in other aspects, like estimating large-scale $$k_{{cat}}$$

k

cat

values, predicting the differential expression of enzymes under different growth conditions.

Conclusions

This study shows that incorporating enzymes’ abundance information into GSMM is very effective for improving model performance with A. niger. Enzyme-constrained model can be used as a powerful tool for predicting the metabolic phenotype of A. niger by incorporating proteome data. In the foreseeable future, with the fast development of measurement techniques, and more precise and rich proteomics quantitative data being obtained for A. niger, the enzyme-constrained GSMM model will show greater application space on the system level.
Customized yeast cell factories for biopharmaceuticals: from cell engineering to process scale up
Authors: Madhavan Aravind , Arun K. B. , Sindhu Raveendran , Krishnamoorthy Jayaram , Reshmy R. , Sirohi Ranjna , Pugazhendi Arivalagan , Awasthi Mukesh Kumar , Szakacs George , Binod Parameswaran
Published: June 2021

The manufacture of recombinant therapeutics is a fastest-developing section of therapeutic pharmaceuticals and presently plays a significant role in disease management. Yeasts are established eukaryotic host for heterologous protein production and offer distinctive benefits in synthesising pharmaceutical recombinants. Yeasts are proficient of vigorous growth on inexpensive media, easy for gene manipulations, and are capable of adding post translational changes of eukaryotes. Saccharomyces cerevisiae is model yeast that has been applied as a main host for the manufacture of pharmaceuticals and is the major tool box for genetic studies; nevertheless, numerous other yeasts comprising Pichia pastoris, Kluyveromyces lactis, Hansenula polymorpha, and Yarrowia lipolytica have attained huge attention as non-conventional partners intended for the industrial manufacture of heterologous proteins. Here we review the advances in yeast gene manipulation tools and techniques for heterologous pharmaceutical protein synthesis. Application of secretory pathway engineering, glycosylation engineering strategies and fermentation scale-up strategies in customizing yeast cells for the synthesis of therapeutic proteins has been meticulously described.
The underlying molecular mechanisms and prognostic factors of RNA binding protein in colorectal cancer: a study based on multiple online databases
Authors: He Qinglian , Li Ziqi , Lei Xue , Zou Qian , Yu Haibing , Ding Yuanlin , Xu Guangxian , Zhu Wei
Published: June 2021

Background

RNA binding protein (RBP) is an active factor involved in the occurrence and development of colorectal cancer (CRC). Therefore, the potential mechanism of RBP in CRC needs to be clarified by dry-lab analyses or wet-lab experiments.

Methods

The differential RBP gene obtained from the GEPIA 2 (Gene Expression Profiling Interactive Analysis 2) were performed functional enrichment analysis. Then, the alternative splicing (AS) events related to survival were acquired by univariate regression analysis, and the correlation between RBP and AS was analyzed by R software. The online databases were conducted to analyze the mutation and methylation of RBPs in CRC. Moreover, 5 key RBP signatures were obtained through univariate and multivariate Cox regression analysis and established as RBP prognosis model. Subsequently, the above model was verified through another randomized group of TCGA CRC cohorts. Finally, multiple online databases and qRT-PCR analysis were carried to further confirm the expression of the above 5 RBP signatures in CRC.

Results

Through a comprehensive bioinformatics analysis, it was revealed that RBPs had genetic and epigenetic changes in CRC. We obtained 300 differentially expressed RBPs in CRC samples. The functional analysis suggested that they mainly participated in spliceosome. Then, a regulatory network for RBP was established to participate in AS and DDX39B was detected to act as a potentially essential factor in the regulation of AS in CRC. Our analysis discovered that 11 differentially expressed RBPs with a mutation frequency higher than 5%. Furthermore, we found that 10 differentially expressed RBPs had methylation sites related to the prognosis of CRC, and a prognostic model was constructed by the 5 RBP signatures. In another randomized group of TCGA CRC cohorts, the prognostic performance of the 5 RBP signatures was verified.

Conclusion

The potential mechanisms that regulate the aberrant expression of RBPs in the development of CRC was explored, a network that regulated AS was established, and the RBP-related prognosis model was constructed and verified, which could improve the individualized prognosis prediction of CRC.
Epigenetic roles of PIWI proteins and piRNAs in colorectal cancer
Authors: Sadoughi Fatemeh , Mirhashemi Seyyed Mehdi , Asemi Zatollah
Published: June 2021

Small non‐coding RNAs (sncRNAs) are a subgroup of non‐coding RNAs, with less than 200 nucleotides length and no potential for coding proteins. PiRNAs, a member of sncRNAs, were first discovered more than a decade ago and have attracted researcher’s attention because of their gene regulatory function both in the nucleus and in the cytoplasm. Recent investigations have found that the abnormal expression of these sncRNAs is involved in many human diseases, including cancers. Colorectal cancer (CRC), as a common gastrointestinal malignancy, is one of the important causes of cancer‐related deaths through the entire world and appears to be a consequence of mutation in the genome and epigenetic alterations. The aim of this review is to realize whether there is a relationship between CRC and piRNAs or not.
Serum EA-IgA and d-dimer, but not VCA-IgA, are associated with prognosis in patients with nasopharyngeal carcinoma: a meta-analysis
Authors: Liang Tianhao , Liu Weixing , Xie Junyang , Wang Yiyan , Chen Gui , Liao Wenjing , Song Lijuan , Zhang Xiaowen
Published: June 2021

Background

Patients with nasopharyngeal cancer (NPC) differ in prognosis, even at the same stage; therefore, new biomarkers are urgently required to identify early-stage NPC patients at high risk of poor prognosis. Although Epstein–Barr virus (EBV) DNA has been used for prognosis, the value of many other biomarkers expressed during the infection cycle of EBV remains unclarified. This study aimed to evaluate the prognostic potential of EA-IgA, VCA-IgA and d-dimer in patients with NPC.

Methods

Electronic databases, including PubMed, Embase and Web of Science, were searched up to February 1, 2021. Pooled data were extracted from studies that evaluated the relationship between NPC and overall survival (OS), distant metastasis-free survival (DMFS) or disease-free survival (DFS) and then were subjected to a meta-analysis.

Results

Nine studies with 5729 patients were included in this meta-analysis. In patients with NPC, EA-IgA levels significantly predicted OS (HR = 1.63, 95% CI 1.07–2.48). d-Dimer levels significantly predicted OS (HR = 1.75, 95% CI 1.24–2.47) and DMFS (HR = 1.91, 95% CI 1.31–2.79). However, high levels of VCA-IgA were not associated with OS (HR = 1.24, 95% CI 0.95–1.60), DMFS (HR = 1.41, 95% CI 0.92–2.17) or DFS (HR = 2.39, 95% CI 0.78–7.26).

Conclusions

The present findings reveal that EA-IgA and d-dimer, but not VCA-IgA, can be used as prognostic biomarkers in NPC.
An image fusion system for corrective osteotomy of distal radius malunion
Authors: Yoshii Yuichi , Ogawa Takeshi , Hara Yuki , Totoki Yasukazu , Ishii Tomoo
Published: June 2021

Background

To provide surgical support for corrective osteotomy, we developed an image fusion system for three-dimensional (3D) preoperative planning and fluoroscopy. To assess the utility of this image fusion system, we evaluated the reproducibility of preoperative planning for corrective osteotomy of dorsally angulated distal radius malunion using the system and compared reproducibility without using the system.

Methods

Ten wrists from 10 distal radius malunion patients who underwent corrective osteotomy were evaluated. 3D preoperative planning and the image fusion system were used for the image fusion group (n = 5). Only 3D preoperative planning was used for the control group (n = 5). 3D preoperative planning was performed for both groups in order to assess reduction, placement, and the choice of implants. In the image fusion group, the outline of the planned image was displayed on a monitor and overlapped with fluoroscopy images during surgery. Reproducibility was evaluated using preoperative plan and postoperative 3D images. Images were compared with the 3D coordinates of the radial styloid process (1), the volar and dorsal edges of the sigmoid notch (2) (3), and the barycentric coordinates of the three reference points. The reproducibility of the preoperative plan was evaluated by the distance of the coordinates between the plan and postoperative images for the reference points.

Results

The distances between preoperative planning and postoperative reduction in the image fusion group were 2.1 ± 1.1 mm, 1.8 ± 0.7 mm, 1.9 ± 0.9 mm, and 1.4 ± 0.7 mm for reference points (1), (2), (3), and the barycenter, respectively. The distances between preoperative planning and postoperative reduction in the control group were 3.7 ± 1.0 mm, 2.8 ± 2.0 mm, 1.7 ± 0.8 mm, and 1.8 ± 1.2 mm for reference points (1), (2), (3), and the barycenter, respectively. The difference in reference point (1) was significantly smaller in the image fusion group than in the control group (P < 0.05).

Conclusion

Corrective osteotomy using an image fusion system will become a new surgical support method for fracture malunion.

Trial registration Registered as NCT03764501 at ClinicalTrials.gov.
Evaluation of prenatal changes in fetal cardiac morphology and function in maternal diabetes mellitus using a novel fetal speckle-tracking analysis: a prospective cohort study
Authors: Wang Dong , Liu Caixia , Liu Xinyu , Zhang Ying , Wang Yu
Published: June 2021

Background

Due to metabolic changes in the second trimester and the increasing number of pregnant women with obesity and advanced maternal age, the incidence of gestational diabetes mellitus (GDM) remains high. This study aimed to evaluate the effects of GDM on fetal cardiac morphology and function, and to determine whether these changes increase with increasing estimated fetal weight (EFW).

Methods

Fifty-eight women with GDM (GDM group) and 58 women with a healthy pregnancy (control group) were included in this prospective observational cohort study. Each group included subgroups of 31 pregnant women with a gestational age between 24+0 weeks and 27+6 weeks as well as 27 pregnant women with a gestational age between 28+0 weeks and 40+0 weeks. For all fetuses, a cine of 2–3 s in the four-chamber view was obtained, and online speckle-tracking analysis was performed using the GE Automatic Fetal Heart Assessment Tool (fetal HQ; General Electric Healthcare Ultrasound, Zipf, Austria) to measure the global sphericity index (GSI), global longitudinal strain (GLS), fractional area change (FAC), 24-segment sphericity index (SI), and 24-segment end-diastolic diameter of the left ventricle (LV) and right ventricle (RV). Data were analyzed using the independent t-test and Wilcoxon rank-sum test, as applicable.

Results

The GDM group (mean HbA1c value was 5.3 ± 0.57 mmol/L) showed a lower GSI value than the control group (1.21 vs. 1.27, P = 0.000), which indicated a rounder shape of the heart. In addition, fetuses in the GDM group demonstrated significant impairment in cardiac function compared to those in the control group (LV-GLS: -18.26% vs. -22.70%, RV-GLS: -18.52% vs. -22.74%, LV-FAC: 35.30% vs. 42.36%, RV-FAC: 30.89% vs. 36.80%; P = 0.000 for all). Subgroup analyses according to gestational age (24+0–27+6 weeks and 28+0–40+0 weeks) showed that the statistical differences were retained between the GDM and control groups in each subgroup.

Conclusions

Fetuses of women with GDM present with signs of biventricular systolic dysfunction according to deformation analysis using fetal HQ. Additionally, the heart had a rounder shape in the GDM group than in the control group. This study showed that fetal HQ can be used to assess fetal cardiac morphology and function easily and quickly, and the effects of GDM on fetal cardiac morphology and function appeared from the second trimester. Thus, whether earlier and stricter clinical intervention was necessary remained to be further studied. Furthermore, future studies will need to supplement the effects of blood glucose levels on GLS, FAC, GSI, and 24-segment SI. Additionally, the long-term follow-up after birth should also be improved to observe the influence of changes in the indicators on the prognosis.
PIM kinases inhibit AMPK activation and promote tumorigenicity by phosphorylating LKB1
Authors: Mung Kwan Long , Eccleshall William B. , Santio Niina M. , Rivero-Müller Adolfo , Koskinen Päivi J.
Published: June 2021

Background

The oncogenic PIM kinases and the tumor-suppressive LKB1 kinase have both been implicated in the regulation of cell growth and metabolism, albeit in opposite directions. Here we investigated whether these kinases interact with each other to influence AMPK activation and tumorigenic growth of prostate and breast cancer cells.

Methods

We first determined how PIM and LKB1 kinases affect AMPK phosphorylation levels. We then used in vitro kinase assays to demonstrate that LKB1 is phosphorylated by PIM kinases, and site-directed mutagenesis to identify the PIM target sites in LKB1. The cellular functions of PIM and LKB1 kinases were evaluated using either pan-PIM inhibitors or CRISPR/Cas9 genomic editing, with which all three PIM family members and/or LKB1 were knocked out from PC3 prostate and MCF7 breast cancer cell lines. In addition to cell proliferation assays, we examined the effects of PIM and/or LKB1 loss on tumor growth using the chick embryo chorioallantoic membrane (CAM) xenograft model.

Results

We provide both genetic and pharmacological evidence to demonstrate that inhibition of PIM expression or activity increases phosphorylation of AMPK at Thr172 in both PC3 and MCF7 cells, but not in their derivatives lacking LKB1. This is explained by our observation that all three PIM family kinases can phosphorylate LKB1 at Ser334. Wild-type LKB1, but not its phosphodeficient derivative, can restore PIM inhibitor-induced AMPK phosphorylation in LKB1 knock-out cells. In the CAM model, loss of LKB1 enhances tumorigenicity of PC3 xenografts, while cells lacking both LKB1 and PIMs exhibit slower proliferation rates and form smaller tumors.

Conclusion

PIM kinases are novel negative regulators of LKB1 that affect AMPK activity in an LKB1-dependent fashion. The impairment of cell proliferation and tumor growth in cells lacking both LKB1 and PIMs indicates that these kinases possess a shared signaling role in the context of cancer. These data also suggest that PIM inhibitors may be a rational therapeutic option for LKB1-deficient tumors.