bluuebunny/crossref_metadata_2025 huggingface dataset:
Unilateral premature osteoarthritis of the hip with excessive anteversion of the femoral neck developing in the early second decade: two surgical cases
Authors: Nishimura Takahiro , Watanabe Hideaki , Taki Naoya , Onuma Saki , Kikkawa Ichiro
Published: June 2021

Background

Osteoarthritis (OA) of the hip rarely develops in the early second decade. As the incidence of this disease is low, no treatment method has been established. We report two patients with unilateral OA in their early teens in whom the anteversion angle of the femoral neck on the affected side was greater than that on the unaffected side.

Case presentation

Case 1 was an 11-year-old girl with left coxalgia and limited range of motion. There was no history of femoroacetabular impingement (FAI) or developmental dysplasia of the hip (DDH). Plain X-rays revealed the disappearance of the Y cartilage, joint space narrowing of the left hip, and acetabular/femoral head osteosclerosis. In CT images, the anteversion angle of the femoral neck (lt/rt) was 45/35 degrees. As osteoarthritis was severe, proximal femoral flexional derotational varus osteotomy (PFFDVO) and triple pelvic osteotomy (TPO) were performed.

Case 2 was a 13-year-old girl with left coxalgia and limited range of motion. There was no history of FAI or DDH. Plain X-ray revealed irregularity of the left anterolateral femoral head, and a subcartilaginous cyst. In CT images, the anteversion angle of the femoral neck (lt/rt) was 30/20 degrees. As osteoarthritis was severe, PFFDVO was performed. In addition, we resected bone spurs on the femoral head because flexion was limited owing to the presence of osteophytes. In both patients, coxalgia and claudication/gait disorder resolved postoperatively, and joint space narrowing and osteosclerosis improved. However, in Case 1, there was a 3-cm difference in the leg length, and in Case 2, range-of-motion limits remained.

Conclusions

We present the findings in two patients with unilateral OA in their early second decade in whom the femoral anteversion angle on the affected side was greater than that on the unaffected side. PFFDVO + TPO was performed in Case 1, and PFFDVO + bone spur resection on the femoral head was performed in Case 2. Coxalgia resolved, and plain X-ray demonstrated improvements in OA; however, a difference in the leg length and range-of-motion limits remained.
Insights from molecular docking and molecular dynamics on the potential of vitexin as an antagonist candidate against lipopolysaccharide (LPS) for microglial activation in neuroinflammation
Authors: Yahaya M. A. F. , Bakar A. R. Abu , Stanslas J. , Nordin N. , Zainol M. , Mehat M. Z.
Published: June 2021

Background

Neuroinflammation has been identified to be the key player in most neurodegenerative diseases. If neuroinflammation is left to be unresolved, chronic neuroinflammation will be establish. Such situation is due to the overly-activated microglia which have the tendency to secrete an abundance amount of pro-inflammatory cytokines into the neuron microenvironment. The abundance of pro-inflammatory cytokines will later cause toxic and death to neurons. Toll-like receptor 4 (TLR4)/MD-2 complex found on the cell surface of microglia is responsible for the attachment of LPS and activation of nuclear factor-κB (NF-κB) downstream signalling pathway. Albeit vitexin has been shown to possess anti-inflammatory property, however, little is known on its ability to bind at the binding site of TLR4/MD-2 complex of microglia as well as to be an antagonist for LPS.

Results

The present study reveals that both vitexin and donepezil are able to bind at the close proximity of LPS binding site located at the TLR4/MD-2 complex with the binding energy of − 4.35 and − 9.14 kcal/mol, respectively. During molecular dynamic simulations, both vitexin and donepezil formed stable complex with TLR4/MD-2 throughout the 100 ns time length with the root mean square deviation (RMSD) values of 2.5 Å and 4.0 Å, respectively. The root mean square fluctuation (RMSF) reveals that both compounds are stable. Interestingly, the radius of gyration (rGyr) for donepezil shows notable fluctuations when compare with vitexin. The MM-GBSA results showed that vitexin has higher binding energy in comparison with donepezil.

Conclusions

Taken together, the findings suggest that vitexin is able to bind at the binding site of TLR4/MD-2 complex with more stability than donepezil throughout the course of 100 ns simulation. Hence, vitexin has the potential to be an antagonist candidate for LPS.
Effect of tetracyclines on pulpal and periodontal healing after tooth replantation: a systematic review of human and animal studies
Authors: Meng Mingmei , Chen Yandi , Ren Huidi , Zhang Qiong , Chen Song , Zhou Xuedong , Zou Jing
Published: June 2021

Background

Pulpal and periodontal healing are two main concerns of delayed replantation of avulsed teeth. The objective of this review was to evaluate the effectiveness of topical and systemic application of tetracyclines on pulpal and periodontal healing after tooth replantation.

Methods

A comprehensive electronic search was conducted in six databases. This systematic review was carried out according to Cochrane Handbook and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.

Results

After exclusion of 246 irrelevant papers, 14 animal studies and one human study were included in this review. The human study showed that avulsed permanent teeth treated with doxycycline did not show a better clinical outcome for pulp and periodontal healing compared with treatment with normal saline. As for animal studies, significant more pulpal healing was observed in immature teeth treated with topical doxycycline in two researches, while another one study showed that there is no difference between teeth treated with normal saline and teeth treated with doxycycline. Systemic doxycycline exerted no significant effect on pulpal revascularization illustrated by one research. Only one out of four articles illustrated the positive effect of systemic tetracyclines on periodontal healing. One paper reported that intracanal application of demeclocycline promoted favorable periodontal healing. Two articles showed topical doxycycline contributed to favorable periodontal healing, while five studies showed no significant effect of topical tetracyclines on periodontal healing.

Conclusions

As a result of data heterogeneity and limitations of the studies, the effect of topical or systemic application of tetracyclines on pulpal and periodontal healing is inconclusive. More studies are required to get more clinically significant conclusions.
Disrupted mothering in Iranian mothers with breast cancer: a hybrid concept analysis
Authors: Mazaheri Effat , Ghahramanian Akram , Valizadeh Leila , Zamanzadeh Vahid , Onyeka Tonia C.
Published: June 2021

Background

Defining the disrupted mothering would contribute to developing strategies to support mothers with breast cancer. The aim of this study was to analyze the concept of mothering disruption using a hybrid model.

Methods

The Hybrid method for concept analysis was implemented consisting of three phases: theoretical, fieldwork, and final analysis. In the theoretical phase, the literature was searched using electronic databases including PubMed, ScienceDirect, Scopus, ProQuest, Google Scholar, CINAHL, Wiley, Ovid, Magiran, and SID from 2000 to 2020. Any quantitative or qualitative studies published in English or Persian, which were focused on mothering disruption in mothers with breast cancer were included in the study. In the phase of fieldwork, 20 mothers were interviewed to explore the aspects of mothering disruption. The interviews were transcribed and analyzed with conventional content analysis. In the final phase, an overall analysis of the two previous phases was performed.

Results

In the theoretical phase, the following attributes were determined: “disturbance in maternal identity and roles”, “maternal insensitivity and unresponsiveness: disconnection physically and psychologically”, “the career disruption process” and “biographical disruption”. The fieldwork phase explored three themes including “the unbalance between multiple roles”, “role failure”, and “reduced maternal sensitivity”. The final synthesis yielded that the main integrated elements of mothering disruption are “disease as threating maternal role and identity”, “inability to interpret and respond to child behaviors and needs”, and “support for transitioning from being patient toward maternal competency”.

Conclusion

With a deeper understanding of the term ‘disrupted mothering’ or ‘mothering disruption’, healthcare providers will have a foundation to improve cancer care, deliver effective communication and help such mothers cross this disruption and achieve restoration of their mothering role. Future research is needed to validate this concept and explore connections with health outcomes.
Understanding the lived experiences of medical learners in a narrative medicine course: a phenomenological study
Authors: Liao Kuo-Chen , Peng Chang-Hsuan , Snell Linda , Wang Xihui , Huang Chien-Da , Saroyan Alenoush
Published: June 2021

Background

Reflection and various approaches to foster reflection have been regarded as an indispensable element in enhancing professional practice across different disciplines. With its inherent potential to engage learners in reflection and improvement, narrative medicine has been adopted in various settings. However, the relevance and effectiveness of reflection remains underexplored in the context of narrative medicine, specifically in regard to the concern about variability of learner acceptance and the way learners really make sense of these reflective activities. This study aimed to explore what medical learners experience through narrative medicine and the meanings they ascribe to the phenomenon of this narrative-based learning.

Methods

Using a transcendental phenomenology approach, twenty medical learners were interviewed about their lived experiences of taking a narrative medicine course during their internal medicine clerkship rotation. Moustakas’ phenomenological analysis procedures were applied to review the interview data.

Results

Six themes were identified: feeling hesitation, seeking guidance, shifting roles in narratives, questioning relationships, experiencing transformation, and requesting a safe learning environment. These themes shaped the essence of the phenomenon and illustrated what and how medical learners set out on a reflective journey in narrative medicine. These findings elucidate fundamental elements for educators to consider how narrative approaches can be effectively used to engage learners in reflective learning and practice.

Conclusion

Adopting Moustakas’ transcendental phenomenology approach, a better understanding about the lived experiences of medical learners regarding learning in narrative medicine was identified. Learner hesitancy should be tackled with care by educators so as to support learners with strategies that address guidance, relationship, and learning environment. In so doing, medical learners can be facilitated to develop reflective capabilities for professional and personal growth.
A qualitative study of what care workers do to provide patient safety at home through telecare
Authors: Stokke Randi , Melby Line , Isaksen Jørn , Obstfelder Aud , Andreassen Hege
Published: June 2021

Background

In health care, the work of keeping the patient safe and reducing the risk of harm is defined as safety work. In our digitised and technology-rich era, safety work usually involves a relationship between people and technologies. Telecare is one of the fastest-growing technology-domains in western health care systems. In the marketing of telecare, the expectation is that safety is implicit simply by the presence of technology in patients’ homes. Whilst both researchers and health authorities are concerned with developing cost-benefit analyses and measuring effects, there is a lack of attention to the daily work needed to ensure that technologies contribute to patient safety.

This paper aims to describe how patient safety in home care is addressed through and with telecare. We base our exploration on the social alarm, an established technology that care workers are expected to handle as an integrated part of their ordinary work.

Methods

The study has a qualitative explorative design where we draw on empirical data from three case studies, involving five Norwegian municipalities that use social alarm systems in home care services. We analyse observations of practice and interviews with the actors involved, following King’s outline of template analysis.

Results

We identified three co-existing work processes that contributed to patient safety: “Aligning people and technologies”; “Being alert and staying calm”; and “Coordinating activities based on people and technology”. Attention to these work processes exposes safety practices, and how safety is constructed in relational practices involving multiple people and technologies.

Conclusions

We conclude that the three work processes identified are essential if the safety alarm is to function for the end user’s safety. The safety of home-dwelling patients is reliant on the person-technology interface. The efforts of care workers and their interface with technology are a central feature of creating safety in a patient’s home, and in doing so, they utilise a repertoire of skills and knowledge.
Telemedicine remote controlled stroke evaluation and treatment, the experience of radiographers, paramedics and junior doctors in a novel rural stroke management team
Authors: Kjelle Elin , Myklebust Aud Mette
Published: June 2021

Background

In the case of ischemic stroke, access to a Computed Tomography (CT) scanner and the start of thrombolytic therapy immediately is imperative. Transport to the nearest hospital from the remote, rural area of Hallingdal in Norway entails a 2–3 h drive. The local medical centre in this area has a CT-scanner operated by radiographers during office hours. Out-of-hours stroke evaluation and treatment has been the focus of a research project. Paramedics position the patient in the CT-scanner. A radiographer at the participating hospital runs a remote-controlled scan and a junior doctor instructs a paramedic in the performance of a neurological examination. The aim of this study was to explore how radiographers, paramedics and junior doctors experience conducting telemedicine-based stroke evaluation and treatment.

Methods

Six semi-structured interviews were conducted with radiographers, paramedics and junior doctors; with remote control, CT examination and stroke management as central issues. Core issues in the interview guide were: communication; cooperation; competence; service quality and training. The study employed thematic content analysis in analysing the data inductively.

Results

The analysis gave an overview of the patient flow and communication routines in this service. Further findings were divided into two main themes, “Teamwork” and “Quality”. The theme “Teamwork” included three categories “Communication”, “Trust and confidence”, and “Task and task shifting”. The theme “Quality” included two categories “Education and training” and “Safety and routines”. The respondents considered the service to be of high quality and that the team functioned at a high level as a result of regular training sessions. However, communication and image reading routines could be improved.

Conclusions

The telemedicine-based, remote controlled, stroke evaluation and treatment was experienced, by the participants, to be well organised and of high quality. Communication and image reading appear to be the salient challenges. Regular training sessions and follow-up, as well as an evaluation of incidents by the project manager, proved to be of great importance in retaining and securing the continued running of the service and ensuring high-quality treatment. Further research is indicated in the comparison of this telemedicine service with stroke treatment given in a mainstream hospital.
Platelet-rich plasma therapy in dogs with bilateral hip osteoarthritis
Authors: Alves J. C. , Santos A. , Jorge P.
Published: June 2021

Background

Osteoarthritis (OA) is the most commonly diagnosed joint disease in companion animals, and hip OA is commonly diagnosed in the canine population. The use of platelet-rich plasma has gained increasing interest for the treatment of musculoskeletal conditions in companion animals. To evaluate the effect of the intra-articular administration of platelet-rich plasma in police working dogs with bilateral hip OA compared to a control group, twenty dogs were assigned to a control group (CG, n = 10) or treatment group (PG, n = 10), using the statistical analysis software. PG received two intra-articular administrations of platelet-rich plasma, 14 days apart, while CG received an intra-articular administration of saline, in the same moments. Response to treatment was determined with the Canine Brief Pain Inventory, Liverpool Osteoarthritis in Dogs, Canine Orthopedic Index, and Hudson Visual Analogue Scale, before treatment, + 8, + 15, + 30, + 60, + 90, + 120, 150, and + 180 days after initial treatment. Kaplan-Meier estimators were conducted and compared with the log-rank test. Cox proportional hazard regression analysis was performed to determine treatment survival, p < 0.05.

Results

The sample comprised 20 animals of both sexes (male n = 12, female n = 8), with a mean age of 8.4 ± 2.4 years and a bodyweight of 31.5 ± 5.7 kg. Joints were classified as moderate (13) and severe (7) according to the Orthopedic Foundation for Animals grading scheme. No differences were found between groups at the initial evaluation. Better results with the majority of scores were observed in the PG, in some cases lasting up to the last evaluation moment. Kaplan-Meier estimators showed that PG produced longer periods with better results in all scores compared to CG. Treatment was the covariate influencing all scores in the Cox regression analysis. OFA hip score also influenced two dimensions of the Canine Orthopedic Index.

Conclusion

The intra-articular administration of platelet-rich plasma can improve pain and functional scores of police working dogs with bilateral hip OA, compared with a control group. Its effects lasted for significantly longer periods, and treatment was the main covariate affecting the improvements observed.
Effect of renal denervation on long-term outcomes in patients with resistant hypertension
Authors: Liang Bo , Liang Yi , Li Rui , Gu Ning
Published: June 2021

Increasing studies strongly prove that renal denervation, a minimally invasive surgery, is a promising new non-drug treatment method that can effectively control blood pressure in patients with resistant hypertension, but the evaluation of the long-term blood pressure control effect of renal denervation for resistant hypertension is still lacking. Here, we critically review current long-term follow-up data about the use of renal denervation for RH to comprehensively evaluate the effectiveness of renal denervation for RH, and to provide practical guidance for practitioners who are establishing a renal denervation service. Limited by the current research, many problems need to be solved before renal denervation is applied to RH. In addition, ambulatory blood pressure should be the first choice for the evaluation of blood pressure. Finally, the continuous antihypertensive effect of renal denervation in different renal denervation systems also needs to be strictly compared.
Emerging prospects of macro- and microalgae as prebiotic
Authors: Patel Anil Kumar , Singhania Reeta Rani , Awasthi Mukesh Kumar , Varjani Sunita , Bhatia Shashi Kant , Tsai Mei-Ling , Hsieh Shu-Ling , Chen Chiu-Wen , Dong Cheng-Di
Published: June 2021

Macro- and microalgae-based foods are becoming popular due to their high nutritious value. The algal biomass is enriched with polysaccharides, protein, polyunsaturated fatty acids, carotenoids, vitamins and minerals. However, the most promising fraction is polysaccharides (PS) or their derivatives (as dietary fibers) which are not entirely fermented by colonic bacteria hence act as potential prebiotic. Primarily, algae become famous as prominent protein sources. Recently, these are widely adopted as functional food (e.g., desserts, dairy products, oil-derivatives, pastas etc.) or animal feed (for poultry, cattle, fish etc.). Besides prebiotic and balanced amino acids source, algae derived compounds implied as therapeutics due to comprising bioactive properties to elicit immunomodulatory, antioxidative, anticancerous, anticoagulant, hepato-protective, and antihypertensive responses. Despite the above potentials, broader research determinations are inevitable to explore these algal compounds until microalgae become a business reality for broader and specific applications in all health domains. However, scale up of algal bioprocess remains a major challenge until commercial affordability is accomplished which can be possible by discovering their hidden potentials and increasing their value and application prospects. This review provides an overview of the significance of algae consumption for several health benefits in humans and animals mainly as prebiotics, however their functional food and animal feed potential are briefly covered. Moreover, their potential to develop an algal-based food industry to meet the people's requirements not only as a sustainable food solution with several health benefits but also as therapeutics is inevitable.
FOXH1 promotes lung cancer progression by activating the Wnt/β-catenin signaling pathway
Authors: Zhang Jun , Zhang Xian , Yang Shasha , Bao Yanqiu , Xu Dongyuan , Liu Lan
Published: June 2021

Background

The expression of forkhead box protein H1 (FOXH1) is frequently upregulated in various cancers. However, the molecular mechanisms underlying the association between FOXH1 expression and lung cancer progression still remain poorly understood. Thus, the main objective of this study is to explore the role of FOXH1 in lung cancer.

Methods

The Cancer Genome Atlas dataset was used to investigate FOXH1 expression in lung cancer tissues, and the Kaplan–Meier plotter dataset was used to determine the role of FOXH1 in patient prognosis. A549 and PC9 cells were transfected with short hairpin RNA targeting FOXH1 mRNA. The Cell Counting Kit-8, colony formation, soft agar, wound healing, transwell invasion and flow cytometry assays were performed to evaluate proliferation, migration and invasion of lung cancer cells. Tumorigenicity was examined in a BALB/c nude mice model. Western blot analysis was performed to assess the molecular mechanisms, and β-catenin activity was measured by a luciferase reporter system assay.

Results

Higher expression level of FOXH1 was observed in tumor tissue than in normal tissue, and this was associated with poor overall survival. Knockdown of FOXH1 significantly inhibited lung cancer cell proliferation, migration, invasion, and cycle. In addition, the mouse xenograft model showed that knockdown of FOXH1 suppressed tumor growth in vivo. Further experiments revealed that FOXH1 depletion inhibited the epithelial-mesenchymal transition of lung cancer cells by downregulating the expression of mesenchymal markers (Snail, Slug, matrix metalloproteinase-2, N-cadherin, and Vimentin) and upregulating the expression of an epithelial marker (E-cadherin). Moreover, knockdown of FOXH1 significantly downregulated the activity of β-catenin and its downstream targets, p-GSK-3β and cyclin D1.

Conclusion

FOXH1 exerts oncogenic functions in lung cancer through regulation of the Wnt/β-catenin signaling pathway. FOXH1 might be a potential therapeutic target for patients with certain types of lung cancer.
Inequalities in access to safe drinking water in Peruvian households according to city size: an analysis from 2008 to 2018
Authors: Hernández-Vasquéz Akram , Rojas-Roque Carlos , Marques Sales Denise , Santero Marilina , Bendezu-Quispe Guido , Barrientos-Gutiérrez Tonatiuh , Miranda J. Jaime
Published: June 2021

Background

Peru is one of the countries with the lowest percentage of population with access to safe drinking water in the Latin American region. This study aimed to describe and estimate, according to city size, socioeconomic inequalities in access to safe drinking water in Peruvian households from 2008 to 2018.

Methods

Secondary analysis of cross-sectional data using data from the 2008–2018 ENAHO survey. Access to safe drinking water, determined based on the presence of chlorinated water supplied by the public network, as well as socioeconomic variables were analyzed. A trend analysis from 2008 to 2018, and comparisons between 2008 versus 2018 were performed to understand and describe changes in access to safe drinking water, according to city size. Concentration curves and Erreygers concentration index (ECI) were estimated to measure inequalities in access to safe drinking water.

Results

In 2008, 47% of Peruvian households had access to safe drinking water, increasing to 52% by 2018 (p for trend < 0.001). For small cities, access to safe drinking water did not show changes between 2018 and 2008 (difference in proportions − 0.2 percentage points, p = 0.741); however, there was an increase in access to safe drinking water in medium (difference in proportions 3.3 percentage points, p < 0.001) and large cities (difference in proportions 12.8 percentage points, p < 0.001). The poorest households showed a decreasing trend in access to safe drinking water, while the wealthiest households showed an increasing trend. In small cities, socioeconomic inequalities showed an increase between 2008 and 2018 (ECI 0.045 and 0.140, p < 0.001), while in larger cities, socioeconomic inequality reduced in the same period (ECI: 0.087 and 0.018, p = 0.036).

Conclusions

We report a widening gap in the access to safe drinking water between the wealthiest and the poorest households over the study period. Progress in access to safe drinking water has not been equally distributed throughout the Peruvian population. Promoting and supporting effective implementation of policies and strategies to safe drinking water, including equity-oriented infrastructure development and resource allocation for most vulnerable settings, including emerging small cities, is a priority.
Associations between prenatal exposure to cadmium and lead with neural tube defect risks are modified by single-nucleotide polymorphisms of fetal MTHFR and SOD2: a case–control study
Authors: Liu Mengyuan , Yu Jinhui , Su Zaiming , Sun Ying , Liu Yaqiong , Xie Qing , Li Zhiwen , Wang Linlin , Zhang Jie , Jin Lei , Ren Aiguo
Published: June 2021

Background

Prenatal exposure to heavy metals is implicated in the etiology of birth defects. We investigated whether concentrations of cadmium (Cd) and lead (Pb) in umbilical cord tissue are associated with risk for neural tube defects (NTDs) and whether selected genetic variants of the fetus modify their associations.

Methods

This study included 166 cases of NTD fetuses/newborns and 166 newborns without congenital malformations. Umbilical cord tissue was collected at birth or elective pregnancy termination. Cd and Pb concentrations were assessed by inductively coupled plasma-mass spectrometry, and 20 single-nucleotide polymorphisms (SNPs) in 9 genes were genotyped. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to estimate the risk for NTDs in association with metal concentrations or genotype using logistic regression. Multiplicative-scale interactions between the metals and genotypes on NTD risk were assessed with logistic regression, and additive-scale interactions were estimated with a non-linear mixed effects model.

Results

Higher concentrations of Cd were observed in the NTD group than in the control group, but no difference was found for Pb. Concentrations of Cd above the median level showed a risk effect, while the association between Pb and NTD risk was not significant in univariate analyses. The association of Cd was attenuated after adjusting for periconceptional folic acid supplementation. Fetuses with the AG and GG genotypes of rs4880 in SOD2 (superoxide dismutase 2) tended to have a lower risk, but fetuses with the CT and TT genotypes of rs1801133 in MTHFR (5,10-methylenetetrahydrofolatereductase) have a higher risk for NTDs when compared to their respective wild-type. rs4880 and Cd exhibited a multiplicative-scale interaction on NTD risk: the association between higher Cd and the risk for NTDs was increased by over fourfold in fetuses carrying the G allele [OR 4.43 (1.30–15.07)] compared to fetuses with the wild-type genotype. rs1801133 and Cd exposure showed an additive interaction, with a significant relative excess risk of interaction [RERI 0.64 (0.02–1.25)].

Conclusions

Prenatal exposure to Cd may be a risk factor for NTDs, and the risk effect may be enhanced in fetuses who carry the G allele of rs4880 in SOD2 and T allele of rs1801133 in MTHFR.
CHEK1 and circCHEK1_246aa evoke chromosomal instability and induce bone lesion formation in multiple myeloma
Authors: Gu Chunyan , Wang Wang , Tang Xiaozhu , Xu Tingting , Zhang Yanxin , Guo Mengjie , Wei Rongfang , Wang Yajun , Jurczyszyn Artur , Janz Siegfried , Beksac Meral , Zhan Fenghuang , Seckinger Anja , Hose Dirk , Pan Jingxuan , Yang Ye
Published: June 2021

Background

Multiple myeloma (MM) is still incurable and characterized by clonal expansion of plasma cells in the bone marrow (BM). Therefore, effective therapeutic interventions must target both myeloma cells and the BM niche.

Methods

Cell proliferation, drug resistance, and chromosomal instability (CIN) induced by CHEK1 were confirmed by Giemsa staining, exon sequencing, immunofluorescence and xenograft model in vivo. Bone lesion was evaluated by Tartrate-resistant acid phosphatase (TRAP) staining. The existence of circCHEK1_246aa was evaluated by qPCR, Sanger sequencing and Mass Spectrometer.

Results

We demonstrated that CHEK1 expression was significantly increased in human MM samples relative to normal plasma cells, and that in MM patients, high CHEK1 expression was associated with poor outcomes. Increased CHEK1 expression induced MM cellular proliferation and evoked drug-resistance in vitro and in vivo. CHEK1-mediated increases in cell proliferation and drug resistance were due in part to CHEK1-induced CIN. CHEK1 activated CIN, partly by phosphorylating CEP170. Interestingly, CHEK1 promoted osteoclast differentiation by upregulating NFATc1 expression. Intriguingly, we discovered that MM cells expressed circCHEK1_246aa, a circular CHEK1 RNA, which encoded and was translated to the CHEK1 kinase catalytic center. Transfection of circCHEK1_246aa increased MM CIN and osteoclast differentiation similarly to CHEK1 overexpression, suggesting that MM cells could secrete circCHEK1_246aa in the BM niche to increase the invasive potential of MM cells and promote osteoclast differentiation.

Conclusions

Our findings suggest that targeting the enzymatic catalytic center encoded by CHEK1 mRNA and circCHEK1_246aa is a promising therapeutic modality to target both MM cells and BM niche.
Left ventricular global longitudinal strain predicts elevated cardiac pressures and poor clinical outcomes in patients with non-ischemic dilated cardiomyopathy
Authors: Kažukauskienė Ieva , Balčiūnaitė Giedrė , Baltrūnienė Vaida , Čelutkienė Jelena , Maneikienė Vytė Valerija , Čibiras Sigitas , Ručinskas Kęstutis , Grabauskienė Virginija
Published: June 2021

Background

Risk stratification in patients with non-ischemic dilated cardiomyopathy (NI-DCM) is essential to treatment planning. Global longitudinal strain (GLS) predicts poor prognosis in various cardiac diseases, but it has not been evaluated in a cohort of exclusively NI-DCM. Although deformation parameters have been shown to reflect diastolic function, their association with other hemodynamic parameters needs further elucidation. We aimed to evaluate the association between GLS and E/GLS and invasive hemodynamic parameters and assess the prognostic value of GLS and E/GLS in a prospective well-defined pure NI-DCM cohort.

Methods and results

Forty-one patients with NI-DCM were enrolled in the study. They underwent a standard diagnostic workup, including transthoracic echocardiography and right heart catheterization. During a five-year follow-up, 20 (49%) patients reached the composite outcome measure: LV assist device implantation, heart transplantation, or cardiovascular death.

Pulmonary capillary wedge pressure (PCWP), mean pulmonary artery pressure, pulmonary vascular resistance (PVR) correlated with GLS and E/GLS (p < 0.05). ROC analysis revealed that GLS and E/GLS could identify elevated PCWP (≥ 15 mmHg) and PVR (> 3 Wood units). Survival analysis showed GLS and E/GLS to be associated with short- and long-term adverse cardiac events (p < 0.05). GLS values above thresholds of –5.34% and -5.96% indicated 18- and 12-fold higher risk of poor clinical outcomes at one and five years, respectively. Multivariate Cox regression analysis revealed that GLS is an independent long-term outcome predictor.

Conclusion

GLS and E/GLS correlate with invasive hemodynamics parameters and identify patients with elevated PCWP and high PVR. GLS and E/GLS predict short- and long-term adverse cardiac events in patients with NI-DCM. Worsening GLS is associated with incremental risk of long-term adverse cardiac events and might be used to identify high-risk patients.
The functional characterization of phosphorylation of tristetraprolin at C-terminal NOT1-binding domain
Authors: Hsieh Hsin-Hui , Chen Yen-An , Chang Yao-Jen , Wang Hsin-Hui , Yu Ya-Han , Lin Sheng-Wei , Huang Yin-Jung , Lin Steven , Chang Ching-Jin
Published: June 2021

Background

Tristetraprolin (TTP) family proteins contain conserved tandem CCCH zinc-finger binding to AU-rich elements and C-terminal NOT1-binding domain. TTP is phosphorylated extensively in cells, and its mRNA destabilization activity is regulated by protein phosphorylation.

Methods

We generated an antibody against phospho-Serine316 located at the C-terminal NOT1-binding site and examined TTP phosphorylation in LPS-stimulated RAW264.7 cells. Knockout of TTP was created in RAW264.7 cells using CRISPR/Cas9 gene editing to explore TTP functions.

Results

We demonstrated that Ser316 was phosphorylated by p90 ribosomal S6 kinase 1 (RSK1) and p38-activated protein kinase (MK2) and dephosphorylated by Protein Phosphatase 2A (PP2A). A phosphorylation-mimic mutant of S316D resulted in dissociation with the CCR4-NOT deadenylase complex through weakening interaction with CNOT1. Furthermore, Ser316 and serines 52 and 178 were independently contributed to the CCR4-NOT complex recruitment in the immunoprecipitation assay using phosphor-mimic mutants. In RAW264.7 macrophages, TTP was induced, and Ser316 was phosphorylated through RSK1 and MK2 by LPS stimulation. Knockout of TTP resulted in TNFα mRNA increased due to mRNA stabilization. Overexpression of non-phosphorylated S316A TTP mutant can restore TTP activity and lead to TNFα mRNA decreased. GST pull-down and RNA pull-down analyses demonstrated that endogenous TTP with Ser316 phosphorylation decreased the interaction with CNOT1.

Conclusions

Our results suggest that the TTP-mediated mRNA stability is modulated by Ser316 phosphorylation via regulating the TTP interaction with the CCR4-NOT deadenylase complex.
Research advances on the immune research and prospect of immunotherapy in pituitary adenomas
Authors: Nie Ding , Fang Qiuyue , Li Bin , Cheng Jianhua , Li Chuzhong , Gui Songbai , Zhang Yazhuo , Zhao Peng
Published: June 2021

Background

Pituitary adenomas are one type of intracranial tumor, which can be divided into microadenoma (≤ 1 cm), macroadenoma (> 1 cm), and giant adenoma (≥ 4 cm) according to their diametral sizes. They are benign, typically slow-progressing, whereas the biological behavior of some of them is invasive, which presents a major clinical challenge. Treatment of some pituitary adenomas is still difficult due to drug resistance or multiple relapses, usually after surgery, medication, and radiation. At present, no clear prediction and treatment biomarkers have been found in pituitary adenomas and some of them do not cause clinical symptoms, so patients are often found to be ill through physical examination, and some are even found through autopsy. With the development of research on pituitary adenomas, the immune response has become a hot spot and may serve as a novel disease marker and therapeutic target.

The distribution and function of immune cells and their secreted molecules in pituitary adenomas are extremely complex. Researchers found that infiltration of immune cells may have a positive effect on the treatment and prognosis of pituitary adenomas. In this review, we summarized the advance of tumor immunity in pituitary adenomas, revealing the immunity molecules as potential biomarkers as well as therapeutic agents for pituitary adenomas.

Conclusion

The immune studies related to pituitary adenomas may help us find relevant immune markers. At the same time, the exploration of immunotherapy also provides new options for the treatment of pituitary adenomas.
Sequence determinants of in cell condensate morphology, dynamics, and oligomerization as measured by number and brightness analysis
Authors: Emenecker Ryan J. , Holehouse Alex S. , Strader Lucia C.
Published: June 2021

Background

Biomolecular condensates are non-stoichiometric assemblies that are characterized by their capacity to spatially concentrate biomolecules and play a key role in cellular organization. Proteins that drive the formation of biomolecular condensates frequently contain oligomerization domains and intrinsically disordered regions (IDRs), both of which can contribute multivalent interactions that drive higher-order assembly. Our understanding of the relative and temporal contribution of oligomerization domains and IDRs to the material properties of in vivo biomolecular condensates is limited. Similarly, the spatial and temporal dependence of protein oligomeric state inside condensates has been largely unexplored in vivo.

Methods

In this study, we combined quantitative microscopy with number and brightness analysis to investigate the aging, material properties, and protein oligomeric state of biomolecular condensates in vivo. Our work is focused on condensates formed by AUXIN RESPONSE FACTOR 19 (ARF19), a transcription factor integral to the auxin signaling pathway in plants. ARF19 contains a large central glutamine-rich IDR and a C-terminal Phox Bem1 (PB1) oligomerization domain and forms cytoplasmic condensates.

Results

Our results reveal that the IDR amino acid composition can influence the morphology and material properties of ARF19 condensates. In contrast the distribution of oligomeric species within condensates appears insensitive to the IDR composition. In addition, we identified a relationship between the abundance of higher- and lower-order oligomers within individual condensates and their apparent fluidity.

Conclusions

IDR amino acid composition affects condensate morphology and material properties. In ARF condensates, altering the amino acid composition of the IDR did not greatly affect the oligomeric state of proteins within the condensate.
Patient-derived scaffolds influence secretion profiles in cancer cells mirroring clinical features and breast cancer subtypes
Authors: Persson Emma , Gregersson Pernilla , Gustafsson Anna , Fitzpatrick Paul , Rhost Sara , Ståhlberg Anders , Landberg Göran
Published: June 2021

Background

Breast cancer is a common malignancy with varying clinical behaviors and for the more aggressive subtypes, novel and more efficient therapeutic approaches are needed. Qualities of the tumor microenvironment as well as cancer cell secretion have independently been associated with malignant clinical behaviors and a better understanding of the interplay between these two features could potentially reveal novel targetable key events linked to cancer progression.

Methods

A newly developed human derived in vivo-like growth system, consisting of decellularized patient-derived scaffolds (PDSs) recellularized with standardized breast cancer cell lines (MCF7 and MDA-MB-231), were used to analyze how 63 individual patient specific microenvironments influenced secretion determined by proximity extension assays including 184 proteins and how these relate to clinical outcome.

Results

The secretome from cancer cells in PDS cultures varied distinctly from cells grown as standard monolayers and besides a general increase in secretion from PDS cultures, several secreted proteins were only detectable in PDSs. Monolayer cells treated with conditioned media from PDS cultures, further showed increased mammosphere formation demonstrating a cancer stem cell activating function of the PDS culture induced secretion. The detailed secretomic profiles from MCF7s growing on 57 individual PDSs differed markedly but unsupervised clustering generated three separate groups having similar secretion profiles that significantly correlated to different clinical behaviors. The secretomic profile that associated with cancer relapse and high grade breast cancer showed induced secretion of the proteins IL-6, CCL2 and PAI-1, all linked to cancer stem cell activation, metastasis and priming of the pre-metastatic niche. Cancer promoting pathways such as “Suppress tumor immunity” and “Vascular and tissue remodeling” was also linked to this more malignant secretion cluster.

Conclusion

PDSs repopulated with cancer cells can be used to assess how cancer secretion is effected by specific and varying microenvironments. More malignant secretion patterns induced by specific patient based cancer microenvironments could further be identified pinpointing novel therapeutic opportunities targeting micro environmentally induced cancer progression via secretion of potent cytokines.
Translational precision medicine: an industry perspective
Authors: Hartl Dominik , de Luca Valeria , Kostikova Anna , Laramie Jason , Kennedy Scott , Ferrero Enrico , Siegel Richard , Fink Martin , Ahmed Sohail , Millholland John , Schuhmacher Alexander , Hinder Markus , Piali Luca , Roth Adrian
Published: June 2021

In the era of precision medicine, digital technologies and artificial intelligence, drug discovery and development face unprecedented opportunities for product and business model innovation, fundamentally changing the traditional approach of how drugs are discovered, developed and marketed. Critical to this transformation is the adoption of new technologies in the drug development process, catalyzing the transition from serendipity-driven to data-driven medicine. This paradigm shift comes with a need for both translation and precision, leading to a modern Translational Precision Medicine approach to drug discovery and development. Key components of Translational Precision Medicine are multi-omics profiling, digital biomarkers, model-based data integration, artificial intelligence, biomarker-guided trial designs and patient-centric companion diagnostics. In this review, we summarize and critically discuss the potential and challenges of Translational Precision Medicine from a cross-industry perspective.
Collaborative relationships in translational medical research among Chinese clinicians: an internet-based cross-sectional survey
Authors: Li Meina , Lian Bin , Xu Xiaoxiong , Zhao Pan , Tang Bihan , Hu Chaoqun , Liu Xiang , Yu Wenya , Zhang Lulu
Published: June 2021

Background

This study aimed to explore the collaborative relationship in translational medical research from the perspective of clinicians in China. The findings are expected to help practitioners optimize and experience the greatest advantages of collaboration.

Methods

We conducted a national internet-based survey from July 29 to October 12, 2020. Of the 806 responses, 804 were completed with valid responses (valid response rate = 99.8%). The collected data were presented as descriptive statistics and analyzed using nonparametric tests (including the Wilcoxon rank test and Kruskal–Wallis H test) and stepwise logistic regression.

Results

Of the 804 participants, 733 were either willing or very willing to collaborate in translational medical research. Clinicians’ willingness was influenced by their current research type, role in current translational medical research, burdens of their present research, preferred partners for collaboration at the institutional or individual level, and preferences for independent or dependent relationships.

Conclusions

Clinicians should evaluate their time, role, burdens, personal preferences for research relationships, and appropriate partners based on their current translational medical research and its goals, before deciding to collaborate.
SARS-CoV-2 complete genome sequencing from the Italian Campania region using a highly automated next generation sequencing system
Authors: Rachiglio Anna Maria , De Sabato Luca , Roma Cristin , Cennamo Michele , Fiorenza Mariano , Terracciano Daniela , Pasquale Raffaella , Bergantino Francesca , Cavalcanti Ernesta , Botti Gerardo , Vaccari Gabriele , Portella Giuseppe , Normanno Nicola
Published: June 2021

Background

Since the first complete genome sequencing of SARS-CoV-2 in December 2019, more than 550,000 genomes have been submitted into the GISAID database. Sequencing of the SARS-CoV-2 genome might allow identification of variants with increased contagiousness, different clinical patterns and/or different response to vaccines. A highly automated next generation sequencing (NGS)-based method might facilitate an active genomic surveillance of the virus.

Methods

RNA was extracted from 27 nasopharyngeal swabs obtained from citizens of the Italian Campania region in March–April 2020 who tested positive for SARS-CoV-2. Following viral RNA quantification, sequencing was performed using the Ion AmpliSeq SARS-CoV-2 Research Panel on the Genexus Integrated Sequencer, an automated technology for library preparation and sequencing. The SARS-CoV-2 complete genomes were built using the pipeline SARS-CoV-2 RECoVERY (REconstruction of COronaVirus gEnomes & Rapid analYsis) and analysed by IQ-TREE software.

Results

The complete genome (100%) of SARS-CoV-2 was successfully obtained for 21/27 samples. In particular, the complete genome was fully sequenced for all 15 samples with high viral titer (> 200 copies/µl), for the two samples with a viral genome copy number < 200 but greater than 20, and for 4/10 samples with a viral load < 20 viral copies. The complete genome sequences classified into the B.1 and B.1.1 SARS-CoV-2 lineages. In comparison to the reference strain Wuhan-Hu-1, 48 total nucleotide variants were observed with 26 non-synonymous substitutions, 18 synonymous and 4 reported in untranslated regions (UTRs). Ten of the 26 non-synonymous variants were observed in ORF1ab, 7 in S, 1 in ORF3a, 2 in M and 6 in N genes.

Conclusions

The Genexus system resulted successful for SARS-CoV-2 complete genome sequencing, also in cases with low viral copies. The use of this highly automated system might facilitate the standardization of SARS-CoV-2 sequencing protocols and make faster the identification of novel variants during the pandemic.