bluuebunny/crossref_metadata_2025 huggingface dataset:
Protein over-expression in Escherichia coli triggers adaptation analogous to antimicrobial resistance
Authors: James Jack , Yarnall Benjamin , Koranteng Andy , Gibson Jane , Rahman Tahmina , Doyle Declan A.
Published: January 2021

Background

The E. coli pET system is the most widely used protein over-expression system worldwide. It relies on the assumption that all cells produce target protein and it is generally believed that integral membrane protein (IMP) over-expression is more toxic than their soluble counterparts.

Results

Using GFP-tagged proteins, high level over-expression of either soluble or IMP targets results in > 99.9% cell loss with survival rate of only < 0.03%. Selective pressure generates three phenotypes: large green, large white and small colony variants. As a result, in overnight cultures, ~ 50% of the overall cell mass produces no protein. Genome sequencing of the phenotypes revealed genomic mutations that causes either the loss of T7 RNAP activity or its transcriptional downregulation. The over-expression process is bactericidal and is observed for both soluble and membrane proteins.

Conclusions

We demonstrate that it is the act of high-level over-expression of exogenous proteins in E. coli that sets in motion a chain of events leading to > 99.9% cell death. These results redefine our understanding of protein over-production and link it to the adaptive survival response seen in the development of antimicrobial resistance.
LncRNA HOXA-AS2 promotes glioblastoma carcinogenesis by targeting miR-885-5p/RBBP4 axis
Authors: Shou Jixin , Gao Haidong , Cheng Sen , Wang Bingbing , Guan Haibo
Published: January 2021

Background

LncRNA HOXA-AS2 has been found in the literature to deteriorate glioblastoma. However, its regulatory mechanism is yet to be fully investigated. Our study focused chiefly on the interaction and role of the HOXA-AS2/miR-885-5p/RBBP4 axis in the development of glioblastoma.

Methods

qRT-PCR analysis was performed to detect the expression of lncRNA, miRNA and mRNA in glioblastoma tissues and cells. Dual-luciferase assay, RIP assay and RNA pull-down assay were later carried out to reveal the interactions among HOXA-AS2, miR-885-5p and RBBP4. After that, CCK-8 assay, BrdU assay, nude mice xenografting assay, western blot assay, and flow cytometry were carried out to analyze the effect of the HOXA-AS2/miR-885-5p/RBBP4 axis on glioblastoma samples.

Results

HOXA-AS2 and RBBP4 were found to be overexpressed in glioblastoma. Experimental results showed that HOXA-AS2 and RBBP4 contributed to the tumorigenesis of glioblastoma cells. However, miR-885-5p was observed to be downregulated in glioblastoma. Findings also indicated that HOXA-AS2 could negatively regulate miR-885-5p, thereby enhancing RBBP4 expression.

Conclusion

Overall, HOXA-AS2 promoted the tumorigenesis of glioblastoma by targeting and regulating miR-885-5p to induce the expression of RBBP4.
The role of JMJD6/U2AF65/AR-V7 axis in castration-resistant prostate cancer progression
Authors: Tong Dali
Published: January 2021

Castration-resistant prostate cancer (CRPC) remains prostate cancer research and treatment bottleneck. Abnormal androgen receptor (AR) activation still has a pivotal role in CRPC. Multiple mechanisms involve the process, of which overabundant AR-V7 mRNA splicing production is currently focused and increasingly studied. However, factually, there is no definite conclusion about regulation of AR-V7 mRNA splicing. Recently developed knowledge has demonstrated that JMJD6 and U2AF65 as a hopeful approach in mRNA splicing regulation. The authors propose a novel possible mechanism elucidating AR mRNA splicing for CRPC progression using dual-function enzyme JMJD6 and its induced JMJD6/U2AF65/AR-V7 axis. In this hypothesis JMJD6 introduces to AR promoter to demethylate H3R or H4R and promotes AR mRNA transcription via its demethylase activity and interaction with U2AF65. It is expected that JMJD6 could further effectively perform U2AF65 hydroxylation to achieve AR-V7 mRNA splicing via its hydroxylase activity.
TIMELESS inhibits breast cancer cell invasion and metastasis by down-regulating the expression of MMP9
Authors: Li Bowen , Mu Liying , Li Yanan , Xia Kangkai , Yang Yuxi , Aman Sattout , Ahmad Bashir , Li Shujing , Wu Huijian
Published: January 2021

Breast cancer is the first killer leading to female death, and tumor metastasis is one of the important factors leading to the death of patients, but the specific mechanism of breast cancer metastasis is not very clear at present. Our study showed that overexpression of TIMELESS could significantly inhibit the invasion and metastasis of breast cancer cells ZR-75-30 and the assembly of F-actin protein. On the contrary, knockdown of TIMELESS promoted the invasion and metastasis of breast cancer cells. Further study revealed that TIMELESS overexpression decreased the mRNA and protein levels of MMP9. Furthermore, TIMELESS could interact with p65, leading to repress the association of p65 and its acetyltransferase CBP and down-regulating the acetylation level of p65, which inhibited the activation of NF-κB signal pathway. In conclusion, our research showed that TIMELESS may repress the invasion and metastasis of breast cancer cells via inhibiting the acetylation of p65, inhibiting the activation of NF-κB, thus down-regulating the expression of MMP9, and then inhibiting the invasion and metastasis of breast cancer cells.
Isolation and light chain shuffling of a Plasmodium falciparum AMA1-specific human monoclonal antibody with growth inhibitory activity
Authors: Seidel-Greven Melanie , Addai-Mensah Otchere , Spiegel Holger , Chiegoua Dipah Gwladys Nina , Schmitz Stefan , Breuer Gudrun , Frempong Margaret , Reimann Andreas , Klockenbring Torsten , Fischer Rainer , Barth Stefan , Fendel Rolf
Published: January 2021

Background

Plasmodium falciparum, the parasite causing malaria, affects populations in many endemic countries threatening mainly individuals with low malaria immunity, especially children. Despite the approval of the first malaria vaccine Mosquirix™ and very promising data using cryopreserved P. falciparum sporozoites (PfSPZ), further research is needed to elucidate the mechanisms of humoral immunity for the development of next-generation vaccines and alternative malaria therapies including antibody therapy. A high prevalence of antibodies against AMA1 in immune individuals has made this antigen one of the major blood-stage vaccine candidates.

Material and methods

Using antibody phage display, an AMA1-specific growth inhibitory human monoclonal antibody from a malaria-immune Fab library using a set of three AMA1 diversity covering variants (DiCo 1–3), which represents a wide range of AMA1 antigen sequences, was selected. The functionality of the selected clone was tested in vitro using a growth inhibition assay with P. falciparum strain 3D7. To potentially improve affinity and functional activity of the isolated antibody, a phage display mediated light chain shuffling was employed. The parental light chain was replaced with a light chain repertoire derived from the same population of human V genes, these selected antibodies were tested in binding tests and in functionality assays.

Results

The selected parental antibody achieved a 50% effective concentration (EC50) of 1.25 mg/mL. The subsequent light chain shuffling led to the generation of four derivatives of the parental clone with higher expression levels, similar or increased affinity and improved EC50 against 3D7 of 0.29 mg/mL. Pairwise epitope mapping gave evidence for binding to AMA1 domain II without competing with RON2.

Conclusion

We have thus shown that a compact immune human phage display library is sufficient for the isolation of potent inhibitory monoclonal antibodies and that minor sequence mutations dramatically increase expression levels in Nicotiana benthamiana. Interestingly, the antibody blocks parasite inhibition independently of binding to RON2, thus having a yet undescribed mode of action.
Trends in out of pocket payments and catastrophic health expenditure in the Kyrgyz Republic post “Manas Taalimi” and “Den Sooluk” health reforms, 2012–2018
Authors: Iamshchikova Mariia , Mogilevskii Roman , Onah Michael Nnachebe
Published: January 2021

Background

Over the years, the Kyrgyz Republic has implemented health reforms that target health financing with the aim of removing financial barriers to healthcare including out-of-pocket health payments (OOPPs). This study examines the trends in OOPPs, and the incidence of catastrophic health expenditure (CHE) post the “Manas Taalimi” and “Den Sooluk” health reforms.

Methods

We used data from the Kyrgyzstan Integrated Household Surveys (2012–2018). Population-weighted descriptive statistics were used to examine the trends in OOPPs and CHE at three thresholds; 10 percent of total household consumption expenditure (Cata10), 25 percent of total household consumption expenditure (Cata25) and 40 percent of total household non-food consumption expenditure (Cata40). Panel and cross-sectional logistic regression with marginal effects were used to examine the predictors of Cata10 and Cata40.

Findings

Between 2012 and 2018, OOPPs increased by about US $6 and inpatient costs placed the highest cost burden on users (US $13.6), followed by self-treatment (US $10.7), and outpatient costs (US $9). Medication continues to predominantly drive inpatient, outpatient, and self-treatment OOPPs. About 0.378 to 2.084 million people (6 – 33 percent) of the population incurred catastrophic health expenditure at the three thresholds between 2012 and 2018. Residing in households headed by a widowed or single head, or residing in rural regions, increases the likelihood of incurring catastrophic health expenditure.

Conclusions

The initial gains in the reduction of OOPPs and catastrophic health expenditure appear to gradually erode since costs continue to increase after an initial decline and catastrophic health expenditure continues to rise unabated. This implies that households are increasingly incurring economic hardship from seeking healthcare. Considering that this could result to forgone expenditure on essential items including food and education, efforts should target the sustainability of these health reforms to maintain and grow the reduction of catastrophic health payments and its dire consequences.
Designing for Scale and taking scale to account: lessons from a community score card project in Uganda
Authors: Kiracho Elizabeth Ekirapa , Aanyu Christine , Apolot Rebecca Racheal , Kiwanuka Suzanne Namusoke , Paina Ligia
Published: January 2021

Background

Planning for the implementation of community scorecards (CSC) is an important, though seldom documented process. Makerere University School of Public Health (MakSPH) and Future Health Systems Consortium set out to develop and test a sustainable and scalable CSC model. This paper documents the process of planning and adapting the design of the CSC, incorporating key domains of the scalable model such as embeddedness, legitimacy, feasibility and ownership, challenges encountered in this process and how they were mitigated.

Methods

The CSC intervention comprised of five rounds of scoring in five sub counties and one town council of Kibuku district. Data was drawn from ten focus group discussions, seven key informant interviews with local and sub national leaders, and one reflection meeting with the project team from MakSPH. More data was abstracted from notes of six quarterly stakeholder meetings and six quarterly project meetings. Data was analyzed using a thematic approach, drawing constructs outlined in the project’s theory of change.

Results

Embeddedness, legitimacy and ownership were promoted through aligning the model with existing processes and systems as well as the meaningful and strategic involvement of stakeholders and leaders at local and sub national level. The challenges encountered included limited technical capacity of stakeholders facilitating the CSC, poor functionality of existing community engagement platforms, and difficulty in promoting community participation without financial incentives. However, these challenges were mitigated through adjustments to the intervention design based on the feedback received.

Conclusion

Governments seeking to scale up CSCs and to take scale to account should keenly adapt existing models to the local implementation context with strategic and meaningful involvement of key legitimate local and sub national leaders in decision making during the design and implementation process. However, they should watch out for elite capture and develop mitigating strategies. Social accountability practitioners should document their planning and adaptive design efforts to share good practices and lessons learned. Enhancing local capacity to implement CSCs should be ensured through use of existing local structures and provision of technical support by external or local partners familiar with the skill until the local partners are competent.
Unraveling tumour microenvironment heterogeneity in nasopharyngeal carcinoma identifies biologically distinct immune subtypes predicting prognosis and immunotherapy responses
Authors: Chen Yu-Pei , Lv Jia-Wei , Mao Yan-Ping , Li Xiao-Min , Li Jun-Yan , Wang Ya-Qin , Xu Cheng , Li Ying-Qin , He Qing-Mei , Yang Xiao-Jing , Lei Yuan , Shen Jia-Yi , Tang Ling-Long , Chen Lei , Zhou Guan-Qun , Li Wen-Fei , Du Xiao-Jing , Guo Rui , Liu Xu , Zhang Yuan , Zeng Jing , Yun Jing-Ping , Sun Ying , Liu Na , Ma Jun
Published: January 2021

Currently, there is no strong evidence of the well-established biomarkers for immune checkpoint inhibitors (ICIs) in nasopharyngeal carcinoma (NPC). Here, we aimed to reveal the heterogeneity of tumour microenvironment (TME) through virtual microdissection of gene expression profiles. An immune-enriched subtype was identified in 38% (43/113) of patients, which was characterized by significant enrichment of immune cells or immune responses. The remaining patients were therefore classified as a non-Immune Subtype (non-IS), which exhibited highly proliferative features. Then we identified a tumour immune evasion state within the immune-enriched subtype (18/43, 42%), in which high expression of exclusion- and dysfunction-related signatures was observed. These subgroups were designated the Evaded and Active Immune Subtype (E-IS and A-IS), respectively. We further demonstrated that A-IS predicted favourable survival and improved ICI response as compared to E-IS and non-IS. In summary, this study introduces the novel immune subtypes and demonstrates their feasibility in tailoring immunotherapeutic strategies.
Circular RNAs in body fluids as cancer biomarkers: the new frontier of liquid biopsies
Authors: Wang Sumeng , Zhang Ke , Tan Shanyue , Xin Junyi , Yuan Qianyu , Xu Huanhuan , Xu Xian , Liang Qi , Christiani David C. , Wang Meilin , Liu Lingxiang , Du Mulong
Published: January 2021

Cancer is a leading cause of death worldwide, particularly because of its high mortality rate in patients who are diagnosed at late stages. Conventional biomarkers originating from blood are widely used for cancer diagnosis, but their low sensitivity and specificity limit their widespread application in cancer screening among the general population. Currently, emerging studies are exploiting novel, highly-accurate biomarkers in human body fluids that are obtainable through minimally invasive techniques, which is defined as liquid biopsy. Circular RNAs (circRNAs) are a newly discovered class of noncoding RNAs generated mainly by pre-mRNA splicing. Following the rapid development of high-throughput transcriptome analysis techniques, numerous circRNAs have been recognized to exist stably and at high levels in body fluids, including plasma, serum, exosomes, and urine. CircRNA expression patterns exhibit distinctly differences between patients with cancer and healthy controls, suggesting that circRNAs in body fluids potentially represent novel biomarkers for monitoring cancer development and progression. In this study, we summarized the expression of circRNAs in body fluids in a pan-cancer dataset and characterized their clinical applications in liquid biopsy for cancer diagnosis and prognosis. In addition, a user-friendly web interface was developed to visualize each circRNA in fluids (https://mulongdu.shinyapps.io/circrnas_in_fluids/).
Nebulised surface-active hybrid nanoparticles of voriconazole for pulmonary Aspergillosis demonstrate clathrin-mediated cellular uptake, improved antifungal efficacy and lung retention
Authors: Kaur Ranjot , Dennison Sarah R. , Burrow Andrea J. , Rudramurthy Shivaprakash M. , Swami Rajan , Gorki Varun , Katare O. P. , Kaushik Anupama , Singh Bhupinder , Singh Kamalinder K.
Published: January 2021

Background

Incidence of pulmonary aspergillosis is rising worldwide, owing to an increased population of immunocompromised patients. Notable potential of the pulmonary route has been witnessed in antifungal delivery due to distinct advantages of direct lung targeting and first-pass evasion. The current research reports biomimetic surface-active lipid-polymer hybrid (LPH) nanoparticles (NPs) of voriconazole, employing lung-specific lipid, i.e., dipalmitoylphosphatidylcholine and natural biodegradable polymer, i.e., chitosan, to augment its pulmonary deposition and retention, following nebulization.

Results

The developed nanosystem exhibited a particle size in the range of 228–255 nm and drug entrapment of 45–54.8%. Nebulized microdroplet characterization of NPs dispersion revealed a mean diameter of  ≤ 5 μm, corroborating its deep lung deposition potential as determined by next-generation impactor studies. Biophysical interaction of LPH NPs with lipid-monolayers indicated their surface-active potential and ease of intercalation into the pulmonary surfactant membrane at the air-lung interface. Cellular viability and uptake studies demonstrated their cytocompatibility and time-and concentration-dependent uptake in lung-epithelial A549 and Calu-3 cells with clathrin-mediated internalization. Transepithelial electrical resistance experiments established their ability to penetrate tight airway Calu-3 monolayers. Antifungal studies on laboratory strains and clinical isolates depicted their superior efficacy against Aspergillus species. Pharmacokinetic studies revealed nearly 5-, 4- and threefolds enhancement in lung AUC, Tmax, and MRT values, construing significant drug access and retention in lungs.

Conclusions

Nebulized LPH NPs were observed as a promising solution to provide effective and safe therapy for the management of pulmonary aspergillosis infection with improved patient compliance and avoidance of systemic side-effects.
Decrease in membrane fluidity and traction force induced by silica-coated magnetic nanoparticles
Authors: Shin Tae Hwan , Ketebo Abdurazak Aman , Lee Da Yeon , Lee Seungah , Kang Seong Ho , Basith Shaherin , Manavalan Balachandran , Kwon Do Hyeon , Park Sungsu , Lee Gwang
Published: January 2021

Background

Nanoparticles are being increasingly used in biomedical applications owing to their unique physical and chemical properties and small size. However, their biophysical assessment and evaluation of side-effects remain challenging. We addressed this issue by investigating the effects of silica-coated magnetic nanoparticles containing rhodamine B isothiocyanate [MNPs@SiO2(RITC)] on biophysical aspects, such as membrane fluidity and traction force of human embryonic kidney 293 (HEK293) cells. We further extended our understanding on the biophysical effects of nanoparticles on cells using a combination of metabolic profiling and transcriptomic network analysis.

Results

Overdose (1.0 μg/µL) treatment with MNPs@SiO2(RITC) induced lipid peroxidation and decreased membrane fluidity in HEK293 cells. In addition, HEK293 cells were morphologically shrunk, and their aspect ratio was significantly decreased. We found that each traction force (measured in micropillar) was increased, thereby increasing the total traction force in MNPs@SiO2(RITC)-treated HEK293 cells. Due to the reduction in membrane fluidity and elevation of traction force, the velocity of cell movement was also significantly decreased. Moreover, intracellular level of adenosine triphosphate (ATP) was also decreased in a dose-dependent manner upon treatment with MNPs@SiO2(RITC). To understand these biophysical changes in cells, we analysed the transcriptome and metabolic profiles and generated a metabotranscriptomics network, which revealed relationships among peroxidation of lipids, focal adhesion, cell movement, and related genes and metabolites. Furthermore, in silico prediction of the network showed increment in the peroxidation of lipids and suppression of focal adhesion and cell movement.

Conclusion

Taken together, our results demonstrated that overdose of MNPs@SiO2(RITC) impairs cellular movement, followed by changes in the biophysical properties of cells, thus highlighting the need for biophysical assessment of nanoparticle-induced side-effects.
COVID-19-induced sarcopenia and physical deconditioning may require reassessment of surgical risk for patients with cancer
Authors: Casey Patrick , Ang Yeng , Sultan Javed
Published: January 2021

Background

The long-term physiological consequences of SARS-CoV-2 (severe acute respiratory syndrome coronavirus) infection are not known. The ability of COVID-19 to cause chronic illness, sarcopenia, and physical deconditioning may be underestimated and go beyond the anticipated respiratory sequelae. Myalgia, lethargy, and anorexia are common symptoms even in mild to moderate cases and have the potential to exacerbate frailty. How this impacts on risk-stratification for patients requiring surgery for time-critical conditions, such as malignancy, requires further urgent investigation.

Main body

The deleterious effect of sarcopenia and poor physical capacity are well recognised in cancer surgery. This review commentary highlights current evidence which suggests skeletal muscle as an under recognised cause of COVID-19-related functional deconditioning. The mechanisms behind this are via direct (viral induced myositis, nutritional decline, cytokine-mediated myopathy) and indirect mechanisms (social isolation, inactivity, and psychological consequences).

Conclusion

Further mechanistic research is required to explore the processes behind the deconditioning effects of SARS-CoV-2 infection and how this impacts on treatment of malignant disease.
Effects of therapeutic probiotics on modulation of microRNAs
Authors: Davoodvandi Amirhossein , Marzban Havva , Goleij Pouya , Sahebkar Amirhossein , Morshedi Korosh , Rezaei Samaneh , Mahjoubin-Tehran Maryam , Tarrahimofrad Hossein , Hamblin Michael R. , Mirzaei Hamed
Published: January 2021

Probiotics are beneficial bacteria that exist within the human gut, and which are also present in different food products and supplements. They have been investigated for some decades, due to their potential beneficial impact on human health. Probiotics compete with pathogenic microorganisms for adhesion sites within the gut, to antagonize them or to regulate the host immune response resulting in preventive and therapeutic effects. Therefore, dysbiosis, defined as an impairment in the gut microbiota, could play a role in various pathological conditions, such as lactose intolerance, gastrointestinal and urogenital infections, various cancers, cystic fibrosis, allergies, inflammatory bowel disease, and can also be caused by antibiotic side effects. MicroRNAs (miRNAs) are short non-coding RNAs that can regulate gene expression in a post-transcriptional manner. miRNAs are biochemical biomarkers that play an important role in almost all cellular signaling pathways in many healthy and disease states. For the first time, the present review summarizes current evidence suggesting that the beneficial properties of probiotics could be explained based on the pivotal role of miRNAs.
Consolidating evidence on the effectiveness of interventions promoting fruit and vegetable consumption: an umbrella review
Authors: Wolfenden Luke , Barnes Courtney , Lane Cassandra , McCrabb Sam , Brown Hannah M. , Gerritsen Sarah , Barquera Simon , Véjar Lesly Samara , Munguía Ana , Yoong Sze Lin
Published: January 2021

Background

The overarching objective was to examine the effectiveness of intervention strategies to promote fruit and vegetable consumption. To do this, systematic review evidence regarding the effects of intervention strategies was synthesized; organized, where appropriate, by the setting in which the strategies were implemented. Additionally, we sought to describe gaps in the review of evidence; that is, where evidence regarding the effectiveness of recommended policy actions had not been systematically synthesised.

Methods

We undertook a systematic search of electronic databases and the grey literature to identify systematic reviews describing the effects of any intervention strategy targeting fruit and/or vegetable intake in children or adults of any age.

Results

The effects of 32 intervention strategies were synthesised from the 19 included reviews. The strategies were mapped across all three broad domains of the NOURISHING framework (i.e. food environment, food system and behaviour change communication), but covered just 14 of the framework’s 65 sub-policy areas. There was evidence supporting the effectiveness of 19 of the 32 intervention strategies. The findings of the umbrella review suggest that intervention strategies implemented within schools, childcare services, homes, workplaces and primary care can be effective, as can eHealth strategies, mass media campaigns, household food production strategies and fiscal interventions.

Conclusions

A range of effective strategy options are available for policy makers and practitioners interested in improving fruit and/or vegetable intake. However, the effects of many strategies – particularly those targeting agricultural production practices, the supply chain and the broader food system – have not been reported in systematic reviews. Primary studies assessing the effects of these strategies, and the inclusion of such studies in systematic reviews, are needed to better inform national and international efforts to improve public health nutrition.

Trial registration

The review protocol was deposited in a publicly available Open Science framework prior to execution of the search strategy. https://osf.io/unj7x/.
Behavioral and neurophysiological effects of an intensified robot-assisted therapy in subacute stroke: a case control study
Authors: Sehle Aida , Stuerner Jana , Hassa Thomas , Spiteri Stefan , Schoenfeld Mircea A. , Liepert Joachim
Published: January 2021

Background

Physical training is able to induce changes at neurophysiological and behavioral level associated with performance changes for the trained movements. The current study explores the effects of an additional intense robot-assisted upper extremity training on functional outcome and motor excitability in subacute stroke patients.

Methods

Thirty moderately to severely affected patients < 3 months after stroke received a conventional inpatient rehabilitation. Based on a case–control principle 15 patients were assigned to receive additional 45 min of robot-assisted therapy (Armeo®Spring) 5 times per week (n = 15, intervention group, IG). The Fugl-Meyer Assessment for the Upper Extremity (FMA-UE) was chosen as primary outcome parameter. Patients were tested before and after a 3-week treatment period as well as after a follow-up period of 2 weeks. Using transcranial magnetic stimulation motor evoked potentials (MEPs) and cortical silent periods were recorded from the deltoid muscle on both sides before and after the intervention period to study effects at neurophysiological level. Statistical analysis was performed with non-parametric tests. Correlation analysis was done with Spearman´s rank correlation co-efficient.

Results

Both groups showed a significant improvement in FMA-UE from pre to post (IG: + 10.6 points, control group (CG): + 7.3 points) and from post to follow-up (IG: + 3.9 points, CG: + 3.3 points) without a significant difference between them. However, at neurophysiological level post-intervention MEP amplitudes were significantly larger in the IG but not in the CG. The observed MEP amplitudes changes were positively correlated with FMA-UE changes and with the total amount of robot-assisted therapy.

Conclusion

The additional robot-assisted therapy induced stronger excitability increases in the intervention group. However, this effect did not transduce to motor performance improvements at behavioral level.

Trial registrationThe trial was registered in German Clinical Trials Register. Clinical trial registration number: DRKS00015083. Registration date: September 4th, 2018.https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00015083. Registration was done retrospectively
Total hip arthroplasty through the direct anterior approach with and without the use of a traction table: a matched-control, retrospective, single-surgeon study
Authors: Wernly Diane , Wegrzyn Julien , Lallemand Geoffroi , Mahlouly Jaad , Tissot Christophe , Antoniadis Alexander
Published: January 2021

Background

Hip surgeons performing total hip arthroplasty (THA) through the direct anterior approach (DAA) commonly use a traction table to facilitate exposure. Even though performing THA through DAA without a traction table could be technically more demanding, this technique offers the advantage of intraoperative leg length comparison. Therefore, this study aimed to compare clinical outcomes, complication rates, component positioning, and leg length discrepancy (LLD) after THA through the DAA performed with or without a traction table.

Methods

A single-surgeon continuous series of 75 patients who underwent DAA THA performed with a traction table was matched for gender, age, and BMI with 75 patients who underwent DAA THA performed without a traction table (male, 62; female, 88, with an average age of 68 years old). Clinical and radiological outcomes, intra- and postoperative complications, and LLD were retrospectively assessed.

Results

No statistically significant difference was detected in surgical time, hospital stay, Harris Hip Score (HHS), complication rates, and implant positioning between the two groups. Leg length restoration was significantly more accurate in the group performed without a traction table (2.4 ± 2 mm vs. 3.7 ± 3.1 mm; p value ≤ 0.05). No LLD > 10 mm was reported in the group performed without a traction table, whereas two cases (2.7%) were reported in those performed with a traction table.

Conclusion

Performing THA through DAA without a traction table was associated with a significantly more accurate leg length restoration without a significant increase in the rates of intra- and postoperative complications.
Hybrid stepwise external wrapping for type a acute aortic dissection with cerebral Malperfusion
Authors: Suematsu Yoshihiro , Nishi Satoshi , Arima Daisuke , Yoshimoto Akihiro
Published: January 2021

Background

Acute aortic dissection (AAD) is a life-threatening condition which can lead to coronary, brachiocephalic or branch vessel malperfusion, as well as aortic valve insufficiency, or aortic rupture. Mortality of surgical treatment in high-risk or elderly patients with Type A AAD (TAAAD) still remains high, and treatment for such patients remains controversial. We report a successful treatment of TAAAD with a communicating false lumen in a 60-year-old man with acute hemi-cerebral malperfusion.

Case presentation

The ascending aorta was wrapped with stepwise external wrapping (SEW) procedure, and subsequent thoracic endovascular aortic repair (TEVAR) was successfully performed. The patient was discharged in good physical condition without any complications.

Conclusions

Hybrid therapy with SEW and TEVAR with TAAAD associated with major cerebral malperfusion should be considered, especially in patients for whom open surgery is extremely risky.
Enhancing mental health pre-service training with the WHO mhGAP Intervention Guide: experiences learned and the way forward
Authors: Iversen Silje Akselberg , Ogallo Brian , Belfer Myron , Fung Daniel , Hoven Christina W. , Carswell Kenneth , Skokauskas Norbert
Published: January 2021

There is currently a high global demand for mental health professionals, including child and adolescent mental health professionals. In 2020, the World Health Organization (WHO) published “Enhancing mental health pre-service training with the mhGAP-Intervention Guide: experiences and lessons learned” to address the proposition of implementing Mental Health Gap Action Programme Intervention Guide (mhGAP-IG) materials and principles as a component of pre-service training. By integrating the mhGAP-IG within pre-service training, future healthcare providers will acquire theoretical knowledge and early exposure to practical knowledge and will be better prepared for their future work.

Examples demonstrate that mhGAP-IG pre-service training can be successfully implemented in diverse settings and in various pre-service training programs. It can be used in small group learning activities and short courses, taught through lectures, used as a clinical tool to teach students (i.e. medical, nursing students) and medical doctors in training. We can enhance pre-service training with the mhGAP-IG and contribute to a learning environment, which nurtures knowledge and skills required to help people with mental health needs.
Identification of the active substances and mechanisms of ginger for the treatment of colon cancer based on network pharmacology and molecular docking
Authors: Zhang Meng-Meng , Wang Dan , Lu Feng , Zhao Rong , Ye Xun , He Lin , Ai Li , Wu Chun-Jie
Published: January 2021

Background and objective

Colon cancer is occurring at an increasing rate and ginger (Zingiber officinale), as a commonly used herbal medicine, has been suggested as a potential agent for colon cancer. This study was aimed to identify the bioactive components and potential mechanisms of ginger for colon cancer prevention by an integrated network pharmacology approach.

Methods

The putative ingredients of ginger and its related targets were discerned from the TCMSP  and Swiss target prediction database. After that, the targets interacting with colon cancer were collected using Genecards, OMIM, and Drugbank databases. KEGG pathway and GO enrichment analysis were performed to explore the signaling pathways related to ginger for colon cancer treatments. The PPI and compound-target-disease networks were constructed using Cytoscape 3.8.1. Finally, Discovery studio software was employed to confirm the key genes and active components from ginger.

Results

Six potential active compounds, 285 interacting targets in addition to 1356 disease-related targets were collected, of which 118 intersection targets were obtained. A total of 34 key targets including PIK3CA, SRC, and TP53 were identified through PPI network analysis. These targets were mainly focused on the biological processes of phosphatidylinositol 3-kinase signaling, cellular response to oxidative stress, and cellular response to peptide hormone stimulus. The KEGG enrichment manifested that three signaling pathways were closely related to colon cancer prevention of ginger, cancer, endocrine resistance, and hepatitis B pathways. TP53, HSP90AA1, and JAK2 were viewed as the most important genes, which were validated by molecular docking simulation.

Conclusion

This study demonstrated that ginger produced preventive effects against colon cancer by regulating multi-targets and multi-pathways with multi-components. And, the combined data provide novel insight for ginger compounds developed as new drug for anti-colon cancer.
Pegylated liposomal doxorubicin in patients with epithelial ovarian cancer
Authors: Yuan Zhen , Zhang Ying , Cao Dongyan , Shen Keng , Li Qingshui , Zhang Guonan , Wu Xiaohua , Cui Manhua , Yue Ying , Cheng Wenjun , Wang Li , Qu Pengpeng , Tao Guangshi , Hou Jianqing , Sun Lixin , Meng Yuanguang , Li Guiling , Li Changzhong , Shi Huirong , Chen Yaqing
Published: January 2021

Objective

To evaluate the efficacy and safety of PLD in treating of in patients who experience epithelial ovarian, fallopian tubal, and peritoneal cancer progression within 12 months after the first-line platinum-based therapy.

Methods

This was an open-label, single-arm and multicenter clinical trial. The ORR was the interim primary objective, and the DCR, AEs and QOL were the secondary objectives. The impact of factors on efficacy outcomes, the change trend of CA125 and the artificial platinum-free interval were exploratory endpoints.

Results

Totally, 115 patients were enrolled in this study and included in the ITT population. Moreover, 101 patients were included in the safety population. The median follow-up time was 4 months (IQR 2–6). In the ITT population, the confirmed ORR was 37.4% (95% CI, 28.4–46.4%), and the DCR was 65.2% (95% CI, 56.4–74.1%). The previous response status to platinum-based chemotherapy and baseline CA125 levels were significantly correlated with the ORR. The ORR was significantly higher in patients with a CA125 decrease after the first cycle than in the patients with a CA125 increase. The most common grade 3 or higher AE was hand-foot syndrome (3 [3.0%] of 101 patients). No statistically significant differences existed between the baseline and the postbaseline questionnaires.

Conclusions

For patients who experience platinum-resistant and platinum-refractory relapse, the use of PLD may be acceptable because of the associated satisfactory efficacy, low frequency of AEs and high patient QOL. Moreover, a low CA125 level at baseline and a reduction in CA125 after the first cycle are predictive factors for satisfactory efficacy.
Human recombinant arginase I [HuArgI (Co)-PEG5000]-induced arginine depletion inhibits ovarian cancer cell adhesion and migration through autophagy-mediated inhibition of RhoA
Authors: El-Mais Nour , Fakhoury Isabelle , Abdellatef Sandra , Abi-Habib Ralph , El-Sibai Mirvat
Published: January 2021

Ovarian carcinoma is the second most common malignancy of the female reproductive system and the leading cause of death from female reproductive system malignancies. Cancer cells have increased proliferation rate and thus require high amounts of amino acids, including arginine. L-arginine is a non-essential amino acid synthesized from L-citrulline by the Arginosuccinate synthetase (ASS1) enzyme. We have previously shown that the ovarian cancer cells, SKOV3, are auxotrophic to arginine, and that arginine deprivation by treatment with the genetically engineered human arginase I (HuArgI (Co)-PEG5000) triggers the death of SKOV3 cells by autophagy. In this study we examine the effect of HuArgI (Co)-PEG5000 on ovarian cancer cell migration and we dissect the mechanism involved. Wound healing assays, 2D random cell migration assays and cell adhesion analysis indicate that arginine deprivation decreases SKOV3 cell migration and adhesion. This effect was mimicked when autophagy was induced through rapamycin and reversed with the autophagy inhibitor chloroquine when autophagy was inhibited. This proved that arginine deprivation leads to the inhibition of cancer cell migration through autophagy, in addition to cell death. In addition, we were able to establish through pull-down assays and reversal experiments, that arginine deprivation-mediated autophagy inhibits cell migration through a direct inhibition of RhoA, member of the Rho family of GTPases. In conclusion, here we identify, for the first time, an autophagy-mediated inhibition of RhoA that plays an important role in regulating ovarian cancer cells motility and adhesion in response to arginine depletion.
Minimally Invasive Versus open AbdominoThoracic Esophagectomy for esophageal carcinoma (MIVATE) — study protocol for a randomized controlled trial DRKS00016773
Authors: Nickel Felix , Probst Pascal , Studier-Fischer Alexander , Nienhüser Henrik , Pauly Jana , Kowalewski Karl-Friedrich , Weiterer Sebastian , Knebel Philipp , Diener Markus K. , Weigand Markus A. , Büchler Markus W. , Schmidt Thomas , Müller-Stich Beat P.
Published: January 2021

Background

The only curative treatment for most esophageal cancers is radical esophagectomy. Minimally invasive esophagectomy (MIE) aims to reduce postoperative morbidity, but is not yet widely established. Linear stapled anastomosis is a promising technique for MIE because it is quite feasible even without robotic assistance. The aim of the present study is to compare total MIE with linear stapled anastomosis to open esophagectomy (OE) with circular stapled anastomosis with special regard to postoperative morbidity in an expertise-based randomized controlled trial (RCT).

Methods/design

This superiority RCT compares MIE with linear stapled anastomosis (intervention) to OE with circular stapled anastomosis (control) for Ivor-Lewis esophagectomy. It was initiated in February 2019, and recruitment is expected to last for 3 years. For inclusion, patients must be 18 years of age or more with a resectable primary malignancy in the distal esophagus. Participants with tumor localizations above the azygos vein, metastasis, or infiltration into adjacent tissue will be excluded. In an expertise-based approach, the allocated treatment will only be carried out by the single most experienced surgeon of the surgical center for each respective technique. The sample size was calculated with 20 participants per group for the primary endpoint postoperative morbidity according to comprehensive complication index (CCI) within 30 postoperative days. Secondary endpoints include anastomotic insufficiency, pulmonary complications, other intra- and postoperative outcome parameters such as estimated blood loss, operative time, length of stay, short-term oncologic endpoints, adherence to a standardized fast-track protocol, postoperative pain, and postoperative recovery (QoR-15). Quality of life (SF-36, CAT EORTC QLQ-C30, CAT EORTC QLQ-OES18) and oncological outcomes are evaluated with 60 months follow-up.

Discussion

MIVATE is the first RCT to compare OE with circular stapled anastomosis to total MIE with linear stapled anastomosis exclusively for intrathoracic anastomosis. The expertise-based approach limits bias due to heterogeneity of surgical expertise. The use of a dedicated fast-track protocol in both OE and MIE will shed light on the role of the access strategy alone in this setting. The findings of this study will serve to define which approach has the best perioperative outcome for patients requiring esophagectomy.

Trial registration

German Clinical Trials Register DRKS00016773. Registered on 18 February 2019.
Viral load-guided immunosuppression after lung transplantation (VIGILung)—study protocol for a randomized controlled trial
Authors: Gottlieb Jens , Reuss Alexander , Mayer Konstantin , Weide Karin , Schade-Brittinger Carmen , Hoyer Susanne , Jaksch Peter
Published: January 2021

Background

Immunosuppression including high-dose calcineurin inhibitors (CNI) is essential after lung transplantation. Dosing is usually guided by therapeutic drug monitoring adjusted to target trough levels of CNIs to keep the balance between over-dose causing severe toxicity and increased risk of infections or under-dose with a risk of graft injury. Adaptation of CNI-based immunosuppression by monitoring of torque teno virus (TTV), a latent nonpathogenic DNA virus, measured in the whole blood in addition to conventional therapeutic drug monitoring may reduce the toxicity of immunosuppression with similar efficacy.

Methods/design

An open-label, randomized, controlled, parallel-group, multicenter trial in lung transplant recipients will be conducted to investigate the safety and efficacy of immunosuppression guided by TTV monitoring as an add-on to conventional therapeutic drug monitoring. Adult lung transplant recipients 21 to 42 days after transplantation are eligible to participate. Patients (N = 144) will be randomized 1:1 to the experimental intervention (arm 1: immunosuppression guided by TTV monitoring in addition to conventional therapeutic drug monitoring of tacrolimus trough levels) and control intervention (arm 2: conventional therapeutic drug monitoring). Outcomes will be assessed 12 months after randomization with the change in glomerular filtration rate as the primary endpoint. Secondary endpoints will be additional measurements of renal function, allograft function, incidence of acute rejections, incidence of chronic lung allograft dysfunction, graft loss, and infections.

Discussion

The results of this randomized controlled trial may reduce the toxicity of immunosuppression after lung transplantation while maintaining the efficacy of immunosuppression. Study results are transferable to all other solid organ transplantations.

Trial registration

ClinicalTrials.gov NCT04198506. Registered on 12 December 2019
Prevalence of asymptomatic visceral leishmaniasis in human and dog, Benishangul Gumuz regional state, Western Ethiopia
Authors: Bejano Shibabaw , Shumie Girma , Kumar Ashwani , Asemahagn Eyuel , Damte Demekech , Woldie Sinkinesh , Mulugeta Abate , Manaye Nigus , Genetu Abebe , Gadisa Endalamaw , Mamo Gezahegn
Published: January 2021

Background

The Benishangul-Gumuz region is an important development corridor in Ethiopia. Large-scale projects such as the Great Renaissance Dam, mining and agriculture have entailed huge environmental modifications and settlement pattern changes. There is no detailed epidemiological information on visceral leishmaniasis (VL) in the region.

Materials and methods

A cross-sectional study was carried out to assess the epidemiology and risk factors associated with Leishmania infection. A leishmanin skin test (LST) was done for 1342 participants, and for 253 of them rK39 and DAT were carried out. Thirty-six dogs owned by households with LST-positive member(s) were rK39 and DAT tested. A pretested questionnaire was used to capture individual and household characteristics.

Results

Of the 89.2% (1197/1342) who availed themselves of the LST reading, 6.0% were positive. The rk39 and DAT positivity among the 253 tested were 3.2% and 5.9%, respectively. In dogs, positivity rates by rK39 and DAT were 13.9% and 5.6%, respectively. Of the household and individual risk factors, presence of a dog in the household (P = 0.005), male sex (0.003), residence woreda (0.000) and occupation (0.023) showed a strong positive association with LST positivity. Individuals who lived in households that had dogs were 2.6 times more likely to be LST positive (AOR = 2.6; 95% CI = 1.54, 4.40). Being female decreased the probability of being LST positive by 0.38 times (AOR = 0.38; 95% CI = 0.20, 0.72). People living in Guba and Kurmuk had 4.7 (AOR = 4.74, 95% CI 1.83, 12.31) and 5.9 (AOR = 5.85, 95% CI 2.27, 15.09) times more risk of being infected.

Conclusions

We demonstrated the presence of active VL transmission in the areas. Thus, we underline the need to establish the responsible vector(s) and reservoir(s) for comprehensive early containment plans to prevent potentially harmful public health and economic consequences.

Graphical Abstract