bluuebunny/crossref_metadata_2025 huggingface dataset:
Systemic lupus Erythematosus activity and Hydroxychloroquine use before and after end-stage renal disease
Authors: Salgado Guerrero Maria , Londono Jimenez Alejandra , Dobrowolski Chrisanna , Mowrey Wenzhu B. , Goilav Beatrice , Wang Shudan , Broder Anna
Published: October 2020

Background

SLE manifestations after ESRD may be underdiagnosed and undertreated, contributing to increased morbidity and mortality. Whether specific symptoms persist after ESRD or a shift towards new manifestations occurs has not been extensively studied, especially in the non-Caucasian patients in the United States. In addition, hydroxychloroquine (HCQ) prescribing patterns post-ESRD have not been described. The objective of this study was to assess lupus activity and HCQ prescribing before and after ESRD development. Knowledge gained from this study may aid in the identification of SLE manifestations and improve medication management post-ESRD.

Methods

We performed a retrospective cohort study of SLE patients with incident ESRD between 2010 and 2017. SLE-related symptoms, serologic markers of disease activity, and medication use were collected from medical records before and after ESRD development.

Results

Fifty-nine patients were included in the study. Twenty-five (43%) patients had at least one clinical (non-renal) SLE manifestation documented within 12 months before ESRD. Of them, 11/25 (44%) continued to experience lupus symptoms post-ESRD; 9 patients without clinical or serological activity pre-ESRD developed new symptoms of active SLE. At the last documented visit post-ESRD, 42/59 (71%) patients had one or more clinical or serological markers of lupus activity; only 17/59 (29%) patients achieved clinical and serological remission.

Thirty-three of 59 (56%) patients had an active HCQ prescription at the time of ESRD. Twenty-six of the 42 (62%) patients with active SLE manifestations post-ESRD were on HCQ. Patients who continued HCQ post-ESRD were more likely to be followed by a rheumatologist (26 [87%] vs 17 [61%],p = 0.024), had a higher frequency of documented arthritis (10 [32%] vs 1 [4%],p = 0.005), CNS manifestations (6 [20%] vs 1 [4%],p = 0.055), and concurrent immunosuppressive medication use (22 [71%] vs 12 [43%],p = 0.029).

Conclusions

Lupus activity may persist after the development of ESRD. New onset arthritis, lupus-related rash, CNS manifestations, low complement and elevated anti-dsDNA may develop. HCQ may be underutilized in patients with evidence of active disease pre- and post ESRD. Careful clinical and serological monitoring for signs of active disease and frequent rheumatology follow up is advised in SLE patients both, pre and post-ESRD.
Kidney transplantation from living donor with monolateral renal artery fibromuscular dysplasia using a cryopreserved iliac graft for arterial reconstruction: a case report and review of the literature
Authors: Nguefouet Momo Rostand Emmanuel , Donato Paola , Ugolini Gabriele , Nacchia Francesco , Mezzetto Luca , Veraldi Gian Franco , Marletta Stefano , Cavallo Enrico , Eccher Albino , Giambanco Annamaria , Cenzi Daniela , Boschiero Luigino
Published: October 2020

Background

Aging and mortality of patients on waiting lists for kidney transplantation have increased, as a result of the shortage of organs available all over the world. Living donor grafts represent a significant source to maintain the donor pool, and resorting successfully to allografts with arterial disease has become a necessity. The incidence of renal artery fibromuscular dysplasia (FMD) in potential living renal donors is reported to be 2–6%, and up to 4% of them present concurrent extra-renal involvement.

Case presentation

We present a case of renal transplantation using a kidney from a living donor with monolateral FMD. Resection of the affected arterial segment and its subsequent replacement with a cryopreserved iliac artery graft from a deceased donor were performed. No intraoperative nor post-operative complications were reported. The allograft function promptly resumed, with satisfying creatinine clearance, and adequate patency of the vascular anastomoses was detected by Doppler ultrasounds.

Conclusion

Literature lacks clear guidelines on the eligibility of potential living renal donors with asymptomatic FMD. Preliminary assessment of the FMD living donor should always rule out any extra-renal involvement. Whenever possible, resection and reconstruction of the affected arterial segment should be taken into consideration as this condition may progress after implantation.
Integrated genomic and transcriptomic analysis revealed mutation patterns of de-differentiated liposarcoma and leiomyosarcoma
Authors: Liu Wenshuai , Tong Hanxing , Zhang Chenlu , Zhuang Rongyuan , Guo He , Lv Chentao , Yang Hua , Lin Qiaowei , Guo Xi , Wang Zhiming , Wang Yan , Shen Feng , Wang Shengzhou , Dai Chun , Wang Guan , Liu Jun , Lu Weiqi , Zhang Yong , Zhou Yuhong
Published: October 2020

Background

Treating patients with advanced sarcomas is challenging due to great histologic diversity among its subtypes. Leiomyosarcoma (LMS) and de-differentiated liposarcoma (DDLPS) are two common and aggressive subtypes of soft tissue sarcoma (STS). They differ significantly in histology and clinical behaviors. However, the molecular driving force behind the difference is unclear.

Methods

We collected 20 LMS and 12 DDLPS samples and performed whole exome sequencing (WES) to obtain their somatic mutation profiles. We also performed RNA-Seq to analyze the transcriptomes of 8 each of the LMS and DDLPS samples and obtained information about differential gene expression, pathway enrichment, immune cell infiltration in tumor microenvironment, and chromosomal rearrangement including gene fusions. Selected gene fusion events from the RNA-seq prediction were checked by RT-PCR in tandem with Sanger sequencing.

Results

We detected loss of function mutation and deletion of tumor suppressors mostly in LMS, and oncogene amplification mostly in DDLPS. A focal amplification affecting chromosome 12q13–15 region which encodesMDM2,CDK4andHMGA2is notable in DDLPS. Mutations inTP53,ATRX,PTEN, andRB1are identified in LMS but not DDLPS, while mutation of HERC2 is only identified in DDLPS but not LMS. RNA-seq revealed overexpression ofMDM2,CDK4andHMGA2in DDLPS and down-regulation ofTP53andRB1in LMS. It also detected more fusion events in DDLPS than LMS (4.5 vs. 1,p = 0.0195), and the ones involving chromosome 12 in DDLPS stand out. RT-PCR and Sanger sequencing verified the majority of the fusion events in DDLPS but only one event in LMS selected to be tested. The tumor microenvironmental signatures are highly correlated with histologic types. DDLPS has more endothelial cells and fibroblasts content than LMS.

Conclusions

Our analysis revealed different recurrent genetic variations in LMS and DDLPS including simultaneous upregulation of gene expression and gene copy number amplification ofMDM2andCDK4. Up-regulation of tumor related genes is favored in DDLPS, while loss of suppressor function is favored in LMS. DDLPS harbors more frequent fusion events which can generate neoepitopes and potentially targeted by personalized immune treatment.
Increased E2F2 predicts poor prognosis in patients with HCC based on TCGA data
Authors: Zeng Zhili , Cao Zebiao , Tang Ying
Published: October 2020

Background

The E2F family of transcription factor 2 (E2F2) plays an important role in the development and progression of various tumors, but its association with hepatocellular carcinoma (HCC) remains unknown. Our study aimed to investigate the role and clinical significance of E2F2 in HCC.

Methods

HCC raw data were extracted from The Cancer Genome Atlas (TCGA). Wilcoxon signed-rank test, Kruskal-Wallis test and logistic regression were applied to analyze the relationship between the expression of E2F2 and clinicopathologic characteristics. Cox regression and Kaplan-Meier were employed to evaluate the correlation between clinicopathologic features and survival. The biological function of E2F2 was annotated by Gene Set Enrichment Analysis (GSEA).

Results

The expression of E2F2 was increased in HCC samples. The expression of elevated E2F2 in HCC samples was prominently correlated with histologic grade (OR = 2.62 for G3–4 vs. G1–2, p = 1.80E-05), clinical stage (OR = 1.74 for III-IV vs. I-II, p = 0.03), T (OR = 1.64 for T3–4 vs.T1–2, p = 0.04), tumor status (OR = 1.88 for with tumor vs. tumor free, p = 3.79E-03), plasma alpha fetoprotein (AFP) value (OR = 3.18 for AFP ≥ 400 vs AFP<20, p = 2.16E-04; OR = 2.50 for 20 ≤ AFP<400 vs AFP<20, p = 2.56E-03). Increased E2F2 had an unfavorable OS (p = 7.468e− 05), PFI (p = 3.183e− 05), DFI (p = 0.001), DSS (p = 4.172e− 05). Elevated E2F2 was independently bound up with OS (p = 0.004, hazard ratio [HR] = 2.4 (95% CI [1.3–4.2])), DFI (P = 0.029, hazard ratio [HR] = 2.0 (95% CI [1.1–3.7])) and PFI (P = 0.005, hazard ratio [HR] = 2.2 (95% CI [1.3–3.9])). GSEA disclosed that cell circle, RNA degradation, pyrimidine metabolism, base excision repair, aminoacyl tRNA biosynthesis, DNA replication, p53 signaling pathway, nucleotide excision repair, ubiquitin-mediated proteolysis, citrate cycle TCA cycle were notably enriched in E2F2 high expression phenotype.

Conclusions

Elevated E2F2 can be a promising independent prognostic biomarker and therapeutic target for HCC. Additionally, cell cycle, pyrimidine metabolism, DNA replication, p53 signaling pathway, ubiquitin-mediated proteolysis, the citrate cycle TCA cycle may be the key pathway by which E2F2 participates in the initial and progression of HCC.
The majority of β-catenin mutations in colorectal cancer is homozygous
Authors: Arnold Alexander , Tronser Moritz , Sers Christine , Ahadova Aysel , Endris Volker , Mamlouk Soulafa , Horst David , Möbs Markus , Bischoff Philip , Kloor Matthias , Bläker Hendrik
Published: October 2020

Background

β-catenin activation plays a crucial role for tumourigenesis in the large intestine but except for Lynch syndrome (LS) associated cancers stabilizing mutations of β-catenin gene (CTNNB1) are rare in colorectal cancer (CRC). Previous animal studies provide an explanation for this observation. They showed that CTNNB1 mutations induced transformation in the colon only when CTNNB1 was homozygously mutated or when membranous β-catenin binding was hampered by E-cadherin haploinsufficiency. We were interested, if these mechanisms are also found in human CTNNB1 mutated CRCs.

Results

Among 869 CRCs stabilizing CTNNB1 mutations were found in 27 cases. Homo- or hemizygous CTNNB1 mutations were detected in 74% of CTNNB1 mutated CRCs (13 microsatellite instabile (MSI-H), 7 microsatellite stabile (MSS)) but only in 3% (1/33) of extracolonic CTNNB1 mutated cancers. In contrast to MSS CRC, CTNNB1 mutations at codon 41 or 45 were highly selected in MSI-H CRC. Of the examined three CRC cell lines, β-catenin and E-cadherin expression was similar in cell lines without or with hetereozygous CTNNB1 mutations (DLD1 and HCT116), while a reduced E-cadherin expression combined with cytoplasmic accumulation of β-catenin was found in a cell line with homozygous CTNNB1 mutation (LS180). Reduced expression of E-cadherin in human MSI-H CRC tissue was identified in 60% of investigated cancers, but no association with the CTNNB1 mutational status was found.

Conclusions

In conclusion, this study shows that in contrast to extracolonic cancers stabilizing CTNNB1 mutations in CRC are commonly homo- or hemizygous indicating a higher threshold of β-catenin stabilization to be required for transformation in the colon as compared to extracolonic sites. Moreover, we found different mutational hotspots in CTNNB1 for MSI-H and MSS CRCs suggesting a selection of different effects on β-catenin stabilization according to the molecular pathway of tumourigenesis. Reduced E-cadherin expression in CRC may further contribute to higher levels of transcriptionally active β-catenin, but it is not directly linked to the CTNNB1 mutational status.
Determining the effects of trastuzumab, cetuximab and afatinib by phosphoprotein, gene expression and phenotypic analysis in gastric cancer cell lines
Authors: Ebert Karolin , Zwingenberger Gwen , Barbaria Elena , Keller Simone , Heck Corinna , Arnold Rouven , Hollerieth Vanessa , Mattes Julian , Geffers Robert , Raimúndez Elba , Hasenauer Jan , Luber Birgit
Published: October 2020

Background

Gastric cancer is the fifth most frequently diagnosed cancer and the third leading cause of cancer death worldwide. The molecular mechanisms of action for anti-HER-family drugs in gastric cancer cells are incompletely understood. We compared the molecular effects of trastuzumab and the other HER-family targeting drugs cetuximab and afatinib on phosphoprotein and gene expression level to gain insights into the regulated pathways. Moreover, we intended to identify genes involved in phenotypic effects of anti-HER therapies.

Methods

A time-resolved analysis of downstream intracellular kinases following EGF, cetuximab, trastuzumab and afatinib treatment was performed by Luminex analysis in the gastric cancer cell lines Hs746T, MKN1, MKN7 and NCI-N87. The changes in gene expression after treatment of the gastric cancer cell lines with EGF, cetuximab, trastuzumab or afatinib for 4 or 24 h were analyzed by RNA sequencing. Significantly enriched pathways and gene ontology terms were identified by functional enrichment analysis. Furthermore, effects of trastuzumab and afatinib on cell motility and apoptosis were analyzed by time-lapse microscopy and western blot for cleaved caspase 3.

Results

The Luminex analysis of kinase activity revealed no effects of trastuzumab, while alterations of AKT1, MAPK3, MEK1 and p70S6K1 activations were observed under cetuximab and afatinib treatment. On gene expression level, cetuximab mainly affected the signaling pathways, whereas afatinib had an effect on both signaling and cell cycle pathways. In contrast, trastuzumab had little effects on gene expression. Afatinib reduced average speed in MKN1 and MKN7 cells and induced apoptosis in NCI-N87 cells. Following treatment with afatinib, a list of 14 genes that might be involved in the decrease of cell motility and a list of 44 genes that might have a potential role in induction of apoptosis was suggested. The importance of one of these genes (HBEGF) as regulator of motility was confirmed by knockdown experiments.

Conclusions

Taken together, we described the different molecular effects of trastuzumab, cetuximab and afatinib on kinase activity and gene expression. The phenotypic changes following afatinib treatment were reflected by altered biological functions indicated by overrepresentation of gene ontology terms. The importance of identified genes for cell motility was validated in case of HBEGF.
Supporting mental health service users to stop smoking: findings from a process evaluation of the implementation of smokefree policies into two mental health trusts
Authors: Jones S. E. , Mulrine S. , Clements H. , Hamilton S.
Published: October 2020

Background

Life expectancy is 10–20 years lower among people with a severe mental health disorder. Most of these early deaths are due to chronic conditions, including cardiovascular and respiratory diseases. Smoking is a major risk factor for these conditions and introducing smokefree policies has been recommended to mental health service providers in England by the National Institute for Health and Care Excellence (NICE), in their Public Health Guideline 48: Smoking: acute, maternity and mental health services. This paper reports a process evaluation of introducing these policy recommendations, which were updated in 2013.

Method

Process data were collected through semi-structured interviews with staff (n = 51), members of partnering organisations (n = 5), service users (n = 7) and carers (n = 2) between November 2016 – April 2017. Normalization Process Theory (NPT) was used to design the data collection tools and analyse the data. A framework approach was taken with the analysis, using the four concepts of NPT: coherence, cognitive participation, collective action and reflexive monitoring.

Results

The policy made sense to some staff, patients and carers (coherence) who ‘bought-into’ the idea (cognitive participation) but other participants disagreed. Although smokefree policies were operationalised (collective action), sometimes they were opposed. Progress was made, especially in some units, but continued to be resisted in others. Informal appraisal of progress (reflexive monitoring) presented a varied picture.

Conclusion

Some progress has been made in terms of changing an entrenched, smoking culture into one that is smokefree on Trust sites across the region. Perseverance and resourcing over the long-term is required to establish a non-smoking culture in on-site provision of mental health services.
Adherence to recommendations for ART and targeted PrEP use among HIV serodiscordant couples in East Africa: the “PrEP as a bridge to ART” strategy
Authors:   on behalf of the Partners Demonstration Project Team, Musinguzi Nicholas , Kidoguchi Lara , Mugo Nelly R. , Ngure Kenneth , Katabira Elly , Celum Connie L. , Baeten Jared M. , Heffron Renee , Haberer Jessica E.
Published: October 2020

Background

PrEP use should be aligned with periods of risk for HIV acquisition. For HIV serodiscordant couples, PrEP can be used as a bridge until the partner living with HIV takes antiretroviral therapy (ART) long enough to achieve viral suppression (the “PrEP as a Bridge to ART” strategy). However, adherence to this strategy is unknown.

Methods

In a demonstration project in Kenya and Uganda, HIV-uninfected partners of serodiscordant couples were advised to take PrEP until the partner living with HIV took ART for ≥ 6 months. PrEP discontinuation was then recommended unless there were concerns about ART adherence, immediate fertility intentions, or outside partners with unknown HIV/ART status. Electronic adherence monitoring and socio-behavioral questionnaire data were used in logistic regression models to explore completion of this strategy and continuation of PrEP beyond recommendations to stop its use.

Results

Among 833 serodiscordant couples, 436 (52%) HIV-uninfected partners completed ≥ 6 months of PrEP as a bridge to ART. Strategy completion was associated with older age (aOR per 5 years = 1.1; p = 0.008) and having fewer children (aOR = 0.9; p = 0.019). Of the 230 participants encouraged to stop PrEP according to strategy recommendations, 170 (74%) did so. PrEP continuation among the remaining 60 participants was associated with more education (aOR = 1.1; p = 0.029), a preference for PrEP over ART (aOR = 3.6; p = 0.026), comfort with managing their serodiscordant relationship (aOR = 0.6; p = 0.046), and believing PrEP makes sex safe (aOR = 0.5; p = 0.026).

Conclusion

Half of participants completed the PrEP as a bridge to ART strategy and the majority stopped PrEP as recommended. These findings suggest that targeting PrEP to periods of risk is a promising approach; however, tailoring counseling around aligning PrEP use and HIV risk will be important for optimal strategy implementation.
Sleep duration and mortality in Korean adults: a population-based prospective cohort study
Authors: Kwon Sohyeon , Lee Hyeyoung , Lee Jong-Tae , Shin Min-Jeong , Choi Sangbum , Oh Hannah
Published: October 2020

Background

Increasing evidence suggests that sleep duration is associated with risks of various diseases including type 2 diabetes, cardiovascular disease (CVD), and certain types of cancer. However, the relationship with mortality is not clear, particularly in non-European populations. In this study, we investigated the association between sleep duration and mortality in a population-based prospective cohort of Korean adults.

Methods

This analysis included 34,264 participants (14,704 men and 19,560 women) of the Korea National Health and Nutrition Examination Survey (KNHANES) 2007–2013 who agreed to mortality follow-up through December 31, 2016. Sleep duration was self-reported at baseline and was categorized into four groups: ≤4, 5–6, 7–8, and ≥ 9 h/day. Cox proportional hazards models were performed to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the associations with mortality (all-cause as well as CVD- and cancer-specific), adjusting for potential confounders.

Results

During up to 9.5 years of follow-up, we identified a total of 1028 deaths. We observed the lowest mortality at 5–6 h/day sleep. Compared with 7–8 h/day of sleep, short (≤4 h/day) and long (≥9 h/day) sleep were associated with a 1.05-fold (95% CI = 0.79–1.39) and 1.47-fold (95% CI = 1.15–1.87) higher all-cause mortality, respectively. After additional adjustment for self-rated health, the positive association with short sleep disappeared (HR = 0.99, 95% CI = 0.75–1.32) and the association with long sleep was slightly attenuated (HR = 1.38, 95% CI = 1.08–1.76). Long sleep was also nonsignificantly positively associated with both cancer-mortality (HR = 1.30, 95% CI = 0.86–1.98) and CVD-mortality (HR = 1.27, 95% CI = 0.73–2.21). There was no statistically significant evidence for nonlinearity in the relationships between sleep duration and mortality (all-cause as well as CVD- and cancer-specific). Effect modification by age, sex, education, and occupation were not statistically significant.

Conclusions

Our findings suggest that long sleep duration is associated with an increased all-cause mortality in Korean adults.
532 nm green-light laser vaporization of upper tract urothelial carcinoma
Authors: Dursun F. , Pan M. M. , Morgan M. , Gonzalez R. R. , Satkunasivam R.
Published: October 2020

Background

Endoscopic management of low risk upper tract urothelial carcinoma (UTUC) may be considered in select clinical scenarios, which allows sparing the morbidity of radical nephroureterectomy while achieving acceptable oncological outcomes and preservation of kidney function. Herein, we present a case with UTUC in a solitary kidney managed with 532 nm laser vaporization through a percutaneous approach.

Case presentation

The patient in this video (Additional file 1) is an 85-year-old woman who presented with a bulky tumor in the collecting system of a congenital solitary left kidney, which was a biopsy proven low grade urothelial carcinoma. Prior to the procedure, a lower pole percutaneous nephrostomy tube was successfully placed under sedation by Interventional Radiology. The procedure was done in a prone split leg position. The mass, which was predominantly localized to the renal pelvis was efficiently vaporized with the 532 nm laser in a systematic manner with continuous irrigation of normal saline through the cystoscope. The patient was discharged home on postoperative day 2 with the nephroureterostomy catheter open to drainage. This catheter was subsequently clamped and removed two weeks later without complications. Follow up uretroscopy showed excellent treatment response and the patient remains well without complications.

Conclusion

This case report details the potential utility of 532 nm laser vaporization of UTUC, however, ongoing studies are required to demonstrate peri-operative safety and durable oncologic efficacy.
Redundant trials can be prevented, if the EU clinical trial regulation is applied duly
Authors: Kim Daria , Hasford Joerg
Published: October 2020

The problem of wasteful clinical trials has been debated relentlessly in the medical community. To a significant extent, it is attributed to redundant trials – studies that are carried out to address questions, which can be answered satisfactorily on the basis of existing knowledge and accessible evidence from prior research. This article presents the first evaluation of the potential of the EU Clinical Trials Regulation 536/2014, which entered into force in 2014 but is expected to become applicable at the end of 2021, to prevent such trials. Having reviewed provisions related to the trial authorisation, we propose how certain regulatory requirements for the assessment of trial applications can and should be interpreted and applied by national research ethics committees and other relevant authorities in order to avoid redundant trials and, most importantly, preclude the unnecessary recruitment of trial participants and their unjustified exposure to health risks.
Correction to: Synergy between hemagglutinin 2 (HA2) subunit of influenza fusogenic membrane glycoprotein and oncolytic Newcastle disease virus suppressed tumor growth and further enhanced by Immune checkpoint PD-1 blockade
Authors: Miri Seyed Mohammad , Ebrahimzadeh Mir Saeed , Abdolalipour Elahe , Yazdi Mahsa , Ravandi Hassan Hosseini , Ghaemi Amir
Published: October 2020

An amendment to this paper has been published and can be accessed via the original article.
Effects of selectively assisting impaired subtasks of walking in chronic stroke survivors
Authors: Fricke Simone S. , Smits Hilde J. G. , Bayón Cristina , Buurke Jaap H. , van der Kooij Herman , van Asseldonk Edwin H. F.
Published: October 2020

Background

Recently developed controllers for robot-assisted gait training allow for the adjustment of assistance for specific subtasks (i.e. specific joints and intervals of the gait cycle that are related to common impairments after stroke). However, not much is known about possible interactions between subtasks and a better understanding of this can help to optimize (manual or automatic) assistance tuning in the future. In this study, we assessed the effect of separately assisting three commonly impaired subtasks after stroke: foot clearance (FC, knee flexion/extension during swing), stability during stance (SS, knee flexion/extension during stance) and weight shift (WS, lateral pelvis movement). For each of the assisted subtasks, we determined the influence on the performance of the respective subtask, and possible effects on other subtasks of walking and spatiotemporal gait parameters.

Methods

The robotic assistance for the FC, SS and WS subtasks was assessed in nine mildly impaired chronic stroke survivors while walking in the LOPES II gait trainer. Seven trials were performed for each participant in a randomized order: six trials in which either 20% or 80% of assistance was provided for each of the selected subtasks, and one baseline trial where the participant did not receive subtask-specific assistance. The influence of the assistance on performances (errors compared to reference trajectories) for the assisted subtasks and other subtasks of walking as well as spatiotemporal parameters (step length, width and height, swing and stance time) was analyzed.

Results

Performances for the impaired subtasks (FC, SS and WS) improved significantly when assistance was applied for the respective subtask. Although WS performance improved when assisting this subtask, participants were not shifting their weight well towards the paretic leg. On a group level, not many effects on other subtasks and spatiotemporal parameters were found. Still, performance for the leading limb angle subtask improved significantly resulting in a larger step length when applying FC assistance.

Conclusion

FC and SS assistance leads to clear improvements in performance for the respective subtask, while our WS assistance needs further improvement. As effects of the assistance were mainly confined to the assisted subtasks, tuning of FC, SS and WS can be done simultaneously. Our findings suggest that there may be no need for specific, time-intensive tuning protocols (e.g. tuning subtasks after each other) in mildly impaired stroke survivors.
Immersive Virtual Environments and Wearable Haptic Devices in rehabilitation of children with neuromotor impairments: a single-blind randomized controlled crossover pilot study
Authors: Bortone Ilaria , Barsotti Michele , Leonardis Daniele , Crecchi Alessandra , Tozzini Alessandra , Bonfiglio Luca , Frisoli Antonio
Published: October 2020

Background

The past decade has seen the emergence of rehabilitation treatments using virtual reality. One of the advantages in using this technology is the potential to create positive motivation, by means of engaging environments and tasks shaped in the form of serious games. The aim of this study is to determine the efficacy of immersive Virtual Environments and weaRable hAptic devices (VERA) for rehabilitation of upper limb in children with Cerebral Palsy (CP) and Developmental Dyspraxia (DD).

Methods

A two period cross-over design was adopted for determining the differences between the proposed therapy and a conventional treatment. Eight children were randomized into two groups: one group received the VERA treatment in the first period and the manual therapy in the second period, and viceversa for the other group. Children were assessed at the beginning and the end of each period through both the Nine Hole Peg Test (9-HPT, primary outcome) and Kinesiological Measurements obtained during the performing of similar tasks in a real setting scenario (secondary outcomes).

Results

All subjects, not depending from which group they come from, significantly improved in both the performance of the 9-HPT and in the parameters of the kinesiological measurements (movement error and smoothness). No statistically significant differences have been found between the two groups.

Conclusions

These findings suggest that immersive VE and wearable haptic devices is a viable alternative to conventional therapy for improving upper extremity function in children with neuromotor impairments.

Trial registration ClinicalTrials, NCT03353623. Registered 27 November 2017-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03353623
RETRACTED ARTICLE: NF-κB maintains the stemness of colon cancer cells by downregulating miR-195-5p/497–5p and upregulating MCM2
Authors: Wang Longgang , Guo Jinxiang , Zhou Jin , Wang Dongyang , Kang Xiuwen , Zhou Lei
Published: October 2020

Background

Colon cancer represents one of the leading causes of gastrointestinal tumors in industrialized countries, and its incidence appears to be increasing at an alarming rate. Accumulating evidence has unveiled the contributory roles of cancer stem cells (CSCs) in tumorigenicity, recurrence, and metastases. The functions of NF-kappa B (NF-κB) activation on cancer cell survival, including colon cancer cells have encouraged us to study the role of NF-κB in the maintenance of CSCs in colon cancer.

Methods

Tumor samples and matched normal samples were obtained from 35 colon cancer cases. CSCs were isolated from human colon cancer cell lines, where the stemness of the cells was evaluated by cell viability, colony-forming, spheroid-forming, invasion, migration, and apoptosis assays. NF-κB activation was then performed in subcutaneous tumor models of CSCs by injecting lipopolysaccharides (LPS) i.p.

Results

We found that NF-κB activation could reduce the expression of miR-195-5p and miR-497-5p, where these two miRNAs were determined to be downregulated in colon cancer tissues, cultured colon CSCs, and LPS-injected subcutaneous tumor models. Elevation of miR-195-5p and miR-497-5p levels by their specific mimic could ablate the effects of NF-κB on the stemness of colon cancer cells in vivo and in vitro, suggesting that NF-κB could maintain the stemness of colon cancer cells by downregulating miR-195-5p/497–5p. MCM2 was validated as the target gene of miR-195-5p and miR-497-5p in cultured colon CSCs. Overexpression of MCM2 was shown to restore the stemness of colon cancer cells in the presence of miR-195-5p and miR-497-5p, suggesting that miR-195-5p and miR-497-5p could impair the stemness of colon cancer cells by targeting MCM2 in vivo and in vitro.

Conclusions

Our work demonstrates that the restoration of miR-195-5p and miR-497-5p may be a therapeutic strategy for colon cancer treatment in relation to NF-κB activation.
KRAS wild-type pancreatic ductal adenocarcinoma: molecular pathology and therapeutic opportunities
Authors: Luchini Claudio , Paolino Gaetano , Mattiolo Paola , Piredda Maria L. , Cavaliere Alessandro , Gaule Marina , Melisi Davide , Salvia Roberto , Malleo Giuseppe , Shin Jae Il , Cargnin Sarah , Terrazzino Salvatore , Lawlor Rita T. , Milella Michele , Scarpa Aldo
Published: October 2020

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease, whose main molecular trait is the MAPK pathway activation due toKRASmutation, which is present in 90% of cases.

The genetic landscape ofKRASwild type PDAC can be divided into three categories. The first is represented by tumors with an activated MAPK pathway due toBRAFmutation that occur in up to 4% of cases. The second includes tumors with microsatellite instability (MSI) due to defective DNA mismatch repair (dMMR), which occurs in about 2% of cases, also featuring a high tumor mutational burden. The third category is represented by tumors with kinase fusion genes, which marks about 4% of cases. While therapeutic molecular targeting ofKRASis an unresolved challenge,KRAS-wild type PDACs have potential options for tailored treatments, includingBRAFantagonists and MAPK inhibitors for the first group, immunotherapy with anti-PD-1/PD-L1 agents for the MSI/dMMR group, and kinase inhibitors for the third group.

This calls for a complementation of the histological diagnosis of PDAC with a routine determination ofKRASfollowed by a comprehensive molecular profiling ofKRAS-negative cases.
Ascorbic acid (vitamin C) synergistically enhances the therapeutic effect of targeted therapy in chronic lymphocytic leukemia
Authors: Darwiche Walaa , Gomila Cathy , Ouled-Haddou Hakim , Naudot Marie , Doualle Cécile , Morel Pierre , Nguyen-Khac Florence , Garçon Loïc , Marolleau Jean-Pierre , Ghamlouch Hussein
Published: October 2020

Background

Novel, less toxic, cost-effective and safe therapeutic strategies are needed to improve treatment of chronic lymphocytic leukemia (CLL). Ascorbic acid (AA, vitamin C) has shown a potential anti-cancer therapeutic activity in several cancers. However, the anti-cancer effects of ascorbic acid on CLL B-cells have not been extensively studied. We aimed in this study to evaluate the in vitro therapeutic activity using clinically relevant conditions.

Methods

Primary CLL B-cells and two CLL cell lines were exposed to a dose that is clinically achievable by AA oral administration (250 μM), and cell death and potential mechanisms were assessed. The role of the protective CLL microenvironment was studied. Synergistic interaction between AA and CLL approved drugs (Ibrutinib, Idelalisib and Venetoclax) was also evaluated.

Results

Ascorbic acid is cytotoxic for CLL B-cells at low dose (250 μM) but spares healthy B-cells. Ascorbic-acid-induced cytotoxicity involved pro-oxidant damage through the generation of reactive oxygen species in the extracellular media and in CLL cells, and induced caspase-dependent apoptosis. We also found that AA treatment overcame the supportive survival effect provided by microenvironment including bone marrow mesenchymal stem cells, T-cell cues (CD40L + IL-4), cytokines and hypoxia. Our data suggest that resistance to AA could be mediated by the expression of the enzyme catalase in some CLL samples and by the glucose metabolite pyruvate. We also demonstrated that AA synergistically potentiates the cytotoxicity of targeted therapies used in or being developed for CLL.

Conclusion

These preclinical results point to AA as an adjuvant therapy with potential to further improve CLL treatments in combination with targeted therapies.
Dandelion extract relaxes mouse airway smooth muscle by blocking VDLCC and NSCC channels
Authors: Zhao Ping , Liu Jia , Ming Qian , Tian Di , He Jingwen , Yang Ziwei , Shen Jinhua , Liu Qing-Hua , Yang Xinzhou
Published: October 2020

Background

Asthma is one of the main intractable diseases recognized by the international medical community. The current widely used bronchodilators for asthma—β2-adrenal receptor agonists—have limited therapeutic effects, necessitating the development of novel antiasthma drugs with increased efficacy and fewer adverse effects. In this study, we investigated the relaxant effects and underlying mechanism of an ethyl acetate extract from dandelion (EAED) on mouse airway smooth muscle.

Methods

The effects of EAED on agonist-induced precontraction in mouse airway smooth muscle were evaluated with force measurement. Mouse lung slices were used to study the effects of EAED on bronchial smooth muscle. The intracellular Ca2+ concentration was measured using a calcium imaging system. L-type voltage-dependent calcium channel (VDLCC) and non-selective cationic channel (NSCC) currents were measured by patch-clamp. The lung functions of healthy and asthmatic mouse groups were assessed via the forced oscillation technique.

Results

EAED inhibits acetylcholine-induced sustained contractions of whole airway smooth muscle by inhibiting VDLCCs, NSCCs, and some unknown channels, reduces the agonist-induced increase in the cytosolic free Ca2+ concentration in airway smooth muscle cells, blocks VDLCC and NSCC currents, and relieves the respiratory resistance of healthy and asthmatic mice.

Conclusions

EAED may have potential beneficial effects on mitigating asthma attacks.
Numbers, graphs and words – do we really understand the lab test results accessible via the patient portals?
Authors: Bar-Lev Shirly , Beimel Dizza
Published: October 2020

Background

The heavy reliance on remote patient care (RPC) during the COVID-19 health crisis may have expedited the emergence of digital health tools that can contribute to safely and effectively moving the locus of care from the hospital to the community. Understanding how laypersons interpret the personal health information accessible to them via electronic patient records (EPRs) is crucial to healthcare planning and the design of services. Yet we still know little about how the format in which personal medical information is presented in the EPR (numerically, verbally, or graphically) affects individuals’ understanding of the information, their assessment of its gravity, and the course of action they choose in response.

Methods

We employed an online questionnaire to assess respondents’ reactions to 10 medical decision-making scenarios, where the same information was presented using different formats. In each scenario, respondents were presented with real (anonymized) patient lab results using either numeric expressions, graphs, or verbal expressions. Participants were asked to assess the gravity of the hypothetical patient’s condition and the course of action they would follow if they were that patient. The questionnaire was distributed to more than 300 participants, of whom 225 submitted usable responses.

Results

Laypersons were more likely to overestimate the gravity of the information when it was presented either numerically or graphically compared to the narrative format. High perceived gravity was most likely to produce an inclination to actively seek medical attention, even when unwarranted. “Don’t know” responses were most likely to produce an inclination to either search the Internet or wait for the doctor to call.

Policy recommendations

We discuss the study’s implications for the effective design of lab results in the patient portals. We suggest (1) that graphs, tables, and charts would be easier to interpret if coupled with a brief verbal explanation; (2) that highlighting an overall level of urgency may be more helpful than indicating a diversion from the norm; and (3) that statements of results should include the type of follow-up required.
Gridless DOA estimation with finite rate of innovation reconstruction based on symmetric Toeplitz covariance matrix
Authors: Chen Tao , Shi Lin , Yu Yongzhi
Published: October 2020

Due to the rapid development and wide application of compressed sensing and sparse reconstruction theory, there exists a series of sparsity-based methods for the antenna sensor array direction of arrival (DOA) estimation with excellent performance. However, it is known that this kind of algorithms always suffers from the problem of grid mismatch. To overcome this shortcoming, a gridless DOA estimation algorithm with finite rate of innovation (FRI) based on a symmetric Toeplitz covariance matrix is proposed for uniform linear array (ULA) in this paper. In particular, a multiple measurement vector (MMV) FRI reconstruction model is built by exploiting the covariance data denoised according to covariance fitting criteria rather than the direct data or the original covariance data, which is commonly used in other representative gridless DOA estimation methods. Next, DOA can be retrieved from the recovered covariance matrix by utilizing an annihilating filter because each covariance data is a linear combination of complex exponentials. It guarantees to produce an exact spatial sparse estimate without discretization required by existing sparsity-based DOA estimation methods. Finally, the effectiveness and superiority of the proposed algorithm are demonstrated by numerical simulations.
Survival analysis of a stochastic delay single-species system in polluted environment with psychological effect and pulse toxicant input
Authors: Dai Xiangjun , Wang Suli , Xiong Weizhi , Li Ni
Published: October 2020

We propose and study a stochastic delay single-species population system in polluted environment with psychological effect and pulse toxicant input. We establish sufficient conditions for the extinction, nonpersistence in the mean, weak persistence, and strong persistence of the single-species population and obtain the threshold value between extinction and weak persistence. Finally, we confirm the efficiency of the main results by numerical simulations.
Correction to: Hill-based dissimilarity indices and null models for analysis of microbial community assembly
Authors: Modin Oskar , Liébana Raquel , Saheb-Alam Soroush , Wilén Britt-Marie , Suarez Carolina , Hermansson Malte , Persson Frank
Published: October 2020

An amendment to this paper has been published and can be accessed via the original article.
The importance of individual movement and feeding behaviour for long-distance seed dispersal by red deer: a data-driven model
Authors: Wright Stephen J. , Heurich Marco , Buchmann Carsten M. , Böcker Reinhard , Schurr Frank M.
Published: October 2020

Background

Long-distance seed dispersal (LDD) has strong impacts on the spatiotemporal dynamics of plants. Large animals are important LDD vectors because they regularly transport seeds of many plant species over long distances. While there is now ample evidence that behaviour varies considerably between individual animals, it is not clear to what extent inter-individual variation in behaviour alters seed dispersal by animals.

Methods

We study how inter-individual variation in the movement and feeding behaviour of one of Europe’s largest herbivores (the red deer,Cervus elaphus) affects internal seed dispersal (endozoochory) of multiple plant species. We combine movement data of 21 individual deer with measurements of seed loads in the dung of the same individuals and with data on gut passage time. These data serve to parameterize a model of passive dispersal that predicts LDD in three orientations (horizontal as well as upward and downward in elevation).

With this model we investigate to what extent per-seed probabilities of LDD and seed load vary between individuals and throughout the vegetation period (May–December). Subsequently, we test whether per-seed LDD probability and seed load are positively (or negatively) correlated so that more mobile animals disperse more (or less) seeds. Finally, we examine whether non-random associations between per-seed LDD probability and seed load affect the LDD of individual plant species.

Results

The studied deer dispersed viable seeds of at least 62 plant species. Deer individuals varied significantly in per-seed LDD probability and seed loads. However, more mobile animals did not disperse more or less seeds than less mobile ones. Plant species also did not differ significantly in the relationship between per-seed LDD probability and seed load. Yet plant species differed in how their seed load was distributed across deer individuals and in time, and this caused their LDD potential to differ more than twofold. For several plant species, we detected non-random associations between per-seed LDD probability and seed load that generally increased LDD potential.

Conclusions

Inter-individual variation in movement and feeding behaviour means that certain deer are substantially more effective LDD vectors than others. This inter-individual variation reduces the reliability of LDD and increases the sensitivity of LDD to the decline of deer populations. Variation in the dispersal services of individual animals should thus be taken into account in models in order to improve LDD projections.
Genetic predisposition to longer telomere length and risk of childhood, adolescent and adult-onset ependymoma
Authors:   The Glioma International Case-Control Study (GICC), Zhang Chenan , Ostrom Quinn T. , Semmes Eleanor C. , Ramaswamy Vijay , Hansen Helen M. , Morimoto Libby , de Smith Adam J. , Pekmezci Melike , Vaksman Zalman , Hakonarson Hakon , Diskin Sharon J. , Metayer Catherine , Taylor Michael D. , Wiemels Joseph L. , Bondy Melissa L. , Walsh Kyle M.
Published: October 2020

Ependymoma is the third most common brain tumor in children, with well-described molecular characterization but poorly understood underlying germline risk factors. To investigate whether genetic predisposition to longer telomere length influences ependymoma risk, we utilized case–control data from three studies: a population-based pediatric and adolescent ependymoma case–control sample from California (153 cases, 696 controls), a hospital-based pediatric posterior fossa type A (EPN-PF-A) ependymoma case–control study from Toronto’s Hospital for Sick Children and the Children’s Hospital of Philadelphia (83 cases, 332 controls), and a multicenter adult-onset ependymoma case–control dataset nested within the Glioma International Case-Control Consortium (GICC) (103 cases, 3287 controls). In the California case–control sample, a polygenic score for longer telomere length was significantly associated with increased risk of ependymoma diagnosed at ages 12–19 (P = 4.0 × 10−3), but not with ependymoma in children under 12 years of age (P = 0.94). Mendelian randomization supported this observation, identifying a significant association between genetic predisposition to longer telomere length and increased risk of adolescent-onset ependymoma (ORPRS = 1.67; 95% CI 1.18–2.37; P = 3.97 × 10−3) and adult-onset ependymoma (PMR-Egger = 0.042), but not with risk of ependymoma diagnosed before age 12 (OR = 1.12; 95% CI 0.94–1.34; P = 0.21), nor with EPN-PF-A (PMR-Egger = 0.59). These findings complement emerging literature suggesting that augmented telomere maintenance is important in ependymoma pathogenesis and progression, and that longer telomere length is a risk factor for diverse nervous system malignancies.