Miracle-dz/UniFAR-FTUs huggingface dataset:
How to Report on Distal Resection Margins in Trials on Rectal Cancer Surgery.

To the Editor–With great interest we read the recent publication by Persiani and coworkers on a propensity-scored matched comparison of transanal total mesorectal excision (TaTME) and laparoscopic total mesorectal excision (TME) published in the June 2018 issue of Diseases of the Colon and Rectum. It is the first study providing a higher level of evidence for a significant reduction of the rate of conversion to open surgery with the TaTME technique. Based on this work we would like to discuss one general weaknesses of several corresponding studies. The point of criticism is that we do not agree with the presentation of larger distal resection margins (DRMs) in the TaTME group as an advantage of the procedure. In fact, there is a rationale behind this idea that has already been pointed out earlier. However, the authors of this trial, as well as those of earlier studies, do not provide sufficient data to support this theory. First, Persiani et al do not describe whether those patients who had end colostomies for functional reasons, who were presumably treated with intersphincteric abdominoperineal resections, were included in the analysis. Specimens from intersphincteric abdominoperineal resections usually show large DRMs. The reason is that the specimens contain the anal canal; however, in these patients, it is not for oncologic reasons. Because end colostomies for functional reasons had been performed 3 times more frequently after TaTME (6/46 (TaTME) vs 2/46 (laparoscopic TME)), the inclusion of these patients could have significantly influenced the presented data. Furthermore, in patients with low rectal cancer who were subjected to sphincter-preserving TME, the DRM should be as long as oncologically necessary but also as short as oncologically acceptable. Achieving DRMs of <60 mm does not necessarily mean a better oncologic outcome but rather an inferior functional result, because unnecessarily wide DRMs will result in unnecessarily low anastomoses. The relevant information needed to evaluate the appropriateness of the DRM cannot be extracted from the data provided by the authors, because only the median and range are presented. To document the appropriateness of the DRM in a cohort of treated patients, the proportion of patients need to be presented in which appropriate DRMs were achieved. A DRM as low as 5 mm can be acceptable for very low rectal tumors after neoadjuvant radiochemotherapy,4 and even a 1-mm clear margin approved microscopically by intraoperative frozen sections can be acceptable under these circumstances. For tumors located in the lower part of the middle rectum, usually an intramural DRM of 2 cm is deemed to be appropriate, provided a proper TME is performed. To document the appropriateness of the DRM in future comparative trials on surgery for low and middle rectal cancer, we recommend to report on DRM as follows:
Gastric Adenocarcinoma Predictive Long Intergenic Non-Coding RNA Promotes Tumor Occurrence and Progression in Non-Small Cell Lung Cancer via Regulation of the miR-661/eEF2K Signaling Pathway

Background/Aims: Long non-coding RNAs (lncRNAs) play vital roles in carcinogenesis as oncogenes or tumor suppressor genes. This study explored the biological function of lncRNA gastric adenocarcinoma predictive long intergenic non-coding RNA (GAPLINC) in human non-small cell lung cancer (NSCLC). Methods: GAPLINC expression in NSCLC specimens and cell lines was detected by qRT-PCR and Western blot. The effect of GAPLINC on cell proliferation was investigated using CCK8-assay, colony formation assay, and xenograft model. The effects of GAPLINC on apoptosis and cell cycle were determined using flow cytometry. The mechanism of GAPLINC involved in NSCLC was explored using Western blot, luciferase reporter assay, and RNA fluorescence in situ hybridization. Results: We found that GAPLINC expression was up-regulated in NSCLC tissues and cell lines. Overexpression of GAPLINC was associated with poor prognosis in patients with NSCLC. Silencing of GAPLINC significantly inhibited cell proliferation, promoted apoptosis, and induced cell cycle arrest in the G0/G1 phase. Results from xenograft transplantation showed that GAPLINC silencing inhibited the tumor growth in vivo. Interestingly, GAPLINC silencing decreased the expression of eukaryotic elongation factor-2 kinase (eEF2K) protein both in vivo and in vitro. Bioinformatic analysis and luciferase reporter confirmed that miR-661 targeted GAPLINC and eEF2K 3’-UTR and was negatively correlated with the expression of GAPLINC and eEF2K. Conclusion: Our findings indicate that GAPLINC promotes NSCLC tumorigenesis by regulating miR-661/eEF2K cascade and provide new insights for the pathogenesis underlying NSCLC and potential targets for therapeutic strategy.
Contrasting effects of acute and chronic stress on the transcriptome, epigenome, and immune response of Atlantic salmon

Early-life stress can have long-lasting effects on immunity, but the underlying molecular mechanisms are unclear. We examined the effects of acute stress (cold-shock during embryogenesis) and chronic stress (absence of tank enrichment during larval-stage) on the gill transcriptome and methylome of Atlantic salmon four months after hatching. While only chronic stress induced pronounced transcriptional effects, both acute and chronic stress caused lasting, and contrasting, changes in the methylome. Crucially, we found that acute stress enhanced immune response to a pathogenic challenge (lipopolysaccharide), while chronic stress suppressed it. We identified stress-induced changes in promoter or gene-body methylation that were associated with altered expression for a small proportion of genes, and also evidence of wider epigenetic regulation within signalling pathways involved in immune response. Our study suggests that early-life stress can affect immuno-competence through epigenetic mechanisms, a finding that could open the way for improved stress and disease management of farmed fish.
A polyphasic approach to the delimitation of diatom species: a case study for the genus Pinnularia (Bacillariophyta)

Diatoms are one of the most abundant and arguably the most species‐rich group of protists. Diatom species delimitation has often been based exclusively on the recognition of morphological discontinuities without investigation of other lines of evidence. Even though DNA sequences and reproductive experiments have revealed several examples of (pseudo)cryptic diversity, our understanding of diatom species boundaries and diversity remains limited. The cosmopolitan pennate raphid diatom genus Pinnularia represents one of the most taxon‐rich diatom genera. In this study, we focused on the delimitation of species in one of the major clades of the genus, the Pinnularia subgibba group, based on 105 strains from a worldwide origin. We compared genetic distances between the sequences of seven molecular markers and selected the most variable pair, the mitochondrial cox1 and nuclear encoded LSU rDNA, to formulate a primary hypothesis on the species limits using three single‐locus automated species delimitation methods. We compared the DNA‐based primary hypotheses with morphology and with other available lines of evidence. The results indicate that our data set comprised 15 species of the P. subgibba group. The vast majority of these taxa have an uncertain taxonomic identity, suggesting that several may be unknown to science and/or members of (pseudo)cryptic species complexes within the P. subgibba group.
Type I interferon receptor blockade with anifrolumab corrects innate and adaptive immune perturbations of SLE

Objective Anifrolumab is a fully human immunoglobulin G1 κ monoclonal antibody specific for subunit 1 of the type I interferon (IFN) α receptor. In a phase IIb study of adults with moderate to severe SLE, anifrolumab treatment demonstrated substantial reductions in multiple clinical endpoints. Here, we evaluated serum proteins and immune cells associated with SLE pathogenesis, type I interferon gene signature (IFNGS) test status and disease activity, and how anifrolumab affected these components. Methods Whole blood samples were collected from patients enrolled in MUSE (NCT01438489) for serum protein and cellular assessments at baseline and subsequent time points. Data were parsed by IFNGS test status (high/low) and disease activity. Protein expression and immune cell subsets were measured using multiplex immunoassay and flow cytometry, respectively. Blood samples from healthy donors were analysed for comparison. Results Baseline protein expression differed between patients with SLE and healthy donors, IFNGS test-high and -low patients, and patients with moderate and severe disease. Anifrolumab treatment lowered concentrations of IFN-induced chemokines associated with B, T and other immune cell migration in addition to proteins associated with endothelial activation that were dysregulated at baseline. IFNGS test-high patients and those with high disease activity were characterised by low baseline numbers of lymphocytes, circulating memory T-cell subsets and neutrophils. Anifrolumab treatment reversed lymphopenia and neutropenia in the total population, and normalised multiple T-cell subset counts in IFNGS test-high patients compared with placebo. Conclusions Anifrolumab treatment reversed IFN-associated changes at the protein and cellular level, indicating multiple modes of activity. Trial registration number NCT01438489.
Role of a fluid-phase PRR in fighting an intracellular pathogen: PTX3 in Shigella infection

Shigella spp. are pathogenic bacteria that cause bacillary dysentery in humans by invading the colonic and rectal mucosa where they induce dramatic inflammation. Here, we have analyzed the role of the soluble PRR Pentraxin 3 (PTX3), a key component of the humoral arm of innate immunity. Mice that had been intranasally infected with S. flexneri were rescued from death by treatment with recombinant PTX3. In vitro PTX3 exerts the antibacterial activity against Shigella, impairing epithelial cell invasion and contributing to the bactericidal activity of serum. PTX3 is produced upon LPS-TLR4 stimulation in accordance with the lipid A structure of Shigella. In the plasma of infected patients, the level of PTX3 amount only correlates strongly with symptom severity. These results signal PTX3 as a novel player in Shigella pathogenesis and its potential role in fighting shigellosis. Finally, we suggest that the plasma level of PTX3 in shigellosis patients could act as a biomarker for infection severity.
Staurosporine, an inhibitor of hormonally up-regulated neu-associated kinase

HUNK is a protein kinase that is implicated in HER2-positive (HER2+) breast cancer progression and resistance to HER2 inhibitors. Though prior studies suggest there is therapeutic potential for targeting HUNK in HER2+ breast cancer, pharmacological agents that target HUNK are yet to be identified. A recent study showed that the broad-spectrum kinase inhibitor staurosporine binds to the HUNK catalytic domain, but the effect of staurosporine on HUNK enzymatic activity was not tested. We now show that staurosporine inhibits the kinase activity of a full length HUNK protein. Our findings further suggest that inhibiting HUNK with staurosporine has a strong effect on suppressing cell viability of HER2/neu mammary and breast cancer cells, which express high levels of HUNK protein and are dependent on HUNK for survival. Significantly, we use in vitro and in vivo methods to show that staurosporine synergizes with the HER2 inhibitor lapatinib to restore sensitivity toward HER2 inhibition in a HER2 inhibitor resistant breast cancer model. Collectively, these studies indicate that pharmacological inhibition of HUNK kinase activity has therapeutic potential for HER2+ breast cancers, including HER2+ breast cancers that have developed drug resistance.
The liminal space palliative care volunteers occupy and their roles within it: a qualitative study

Objectives Volunteers have an important place in palliative care (PC), positively influencing quality of care for seriously ill people and those close to them and providing a link to the community. However, it is not well understood where volunteers fit into PC provision or how to support them adequately. We therefore chose to describe volunteer roles across care settings through the perspective of those closely involved in the care of terminally ill people. Methods A qualitative study was conducted using both focus groups with volunteers, nurses, psychologists and family physicians and individual semistructured interviews with patients and family caregivers. Participants were recruited from hospital, home, day care and live-in services. Results 79 people participated in the study. Two volunteer roles were identified. The first was ‘being there’ for the dying person. Volunteers represent a more approachable face of care, focused on psychological, social and existential care and building relationships. The second was the ‘liaison’ role. Volunteers occupy a liminal space between the professional and the family domain, through which they notice and communicate patient needs missed by other caregivers. Patient-volunteer matching was a facilitator for role performance; barriers were lack of communication opportunities with professional caregivers and lack of volunteer coordination. Conclusion Volunteers complement professional caregivers by (1) occupying a unique space between professionals, family and patients and fulfilling a liaison function and (2) being a unique face of care for patients. Healthcare services and policy can support volunteer role performance by ensuring frequent communication opportunities and volunteer coordination.
Brain pathways of pain empathy activated by pained facial expressions: a meta-analysis of fMRI using the activation likelihood estimation method

Objective: The objective of this study is to summarize and analyze the brain signal patterns of empathy for pain caused by facial expressions of pain utilizing activation likelihood estimation, a meta-analysis method. Data Sources: Studies concerning the brain mechanism were searched from the Science Citation Index, Science Direct, PubMed, DeepDyve, Cochrane Library, SinoMed, Wanfang, VIP, China National Knowledge Infrastructure, and other databases, such as SpringerLink, AMA, Science Online, Wiley Online, were collected. A time limitation of up to 13 December 2016 was applied to this study. Data Selection: Studies presenting with all of the following criteria were considered for study inclusion: Use of functional magnetic resonance imaging, neutral and pained facial expression stimuli, involvement of adult healthy human participants over 18 years of age, whose empathy ability showed no difference from the healthy adult, a painless basic state, results presented in Talairach or Montreal Neurological Institute coordinates, multiple studies by the same team as long as they used different raw data. Outcome Measures: Activation likelihood estimation was used to calculate the combined main activated brain regions under the stimulation of pained facial expression. Results: Eight studies were included, containing 178 subjects. Meta-analysis results suggested that the anterior cingulate cortex (BA32), anterior central gyrus (BA44), fusiform gyrus, and insula (BA13) were activated positively as major brain areas under the stimulation of pained facial expression. Conclusion: Our study shows that pained facial expression alone, without viewing of painful stimuli, activated brain regions related to pain empathy, further contributing to revealing the brain’s mechanisms of pain empathy.
Evaluation of transforming growth factor beta 1 in dogs with osteoarthritis

Osteoarthritis is a common problem in daily veterinary practice with insufficient knowledge about disease mechanism. Because fibrosis is a part of the alteration in the effected joints, we investigated the transforming growth factor beta 1 (TGF-β1) as an important regulation molecule of tissue fibrosis. We chose Osteoarthritis following a cruciate ligament rupture (CLR) because it is a common model of osteoarthritis. A total of 13 healthy dogs and 38 dogs suffering from CLR were included in this prospective study. The concentration of TGF-β1 was measured in synovial fluid using the “Quantikine Human TGF-β1 Immunoassay” (Fa. R & D Systems, Minneapolis, USA). There was a significant difference in the TGF-β1 concentration of the synovial fluid of healthy compared to affected patients (p < 0.001). The synovial TGF-β1 concentration also correlated significantly (p = 0.0147) with the synovial viscosity of the affected patients. No significant correlations could be observed to duration of disease, severity of lameness and degree of joint swelling, but also to joint capsule sickness, osteophyte development and degeneration of joint cartilage. The results of our study show an increased TGF-β1 concentration in knees affected with osteoarthritis as consequence of CLR. So we can conclude that TGF-β1 takes part at the osteoarthritic remodelling process, but different phases of the remodelling process cannot be distinguished by the measurement of TGF-β1.
Does Metabolic Rate Increase Linearly with Running Speed in all Distance Runners?

Abstract Running economy (oxygen uptake or metabolic rate for running at a submaximal speed) is one of the key determinants of distance running performance. Previous studies reported linear relationships between oxygen uptake or metabolic rate and speed, and an invariant cost of transport across speed. We quantified oxygen uptake, metabolic rate, and cost of transport in 10 average and 10 sub-elite runners. We increased treadmill speed by 0.45 m·s−1 from 1.78 m·s−1 (day 1) and 2.01 m·s−1 (day 2) during each subsequent 4-min stage until reaching a speed that elicited a rating of perceived exertion of 15. Average runners’ oxygen uptake and metabolic rate vs. speed relationships were best described by linear fits. In contrast, the sub-elite runners’ relationships were best described by increasing curvilinear fits. For the sub-elites, oxygen cost of transport and energy cost of transport increased by 12.8% and 9.6%, respectively, from 3.58 to 5.14 m·s−1. Our results indicate that it is not possible to accurately predict metabolic rates at race pace for sub-elite competitive runners from data collected at moderate submaximal running speeds (2.68–3.58 m·s−1). To do so, metabolic rate should be measured at speeds that approach competitive race pace and curvilinear fits should be used for extrapolation to race pace.
Challenges in delivering personalised support to people with multiple and complex needs: qualitative study

ABSTRACT Personalisation involves placing service users at the centre of service provision to ensure that the support they receive meets their individual needs, hopes and goals. This paper focuses on a programme delivering personalised support to people with multiple and complex needs (‘beneficiaries’). Each beneficiary received a tailored package of support and a £12,000 personal budget. Despite being well-resourced, the programme struggled to recruit and retain beneficiaries. The aim of this paper is to identify the challenges encountered and to share learning. Repeat semi-structured interviews (n = 56) were conducted with beneficiaries, programme workers and external partners. Interviews were audio recorded, transcribed, coded and analysed via Iterative Categorization. Five categories of challenge were identified: 1. poor understanding of the programme; 2. the characteristics and needs of beneficiaries and programme workers; 3. lack of clarity regarding who owned and controlled the budget; 4. strained interprofessional relationships; and 5. excessive bureaucracy combined with difficulties establishing programme outcomes. Findings illustrate how the delivery of person-centred support is compromised by interacting individual, organisational, and system level factors, particularly poor interprofessional collaboration. The data also suggest that personal budgets may undermine personalisation for people with multiple and complex needs.
Association between physical activity and scoliosis: a prospective cohort study.

Background Little is understood about the causes of adolescent onset idiopathic scoliosis (AIS). No prospective studies assessing the association between physical activity and idiopathic adolescent scoliosis have been carried out. We aimed to carry out the first prospective population-based study of this association. Methods The Avon Longitudinal Study of Parents and Children (ALSPAC) collected self-reported measures of physical ability/activity at ages 18 months and 10 years. Objective measures of physical activity were collected by accelerometry at age 11 years. scoliosis was identified using the dxa scoliosis Method at age 15 years. Participants with scoliosis at age 10 years were excluded. Results Of 4640 participants at age 15 years who had DXA scans, 267 (5.8%) had scoliosis. At age 18 months, those infants who were able to stand up without being supported were 66% less likely to have developed scoliosis by age 15 (P = 0.030) compared with infants who could not. Those children whose mothers reported they did most vigorous physical activity at age 10 years were 53% less likely to develop scoliosis (P = 0.027). Those children who did more objectively measured moderate/vigorous physical activity at age 11 were 30% less likely to have developed scoliosis (P < 0.001). Results were not affected by adjustment for age, gender, lean mass, fat mass or back pain. Conclusions We report reduced physical ability and activity as early as age 18 months in those who go on to develop scoliosis by age 15 years. Further research is justified to examine the mechanisms underlying this association.
Functional Probiotic Assessment and In Vivo Cholesterol-Lowering Efficacy of Weissella sp. Associated with Arid Lands Living-Hosts

The research and the selection of novel probiotic strains from novel niches are receiving increased attention on their proclaimed health benefits to both humans and animals. This study aimed to evaluate the functional properties of Weissella strains from arid land living-hosts and to select strains with cholesterol-lowering property in vitro and in vivo, for use as probiotics. They were assessed for acid and bile tolerance, antibiotic susceptibility, membrane properties, antibacterial activity, antiadhesive effect against pathogens to host cell lines, and cholesterol assimilation in vitro. Our results showed that the majority of strains revealed resistance to gastrointestinal conditions. All the strains were nonhemolytic and sensitive to most of the tested antibiotics. They also exhibited high rates of autoaggregation and some of them showed high coaggregation with selected pathogens and high adhesion ability to two different cell lines (Caco-2 and MIM/PPk). Particularly, W. halotolerans F99, from camel feces, presented a broad antibacterial spectrum against pathogens, reduced Enterococcus faecalis and Escherichia coli adhesion to Caco-2 cells, and was found to reduce, in vitro, the cholesterol level by 49 %. Moreover, W. halotolerans F99 was evaluated for the carbohydrate utilization as well as the serum lipid metabolism effect in Wistar rats fed a high-cholesterol diet. W. halotolerans F99 showed an interesting growth on different plant-derivative oligosaccharides as sole carbon sources. Compared with rats fed a high-fat (HF) diet without Weissella administration, total serum cholesterol, low-density lipoprotein cholesterol, and triglycerides levels were significantly (p<0.001) reduced in W. halotolerans F99-treated HF rats, with no significant change in high-density lipoprotein cholesterol HDL-C levels. On the basis of these results, this is the first study to report that W. halotolerans F99, from camel feces, can be developed as cholesterol-reducing probiotic strain. Further studies may reveal their potential and possible biotechnological and probiotic applications.