bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interleukin-6 inhibition in the management of non-infectious uveitis and beyond
Authors: Karkhur Samendra , Hasanreisoglu Murat , Vigil Erin , Halim Muhammad Sohail , Hassan Muhammad , Plaza Carlos , Nguyen Nam V. , Afridi Rubbia , Tran Anh T. , Do Diana V. , Sepah Yasir J. , Nguyen Quan Dong 
Published: September 2019

AbstractBackgroundUveitis consists of a spectrum of inflammatory disorders characterized by ocular inflammation. The underlying pathophysiology consists of a complex interplay of various inflammatory pathways. Interleukin 6 is an important mediator of inflammation in uveitis and constitutes focus of research toward development of newer biological therapies in the management of non-infectious uveitis.Main bodyPan-blockade of the inflammatory pathways with steroids is generally the first step in the management of acute non-infectious uveitis. However, long-term therapy with steroids is associated with systemic and ocular side effects, thereby necessitating the need for development of steroid sparing agents. IL-6 is a cytokine produced by various immune cells, in response to molecular patterns and affects multiple inflammatory cells. In particular, IL-6 is involved in differentiation of CD-4 cells into Th-17 cells that have been shown to play a significant role in various immune-mediated diseases such as uveitis. This broad-spectrum immunomodulatory activity makes IL-6 an excellent target for immunomodulatory therapy. Tocilizumab was the first IL-6 inhibitor to demonstrate efficacy in humans. It inhibits IL-6 from binding to both membrane-bound and soluble receptor and can be administered via intravenous (IV) and subcutaneous (SC) routes. It has been FDA approved for treatment of rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA). Following the approval in systemic diseases, its efficacy was demonstrated in various uveitis studies including a phase 2 clinical trial (STOP-Uveitis). Overall, tocilizumab has shown a good safety profile with the risk of malignancy consistent with that expected in patients with rheumatoid arthritis. However, tocilizumab therapy has been shown to increase the risk for gastrointestinal perforation and dose-dependent neutropenia. Following the success of tocilizumab, several other agents targeting the IL-6 pathway are in the pipeline. These include sirukumab, siltuximab, olokizumab, clazakizumab, and EBI-031 which target IL-6; Sarilumab and ALX-0061 act on the IL-6 receptor.ConclusionStudies have shown that IL-6 inhibitors can be effective in the management of NIU. In addition, the levels of IL-6 are elevated in other ocular vascular diseases such as retinal vein occlusion and diabetic macular edema. The roles of IL-6 inhibition may be broadened in the future to include the management of retinal vascular diseases and non-uveitic macular edema.
HH-suite3 for fast remote homology detection and deep protein annotation
Authors: Steinegger Martin , Meier Markus , Mirdita Milot , Vöhringer Harald , Haunsberger Stephan J. , Söding Johannes 
Published: September 2019

Abstract

Background
HH-suite is a widely used open source software suite for sensitive sequence similarity searches and protein fold recognition. It is based on pairwise alignment of profile Hidden Markov models (HMMs), which represent multiple sequence alignments of homologous proteins.

Results
We developed a single-instruction multiple-data (SIMD) vectorized implementation of the Viterbi algorithm for profile HMM alignment and introduced various other speed-ups. These accelerated the search methods HHsearch by a factor 4 and HHblits by a factor 2 over the previous version 2.0.16. HHblits3 is ∼10× faster than PSI-BLAST and ∼20× faster than HMMER3. Jobs to perform HHsearch and HHblits searches with many query profile HMMs can be parallelized over cores and over cluster servers using OpenMP and message passing interface (MPI). The free, open-source, GPLv3-licensed software is available at https://github.com/soedinglab/hh-suite.

Conclusion
The added functionalities and increased speed of HHsearch and HHblits should facilitate their use in large-scale protein structure and function prediction, e.g. in metagenomics and genomics projects.
Preferential activation of small cutaneous fibers through small pin electrode also depends on the shape of a long duration electrical current
Authors: Hugosdottir Rosa , Mørch Carsten Dahl , Andersen Ole Kæseler , Helgason Thordur , Arendt-Nielsen Lars 
Published: September 2019

Abstract

Background
Electrical stimulation is widely used in experimental pain research but it lacks selectivity towards small nociceptive fibers. When using standard surface patch electrodes and rectangular pulses, large fibers are activated at a lower threshold than small fibers. Pin electrodes have been designed for overcoming this problem by providing a higher current density in the upper epidermis where the small nociceptive fibers mainly terminate. At perception threshold level, pin electrode stimuli are rather selectively activating small nerve fibers and are perceived as painful, but for high current intensity, which is usually needed to evoke sufficient pain levels, large fibers are likely co-activated. Long duration current has been shown to elevate the threshold of large fibers by the mechanism of accommodation. However, it remains unclear whether the mechanism of accommodation in large fibers can be utilized to activate small fibers even more selectively by combining pin electrode stimulation with a long duration pulse.

Results
In this study, perception thresholds were determined for a patch- and a pin electrode for different pulse shapes of long duration. The perception threshold ratio between the two different electrodes was calculated to estimate the ability of the pulse shapes to preferentially activate small fibers. The perception threshold ratios were compared between stimulation pulses of 5- and 50 ms durations and shapes of: exponential increase, linear increase, bounded exponential, and rectangular. Qualitative pain perception was evaluated for all pulse shapes delivered at 10 times perception threshold. The results showed a higher perception threshold ratio for long duration 50 ms pulses than for 5 ms pulses. The highest perception threshold ratio was found for the 50 ms, bounded exponential pulse shape. Results furthermore revealed different strength-duration relation between the bounded exponential- and rectangular pulse shapes. Pin electrode stimulation at high intensity was mainly described as “stabbing”, “shooting”, and “sharp”.

Conclusion
These results indicate that long duration pulses with a bounded exponential increase preferentially activate the small nociceptive fibers with a pin electrode and concurrently cause elevated threshold of large non-nociceptive fibers with patch electrodes.
Does Pentaerytrithyltetranitrate reduce fetal growth restriction in pregnancies complicated by uterine mal-perfusion? Study protocol of the PETN-study: a randomized controlled multicenter-trial
Authors:   for the PETN Study Group, Groten T. , Lehmann T. , Schleußner E. 
Published: September 2019

Abstract

Background
Affecting approximately 10% of pregnancies, fetal growth restriction (FGR), is the most important cause of perinatal mortality and morbidity. Impaired placental function and consequent mal-perfusion of the placenta is the leading cause of FGR. Although, screening for placental insufficiency based on uterine artery Doppler measurement is well established, there is no treatment option for pregnancies threatened by FGR. The organic nitrate pentaerithrityl tetranitrate (PETN) is widely used for the treatment of cardiovascular disease and has been shown to have protective effects on human endothelial cells. In a randomized placebo controlled pilot-study our group could demonstrate a risk reduction of 39% for the development of FGR, and FGR or death, by administering PETN to patients with impaired uterine artery Doppler at mid gestation. To confirm these results a prospective randomized placebo controlled double-blinded multicentre trial was now initiated.

Method
The trial has been initiated in 14 centres in Germany. Inclusion criteria are abnormal uterine artery Doppler, defined by mean PI > 1.6, at 190 to 226 weeks of gestation in singleton pregnancies. Included patients will be monitored in 4-week intervals. Primary outcome measures are development of FGR (birth weight < 10th percentile), severe FGR (birth weight < 3rd centile) and perinatal death. Placental abruption, birth weight below the 3rd, 5th and 10th centile, development of FGR requiring delivery before 34 weeks` gestation, neonatal intensive care unit admission, and spontaneous preterm delivery < 34 weeks` and 37 weeks` gestation will be assessed as secondary endpoints. Patient enrolment was started in August 2017. Results are expected in 2020.

Discussion
During the past decade therapeutic agents with possible perfusion optimizing potential have been evaluated in clinical trials to treat FGR. Meta-analysis and sub-analysis of trials targeting preeclampsia revealed ASS to have a potential in reducing FGR. Phosphodiesterase-type-5 inhibitors have recently been tested in a worldwide RCT for therapy of established FGR, failing to show an effect on neonatal outcome. The ongoing multicenter trial will, by confirming our previous results, finally provide a therapeutic option in cases at risk for FGR.

Trial registration
DRKS00011374 registered at September 29th, 2017 and NCT03669185, registered September 13th, 2018.
Smac mimetics LCL161 and GDC-0152 inhibit osteosarcoma growth and metastasis in mice
Authors: Shekhar Tanmay M. , Burvenich Ingrid J. G. , Harris Michael A. , Rigopoulos Angela , Zanker Damien , Spurling Alex , Parker Belinda S. , Walkley Carl R. , Scott Andrew M. , Hawkins Christine J. 
Published: September 2019

AbstractBackgroundCurrent therapies fail to cure over a third of osteosarcoma patients and around three quarters of those with metastatic disease. “Smac mimetics” (also known as “IAP antagonists”) are a new class of anti-cancer agents. Previous work revealed that cells from murine osteosarcomas were efficiently sensitized by physiologically achievable concentrations of some Smac mimetics (including GDC-0152 and LCL161) to killing by the inflammatory cytokine TNFα in vitro, but survived exposure to Smac mimetics as sole agents.MethodsNude mice were subcutaneously or intramuscularly implanted with luciferase-expressing murine 1029H or human KRIB osteosarcoma cells. The impacts of treatment with GDC-0152, LCL161 and/or doxorubicin were assessed by caliper measurements, bioluminescence,18FDG-PET and MRI imaging, and by weighing resected tumors at the experimental endpoint. Metastatic burden was examined by quantitative PCR, through amplification of a region of the luciferase gene from lung DNA. ATP levels in treated and untreated osteosarcoma cells were compared to assess in vitro sensitivity. Immunophenotyping of cells within treated and untreated tumors was performed by flow cytometry, and TNFα levels in blood and tumors were measured using cytokine bead arrays.ResultsTreatment with GDC-0152 or LCL161 suppressed the growth of subcutaneously or intramuscularly implanted osteosarcomas. In both models, co-treatment with doxorubicin and Smac mimetics impeded average osteosarcoma growth to a greater extent than either drug alone, although these differences were not statistically significant. Co-treatments were also more toxic. Co-treatment with LCL161 and doxorubicin was particularly effective in the KRIB intramuscular model, impeding primary tumor growth and delaying or preventing metastasis. Although the Smac mimetics were effective in vivo, in vitro they only efficiently killed osteosarcoma cells when TNFα was supplied. Implanted tumors contained high levels of TNFα, produced by infiltrating immune cells. Spontaneous osteosarcomas that arose in genetically-engineered immunocompetent mice also contained abundant TNFα.ConclusionsThese data imply that Smac mimetics can cooperate with TNFα secreted by tumor-associated immune cells to kill osteosarcoma cells in vivo. Smac mimetics may therefore benefit osteosarcoma patients whose tumors contain Smac mimetic-responsive cancer cells and TNFα-producing infiltrating cells.
Effect of play-based family-centered psychomotor/psychosocial stimulation on the development of severely acutely malnourished children under six in a low-income setting: a randomized controlled trial
Authors: Abessa Teklu Gemechu , Worku Berhanu Nigussie , Wondafrash Mekitie , Girma Tsinuel , Valy Johan , Lemmens Johan , Bruckers Liesbeth , Kolsteren Patrick , Granitzer Marita 
Published: September 2019

AbstractBackgroundThe World Health Organization (WHO) recommends incorporating psychosocial stimulation into the management of severe acute malnutrition (SAM). However, there is little evidence about the effectiveness of these interventions for SAM children, particularly when serious food shortages and lack of a balanced diet prevail. The objective of this study was to examine whether family-based psychomotor/psychosocial stimulation in a low-income setting improves the development, linear growth, and nutritional outcomes in children with SAM.MethodChildren with SAM (N = 339) admitted for treatment to the Jimma University Specialized Hospital, Ethiopia, were randomized to a control (n = 170) or intervention (n = 169) group. Both groups received routine medical care and nutritional treatment at the hospital. The intervention group additionally received play-based psychomotor/psychosocial stimulation during their hospital stay, and at home for 6 months after being discharged from hospital.The fine motor (FM) and gross motor (GM) functions, language (LA) and personal-social (PS) skills of the children were assessed using adapted Denver II, the social-emotional (SE) behavior was assessed using adapted Ages and Stages Questionnaires: Social-Emotional, and the linear growth and nutritional status were determined through anthropometric assessments. All outcomes were assessed before the intervention, upon discharge from hospital, and 6 months after discharge (as end-line). The overtime changes of these outcomes measured in both groups were compared using Generalized Estimating Equations.ResultsThe intervention group improved significantly on GM during hospital follow-up by 0.88 points (p < 0.001, effect size = 0.26 SD), and on FM functions during the home follow-up by 1.09 points (p = 0.001, effect size = 0.22 SD). Both young and older children benefited similarly from the treatment. The intervention did not contribute significantly to linear growth and nutritional outcomes.ConclusionPsychomotor/psychosocial stimulation of SAM children enhances improvement in gross motor functions when combined with standard nutrient-rich diets, but it can enhance the fine motor functions even when such standard dietary care is not available.Trial registrationThe trial was retrospectively registered on 30 January 2017 at the US National Institute of Health (ClinicalTrials.gov) #NCT03036176.
Laparoscopic vs open colorectal cancer surgery in elderly patients: short- and long-term outcomes and predictors for overall and disease-free survival
Authors: Zhou Sicheng , Wang Xuewei , Zhao Chuanduo , Liu Qian , Zhou Haitao , Zheng Zhaoxu , Zhou Zhixiang , Wang Xishan , Liang Jianwei 
Published: September 2019

Abstract

Background
Colorectal cancer is common in elderly patients. Laparoscopy is widely used to approach this kind of disease. This study was to examine short-term outcomes and long-term survival for laparoscopic and open surgery in elderly patients with colorectal cancer.

Methods
From January 2007 to December 2018, patients with colorectal cancer older than 80 operated at China National Cancer Center were included in the study. Propensity score matching (PSM) was used to minimize the adverse effects. The clinical data between open and laparoscopic surgery was compared, and the effect of factors on overall survival (OS) and disease-free survival (DFS) was analyzed by Cox proportional hazard model.

Results
Ninety-three pairs were selected after PSM. Patients in laparoscopic group had less intraoperative blood loss, postoperative complications, time to first flatus, time to oral feeding, postoperative hospital stay, and higher retrieved lymph node (P < 0.05). The OS and DFS rates were similar (P > 0.05), besides the CEA level, III/IV stage, and perineural invasion were independent predictors of survival (P < 0.05).

Conclusion
In elderly patients with colorectal cancer, laparoscopic surgery had better short-term outcomes than open surgery. CEA level, III/IV stage, and perineural invasion were reliable predictors for OS and DFS.
Patient-reported outcomes in randomised clinical trials of bladder cancer: an updated systematic review
Authors: Van Hemelrijck Mieke , Sparano Francesco , Josephs Debra , Sprangers Mirjam , Cottone Francesco , Efficace Fabio 
Published: September 2019

Abstract

Background
Despite international recommendations of including patient-reported outcomes (PROs) in randomised clinical trials (RCTs), a 2014 review concluded that few RCTs of bladder cancer (BC) report PRO as an outcome. We therefore aimed to update the 2014 review to synthesise current evidence-based knowledge of PROs from RCTs in BC. A secondary objective was to examine whether quality of PRO reporting has improved over time and to provide evidence-based recommendations for future studies in this area.

Methods
We conducted a systematic literature search using PubMed/Medline, from April 2014 until June 2018. We included the RCTs identified in the previous review as well as newly published RCTs. Studies were evaluated using a predefined electronic-data extraction form that included information on basic trial demographics, clinical and PRO characteristics and standards of PRO reporting based on recommendation from the International Society of Quality of Life Research.

Results
Since April 2014 only eight new RCTs for BC included PROs as a secondary outcome. In terms of methodology, only the proportion of RCTs documenting the extent of missing PRO data (75% vs 11.1%, p = 0.03) and the identification of PROs in trial protocols (50% vs 0%, p = 0.015) improved. Statistical approaches for dealing with missing data were not reported in most new studies (75%).

Conclusion
Little improvement into the uptake and assessment of PRO as an outcome in RCTs for BC has been made during recent years. Given the increase in (immunotherapy) drug trials with a potential for severe adverse events, there is urgent need to adopt the recommendations and standards available for PRO use in bladder cancer RCTs.
The synergism of Clinacanthus nutans Lindau extracts with gemcitabine: downregulation of anti-apoptotic markers in squamous pancreatic ductal adenocarcinoma
Authors: Hii Ling-Wei , Lim Swee-Hua Erin , Leong Chee-Onn , Chin Swee-Yee , Tan Ngai-Paing , Lai Kok-Song , Mai Chun-Wai 
Published: September 2019

Abstract

Background
Clinacanthus nutans extracts have been consumed by the cancer patients with the hope that the extracts can kill cancers more effectively than conventional chemotherapies. Our previous study reported its anti-inflammatory effects were caused by inhibiting Toll-like Receptor-4 (TLR-4) activation. However, we are unsure of its anticancer effect, and its interaction with existing chemotherapy.

Methods
We investigated the anti-proliferative efficacy of polar leaf extracts (LP), non-polar leaf extracts (LN), polar stem extract (SP) and non-polar stem extracts (SN) in human breast, colorectal, lung, endometrial, nasopharyngeal, and pancreatic cancer cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, MTT assay. The most potent extracts was tested along with gemcitabine using our established drug combination analysis. The effect of the combinatory treatment in apoptosis were quantified using enzyme-linked immunosorbent assay (ELISA), Annexin V assay, antibody array and immunoblotting. Statistical significance was analysed using one-way analysis of variance (ANOVA) and post hoc Dunnett’s test. A p-value of less than 0.05 (p < 0.05) was considered statistical significance.

Results
All extracts tested were not able to induce potent anti-proliferative effects. However, it was found that pancreatic ductal adenocarcinoma, PDAC (AsPC1, BxPC3 and SW1990) were the cell lines most sensitive cell lines to SN extracts. This is the first report of C. nutans SN extracts acting in synergy with gemcitabine, the first line chemotherapy for pancreatic cancer, as compared to conventional monotherapy. In the presence of SN extracts, we can reduce the dose of gemcitabine 2.38–5.28 folds but still maintain the effects of gemcitabine in PDAC. SN extracts potentiated the killing of gemcitabine in PDAC by apoptosis. Bax was upregulated while bcl-2, cIAP-2, and XIAP levels were downregulated in SW1990 and BxPC3 cells treated with gemcitabine and SN extracts. The synergism was independent of TLR-4 expression in pancreatic cancer cells.

Conclusion
These results provide strong evidence of C. nutans extracts being inefficacious as monotherapy for cancer. Hence, it should not be used as a total substitution for any chemotherapy agents. However, SN extracts may synergise with gemcitabine in the anti-tumor mechanism.
The implementation of the coaching on lifestyle (CooL) intervention: lessons learnt
Authors: van Rinsum Celeste , Gerards Sanne , Rutten Geert , Johannesma Madelon , van de Goor Ien , Kremers Stef 
Published: September 2019

Abstract

Background
Combined lifestyle interventions (CLIs) are designed to help people who are overweight or obese maintain a healthy new lifestyle. The CooL intervention is a CLI in the Netherlands, in which lifestyle coaches counsel adults and children (and/or their parents) who are obese or at high risk of obesity to achieve a sustained healthier lifestyle. The intervention consists of coaching on lifestyle in group and individual sessions, addressing the topics of physical activity, dietary behaviours, sleep, stress management and behavioural change. The aim of this study was to evaluate the implementation process of the Coaching on Lifestyle (CooL) intervention and its facilitating and impeding factors.

Methods
Mixed methods were used in this action-oriented study. Both quantitative (number of referrals, attendance lists of participants and questionnaires) and qualitative (group and individual interviews, observations, minutes and open questions) data were collected among participants, lifestyle coaches, project group members and other stakeholders. The Consolidated Framework for Implementation Research was used to analyse the data.

Results
CooL was evaluated by stakeholders and participants as an accessible and useful programme, because of its design and content and the lifestyle coaches’ approach. However, stakeholders indicated that the lifestyle coaches need to become more familiar in the health care network and public sectors in the Netherlands. Lifestyle coaching is a novel profession and the added value of the lifestyle coach is not always acknowledged by all health care providers. Lifestyle coaches play a crucial role in ensuring the impact of CooL by actively networking, using clear communication materials and creating stakeholders’ support and understanding.

Conclusion
The implementation process needs to be strengthened in terms of creating support for and providing clear information about lifestyle coaching. The CooL intervention was implemented in multiple regions, thanks to the efforts of many stakeholders. Lifestyle coaches should engage in networking activities and entrepreneurship to boost the implementation process. It takes considerable time for a lifestyle coach to become fully incorporated in primary care.

Trial registration
NTR6208; date registered: 13–01-2017; retrospectively registered; Netherlands Trial Register.