bluuebunny/crossref_metadata_2025 huggingface dataset:
A way to understand idiopathic senescence and apoptosis in primary glioblastoma cells – possible approaches to circumvent these phenomena
Authors: Janik Karolina , Treda Cezary , Wlodarczyk Aneta , Peciak Joanna , Rosiak Kamila , Zieba Jolanta , Grot Dagmara , Rutkowska Adrianna , Pawlowska Roza , Och Waldemar , Rieske Piotr , Stoczynska-Fidelus Ewelina
Published: September 2019

Background

Glioblastoma (GB) is considered one of the most lethal tumors. Extensive research at the molecular level may enable to gain more profound insight into its biology and thus, facilitate development and testing of new therapeutic approaches. Unfortunately, stable glioblastoma cell lines do not reflect highly heterogeneous nature of this tumor, while its primary cultures are difficult to maintain in vitro. We previously reported that senescence is one of the major mechanisms responsible for primary GB cells stabilization failure, to a lesser extent accompanied by apoptosis and mitotic catastrophe-related cell death.

Methods

We made an attempt to circumvent difficulties with glioblastoma primary cultures by testing 3 different approaches aimed to prolong their in vitro maintenance, on a model of 10 patient-derived tumor specimens.

Results

Two out of ten analyzed GB specimens were successfully stabilized, regardless of culture approach applied. Importantly, cells transduced with immortalizing factors or cultured in neural stem cell-like conditions were still undergoing senescence/apoptosis. Sequential in vivo/in vitro cultivation turned out to be the most effective, however, it only enabled to propagate cells with preserved molecular profile up to 3rd mice transfer. Nevertheless, it was the only method that impeded these phenomena long enough to provide sufficient amount of material for in vitro/in vivo targeted analyses. Interestingly, our data additionally demonstrated that some subpopulations of several stabilized GB cell lines undergo idiopathic senescence, however, it is counterbalanced by simultaneous proliferation of other cell subpopulations.

Conclusions

In the majority of primary glioma cultures, there has to be an imbalance towards apoptosis and senescence, following few weeks of rapid proliferation. Our results indicate that it has to be associated with the mechanisms other than maintenance of glioblastoma stem cells or dependence on proteins controlling cell cycle.
An economic analysis of human milk supplementation for very low birth weight babies in the USA
Authors: Hampson Grace , Roberts Sarah Louise Elin , Lucas Alan , Parkin David
Published: September 2019

Background

An exclusive human milk diet (EHMD) using human milk based products (pre-term formula and fortifiers) has been shown to lead to significant clinical benefits for very low birth weight (VLBW) babies (below 1250 g). This is expensive relative to diets that include cow’s milk based products, but preliminary economic analyses have shown that the costs are more than offset by a reduction in the cost of neonatal care. However, these economic analyses have not completely assessed the economic implications of EHMD feeding, as they have not considered the range of outcomes affected by it.

Methods

We conducted an economic analysis of EHMD compared to usual practice of care amongst VLBW babies in the US, which is to include cow's milk based products when required. Costs were evaluated from the perspective of the health care payer, with societal costs considered in sensitivity analyses.

Results

An EHMD substantially reduces mortality and improves other health outcomes, as well as generating substantial cost savings of $16,309 per infant by reducing adverse clinical events. Cost savings increase to $117,239 per infant when wider societal costs are included.

Conclusions

An EHMD is dominant in cost-effectiveness terms, that is it is both cost-saving and clinically beneficial, for VLBW babies in a US-based setting.
Diagnosis and management of lumbar spinal stenosis in primary care in France: a survey of general practitioners
Authors: Chagnas Marie-Ombeline , Poiraudeau Serge , Lefèvre-Colau Marie-Martine , Rannou François , Nguyen Christelle
Published: September 2019

Background

Lumbar spinal stenosis (LSS) is a common spinal condition and the most frequent indication for spinal surgery in elderly people. General practitioners (GPs) are on the 1st line for its diagnosis and treatment. We aimed to assess how GPs diagnose and treat people with LSS in France.

Methods

We conducted a cross-sectional survey in a primary care setting. French GPs were selected by a random draw from the French Medical Board. The questionnaire was designed by 3 physicians specialized in physical and rehabilitation medicine and a resident in general practice. A provisional questionnaire was tested in a pilot survey of 11 French GPs. Participants’ feedbacks served to build the final questionnaire. This latter was submitted by e-mail or mail to 330 GPs. GPs were surveyed about the 3 main domains relevant to the management of people with LSS in primary care: 1/ diagnosis, 2/ pharmacological treatments and 3/ non-pharmacological treatments, using self-administered open- and closed-ended questions and visual analog scales.

Results

Overall, 90/330 (27.3%) GPs completed the survey. 51/89 (57.3%) GPs were confident with managing people with LSS. Low back pain 51/87 (58.6%), neurogenic claudication 38/87 (43.7%) and paresthesia in the lower limbs 31/87 (35.6%) were the 3 most frequently cited clinical signs leading to the diagnosis of LSS. Improvement with lumbar flexion was mentioned by 9/87 (10.3%) GPs. 85/86 (98.8%) would consider prescribing lumbar imaging, 60/84 (71.4%) corticoid spinal injections and 42/79 (53.2%) would never prescribe lumbar flexion-based endurance training. All GPs would refer people with LSS to another specialist.

Conclusions

French GPs lack confidence with diagnosing LSS and prescribing pharmacological and non-pharmacological treatments for people with LSS.
Use of prescription analgesic drugs before and after hip or knee replacement in patients with osteoarthritis
Authors: Rajamäki Tuomas J. , Puolakka Pia A. , Hietaharju Aki , Moilanen Teemu , Jämsen Esa
Published: September 2019

Background

Analgesic drugs are recommended to treat pain caused by osteoarthritis, and joint replacement should decrease the need for them. We aimed to determine the user rates of analgesic drugs before and after joint replacement.

Methods

All patients who underwent a primary hip or knee replacement for osteoarthritis from 2002 to 2013 in a region of 0.5 million people were identified. Patients with revision or other joint replacements during the study period (operation date +/− two years) were excluded, leaving 6238 hip replacements (5657 patients) and 7501 knee replacements (6791 patients) for analyses. Medication data were collected from a nationwide Drug Prescription Register and the prevalence (with its 95% confidence intervals) of acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), mild opioids, strong opioids, and medications used for neuropathic pain was calculated in three-month periods two years before and after surgery.

Results

Between two years and three months preoperatively, the proportion of patients who redeemed at least one type of analgesic drug increased from 28% (95% CI, 27–30%) to 48% (47–50%) on hip replacement patients and from 33% (32–34%) to 41% (40–42%) on knee replacement patients. Postoperatively, the proportions decreased to 23% (22–24%) on hip and to 30% (29–31%) on knee patients. Hip replacement patients used more NSAIDs (34% (32–35%) hip vs 26% (25–27%) knee, p < 0.001), acetaminophen (14% (13–15%) vs 12% (11–13%), p < 0.001), and mild opioids (14% (13–15%) vs 9% (8–9%), p < 0.001) than knee patients preoperatively, but postoperatively hip patients used less NSAIDs (12% (11–13%) vs 16% (15–16%), p < 0.001), acetaminophen (9% (8–10%) vs 11% (11–12%), p < 0.001), and mild opioids (5% (5–6%) vs 8% (7–8%), p < 0.001).

Conclusion

Use of analgesic drugs increases prior to joint replacement, and is reduced following surgery. However, a considerable proportion of patients continue to use analgesics in two-year follow-up.
Prevalence of dental caries in children and adolescents with type 1 diabetes: a systematic review and meta-analysis
Authors: Wang Yan , Xing Lin , Yu Hui , Zhao LiJuan
Published: September 2019

Background

Dental caries and type 1 diabetes are responsible for a large burden of global disease; however, the exact prevalence of dental caries among children and adolescents with type 1 diabetes remains controversial, and no quantitative meta-analysis exists. Thus, we performed a meta-analysis to evaluate the prevalence of dental caries among children and adolescents with type 1 diabetes.

Methods

We performed a systematic search strategy using PubMed, EMBASE and China National Knowledge Infrastructure for relevant studies investigating the prevalence of dental caries in children and adolescents with type 1 diabetes from July 1971 until December 2018. The pooled prevalence with 95% confidence intervals (95%CIs) and subgroup analyses were calculated using a random effects model.

Results

After screening 358 non-duplicated articles, a total of 10 articles involving 538 individuals were included. The overall prevalence of dental caries among children and adolescents with type 1 diabetes was 67% (95% CI: 0.56–0.77%;I2 = 83%). The prevalence was highest in South America (84%) and lowest in diabetic patients with good metabolic control (47%).

Conclusions

The prevalence of dental caries was high among children and adolescents with type 1 diabetes. Screening and preventive treatment should be included in dental clinical routines for diabetic children and adolescents, especially in those with poor metabolic control.
Phytochemical, in-vitro biological and chemo-preventive profiling of Arisaema jacquemontii Blume tuber extracts
Authors: Tabassum Saira , Zia Muhammad , Carcahe de Blanco Esperanza J. , Batool Riffat , Aslam Roohi , Hussain Sajid , Wali Qamar , Gulzar Muhammad Mudassar
Published: September 2019

Background

Arisaema jacquemontii is traditionally used in treatment of different diseases. In this study, phytochemical, in vitro biological and chemo-preventive screening of A. jacquemontii was carried out to explore its pharmacological potential.

Methods

The dried tuber of A. jacquemontii was extracted in 11 organic solvent mixture of different polarity. The extracts were screened for phytochemical assays (phenolics and flavonoids), antioxidants potential (free radical scavenging activity, total antioxidant activity, reducing power), biological activities (antibacterial, antifungal, cytotoxic, antileishmanial, protein kinase inhibition), and chemopreventive activities using different cell lines through standard protocols.

Results

Significant amount phenolic contents were determined in EtOH and MeOH extracts (210.3 ± 3.05 and 193.2 ± 3.15 μg GAE/mg, respectively). Maximum flavonoid content was determined in MeOH extract (22.4 ± 4.04 μg QE/mg). Noteworthy, DPPH scavenging activity was also recorded for MeOH extract (87.66%) followed by MeOH+EtOAc extract (85.11%). Considerable antioxidant capacity (7.8 ± 0.12 μg AAE/mg) and reducing power (3.1 ± 0.15 μg AAE/mg) was observed in extract of MeOH. The LC50 against brine shrimp and leishmanial parasite was found 9.01 and 12.87 μg/mL for n-Hex and CHCl3 extracts, respectively. The highest zone of inhibition against Streptomyces hyphae formation (12.5 ± 1.77 mm) by n-Hex extract. Growth zone of inhibition 13.8 ± 1.08 mm was recorded for EtOAc and MeOH extracts, respectively against Micrococcus luteus while 10.0 ± 0.11 mm for MeOH extract against Aspergillus flavus. In-vitro cytotoxic assay showed that n-Hex extract had higher cytotoxicity against DU-145 prostate cancer and HL-60 cancer cell lines. NF-kB and MTP potential showed 34.01 and 44.87 μg/mL for n-Hex and CHCl3 extracts, respectively in chemo-preventive potential.

Conclusion

The study concludes that Arisaema jacquemontii bears significant phytochemical activity and pharmacological activities, this plant can be further explored for isolation of active component against a number of aliments.
Peer-assisted learning (PAL): skills lab tutors’ experiences and motivation
Authors: Bugaj T. J. , Blohm M. , Schmid C. , Koehl N. , Huber J. , Huhn D. , Herzog W. , Krautter M. , Nikendei C.
Published: September 2019

Background

Peer-assisted learning (PAL) is a common teaching and learning method in medical education worldwide. In the setting of skills laboratories (skills labs), student tutors are often employed as an equivalent alternative to faculty teachers. However, to the best of our knowledge, there is a lack of qualitative studies which explore the reasons for the personal commitment of student tutors. The aim of our study was to examine how undergraduate students experienced and evaluated their roles as skills lab student tutors, what their motivation was, and whether social and cognitive congruence played a role in their teaching experiences.

Methods

We conducted in-depth, semi-structured interviews with student tutors who were currently teaching in a skills lab. After the interviews had been transcribed verbatim, two independent investigators performed a qualitative content analysis according to Mayring.

Results

In total, we conducted nine interviews with student tutors. Our results revealed that all student tutors showed great enthusiasm and motivation for their jobs as peer teachers. One of the main motivating factors for student tutors to teach in a skills lab was the possibility to simultaneously share and improve their knowledge and expertise. In general, the participants of our study had high aspirations for their teaching. They found it particularly important to be empathetic with the student learners. At the same time, they thought they would personally benefit from their teaching activities and develop a certain expertise as student tutors.

Conclusions

With the present study we are able to gain some insight into what motivates student tutors to teach in a skills lab and what kind of experiences they have. Our results provide an important input for the future training of highly qualified student tutors.
These may not be the courses you are seeking: a systematic review of open online courses in health professions education
Authors: Rowe Michael , Osadnik Christian R. , Pritchard Shane , Maloney Stephen
Published: September 2019

Introduction

Open Online Courses (OOCs) are increasingly presented as a possible solution to the many challenges of higher education. However, there is currently little evidence available to support decisions around the use of OOCs in health professions education. The aim of this systematic review was to summarise the available evidence describing the features of OOCs in health professions education and to analyse their utility for decision-making using a self-developed framework consisting of point scores around effectiveness, learner experiences, feasibility, pedagogy and economics.

Methods

Electronic searches of PubMed, Medline, Embase, PsychInfo and CINAHL were made up to April 2019 using keywords related to OOC variants and health professions. We accepted any type of full text English publication with no exclusions made on the basis of study quality. Data were extracted using a custom-developed, a priori critical analysis framework comprising themes relating to effectiveness, economics, pedagogy, acceptability and learner experience.

Results

54 articles were included in the review and 46 were of the lowest levels of evidence, and most were offered by institutions based in the United States (n = 11) and United Kingdom (n = 6). Most studies provided insufficient course detail to make any confident claims about participant learning, although studies published from 2016 were more likely to include information around course aims and participant evaluation. In terms of the five categories identified for analysis, few studies provided sufficiently robust evidence to be used in formal decision making in undergraduate or postgraduate curricula.

Conclusion

This review highlights a poor state of evidence to support or refute claims regarding the effectiveness of OOCs in health professions education. Health professions educators interested in developing courses of this nature should adopt a critical and cautious position regarding their adoption.
Utilization of high-fidelity simulation to address challenges with the basic science immunology education of preclinical medical students
Authors: Cavuoto Petrizzo Marie , Barilla-LaBarca Maria-Louise , Lim Youn Seon , Jongco Artemio M. , Cassara Michael , Anglim James , Stern Joel N.H.
Published: September 2019

Background

Immune function and dysfunction are highly complex basic science concepts introduced in the preclinical medical school curriculum. A challenge for early learners is connecting the intricate details and concepts in immunology with clinical manifestations. This impedes relevance and applicability. The impetus in medical education reform is promoting consolidation of basic science and clinical medicine during the first two years of medical school. Simulation is an innovation now widely employed in medical schools to enhance clinical learning. Its use in basic science curriculums is largely deficient. The authors piloted simulation as a novel curricular approach to enhance fundamental immunology knowledge and clinical integration.

Methods

The authors introduced a Primary Immunodeficiency Disease (PIDD) simulation during a basic science immunology course for second-year medical students at the Zucker School of Medicine at Hofstra/Northwell. The simulation tasked small groups of students with evaluating, diagnosing and managing an infant with previously undiagnosed immunodeficiency. Joint facilitation by clinical and science faculty during terminal debriefings engaged students in Socratic discussion. Debriefing aimed to immerse basic science content in the context of the clinical case. Students completed a post-simulation Likert survey, assessing utility in reinforcing clinical reasoning, integration of basic science and clinical immunology, enhanced knowledge and understanding of immunodeficiency, and enhanced learning. A summative Immunodeficiency Objective Structured Clinical Examination (OSCE) question was created by faculty to assess students’ recognition of a PIDD and clinical reasoning.

Results

The simulation was well received by students with > 90% endorsing each of the objectives on the post-simulation survey. The authors also determined a statistically significant score variance on the summative OSCE question. Higher scores were achieved by the cohort of students completing the OSCE post-simulation versus the cohort completing the OSCE pre-simulation.

Conclusions

The innovative use of simulation in a highly complex basic science immunology course provides relevance and consolidation for preclinical learners. Additional data will be collected to continuously assess application of concepts and proficiency stemming from this novel curricular intervention. The authors advocate the initiation and/or expansion of simulation in non-clinical basic science courses such as immunology to bridge the gap between theory and practice.
Strategic elements of residency training in China: transactional leadership, self-efficacy, and employee-orientation culture
Authors: Deng Guangwei , Zhao Di , Lio Jonathan , Chen Xinyu , Ma Xiaopeng , Liang Liang , Feng Chenpeng
Published: September 2019

Background

The standardized training of resident physicians in China is significant and robust. During the training, clinical teachers act as leaders. The training taking place in public hospitals requires a transactional leadership style (TLS), but existing research studies seldom analyze how to promote residents’ performance from this perspective.

Methods

Two hundred and ninety six new residents undertaking standardized training were recruited from five tertiary hospitals in two provinces of China. Hierarchical moderated and mediated regression analyses were used to test the hypotheses. The hypotheses include that TLS is positively related to the training performance; mediating effect of self-efficacy and moderating effect of employee-orientation organizational culture (EOC) are significant.

Results

(1) Two kinds of teachers’ TLS, punishment and reward, have significant positive influence on residents’ performance. (2) Self-efficacy of residents partly mediates the positive relationship. (3) EOC moderates the relationship between the punitive behavior of clinical teachers with TLS and the self-efficacy of the residents.

Conclusions

Empirical evidence has shown the positive relationship between teachers’ TLS and residents’ performance outcomes in China. Teachers can enhance training performance by promoting self-efficacy of residents. This study also advances our understanding of EOC by examining the demonstrated moderating effects of cultural background in the relationship between teachers’ TLS and the self-efficacy of residents.
Relationship between students’ perceptions of the adequacy of M1 and M2 curricula and their performance on USMLE step 1 examination
Authors: Khalil Mohammed K. , Wright William S. , Spearman Kelsey A. , Gaspard Amber C.
Published: September 2019

Background

Performance on United States Medical Licensing Exam® (USMLE®) Step 1 examination (Step 1) is an important milestone for medical students. It is necessary for their graduation, and selection to interview for the National Resident Match Program®. Success on Step 1 examination requires content alignment, and continuous evaluation and improvement of preclinical curriculum. The purpose of this research was to observe the association between students’ perceptions of deficits in the curriculum based on core disciplines and organ systems in relation to students’ performance in those disciplines and systems on USMLE® Step 1 examination.

Methods

An anonymous survey with closed-ended and open-ended questions was sent to 174 medical students, the class of 2018 (77), and 2019 (97) within 2–3 weeks of taking Step 1 examination. Students’ feedback as well as students’ performance on Step 1 examination were organized into disciplines and organ systems to allow for more specific curriculum analyses. The closed-ended questions provide three selections (yes, no and not sure) regarding students’ agreement to the adequacy of M1 and M2 curricula to prepare students for Step 1 examination. Students’ responses on the closed-ended questions were reviewed in conjunction with their Step 1 performance. The open-ended feedback was qualitatively analyzed for emergent themes or similarity with closed-ended questions in identifying any shortcoming of the curriculum.

Results

The data show an apparent relationship between students’ evaluations and students’ performance on Step 1 examinations. A high percentage of students’ disagreement of the curriculum adequacy was also reflected in a lower performance on Step 1 examination. Additionally, the themes that emerged from the qualitative analysis have confirmed the areas of curricular deficiency.

Conclusion

The data collected from this research provides insight into the degree of usefulness of students’ evaluations as a way of assessing curriculum deficits in preparing students for their Step 1 examination.
Adding to the debate on the numbers of options for MCQs: the case for not being limited to MCQs with three, four or five options
Authors: Tweed Mike
Published: September 2019

Background

There is a significant body of literature that indicates that the number of options for single-best answer multiple choice questions (MCQs) can be reduced from five to three or four without adversely affecting the quality of the questions and tests. Three or four options equates to two or three distractors respectively.

Maintext

Whilst these arguments may be true when focusing on psychometric aspects of questions, we should also focus on educational and clinical authenticity aspects of questions. I present reasons for MCQs in tests to have a variable number of options which will usually be more than three, four, or five. These include: decisions related to broad clinical scenarios cannot be limited to a small number of options; options lists should include all possible combinations of option elements; and options that are rarely chosen can provide information regarding students and/or for students.

Conclusion

Finally, given computer based delivery, longer option lists are not impractical for examinees. In the contexts that are appropriate, it is time to consider a move to adopting appropriate and variable numbers of MCQ options and not be limited to MCQs with three, four or five options.
Acquisition of basic ear surgery skills: a randomized comparison between endoscopic and microscopic techniques
Authors: Anschuetz Lukas , Stricker Daniel , Yacoub Abraam , Wimmer Wilhelm , Caversaccio Marco , Huwendiek Sören
Published: September 2019

Background

Endoscopic ear surgery is gaining increasing popularity and has an important impact on teaching middle ear anatomy and basic surgical skills among residents and fellows. Due to the wide-angled views offered, the approach significantly differs from the established microscopic technique. This randomized study compares the acquisition of basic ear-surgery skills using the endoscopic and microscopic technique under standardized conditions. We aim to investigate the required surgical times, attempts and accidental damages to surrounding structures (errors) in surgeons with different training levels.

Methods

Final-year medical students (n = 9), residents (n = 14) and consultants (n = 10) from the Department of Otorhinolaryngology, Head and Neck Surgery at the University Hospital of Bern, Switzerland were enrolled in the present study. After randomization every participant had to complete a standard set of grasping and dissecting surgical tasks in a temporal bone model. After the first session the participants were crossed over to the other technique.

Results

Time required for completion of the surgical tasks was similar for both techniques, but highly dependent on the training status. A significant increase in the number of damages to the ossicular chain was observed with the microscopic as compared to the endoscopic technique (p < 0.001). Moreover, students beginning with the endoscopic technique showed an overall significantly lower amount of time to complete the tasks (p = 0.04). From the subjective feedback a preference towards the endoscopic technique mainly in medical students was observed.

Conclusions

The endoscopic approach is useful and beneficial for teaching basic surgical skills, mainly by providing a reduction of damage to surrounding tissues with similar operating times for both techniques. Moreover, medical students performed significantly faster, when first taught in the endoscopic technique. Especially for young surgeons without previous training in ear surgery, the endoscope should be considered to improve surgical skills in the middle ear.
CCDC74A/B are K-fiber crosslinkers required for chromosomal alignment
Authors: Zhou Haining , Zheng Tao , Wang Tianning , Li Qi , Wang Fulin , Liang Xin , Chen Jianguo , Teng Junlin
Published: September 2019

Background

Spindle microtubule organization, regulated by microtubule-associated proteins, is critical for cell division. Proper organization of kinetochore fiber (K-fiber), connecting spindle poles and kinetochores, is a prerequisite for precise chromosomal alignment and faithful genetic material transmission. However, the mechanisms of K-fiber organization and dynamic maintenance are still not fully understood.

Results

We reveal that two previously uncharacterized coiled-coil domain proteins CCDC74A and CCDC74B (CCDC74A/B) are spindle-localized proteins in mammalian cells. They bind directly to microtubules through two separate domains and bundle microtubules both in vivo and in vitro. These functions are required for K-fiber organization, bipolar spindle formation, and chromosomal alignment. Moreover, CCDC74A/B form homodimers in vivo, and their self-association activity is necessary for microtubule bundling and K-fiber formation.

Conclusions

We characterize CCDC74A and CCDC74B as microtubule-associated proteins that localize to spindles and are important K-fiber crosslinkers required for bipolar spindle formation and chromosome alignment.
Correction to: Vitamin D receptor gene polymorphisms affecting changes in visceral fat, waist circumference and lipid profile in breast cancer survivors supplemented with vitamin D3
Authors: Kazemian Elham , Amouzegar Atieh , Akbari Mohammad Esmaeil , Moradi Nariman , Gharibzadeh Safoora , Jamshidi-Naeini Yasaman , Khademolmele Maryam , As’habi Atefeh , Davoodi Sayed Hossein
Published: September 2019

Following publication of the original article [1], the authors reported that one of the co-authors has a mistake in the author name.
Sialic acid metabolism as a potential therapeutic target of atherosclerosis
Authors: Zhang Chao , Chen Jingyuan , Liu Yuhao , Xu Danyan
Published: September 2019

Sialic acid (Sia), the acylated derivative of the nine-carbon sugar neuraminic acid, is a terminal component of the oligosaccharide chains of many glycoproteins and glycolipids. In light of its important biological and pathological functions, the relationship between Sia and coronary artery disease (CAD) has been drawing great attentions recently. Large-scale epidemiological surveys have uncovered a positive correlation between plasma total Sia and CAD risk. Further research demonstrated that N-Acetyl-Neuraminic Acid, acting as a signaling molecule, triggered myocardial injury via activation of Rho/ROCK-JNK/ERK signaling pathway both in vitro and in vivo. Moreover, there were some evidences showing that the aberrant sialylation of low-density lipoprotein, low-density lipoprotein receptor and blood cells was involved in the pathological process of atherosclerosis. Significantly, the Sia regulates immune response by binding to sialic acid-binding immunoglobulin-like lectin (Siglecs). The Sia-Siglecs axis is involved in the immune inflammation of atherosclerosis. The generation of Sia and sialylation of glycoconjugate both depend on many enzymes, such as sialidase, sialyltransferase and trans-sialidase. Abnormal activation or level of these enzymes associated with atherosclerosis, and inhibitors of them might be new CAD treatments. In this review, we focus on summarizing current understanding of Sia metabolism and of its relevance to atherosclerosis.
Variations in hepatic lipid species of age-matched male mice fed a methionine-choline-deficient diet and housed in different animal facilities
Authors: Rein-Fischboeck Lisa , Haberl Elisabeth M. , Pohl Rebekka , Feder Susanne , Liebisch Gerhard , Krautbauer Sabrina , Buechler Christa
Published: September 2019

Background

Non-alcoholic steatohepatitis (NASH) is a common disease and feeding mice a methionine-choline-deficient (MCD) diet is a frequently used model to study its pathophysiology. Genetic and environmental factors influence NASH development and liver lipid content, which was studied herein using C57BL/6 J mice bred in two different animal facilities.

Methods

Age-matched male C57BL/6 J mice bred in two different animal facilities (later on referred to as WT1 and WT2) at the University Hospital of Regensburg were fed identical MCD or control chows for 2 weeks. Hepatic gene and protein expression and lipid composition were determined.

Results

NASH was associated with increased hepatic triglycerides, which were actually higher in WT1 than WT2 liver in both dietary groups. Cholesterol contributes to hepatic injury but was only elevated in WT2 NASH liver. Ceramides account for insulin resistance and cell death, and ceramide species d18:1/16:0 and d18:1/18:0 were higher in the NASH liver of both groups. Saturated sphingomyelins only declined in WT1 NASH liver. Lysophosphatidylcholine concentrations were quite normal in NASH and only one of the 12 altered phosphatidylcholine species declined in NASH liver of both groups. Very few phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol species were comparably regulated in NASH liver of both animal groups. Seven of these lipid species declined and two increased in NASH. Notably, hepatic mRNA expression of proinflammatory (F4/80, CD68, IL-6, TNF and chemerin) and profibrotic genes (TGF beta and alpha SMA) was comparable in WT1 and WT2 mice.

Conclusions

Mice housed and bred in different animal facilities had comparable disease severity of NASH whereas liver lipids varied among the groups. Thus, there was no specific lipid signature for NASH in the MCD model.
New insights into different adipokines in linking the pathophysiology of obesity and psoriasis
Authors: Kong Yi , Zhang Suhan , Wu Ruifang , Su Xin , Peng Daoquan , Zhao Ming , Su Yuwen
Published: September 2019

Psoriasis is a chronic, systemic, hyper-proliferative immune-mediated inflammatory skin disease. The results of epidemiological investigations have shown that psoriasis affects around 2% of the general population worldwide, and the total number of psoriasis patients is more than 6 million in China. Apart from the skin manifestations, psoriasis has been verified to associate with several metabolic comorbidities, such as insulin resistance, diabetes and obesity. However, the underlying mechanism is still not elucidated. Adipocytes, considered as the active endocrine cells, are dysfunctional in obesity which displays increased synthesis and secretion of adipokines with other modified metabolic properties. Currently, growing evidence has pointed to the central role of adipokines in adipose tissue and the immune system, providing new insights into the effect of adipokines in linking the pathophysiology of obesity and psoriasis. In this review, we summarize the current understanding of the pathological role of adipokines and the potential mechanisms whereby different adipokines link obesity and psoriasis. Furthermore, we also provide evidence which identifies a potential therapeutic target aiming at adipokines for the management of these two diseases.
The role of collagen in cancer: from bench to bedside
Authors: Xu Shuaishuai , Xu Huaxiang , Wang Wenquan , Li Shuo , Li Hao , Li Tianjiao , Zhang Wuhu , Yu Xianjun , Liu Liang
Published: September 2019

Collagen is the major component of the tumor microenvironment and participates in cancer fibrosis. Collagen biosynthesis can be regulated by cancer cells through mutated genes, transcription factors, signaling pathways and receptors; furthermore, collagen can influence tumor cell behavior through integrins, discoidin domain receptors, tyrosine kinase receptors, and some signaling pathways. Exosomes and microRNAs are closely associated with collagen in cancer. Hypoxia, which is common in collagen-rich conditions, intensifies cancer progression, and other substances in the extracellular matrix, such as fibronectin, hyaluronic acid, laminin, and matrix metalloproteinases, interact with collagen to influence cancer cell activity. Macrophages, lymphocytes, and fibroblasts play a role with collagen in cancer immunity and progression. Microscopic changes in collagen content within cancer cells and matrix cells and in other molecules ultimately contribute to the mutual feedback loop that influences prognosis, recurrence, and resistance in cancer. Nanoparticles, nanoplatforms, and nanoenzymes exhibit the expected gratifying properties. The pathophysiological functions of collagen in diverse cancers illustrate the dual roles of collagen and provide promising therapeutic options that can be readily translated from bench to bedside. The emerging understanding of the structural properties and functions of collagen in cancer will guide the development of new strategies for anticancer therapy.
Locomotor skill acquisition in virtual reality shows sustained transfer to the real world
Authors: Kim Aram , Schweighofer Nicolas , Finley James M.
Published: September 2019

Background

Virtual reality (VR) is a potentially promising tool for enhancing real-world locomotion in individuals with mobility impairment through its ability to provide personalized performance feedback and simulate real-world challenges. However, it is unknown whether novel locomotor skills learned in VR show sustained transfer to the real world. Here, as an initial step towards developing a VR-based clinical intervention, we study how young adults learn and transfer a treadmill-based virtual obstacle negotiation skill to the real world.

Methods

On Day 1, participants crossed virtual obstacles while walking on a treadmill, with the instruction to minimize foot clearance during obstacle crossing. Gradual changes in performance during training were fit via non-linear mixed effect models. Immediate transfer was measured by foot clearance during physical obstacle crossing while walking over-ground. Retention of the obstacle negotiation skill in VR and retention of over-ground transfer were assessed after 24 h.

Results

On Day 1, participants systematically reduced foot clearance throughout practice by an average of 5 cm (SD 4 cm) and transferred 3 cm (SD 1 cm) of this reduction to over-ground walking. The acquired reduction in foot clearance was also retained after 24 h in VR and over-ground. There was only a small, but significant 0.8 cm increase in foot clearance in VR and no significant increase in clearance over-ground on Day 2. Moreover, individual differences in final performance at the end of practice on Day 1 predicted retention both in VR and in the real environment.

Conclusions

Overall, our results support the use of VR for locomotor training as skills learned in a virtual environment readily transfer to real-world locomotion. Future work is needed to determine if VR-based locomotor training leads to sustained transfer in clinical populations with mobility impairments, such as individuals with Parkinson’s disease and stroke survivors.
Combining transcranial direct-current stimulation with gait training in patients with neurological disorders: a systematic review
Authors: de Paz Rubén Hernández , Serrano-Muñoz Diego , Pérez-Nombela Soraya , Bravo-Esteban Elisabeth , Avendaño-Coy Juan , Gómez-Soriano Julio
Published: September 2019

Background

Transcranial direct-current stimulation (tDCS) is an easy-to-apply, cheap, and safe technique capable of affecting cortical brain activity. However, its effectiveness has not been proven for many clinical applications.

Objective

The aim of this systematic review was to determine whether the effect of different strategies for gait training in patients with neurological disorders can be enhanced by the combined application of tDCS compared to sham stimulation. Additionally, we attempted to record and analyze tDCS parameters to optimize its efficacy.

Methods

A search in Pubmed, PEDro, and Cochrane databases was performed to find randomized clinical trials that combined tDCS with gait training. A chronological filter from 2010 to 2018 was applied and only studies with variables that quantified the gait function were included.

Results

A total of 274 studies were found, of which 25 met the inclusion criteria. Of them, 17 were rejected based on exclusion criteria. Finally, 8 trials were evaluated that included 91 subjects with stroke, 57 suffering from Parkinson’s disease, and 39 with spinal cord injury. Four of the eight assessed studies did not report improved outcomes for any of its variables compared to the placebo treatment.

Conclusions

There are no conclusive results that confirm that tDCS can enhance the effect of the different strategies for gait training. Further research for specific pathologies, with larger sample sizes and adequate follow-up periods, are required to optimize the existing protocols for applying tDCS.
Low ERCC1 expression is a good predictive marker in lung adenocarcinoma patients receiving chemotherapy based on platinum in all TNM stages - a single-center study
Authors: Piljić Burazer Marina , Mladinov Suzana , Matana Antonela , Kuret Sendi , Bezić Joško , Glavina Durdov Merica
Published: September 2019

Background

High ERCC1 expression is thought to be related with resistance to chemotherapy based on platinum. The aim of this study was to present our institutional observations regarding to the association of ERCC1 and overall survival (OS) of the lung adenocarcinoma patients who received chemotherapy based on platinum.

Material/methods

A total of 253 lung adenocarcinoma patients in all TNM stages were retrospectively investigated. The diagnosis was based on small biopsy samples obtained during bronchoscopy. Depending on the TNM stage of the disease and clinical condition, patients received only the chemotherapy based on platinum, or in combination with radiotherapy or surgery. Tissue sample for ERCC1 immunohistochemical analysis was sufficient in 129 patients. Low from high ERCC1 expression was separated by the semi-quantitative H-score median.

Results

High ERCC1 expression was found in 47.3% patients, and was correlated with higher TNM (p = 0.021), tumor enlargement (p = 0.002), positive lymph nodes (p = 0.001), positive distant metastasis (p = 0.005), and higher relative risk of death (p < 0.001). Furthermore, significance association was observed for low ERCC1 expression and better performance status (ECOG) (p = 0.023). Longer OS was strongly associated with a low ERCC1 expression, not only in the group of patients in TNM stage I-III, who were treated with combination of chemotherapy with surgery or radiotherapy (p = 0.002), but also in the group of patients in TNM stage IV who received only chemotherapy based on platinum (p < 0.001), compared with the patients in the same TNM stage and high ERCC1 expression.

Conclusions

ERCC1 expression in lung adenocarcinoma is a useful prognostic marker and moreover, a useful predictive marker in patients receiving chemotherapy based on platinum in all stages of the disease.
Strategies for the expansion of human induced pluripotent stem cells as aggregates in single-use Vertical-Wheel™ bioreactors
Authors: Nogueira Diogo E. S. , Rodrigues Carlos A. V. , Carvalho Marta S. , Miranda Cláudia C. , Hashimura Yas , Jung Sunghoon , Lee Brian , Cabral Joaquim M. S.
Published: September 2019

Background

Since their inception, human induced pluripotent stem cells (hiPSCs) have held much promise for pharmacological applications and cell-based therapies. However, their potential can only be realised if large numbers of cells can be produced reproducibly on-demand. While bioreactors are ideal systems for this task, due to providing agitation and control of the culture parameters, the common impeller geometries were not designed for the expansion of mammalian cells, potentially leading to sub-optimal results.

Results

This work reports for the first time the usage of the novel Vertical-Wheel single-use bioreactors for the expansion of hiPSCs as floating aggregates. Cultures were performed in the PBS MINI 0.1 bioreactor with 60 mL of working volume. Two different culture media were tested, mTeSR1 and mTeSR3D, in a repeated batch or fed-batch mode, respectively, as well as dextran sulfate (DS) supplementation. mTeSR3D was shown to sustain hiPSC expansion, although with lower maximum cell density than mTeSR1. Dextran sulfate supplementation led to an increase in 97 and 106% in maximum cell number when using mTeSR1 or mTeSR3D, respectively. For supplemented media, mTeSR1 + DS allowed for a higher cell density to be obtained with one less day of culture. A maximum cell density of (2.3 ± 0.2) × 106 cells∙mL− 1 and a volumetric productivity of (4.6 ± 0.3) × 105 cells∙mL− 1∙d− 1 were obtained after 5 days with mTeSR1 + DS, resulting in aggregates with an average diameter of 346 ± 11 μm. The generated hiPSCs were analysed by flow cytometry and qRT-PCR and their differentiation potential was assayed, revealing the maintenance of their pluripotency after expansion.

Conclusions

The results here described present the Vertical-Wheel bioreactor as a promising technology for hiPSC bioprocessing. The specific characteristics of this bioreactor, namely in terms of the innovative agitation mechanism, can make it an important system in the development of hiPSC-derived products under current Good Manufacturing Practices.
Prospects for combining immune checkpoint blockade with PARP inhibition
Authors: Li Anping , Yi Ming , Qin Shuang , Chu Qian , Luo Suxia , Wu Kongming
Published: September 2019

The immunogenicity of a cancer cell is derived from accumulated somatic mutations. However, on the contrary to increased immunogenicity, anti-cancer immune response tends to be feeble. This impaired anti-cancer immunity could be attributed to multiple factors including loss of immunodominant epitopes, downregulation of major histocompatibility complex, and immunosuppressive microenvironment, as well as aberrant negative co-stimulatory signals. Immune checkpoint inhibitors block negative co-stimulatory signals such as programmed cell death-1 and cytotoxic T-lymphocyte-associated protein 4, ultimately reactivating anti-cancer immunity. Immune checkpoint inhibitors elicit potent anti-cancer effect and have been approved for multiple cancers. Nevertheless, there still are significant potential improvements for the applications of checkpoint inhibitor, especially considering frequent resistance. Recent studies demonstrated that additional PARP inhibition could alleviate resistance and enhance efficacy of immune checkpoint blockade therapy via promoting cross-presentation and modifying immune microenvironment. We proposed that PARP inhibitors could enhance the priming and tumor-killing activities of T cell, boost the whole cancer-immunity cycle, and thereby improve the response to immune checkpoint blockade. In this review, we focused the latest understanding of the effect of PARP inhibitors on anti-cancer immunity and PARP inhibitors combining immune checkpoint blockade therapy. Moreover, we summarized the preclinical and clinical evidence and discussed the feasibility of this combination therapy in future clinical practice.