bluuebunny/crossref_metadata_2025_split huggingface dataset:
Claudin-12 is not required for blood–brain barrier tight junction function
Authors:   German Mouse Clinic Consortium, Castro Dias Mariana , Coisne Caroline , Baden Pascale , Enzmann Gaby , Garrett Lillian , Becker Lore , Hölter Sabine M. , Hrabě de Angelis Martin , Deutsch Urban , Engelhardt Britta 
Published: September 2019

Abstract

Background
The blood–brain barrier (BBB) ensures central nervous system (CNS) homeostasis by strictly controlling the passage of molecules and solutes from the bloodstream into the CNS. Complex and continuous tight junctions (TJs) between brain endothelial cells block uncontrolled paracellular diffusion of molecules across the BBB, with claudin-5 being its dominant TJs protein. However, claudin-5 deficient mice still display ultrastructurally normal TJs, suggesting the contribution of other claudins or tight-junction associated proteins in establishing BBB junctional complexes. Expression of claudin-12 at the BBB has been reported, however the exact function and subcellular localization of this atypical claudin remains unknown.

Methods
We created claudin-12-lacZ-knock-in C57BL/6J mice to explore expression of claudin-12 and its role in establishing BBB TJs function during health and neuroinflammation. We furthermore performed a broad standardized phenotypic check-up of the mouse mutant.

Results
Making use of the lacZ reporter allele, we found claudin-12 to be broadly expressed in numerous organs. In the CNS, expression of claudin-12 was detected in many cell types with very low expression in brain endothelium. Claudin-12lacZ/lacZ C57BL/6J mice lacking claudin-12 expression displayed an intact BBB and did not show any signs of BBB dysfunction or aggravated neuroinflammation in an animal model for multiple sclerosis. Determining the precise localization of claudin-12 at the BBB was prohibited by the fact that available anti-claudin-12 antibodies showed comparable detection and staining patterns in tissues from wild-type and claudin-12lacZ/lacZ C57BL/6J mice.

Conclusions
Our present study thus shows that claudin-12 is not essential in establishing or maintaining BBB TJs integrity. Claudin-12 is rather expressed in cells that typically lack TJs suggesting that claudin-12 plays a role other than forming classical TJs. At the same time, in depth phenotypic screening of clinically relevant organ functions of claudin-12lacZ/lacZ C57BL/6J mice suggested the involvement of claudin-12 in some neurological but, more prominently, in cardiovascular functions.
Assessing attitudes of patient-centred care among students in international chiropractic educational programs: a cross-sectional survey
Authors: Hammerich Karin , Stuber Kent , Hogg-Johnson Sheilah , Abbas Anser , Harris Martin , Lauridsen Henrik Hein , Lemeunier Nadège , Maiers Michele , McCarthy Peter , Morales Vanessa , Myburgh Corrie , Petrini Vanessa , Pohlman Katherine , Mior Silvano 
Published: September 2019

Abstract

Background
Patient-centred care is internationally recognized as a foundation of quality patient care. Attitudes of students towards patient-centred care have been assessed in various health professions. However, little is known how chiropractic students’ attitudes towards patient-centred care compare to those of other health professions or whether they vary internationally, and between academic programs.

Objective
To assess the association of select variables on student attitude towards patient-centred care among select chiropractic programs worldwide.

Methods
We conducted a cross-sectional study using the Patient-Practitioner Orientation Scale (PPOS) to assess students’ patient-centred attitudes towards the doctor-patient relationship. Eighteen items were scored on a 1 to 6 Likert scale; higher scores indicating more patient-centredness. All students from seven chiropractic educational programs worldwide were invited to complete an online survey. Results were analyzed descriptively and inferentially for overall, sharing and caring subscales. General linear regression models were used to assess the association of various factors with PPOS scores.

Results
There were 1858 respondents (48.9% response rate). Student average age was 24.7 (range = 17–58) years and 56.2% were female. The average overall PPOS score was 4.18 (SD = 0.48) and average sharing and caring subscale scores were 3.89 (SD = 0.64) and 4.48 (SD = 0.52), respectively. There were small but significant differences in all PPOS scores by gender, age, and program. Year/semester of study within a program typically was not associated with scores, neither was history of previous chiropractic care nor having family members who are health professionals.

Conclusion
This is the first international study assessing students’ attitudes of patient-centred care in chiropractic educational programs. We found small but significantly different PPOS scores between chiropractic programs worldwide that did not change across year/semester of study. Scores tended to be lower than those reported among medical students. Observed differences may be related to curricular content, extent of patient exposure and/or regional cultural realities.
A perspective on Councils on Chiropractic Education accreditation standards and processes from the inside: a narrative description of expert opinion, part 2: Analyses of particular responses to research findings
Authors: Innes Stanley I. , Cope Vicki , Leboeuf-Yde Charlotte , Walker Bruce F. 
Published: September 2019

AbstractBackgroundThis is the second article reporting on a study that sought the views of people with extensive experience in Councils on Chiropractic Education (CCEs) on research that has raised concerns about variability in accreditation standards and processes for chiropractic programs (CPs) and chiropractic practice in general.MethodsThis qualitative study employed in-depth semi-structured interviews that consisted of open-ended questions asking experts about their thoughts and views on a range of issues surrounding accreditation, graduate competency standards and processes. The interviews were audio-recorded, and transcribed verbatim in June and July of 2018. The transcripts were reviewed to develop codes and themes. The study followed the COREQ guidelines for qualitative studies.ResultsThe interviews revealed that these CCE experts were able to discern positive and negative elements of the accreditation standards and processes. They were, in general, satisfied with CCEs accreditation standards, graduating competencies, and site inspection processes. Most respondents believed that it was not possible to implement an identical set of international accreditation standards because of cultural and jurisdictional differences. This was thought more likely to be achieved if based on the notion of equivalence. Also, they expressed positive views toward an evidence-based CP curriculum and an outcomes-based assessment of student learning. However, they expressed concerns that an evidence-based approach may result in the overlooking of the clinician’s experience. Diverse views were found on the presence ofvitalismin CPs. These ranged from thinking vitalism should only be taught in an historical context, it was only a minority who held this view and therefore an insignificant issue. Finally, that CCEs should not regulate these personal beliefs, as this was potentially censorship. The notable absence was that the participants omitted any mention of the implications for patient safety, values and outcomes.ConclusionsExpert opinions lead us to conclude that CCEs should embrace and pursue the widely accepted mainstream healthcare standards of an evidence-based approach and place the interests of the patient above that of the profession. Recommendations are made to this end with the intent of improving CCE standards and processes of accreditation.
Conceptualizing patient-centered care for substance use disorder treatment: findings from a systematic scoping review
Authors: Marchand Kirsten , Beaumont Scott , Westfall Jordan , MacDonald Scott , Harrison Scott , Marsh David C. , Schechter Martin T. , Oviedo-Joekes Eugenia 
Published: September 2019

AbstractBackgroundDespite ongoing efforts aimed to improve treatment engagement for people with substance-related disorders, evidence shows modest rates of utilization as well as client-perceived barriers to care. Patient-centered care (PCC) is one widely recognized approach that has been recommended as an evidence-based practice to improve the quality of substance use disorder treatment. PCC includes four core principles: a holistic and individualized focus to care, shared decision-making and enhanced therapeutic alliance.AimsThis scoping review aimed to explore which PCC principles have been described and how they have defined and measured among people with substance-related disorders.MethodsFollowing the iterative stages of the Arksey and O’Malley scoping review methodology, empirical (from Medline, Embase, PsycINFO, CINAHL and ISI Web of Science) and grey literature references were eligible if they focused on people accessing treatment for substance-related disorders and described PCC. Two reviewers independently screened the title/abstract and full-texts of references. Descriptive analyses and a directed content analysis were performed on extracted data.FindingsOne-hundred and forty-nine references met inclusion from the 2951 de-duplicated references screened. Therapeutic alliance was the most frequent principle of PCC described by references (72%); this was consistently defined by characteristics of empathy and non-judgment. Shared decision-making was identified in 36% of references and was primarily defined by client and provider strategies of negotiation in the treatment planning process. Individualized care was described by 30% of references and included individualized assessment and treatment delivery efforts. Holistic care was identified in 23% of references; it included an integrated delivery of substance use, health and psychosocial services via comprehensive care settings or coordination. Substance use and treatment engagement outcomes were most frequently described, regardless of PCC principle.ConclusionsThis review represents a necessary first step to explore how PCC has been defined and measured for people accessing substance use disorder treatment. The directed content analysis revealed population and context-specific evidence regarding the defining characteristics of PCC-principles that can be used to further support the implementation of PCC.
Icariin alleviates osteoarthritis by inhibiting NLRP3-mediated pyroptosis
Authors: Zu Yan , Mu Yue , Li Qiang , Zhang Shu-Ting , Yan Hong-Juan 
Published: September 2019

Abstract

Background
Osteoarthritis (OA) is the common chronic degenerative joint bone disease that is mainly featured by joint stiffness and cartilage degradation. Icariin (ICA), an extract from Epimedium, has been preliminarily proven to show anti-osteoporotic and anti-inflammatory effects in OA. However, the underlying mechanisms of ICA on chondrocytes need to be elucidated.

Methods
LPS-treated chondrocytes and monosodium iodoacetate (MIA)-treated Wistar rats were used as models of OA in vitro and in vivo, respectively. LDH and MTT assays were performed to detect cytotoxicity and cell viability. The expression levels of NLRP3, IL-1β, IL-18, MMP-1, MMP-13, and collagen II were detected by qRT-PCR and Western blotting. The release levels of IL-1β and IL-18 were detected by ELISA assay. Caspase-1 activity was assessed by flow cytometry. Immunofluorescence and immunohistochemistry were used to examine the level of NLRP3 in chondrocytes and rat cartilage, respectively. The progression of OA was monitored with hematoxylin-eosin (H&E) staining and safranin O/fast green staining.

Results
ICA could suppress LPS-induced inflammation and reduction of collagen formation in chondrocytes. Furthermore, ICA could inhibit NLRP3 inflammasome-mediated caspase-1 signaling pathway to alleviate pyroptosis induced by LPS. Overexpression of NLRP3 reversed the above changes caused by ICA. It was further confirmed in the rat OA model that ICA alleviated OA by inhibiting NLRP3-mediated pyroptosis.

Conclusion
ICA inhibited OA via repressing NLRP3/caspase-1 signaling-mediated pyroptosis in models of OA in vitro and in vivo, suggesting that ICA might be a promising compound in the treatment of OA.
The impact of associated tenotomies on the outcome of incomplete phalangeal osteotomies for lesser toe deformities
Authors: Nieto-García Eduardo , Ferrer-Torregrosa Javier , Ramírez-Andrés Leonor , Nieto-González Elena , Martinez-Nova Alfonso , Barrios Carlos 
Published: September 2019

Abstract

Background
Partial or incomplete osteotomy (IO) of the phalanx is recently described in the literature. However, the clinical outcome and the rate of complications when applied to lesser toe deformities (LTD) have been never addressed. This study aims to find out if the association of tenotomies to incomplete or partial phalanx osteotomies has a significant impact on the clinical outcomes, the occurrence of complications, and the recovery time after surgery.

Methods
A retrospective review of two cohorts of cases operated in our institution for hallux abductus valgus (HAV) and associated LTD from 2008 to 2014 was carried out. The surgical correction of both HAV and the associated LTD was always performed by minimally invasive techniques. The study included a total of 223 patients (723 IO in 556 toes). In 129 cases, the IO for LTD correction was performed without tenotomies, and in 94, the procedure was combined with flexor and/or extensor tenotomies. Patients were assessed with the American Orthopaedic Foot and Ankle Society (AOFAS) questionnaire before surgery and at 6- and 12-month follow-up.

Results
The mean preoperative AOFAS score before surgery was similar in both cohorts. At 12-month follow-up, the cohort without tenotomies showed better recovery (95.7 ± 2.8 versus 92.5 ± 6.8; p < 0.01). AOFAS scores decreased as the number of associated LTD increased (r = − 0.814; p < 0.001). Cases operated on by PO + tenotomy showed a high rate of complications such as delayed union of the osteotomy (p < 0.01), hypertrophic callus (p < 0.01), phalangeal fracture at the osteotomy site (p < 0.01), and lack of correction (p < 0.05). The overall occurrence of adverse events was 38.6% in cases operated by PO + tenotomy and 13.9% in cases receiving PO alone (p < 0.0001). Cases operated on without tenotomy showed a shorter time to complete recovery for daily life activities (37.4 ± 2.3 versus 43.0 ± 1.7 days; p < 0.01).

Conclusion
The performance of associated tenotomies to incomplete phalanx osteotomies provides worse clinical outcomes, higher complication rates, and longer recovery time as compared to similar forefoot surgeries without tenotomies.

Trial registration
The study was based on retrospectively registered data starting on May 24, 2008.
IFN-gamma-induced PD-L1 expression in melanoma depends on p53 expression
Authors: Thiem Alexander , Hesbacher Sonja , Kneitz Hermann , di Primio Teresa , Heppt Markus V. , Hermanns Heike M. , Goebeler Matthias , Meierjohann Svenja , Houben Roland , Schrama David 
Published: September 2019

Abstract

Background
Immune checkpoint inhibition and in particular anti-PD-1 immunotherapy have revolutionized the treatment of advanced melanoma. In this regard, higher tumoral PD-L1 protein (gene name: CD274) expression is associated with better clinical response and increased survival to anti-PD-1 therapy. Moreover, there is increasing evidence that tumor suppressor proteins are involved in immune regulation and are capable of modulating the expression of immune checkpoint proteins. Here, we determined the role of p53 protein (gene name: TP53) in the regulation of PD-L1 expression in melanoma.

Methods
We analyzed publicly available mRNA and protein expression data from the cancer genome/proteome atlas and performed immunohistochemistry on tumors with known TP53 status. Constitutive and IFN-ɣ-induced PD-L1 expression upon p53 knockdown in wildtype, TP53-mutated or JAK2-overexpressing melanoma cells or in cells, in which p53 was rendered transcriptionally inactive by CRISPR/Cas9, was determined by immunoblot or flow cytometry. Similarly, PD-L1 expression was investigated after overexpression of a transcriptionally-impaired p53 (L22Q, W23S) in TP53-wt or a TP53-knockout melanoma cell line. Immunoblot was applied to analyze the IFN-ɣ signaling pathway.

Results
For TP53-mutated tumors, an increased CD274 mRNA expression and a higher frequency of PD-L1 positivity was observed. Interestingly, positive correlations of IFNG mRNA and PD-L1 protein in both TP53-wt and -mutated samples and of p53 and PD-L1 protein suggest a non-transcriptional mode of action of p53. Indeed, cell line experiments revealed a diminished IFN-ɣ-induced PD-L1 expression upon p53 knockdown in both wildtype and TP53-mutated melanoma cells, which was not the case when p53 wildtype protein was rendered transcriptionally inactive or by ectopic expression of p53L22Q,W23S, a transcriptionally-impaired variant, in TP53-wt cells. Accordingly, expression of p53L22Q,W23S in a TP53-knockout melanoma cell line boosted IFN-ɣ-induced PD-L1 expression. The impaired PD-L1-inducibility after p53 knockdown was associated with a reduced JAK2 expression in the cells and was almost abrogated by JAK2 overexpression.

Conclusions
While having only a small impact on basal PD-L1 expression, both wildtype and mutated p53 play an important positive role for IFN-ɣ-induced PD-L1 expression in melanoma cells by supporting JAK2 expression. Future studies should address, whether p53 expression levels might influence response to anti-PD-1 immunotherapy.
The JAK2/STAT3/CCND2 Axis promotes colorectal Cancer stem cell persistence and radioresistance
Authors: Park So-Yeon , Lee Choong-Jae , Choi Jang-Hyun , Kim Jee-Heun , Kim Ji-Won , Kim Ji-Young , Nam Jeong-Seok 
Published: September 2019

Abstract

Background
Radiotherapy (RT) is a highly effective multimodal nonsurgical treatment that is essential for patients with advanced colorectal cancer (CRC). Nevertheless, cell subpopulations displaying intrinsic radioresistance survive after RT. The reactivation of their proliferation and successful colonization at local or distant sites may increase the risk of poor clinical outcomes. Recently, radioresistant cancer cells surviving RT were reported to exhibit a more aggressive phenotype than parental cells, although the underlying mechanisms remain unclear.

Methods
By investigating public databases containing CRC patient data, we explored potential radioresistance-associated signaling pathways. Then, their mechanistic roles in radioresistance were investigated through multiple validation steps using patient-derived primary CRC cells, human CRC cell lines, and CRC xenografts.

Results
Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling was activated in radioresistant CRC tissues in correlation with local and distant metastases. JAK2 was preferentially overexpressed in the CRC stem cell subpopulation, which was accompanied by the phosphorylation of STAT proteins, especially STAT3. JAK2/STAT3 signaling played an essential role in promoting tumor initiation and radioresistance by limiting apoptosis and enhancing clonogenic potential. Mechanistically, the direct binding of STAT3 to the cyclin D2 (CCND2) promoter increased CCND2 transcription. CCND2 expression was required for persistent cancer stem cell (CSC) growth via the maintenance of an intact cell cycle and proliferation with low levels of DNA damage accumulation.

Conclusion
Herein, we first identified JAK2/STAT3/CCND2 signaling as a resistance mechanism for the persistent growth of CSCs after RT, suggesting potential biomarkers and regimens for improving outcomes among CRC patients.
FUBP1 promotes neuroblastoma proliferation via enhancing glycolysis-a new possible marker of malignancy for neuroblastoma
Authors: Jiang Ping , Huang Mao , Qi Weiwei , Wang Fenghua , Yang Tianyou , Gao Tianxiao , Luo Chuanghua , Deng Jing , Yang Zhonghan , Zhou Ti , Zou Yan , Gao Guoquan , Yang Xia 
Published: September 2019

AbstractBackgroundNeuroblastoma (NB) is one of the deadliest paediatric solid tumours due to its rapid proliferative characteristics. Amplified copies of MYCN are considered the most important marker for the prediction of tumour relapse and progression in NB, but they were only detected in 20–30% of NB patients, indicating there might be other oncogenes in the development of NB. The far upstream element binding protein 1 (FUBP1) was first identified as a transcriptional regulator of the proto-oncogene MYC. However, the expression and role of FUBP1 in NB have not been documented.MethodsFUBP1 expression was analysed from GEO database and verified by immunohistochemistry (IHC) and western blotting (WB) in NB tissues and cell lines. Cell proliferation and apoptosis were detected by Cell Counting Kit-8, Colony formation assay, EDU, TUNEL staining and flow cytometric analysis. Several glycolytic metabolites production was confirmed by ELISA and oxygen consuming rate (OCR). Luciferase assay, WB, chromatin immunoprecipitation (CHIP) were used to explore the mechanisms of the effect of FUBP1 on NB.ResultsFUBP1 mRNA levels were increased along with the increase in International Neuroblastoma Staging System (INSS) stages. High expression of FUBP1 with low N-Myc expression accounted for 44.6% of NB patient samples (n = 65). In addition, FUBP1 protein levels were remarkably increased with NB malignancy in the NB tissue microarray (NB: n = 65; ganglioneuroblastoma:n = 31; ganglioneuroma:n = 27). Furthermore, FUBP1 expression was negatively correlated with patient survival rate but positively correlated with ki67 content. In vitro experiments showed that FUBP1 promotes NB cell proliferation and inhibits cell apoptosis via enhancing glycolysis and ATP production. Mechanistically, FUBP1 inhibited the degradation of HIF1α via downregulation of Von Hippel-Lindau (VHL), the E3 ligase for HIF1α, resulting in upregulation of lactate dehydrogenase isoform B (LDHB) expression to enhance glycolysis. Overexpressed or silenced N-Myc could not regulate FUBP1 or LDHB levels.ConclusionsTaken together, our findings demonstrate for the first time that elevated FUBP1 promotes NB glycolysis and growth by targeting HIF1α rather than N-Myc, suggesting that FUBP1 is a novel and powerful oncogene in the development of NB independent of N-Myc and may have potential in the diagnosis and treatment of NB.