bluuebunny/crossref_metadata_2025_split huggingface dataset:
Augmentation of Tendon Graft–Bone Tunnel Interface Healing by Use of Bioactive Platelet-Rich Fibrin Scaffolds
Authors: Wong Chin-Chean , Yeh Yi-Yen , Yang Tsung-Lin , Tsuang Yang-Hwei , Chen Chih-Hwa 
Published: March 2020

Background: Platelet-rich fibrin (PRF) is a bioactive biomaterial wherein cytokines are enmeshed within the interconnecting fibrin network. PRF can be fabricated into a patch to augment healing of the interface between a tendon graft and bone tunnel. Hypothesis: The bioactivity of a PRF scaffold is preserved after PRF is mechanically compressed into a patch. A bioactive PRF patch could promote the incorporation of a tendon graft within the bone tunnel through the formation of a tendon-bone healing zone composed of both fibrocartilaginous tissue and new bone. Study Design: Controlled laboratory study. Methods: Bioactivity of PRF was evaluated through treatment of rabbit tenocytes with PRF-conditioned medium and cultivation of cells on a PRF patch. Cellular morphologic features, viability, and differentiation were analyzed accordingly. In an animal study, a rabbit tendon-bone healing model was established through use of New Zealand White rabbits. The implanted tendon graft was enveloped circumferentially with a bioactive PRF patch before being pulled through a bone tunnel in the proximal tibia. Micro–computed tomography (micro-CT) imaging and histological and biomechanical analyses of the tendon-bone interface were performed at 12 weeks postoperatively. Results: PRF improved the viability of the cultured tenocytes. The effects of PRF on in vitro mineralization of tenocytes were comparable with the effects of standard culture medium. The gene expressions of type I collagen and osteopontin were upregulated upon PRF treatment. For the in vivo study, micro-CT images revealed significant new bone synthesis at the tendon-bone interface in the PRF-enveloped group. The tendon-bone healing zone was characterized by abundant fibrocartilage tissue and new bone formation as demonstrated by histological analysis. Biomechanical testing showed significantly higher ultimate loads in the PRF-enveloped group. Conclusion: Bioactive PRF could effectively augment healing of tendon graft to bone by inducing the formation of a transitional tendon-bone healing zone composed of fibrocartilage and bone. Clinical Relevance: Complete healing of the tendon graft in the bone tunnel is a prerequisite for successful ligament reconstruction, which would allow early and aggressive rehabilitation and rapid return to preinjury activity level. From a translational standpoint, the PRF-augmented healing in this rabbit animal model showed a promising biological approach to enhance tendon graft to bone healing via promotion of the functional anchorage between the 2 different materials.
Clinical and biological implications of target occupancy in CLL treated with the BTK inhibitor acalabrutinib
Authors: Sun Clare , Nierman Pia , Kendall Ellen K. , Cheung Jean , Gulrajani Michael , Herman Sarah E. M. , Pleyer Christopher , Ahn Inhye E. , Stetler-Stevenson Maryalice , Yuan Constance M. , Maric Irina , Gaglione Erika M. , Harris Hailey M. , Pittaluga Stefania , Wang Min Hui , Patel Priti , Farooqui Mohammed Z. H. , Izumi Raquel , Hamdy Ahmed , Covey Todd , Wiestner Adrian 
Published: March 2020

Abstract
Inhibition of the B-cell receptor pathway, and specifically of Bruton tyrosine kinase (BTK), is a leading therapeutic strategy in B-cell malignancies, including chronic lymphocytic leukemia (CLL). Target occupancy is a measure of covalent binding to BTK and has been applied as a pharmacodynamic parameter in clinical studies of BTK inhibitors. However, the kinetics of de novo BTK synthesis, which determines occupancy, and the relationship between occupancy, pathway inhibition and clinical outcomes remain undefined. This randomized phase 2 study investigated the safety, efficacy, and pharmacodynamics of a selective BTK inhibitor acalabrutinib at 100 mg twice daily (BID) or 200 mg once daily (QD) in 48 patients with relapsed/refractory or high-risk treatment-naïve CLL. Acalabrutinib was well tolerated and yielded an overall response rate (ORR) of partial response or better of 95.8% (95% confidence interval [CI], 78.9-99.9) and an estimated progression-free survival (PFS) rate at 24 months of 91.5% (95% CI, 70.0-97.8) with BID dosing and an ORR of 79.2% (95% CI, 57.9-92.9) and an estimated PFS rate at 24 months of 87.2% (95% CI, 57.2-96.7) with QD dosing. BTK resynthesis was faster in patients with CLL than in healthy volunteers. BID dosing maintained higher BTK occupancy and achieved more potent pathway inhibition compared with QD dosing. Small increments in occupancy attained by BID dosing relative to QD dosing compounded over time to augment downstream biological effects. The impact of BTK occupancy on long-term clinical outcomes remains to be determined. This trial was registered at www.clinicaltrials.gov as #NCT02337829.
The prognostic impact of FLT3-ITD and NPM1 mutation in adult AML is age-dependent in the population-based setting
Authors: Juliusson Gunnar , Jädersten Martin , Deneberg Stefan , Lehmann Sören , Möllgård Lars , Wennström Lovisa , Antunovic Petar , Cammenga Jörg , Lorenz Fryderyk , Ölander Emma , Lazarevic Vladimir Lj , Höglund Martin 
Published: March 2020

Abstract
In acute myeloid leukemia (AML) FLT3 internal tandem duplication (ITD) and nucleophosmin 1 (NPM1) mutations provide prognostic information with clinical relevance through choice of treatment, but the effect of age and sex on these molecular markers has not been evaluated. The Swedish AML Registry contains data on FLT3-ITD and NPM1 mutations dating to 2007, and 1570 adult patients younger than 75 years, excluding acute promyelocytic leukemia, had molecular results reported. Females more often had FLT3ITD and/or NPM1mut (FLT3ITD: female, 29%; male, 22% [P = .0015]; NPM1mut: female, 36%; male, 27% [P = .0001]), and more males were double negative (female, 53%; male, 64%; P &lt; .0001). Patients with FLT3ITD were younger than those without (59 vs 62 years; P = .023), in contrast to patients with NPM1mut (62 vs 60 years; P = .059). Interestingly, their prognostic effect had a strong dependence on age: FLT3ITD indicated poor survival in younger patients (&lt;60 years; P = .00003), but had no effect in older patients (60-74 years; P = .5), whereas NPM1mut indicated better survival in older patients (P = .00002), but not in younger patients (P = .95). In FLT3ITD/NPM1mut patients, the survival was less dependent on age than in the other molecular subsets. These findings are likely to have clinical relevance for risk grouping, study design, and choice of therapy.
Expressive language sampling as a source of outcome measures for treatment studies in fragile X syndrome: feasibility, practice effects, test-retest reliability, and construct validity
Authors: Abbeduto Leonard , Berry-Kravis Elizabeth , Sterling Audra , Sherman Stephanie , Edgin Jamie O. , McDuffie Andrea , Hoffmann Anne , Hamilton Debra , Nelson Michael , Aschkenasy Jeannie , Thurman Angela John 
Published: March 2020

AbstractBackgroundThe evaluation of treatment efficacy for individuals with fragile X syndrome (FXS) or intellectual disability (ID) more generally has been hampered by the lack of adequate outcome measures. We evaluated expressive language sampling (ELS) as a procedure for generating outcome measures for treatment research in FXS. We addressed: (a) feasibility, (b) practice effects over two administrations, (c) test-retest reliability over the repeated administrations, and (d) construct validity. We addressed these issues for the full sample as well as for subgroups defined by age, IQ, and ASD status.MethodsParticipants were 106 individuals with FXS between ages 6 and 23 years who had IQs within the range of intellectual disability (IQ< 70). ELS procedures for collecting samples in conversation and narration were followed and analyzed separately. Five measures were derived from transcripts segmented into C-units (i.e., an independent clause and its modifiers): number of C-units per minute (talkativeness), number of different word roots (vocabulary), C-unit length in morphemes (syntax), percentage of C-units containing dysfluency (utterance planning), and percentage of C-units that were fully or partly unintelligible (articulatory quality). ELS procedures were administered twice at 4-week intervals for each participant. Standardized tests and informant reports were administered and provided measures for evaluating construct validity of ELS measures.ResultsWe found low rates of noncompliance, suggesting the task can be completed meaningfully by most individuals with FXS, although noncompliance was higher for younger, lower IQ, and more autistic participants. Minimal practice effects and strong test-retest reliability over the 4-week interval were observed for the full sample and across the range of ages, IQs, and autism symptom severity. Evidence of convergent construct validity was observed for the measures of vocabulary, syntax, and unintelligibility for the full sample and across the range of IQ and autism symptom severity, but not for participants under age 12. Conversation and narration yielded largely similar results in all analyses.ConclusionsThe findings suggest that the ELS procedures are feasible and yield measures with adequate psychometric properties for a majority of 6 to 23 years with FXS who have ID. The procedures work equally well regardless of level of ID or degree of ASD severity. The procedures, however, are more challenging and have somewhat less adequate psychometric properties for individuals with FXS under age 12.
Characterization of the interactions between Codanin-1 and C15Orf41, two proteins implicated in congenital dyserythropoietic anemia type I disease
Authors: Swickley Grace , Bloch Yehoshua , Malka Lidor , Meiri Adi , Noy-Lotan Sharon , Yanai Amiel , Tamary Hannah , Motro Benny 
Published: March 2020

Abstract
Background
Congenital dyserythropoietic anemia type I (CDA I), is an autosomal recessive disease with macrocytic anemia in which erythroid precursors in the bone marrow exhibit pathognomonic abnormalities including spongy heterochromatin and chromatin bridges. We have shown previously that the gene mutated in CDA I encodes Codanin-1, a ubiquitously expressed and evolutionarily conserved large protein. Recently, an additional etiologic factor for CDA I was reported, C15Orf41, a predicted nuclease. Mutations in both CDAN1 and C15Orf41 genes results in very similar erythroid phenotype. However, the possible relationships between these two etiologic factors is not clear.

Results
We demonstrate here that Codanin-1 and C15Orf41 bind to each other, and that Codanin-1 stabilizes C15Orf41. C15Orf41 protein is mainly nuclear and Codanin-1 overexpression shifts it to the cytoplasm. Phylogenetic analyses demonstrated that even though Codanin-1 is an essential protein in mammals, it was lost from several diverse and unrelated animal taxa. Interestingly, C15Orf41 was eliminated in the exact same animal taxa. This is an extreme case of the Phylogenetic Profiling phenomenon, which strongly suggests common pathways for these two proteins. Lastly, as the 3D structure is more conserved through evolution than the protein sequence, we have used the Phyre2 alignment program to find structurally homologous proteins. We found that Codanin-1 is highly similar to CNOT1, a conserved protein which serves as a scaffold for proteins involved in mRNA stability and transcriptional control.

Conclusions
The physical interaction and the stabilization of C15Orf41 by Codanin-1, combined with the phylogenetic co-existence and co-loss of these two proteins during evolution, suggest that the major function of the presumptive scaffold protein, Codanin-1, is to regulate C15Orf41 activities. The similarity between Codanin-1 and CNOT1 suggest that Codanin-1 is involved in RNA metabolism and activity, and opens up a new avenue for the study of the molecular pathways affected in CDAI.
Stress-mediated convergence of splicing landscapes in male and female rock doves
Authors: Lang Andrew S. , Austin Suzanne H. , Harris Rayna M. , Calisi Rebecca M. , MacManes Matthew D. 
Published: March 2020

Abstract
Background
The process of alternative splicing provides a unique mechanism by which eukaryotes are able to produce numerous protein products from the same gene. Heightened variability in the proteome has been thought to potentiate increased behavioral complexity and response flexibility to environmental stimuli, thus contributing to more refined traits on which natural and sexual selection can act. While it has been long known that various forms of environmental stress can negatively affect sexual behavior and reproduction, we know little of how stress can affect the alternative splicing associated with these events, and less still about how splicing may differ between sexes. Using the model of the rock dove (Columba livia), our team previously uncovered sexual dimorphism in the basal and stress-responsive gene transcription of a biological system necessary for facilitating sexual behavior and reproduction, the hypothalamic-pituitary-gonadal (HPG) axis. In this study, we delve further into understanding the mechanistic underpinnings of how changes in the environment can affect reproduction by testing the alternative splicing response of the HPG axis to an external stressor in both sexes.

Results
This study reveals dramatic baseline differences in HPG alternative splicing between males and females. However, after subjecting subjects to a restraint stress paradigm, we found a significant reduction in these differences between the sexes. In both stress and control treatments, we identified a higher incidence of splicing activity in the pituitary in both sexes as compared to other tissues. Of these splicing events, the core exon event is the most abundant form of splicing and more frequently occurs in the coding regions of the gene. Overall, we observed less splicing activity in the 3’UTR (untranslated region) end of transcripts than the 5’UTR or coding regions.

Conclusions
Our results provide vital new insight into sex-specific aspects of the stress response on the HPG axis at an unprecedented proximate level. Males and females uniquely respond to stress, yet exhibit splicing patterns suggesting a convergent, optimal splicing landscape for stress response. This information has the potential to inform evolutionary theory as well as the development of highly-specific drug targets for stress-induced reproductive dysfunction.
Identification of microRNAs and their Endonucleolytic Cleavaged target mRNAs in colorectal cancer
Authors: Zhou Fangbin , Tang Donge , Xu Yong , He Huiyan , Wu Yan , Lin Liewen , Dong Jun , Tan Wenyong , Dai Yong 
Published: March 2020

Abstract
Background
Colorectal cancer (CRC) ranks the third among the most common malignancies globally. It is well known that microRNAs (miRNAs) play vital roles in destabilizing mRNAs and repressing their translations in this disease. However, the mechanism of miRNA-induced mRNA cleavage remains to be investigated.

Method
In this study, high-throughput small RNA (sRNA) sequencing was utilized to identify and profile miRNAs from six pairs of colorectal cancer tissues (CTs) and adjacent tissues (CNs). Degradome sequencing (DS) was employed to detect the cleaved target genes. The Database for Annotation, Visualization and Integrated Discovery (DAVID) software was used for GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis.

Results
In total, 1278 known miRNAs (clustered into 337 families) and 131 novel miRNAs were characterized in the CT and CN libraries, respectively. Of those, 420 known and eight novel miRNAs were defined as differentially expressed miRNAs (DEmiRNAs) by comparing the expression levels observed in the CT and CN libraries. Furthermore, through DS, 9685 and 202 potential target transcripts were characterized as target genes for 268 known and 33 novel miRNAs, respectively. It was further predicted that a total of 264 targeted genes for the 85 DEmiRNAs are involved in proteoglycans in cancer and the AMP-activated protein kinase signaling pathway. After systemic analysis of prognosis-related miRNA targets in those cancer-related signal pathways, we found that two targets ezrin (EZR) and hematopoietic cell-specific Lyn substrate 1 (HCLS1) had the potential prognostic characteristics with CRC regarding over survival (OS) or recurrence.

Conclusion
In total, we found that endonucleolytic miRNA-directed mRNA cleavage occurs in CRC. A number of potential genes targeted by CRC-related miRNAs were identified and some may have the potential as prognosis markers of CRC. The present findings may lead to an improved better appreciation of the novel interaction mode between miRNAs and target genes in CRC.
Clinical characteristics and risk factors of 47 cases with ruptured neuroblastoma in children
Authors: Qin Hong , Yang Shen , Cai Siyu , Ren Qinghua , Han Wei , Yang Wei , Cheng Haiyan , Ma Xiaoli , Wang Huanmin 
Published: March 2020

Abstract
Background
Neuroblastoma (NB) tumor rupture is a rare oncology emergency with a poor prognosis. We aimed to evaluate patient clinical characteristics and risk factors for ruptured NB.

Methods
A retrospective study of 47 patients with confirmed NB rupture between January 2009 and January 2019 at Beijing Children’s Hospital was conducted. To identify tumor rupture risk factors in high-risk NB patients, we included 93 consecutive non-ruptured high-risk NB patients from January 2017 to January 2019.

Results
The median age at presentation was 29 months (adrenal and retroperitoneum origin) for 47 ruptured NB patients. Spontaneous tumor rupture occurred in 22 cases; 18 cases occurred during or after the first chemotherapy cycle, and 7 occurred after core needle biopsy. Five patients died of tumor rupture, and 17 patients’ parents refused further antitumor therapy. Among the 25 remaining patients, 6 survived without disease, 5 received ongoing treatment and achieved stable disease, and 14 died. According to multivariate logistic regression analysis, a maximum primary tumor diameter > 13.20 cm and MYCN gene amplification were independent risk factors for tumor rupture within high-risk NB.

Conclusions
Tumor rupture is an uncommon, life-threatening event for NB patients; these patients are most likely to have poor outcomes due to tumor recurrence or rapid progression. Several treatment modalities, including symptomatic support therapy and chemotherapy, are important for saving lives and for developing NB risk-based treatment in the future.
Challenges in the cultural adaptation of the German Myeloma Patient Outcome Scale (MyPOS): an outcome measure to support routine symptom assessment in myeloma care
Authors: Gerlach Christina , Taylor Katherine , Ferner Marion , Munder Markus , Weber Martin , Ramsenthaler Christina 
Published: March 2020

Abstract
Background
Patients with multiple myeloma report more problems with quality of life (QoL) than other haematological malignancies over the course of their incurable illness. The patient-centred Myeloma Patient Outcome Scale (MyPOS) was developed to assess and monitor symptoms and supportive care factors in routine care. Our aim was to translate and culturally adapt the outcome measure to the German context, and to explore its face and content validity.

Methods
Translation and cultural adaptation following established guidelines used an exploratory, sequential mixed method study design. Steps included: (1) forward translation to German; (2) backward translation to English; (3) expert review; (4) focus groups with the target population (patients, family members, healthcare professionals) to achieve conceptual equivalence; (5) cognitive interviews using Tourangeau’s model with think-aloud technique to evaluate comprehension and acceptability; (6) final review. Results were analysed using thematic analysis.

Results
Cultural and linguistic differences were noted between the German and English original version. The focus groups (n = 11) and cognitive interviews (n = 9) both highlighted the need for adapting individual items and their answer options to the German healthcare context. Greater individuality regarding need for information with the right to not be informed was elaborated by patients. While the comprehensive nature of the tool was appreciated, item wording regarding satisfaction with healthcare was deemed not appropriate in the German context. Before implementation into routine care, patients’ concerns about keeping their MyPOS data confidential need to be addressed as a barrier, whereas the MyPOS itself was perceived as a facilitator/prompt for a patient-centred discussion of QoL issues.

Conclusion
With adaptations to answer options and certain items, the German version of the MyPOS can help monitor symptoms and problems afflicting myeloma patients over the course of the disease trajectory. It can help promote a model of comprehensive supportive and patient-centred care for these patients.
Intraocular endoscopy for the evaluation and treatment of hypotony due to a traumatic cyclodialysis: a case report
Authors: Bair Henry , Lin Chun-Ju , Lai Chun-Ting , Hsia Ning-Yi , Tsai Yi-Yu 
Published: March 2020

Abstract
Background
A cyclodialysis cleft often leads to direct communication between the anterior chamber and the suprachoroidal space. It is a rare condition that is encountered with blunt trauma, and less commonly, after surgery. Hypotony is the major sequelae that may lead to hypotonous maculopathy, optic disc edema, corneal folds, and astigmatism. These may cumulatively lead to visual loss. We describe how endoscopy in a cyclodialysis repair allowed us to accurately locate the cleft and guided its appropriate management avoiding unnecessary cryopexy.

Case presentation
A 41-year-old male experienced a traumatic cyclodialysis cleft, which resulted in persistent hypotony. Pars plana vitrectomy was performed to treat vitreous hemorrhage. Scleral indentation was attempted to visualize the cyclodialysis cleft. However, the depression distorted the visualization. Intraocular endoscopy was therefore used to evaluate the cleft. Guided by this assessment, only intraocular gas tamponade was used to reposition the ciliary body. The patient’s intraocular pressure was restored to 13 mmHg 3 days after the operation, and OCT confirmed cleft closure 1 month after the operation.

Conclusion
Endoscopy-assisted repair of cyclodialysis is an approach that enhances visualization and can guard against common causes of persistent cleft and hypotony, as well as reveal the causes of recurrent failure. Hence, it can eliminate unnecessary cryopexy that might worsen the hypotonous state. In our case, intraocular endoscopy was effective for the evaluation of a cyclodialysis cleft and the subsequent selection of an appropriate management technique, gas tamponade, that was more conservative than other approaches initially considered.