cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.6084/m9.figshare.5129209
title: Supplementary Material for: Aplasia Cutis Congenita of the Scalp, Composite Type: The Criticality and Inseparability of Neurosurgical and Plastic Surgical Management

description: <b><i>Background/Aims:</i></b> The object of this report is to review the management of patients having the composite type of aplasia cutis congenita in the context of the relevant literature on this condition. <b><i>Methods:</i></b> Clinical records, neuroimaging and photographic documentation of identified cases of composite type aplasia cutis congenita, with a comprehensive review of the literature, are the material basis of this report. <b><i>Results:</i></b> Two neonates with composite type aplasia cutis congenita are described as examples of this disorder, and their management, including complications, is discussed. Both had satisfactory outcomes. <b><i>Conclusions:</i></b> Early aggressive surgical management with scalp rotation flaps has a low rate of complications, provides satisfactory functional and esthetic outcome, minimizes hospital stays, and should provide cost-effective care by reduction of the time to secure wound closure. Most bony defects, even large ones, commonly ossify completely. Optimal case management requires a synchronized neurosurgical and plastic surgical team. Intuitive nonsurgical and surgical approaches by the inexperienced can be hazardous.
DOI: 10.6084/m9.figshare.5129212.v1
title: Supplementary Material for: Which Aspects of Stroke Do Animal Models Capture? A Multitracer Micro-PET Study of Focal Ischemia with Endothelin-1

description: <b><i>Background:</i></b> Cortical injections of the vasoconstrictor endothelin-1 (ET1) have widely been used to induce focal circumscribed ischemic lesions in the motor cortex of rodents in the context of stroke recovery studies. In order to apply this model correctly, it is essential to understand the time course of regional flow changes and of the development of penumbra and infarction. <b><i>Methods:</i></b> Multitracer micro-PET of ET1 focal ischemia in rats was performed using [<sup>11</sup>C]-flumazenil ([<sup>11</sup>C]FMZ) as a flow- and viability tracer and [<sup>18</sup>F]-fluoromisonidazole ([<sup>18</sup>F]FMISO) as hypoxia marker in order to characterize the physiological time-course of this model. Nine adult Sprague-Dawley rats received stereotaxic injections of ET1 into the right primary motor cortex, 3 served as controls. PET imaging was started 2, 3 and 20 h after the last ET1 injection. Histology was obtained at the end of the scans. Standardized uptake value ratios reflecting cerebral blood flow (CBF), [<sup>11</sup>C]FMZ-binding and [<sup>18</sup>F]FMISO-retention were calculated for the region of hypoperfusion and the normoperfused cortex. <b><i>Results:</i></b> CBF in the hypoperfused cortex was significantly reduced (p &lt; 0.01) at 5 h (0.58 ± 0.025), 6 h (0.54 ± 0.043) and 23 h (0.66 ± 0.024) compared to controls (1.00 ± 0.011) and moderately reduced (p &lt; 0.05) in the remainder of the affected hemisphere at 5 h (0.93 ± 0.036). [<sup>11</sup>C]FMZ-binding was within the control range at all time points. Significant [<sup>18</sup>F]FMISO-retention (1.16 ± 0.091, p &lt; 0.05) was observed only after 6 h in the ischemic core that later turned into infarct. <b><i>Conclusion:</i></b> ET1 injections yield reproducible, slowly developing ischemic lesions with constant levels of hypoperfusion. This multitracer micro-PET study suggests that the ET1 model is appropriate for inducing chronic circumscribed ischemic lesions but seems to be less suited for studying acute stroke pathophysiology.
DOI: 10.6084/m9.figshare.5129218.v1
title: Supplementary Material for: The Human Glycoprotein Salivary Agglutinin Inhibits the Interaction of DC-SIGN and Langerin with Oral Micro-Organisms

description: Salivary agglutinin (SAG), also known as gp340 or SALSA, is a glycoprotein encoded by the <i>Deleted in Malignant Brain Tumours 1</i> gene and is abundantly present in human saliva. SAG aggregates bacteria and viruses, thereby promoting their clearance from the oral cavity. The mucosa lining the oral cavity contains dendritic cells (DC) and Langerhans cells (LC), which express the C-type lectin receptors (CLR) DC-SIGN and Langerin, respectively. Both DC-SIGN and Langerin recognise mannose and fucose carbohydrate structures on pathogens and self-glycoproteins to regulate immunity and homeostasis. The purpose of this study was to investigate whether SAG interacts with these CLR and whether this interferes with the binding to oral pathogens. We show that whole parotid saliva and SAG, when coated to microplates, strongly interact with DC-SIGN and Langerin, probably via mannose and fucose structures. Also, primary human DC and LC bind parotid saliva and SAG via DC-SIGN and Langerin, respectively. Furthermore, SAG binding to DC-SIGN or Langerin prevented binding to the micro-organisms <i>Candida albicans</i> and <i>Escherichia coli</i> which express mannose and fucose-containing glycan structures. Thus, binding of saliva glycoprotein SAG to DC-SIGN and Langerin may inhibit pathogen-DC/LC interactions, and could prove to be a new immunomodulatory mechanism of SAG.
DOI: 10.6084/m9.figshare.5129206
title: Supplementary Material for: Comparison of HER2 Expression in Primary Tumor and Disseminated Tumor Cells in the Bone Marrow of Breast Cancer Patients

description: <b><i>Objective:</i></b> The aim of this study was to measure the human epidermal growth factor receptor 2 (HER2) status of disseminated tumor cells (DTCs) from bone marrow (BM) aspirates and to assess correspondence or discrepancy with the primary tumor. <b><i>Methods:</i></b> DTCs were isolated from the BM of 156 breast cancer patients. Cytokeratin-positive DTCs were further analyzed by the chromogenic in situ hybridization method to detect HER2 gene amplification. <b><i>Results:</i></b> A significant correlation (p = 0.021) was found between the HER2 status of DTCs and the primary tumors. Sixty-one (68.5%) patients had a corresponding status. However, a shift of phenotype between primary tumor and DTCs was found in the remaining patients. <b><i>Conclusion:</i></b> This study showed a significant grade of discordance of the HER2 status between primary tumors and DTCs in the BM of a relevant subgroup of patients. Detection of HER2 amplification on DTCs could therefore help to better stratify patients for a more tailored therapy, since they would benefit from a HER2-targeted therapy.
DOI: 10.6084/m9.figshare.5129209.v1
title: Supplementary Material for: Aplasia Cutis Congenita of the Scalp, Composite Type: The Criticality and Inseparability of Neurosurgical and Plastic Surgical Management

description: <b><i>Background/Aims:</i></b> The object of this report is to review the management of patients having the composite type of aplasia cutis congenita in the context of the relevant literature on this condition. <b><i>Methods:</i></b> Clinical records, neuroimaging and photographic documentation of identified cases of composite type aplasia cutis congenita, with a comprehensive review of the literature, are the material basis of this report. <b><i>Results:</i></b> Two neonates with composite type aplasia cutis congenita are described as examples of this disorder, and their management, including complications, is discussed. Both had satisfactory outcomes. <b><i>Conclusions:</i></b> Early aggressive surgical management with scalp rotation flaps has a low rate of complications, provides satisfactory functional and esthetic outcome, minimizes hospital stays, and should provide cost-effective care by reduction of the time to secure wound closure. Most bony defects, even large ones, commonly ossify completely. Optimal case management requires a synchronized neurosurgical and plastic surgical team. Intuitive nonsurgical and surgical approaches by the inexperienced can be hazardous.
DOI: 10.6084/m9.figshare.5129203
title: Supplementary Material for: Germline Prolactin Receptor Mutation Is Not a Major Cause of Sporadic Prolactinoma in Humans

description: <b><i>Background/Aims:</i></b> No genetic anomalies specifically predisposing humans to prolactinomas have so far been identified. The prolactin receptor (PRLR) is a good candidate, however, as <i>Prlr</i> knockout mice develop prolactinomas, and a case of familial hyperprolactinemia has been linked to <i>PRLR </i>mutation. The main objective of this study was to detect germline <i>PRLR</i> mutations in patients with sporadic prolactinomas unrelated to <i>AIP</i> or <i>MEN1 </i>mutation. <b><i>Methods:</i></b> We sequenced all <i>PRLR </i>exons and intron-exon junctions on genomic DNA from 88 patients with a median age of 24 years. <b><i>Results:</i></b> We identified 4 <i>PRLR</i> variations (p.Ile76Val, p.Ile146Leu, p.Glu108Lys and p.Glu554Gln) in 16 patients. One patient had the rare variant p.Glu554Gln in the heterozygous state. Another patient had the extremely rare p.Glu108Lys variant described here for the first time. The other 2 variants (p.Ile76Val and p.Ile146Leu) are relatively common in the general population. All these 4 variants have been functionally tested in vitro and have no effect on PRLR expression, localization and signaling after prolactin stimulation. <b><i>Conclusion:</i></b> Inactivating germline variations of <i>PRLR </i>are not associated with sporadic prolactinoma in this series. Nevertheless, somatic disruption of <i>PRLR</i> has not been excluded in this subset of pituitary tumors.
DOI: 10.6084/m9.figshare.5129191
title: Supplementary Material for: The Tyrosine Kinase Pyk2 Contributes to Complement-Mediated Phagocytosis in Murine Macrophages

description: Proline-rich tyrosine kinase 2 (Pyk2) is a member of the focal adhesion kinase (FAK) family and is mainly expressed in neuronal and hematopoietic cells. As FAK family members are involved in signaling connections downstream of integrins, we studied the role of Pyk2 in complement-receptor 3 (CR3, also known as Mac-1, integrin α<sub>M</sub>β<sub>2</sub>, CD11b/CD18)-mediated phagocytosis, a key process in innate immunity. Using 3 independent approaches, we observed that Pyk2 contributes to CR3-dependent phagocytosis by RAW 264.7 macrophages, but is dispensable for Fcγ receptor (FcγR)-mediated uptake. Reduction of Pyk2 expression levels via siRNA, the pharmacological inhibition of Pyk2 kinase activity as well as macrophage treatment with a cell permeable TAT fusion protein containing the C-terminus of Pyk2 (TAT-PRNK) significantly impaired CR3-mediated phagocytosis without affecting FcγR-mediated uptake. In addition, Pyk2 was strongly recruited to complement opsonized <i>Escherichia coli</i> and the pharmacological inhibition of Pyk2 significantly decreased uptake of the bacteria. Finally, CRISPR/Cas-mediated disruption of the <i>pyk2</i> gene in RAW 264.7 macrophages confirmed the role of this protein tyrosine kinase in CR3-mediated phagocytosis. Together, our data demonstrate that Pyk2 selectively contributes to the coordination of phagocytosis-promoting signals downstream of CR3, but is dispensable for FcγR-mediated phagocytosis.
DOI: 10.6084/m9.figshare.5129197
title: Supplementary Material for: Increased Plasma PCSK9 Levels Are Associated with Reduced Endotoxin Clearance and the Development of Acute Organ Failures during Sepsis

description: <b><i>Purpose:</i></b> We have recently shown that PCSK9 reduces the clearance of endotoxin and is therefore a critical regulator of the innate immune response during infection. However, plasma PCSK9 levels during human sepsis and their relationship to outcomes are not known. Our objective was to determine the relationship between plasma PCSK9 levels and the rate of endotoxin clearance, and then correlate PCSK9 levels with the development of acute organ failures in a cohort of patients with sepsis. <b><i>Methods:</i></b> Using human hepatocyte cells, we determined the threshold at which PCSK9 is able to reduce <i>Escherichia coli</i> endotoxin uptake by cultured human hepatocytes. In a single-centre observational cohort at St. Paul's Hospital in Vancouver, Canada, we recruited 200 patients who activated our Emergency Department's sepsis protocol and measured plasma PCSK9 and lipid levels at triage and throughout the admission. Outcomes were the development of sepsis-induced cardiovascular or respiratory failure. <b><i>Results:</i></b> We reviewed the literature and determined that the normal human range of PCSK9 found in plasma is 170-220 ng/ml, while levels of 250 ng/ml and above reduced <i>E. coli</i> endotoxin clearance in cultured human hepatocytes. In septic patients, the median levels associated with new-onset respiratory and cardiovascular failure were 370 (250-500) and 380 (270-530) ng/ml, respectively, versus 270 (220-380) ng/ml in patients who did not go on to develop any organ failure (p = 0.003 and 0.005, respectively). <b><i>Conclusions:</i></b> Plasma PCSK9 levels are greatly increased in sepsis. At normal levels, PCSK9 has no influence upon hepatocyte bacterial endotoxin clearance, but as levels rise, there is a progressive inhibition of clearance. During sepsis, PCSK9 levels are highly correlated with the development of subsequent multiple organ failure. Inhibition of PCSK9 activity is an attractive target for treating the spectrum of sepsis and septic shock.
DOI: 10.6084/m9.figshare.5129200
title: Supplementary Material for: Prevention of Venous Neointimal Hyperplasia by a Multitarget Receptor Tyrosine Kinase Inhibitor

description: <b><i>Background/Aims:</i></b> Venous neointimal hyperplasia (NH) is the predominant cause of stenosis in hemodialysis arteriovenous grafts (AVG), but there is currently no clinically used therapy to prevent NH. <b><i>Methods:</i></b> A porcine AVG model was used to identify potential pharmacological targets to prevent NH. Sunitinib, a broad-spectrum tyrosine kinase inhibitor, was examined as a potential anti-NH drug utilizing in vitro and ex vivo models. <b><i>Results:</i></b> In an in vivo porcine model, PDGF, VEGF and their receptors PDGFR-α and VEGFR-2 were upregulated at the venous anastomosis within 2 weeks after AVG placement, with NH development by 4 weeks. Sunitinib inhibited PDGF-stimulated proliferation, migration, phosphorylation of MAPK and PI3K/Akt proteins and changes in the expression of cell-cycle regulatory proteins in vascular smooth-muscle cells as well as VEGF-stimulated endothelial cell proliferation in vitro. In an ex vivo model, significant NH was observed in porcine vein segments perfused for 12 days under pathological shear stress. Sunitinib (100 nM) inhibited NH formation, with the intima-to-lumen area ratio decreasing from 0.45 ± 0.25 to 0.04 ± 0.02 (p &lt; 0.05) with treatment. <b><i>Conclusion:</i></b> These findings demonstrate sunitinib to be a potential NH-preventive drug as well as the utility of an ex vivo model to investigate pharmacotherapies under pathophysiological flow conditions.
DOI: 10.6084/m9.figshare.5129203.v1
title: Supplementary Material for: Germline Prolactin Receptor Mutation Is Not a Major Cause of Sporadic Prolactinoma in Humans

description: <b><i>Background/Aims:</i></b> No genetic anomalies specifically predisposing humans to prolactinomas have so far been identified. The prolactin receptor (PRLR) is a good candidate, however, as <i>Prlr</i> knockout mice develop prolactinomas, and a case of familial hyperprolactinemia has been linked to <i>PRLR </i>mutation. The main objective of this study was to detect germline <i>PRLR</i> mutations in patients with sporadic prolactinomas unrelated to <i>AIP</i> or <i>MEN1 </i>mutation. <b><i>Methods:</i></b> We sequenced all <i>PRLR </i>exons and intron-exon junctions on genomic DNA from 88 patients with a median age of 24 years. <b><i>Results:</i></b> We identified 4 <i>PRLR</i> variations (p.Ile76Val, p.Ile146Leu, p.Glu108Lys and p.Glu554Gln) in 16 patients. One patient had the rare variant p.Glu554Gln in the heterozygous state. Another patient had the extremely rare p.Glu108Lys variant described here for the first time. The other 2 variants (p.Ile76Val and p.Ile146Leu) are relatively common in the general population. All these 4 variants have been functionally tested in vitro and have no effect on PRLR expression, localization and signaling after prolactin stimulation. <b><i>Conclusion:</i></b> Inactivating germline variations of <i>PRLR </i>are not associated with sporadic prolactinoma in this series. Nevertheless, somatic disruption of <i>PRLR</i> has not been excluded in this subset of pituitary tumors.
DOI: 10.6084/m9.figshare.5129188
title: Supplementary Material for: Caffeine Prevents Hyperoxia-Induced Functional and Structural Lung Damage in Preterm Rabbits

description: <b><i>Background:</i></b> Caffeine is a commonly used drug for apnea of prematurity. It may, however, also have a beneficial effect on bronchopulmonary dysplasia (BPD), which is the most common complication of extreme preterm birth. <b><i>Objectives:</i></b> To study the inflammatory, structural and functional effects of caffeine in an animal model of BPD. <b><i>Methods:</i></b> Preterm New Zealand-Dendermonde rabbits (gestational day 28; term 31) were randomized to three groups: normoxia-placebo (N-P), hyperoxia-placebo (H-P) and hyperoxia-caffeine (H-C). Lung function was assessed on postnatal day 5, along with airway morphometry, vascular morphometry and a score observing airway inflammation. <b><i>Results:</i></b> Caffeine improved lung function by increasing lung volume [mean displaced volume N-P: 40.1 ± 6 ml/kg, H-P: 27.8 ± 8 ml/kg and H-C: 34.4 ± 7 ml/kg (p &lt; 0.05); total lung capacity: N-P: 1.17 ± 0.1 ml, H-P: 0.67 ± 0.1 ml and H-C: 1.1 ± 0.1 ml (p &lt; 0.05)], decreasing tissue damping [N-P: 2.7 ± 0.3 cm H<sub>2</sub>O/ml, H-P: 4.6 ± 0.6 cm H<sub>2</sub>O/ml and H-C: 3.2 ± 0.4 cm H<sub>2</sub>O/ml (p &lt; 0.05)], elastance [N-P: 9.3 ± 2.4 cm H<sub>2</sub>O/ml, H-P: 19.2 ± 7.4 cm H<sub>2</sub>O/ml and H-C: 10.7 ± 2 cm H<sub>2</sub>O/ml (p &lt; 0.05)] and compliance [N-P: 0.06 ± 0.01 cm H<sub>2</sub>O/ml, H-P: 0.054 ± 0.01 cm H<sub>2</sub>O/ml and H-C: 0.07 ± 0.013 cm H<sub>2</sub>O/ml (p &lt; 0.05)]. Caffeine also improved histology by decreasing alveolar size [linear intercepts; N-P: 83.6 ± 1.7, H-P: 82.9 ± 1.6 and H-C: 67.3 ± 1.4 (p &lt; 0.05)], increasing radial alveolar count (N-P: 6.6 ± 0.5, H-P: 5.7 ± 0.6 and H-C: 7.05 ± 0.5) and decreasing the acute inflammation score [N-P: 0.3 ± 0.1, H-P: 0.5 ± 0.1 and H-C: 0.4 ± 0.1 (p &lt; 0.05)]. <b><i>Conclusion:</i></b> In preterm rabbits, caffeine reduces the functional, architectural and inflammatory pulmonary changes induced by hyperoxia in the lung.
DOI: 10.6084/m9.figshare.5129194
title: Supplementary Material for: Global Disorders of Sex Development Update since 2006: Perceptions, Approach and Care

description: The goal of this update regarding the diagnosis and care of persons with disorders of sex development (DSDs) is to address changes in the clinical approach since the 2005 Consensus Conference, since knowledge and viewpoints change. An effort was made to include representatives from a broad perspective including support and advocacy groups. The goal of patient care is focused upon the best possible quality of life (QoL). The field of DSD is continuously developing. An update on the clinical evaluation of infants and older individuals with ambiguous genitalia including perceptions regarding male or female assignment is discussed. Topics include biochemical and genetic assessment, the risk of germ cell tumor development, approaches to psychosocial and psychosexual well-being and an update on support groups. Open and on-going communication with patients and parents must involve full disclosure, with the recognition that, while DSD conditions are life-long, enhancement of the best possible outcome improves QoL. The evolution of diagnosis and care continues, while it is still impossible to predict gender development in an individual case with certainty. Such decisions and decisions regarding surgery during infancy that alters external genital anatomy or removes germ cells continue to carry risk.
DOI: 10.6084/m9.figshare.5129182
title: Supplementary Material for: Routine Use of Probiotics in Preterm Infants: Longitudinal Impact on the Microbiome and Metabolome

description: <b><i>Background:</i></b> Probiotics are live microbial supplements that colonize the gut and potentially exert health benefit to the host. <b><i>Objectives:</i></b> We aimed to determine the impact of a probiotic (Infloran®: <i>Lactobacillus acidophilus</i>-NCIMB701748 and <i>Bifidobacterium bifidum</i>-ATCC15696) on the bacterial and metabolic function of the preterm gut while in the neonatal intensive care unit (NICU) and following discharge. <b><i>Methods:</i></b> Stool samples (n = 88) were collected before, during, and after probiotic intake from 7 patients, along with time-matched controls from 3 patients. Samples were also collected following discharge home from the NICU. Samples underwent bacterial profiling analysis by 16S rRNA gene sequencing and quantitative PCR (qPCR), as well as metabolomic profiling using liquid chromatography mass spectrometry. <b><i>Results:</i></b> Bacterial profiling showed greater <i>Bifidobacterium </i>(15.1%) <i>and Lactobacillus</i> (4.2%) during supplementation compared to the control group (4.0% and 0%, respectively). While <i>Lactobacillus</i> became reduced after the probiotic had been stopped, <i>Bifidobacterium</i> remained high following discharge, suggestive of successful colonisation. qPCR analysis showed a significant increase (p ≤ 0.01) in <i>B. bifidum</i> in infants who received probiotic treatment compared to controls, but no significant increase was observed for <i>L. acidophilus</i> (p = 0.153). Metabolite profiling showed clustering based on receiving probiotic or matched controls, with distinct metabolites associated with probiotic administration. <b><i>Conclusions:</i></b> Probiotic species successfully colonise the preterm gut, reducing the relative abundance of potentially pathogenic bacteria, and effecting gut functioning. <i>Bifidobacterium</i> (but not <i>Lactobacillus</i>) colonised the gut in the long term, suggesting the possibility that therapeutically administered probiotics may continue to exert important functional effects on gut microbial communities in early infancy.
DOI: 10.6084/m9.figshare.5129191.v1
title: Supplementary Material for: The Tyrosine Kinase Pyk2 Contributes to Complement-Mediated Phagocytosis in Murine Macrophages

description: Proline-rich tyrosine kinase 2 (Pyk2) is a member of the focal adhesion kinase (FAK) family and is mainly expressed in neuronal and hematopoietic cells. As FAK family members are involved in signaling connections downstream of integrins, we studied the role of Pyk2 in complement-receptor 3 (CR3, also known as Mac-1, integrin α<sub>M</sub>β<sub>2</sub>, CD11b/CD18)-mediated phagocytosis, a key process in innate immunity. Using 3 independent approaches, we observed that Pyk2 contributes to CR3-dependent phagocytosis by RAW 264.7 macrophages, but is dispensable for Fcγ receptor (FcγR)-mediated uptake. Reduction of Pyk2 expression levels via siRNA, the pharmacological inhibition of Pyk2 kinase activity as well as macrophage treatment with a cell permeable TAT fusion protein containing the C-terminus of Pyk2 (TAT-PRNK) significantly impaired CR3-mediated phagocytosis without affecting FcγR-mediated uptake. In addition, Pyk2 was strongly recruited to complement opsonized <i>Escherichia coli</i> and the pharmacological inhibition of Pyk2 significantly decreased uptake of the bacteria. Finally, CRISPR/Cas-mediated disruption of the <i>pyk2</i> gene in RAW 264.7 macrophages confirmed the role of this protein tyrosine kinase in CR3-mediated phagocytosis. Together, our data demonstrate that Pyk2 selectively contributes to the coordination of phagocytosis-promoting signals downstream of CR3, but is dispensable for FcγR-mediated phagocytosis.