cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.6084/m9.figshare.5128816
title: Supplementary Material for: Perlecan Diversely Regulates the Migration and Proliferation of Distinct Cell Types in vitro

description: Perlecan is a multifunctional component of the extracellular matrix. It shows different effects on distinct cell types, and therefore it is thought to show potential for therapies targeting multiple cell types. However, the full range of multifunctionality of perlecan remains to be elucidated. We cultured various cell types, which were derived from epithelial/endothelial, connective and muscle tissues, in the presence of either antiserum against perlecan or exogenous perlecan, and examined the effects of perlecan on cell migration and proliferation. Cell migration was determined using a scratch assay. Blocking of perlecan by anti-perlecan antiserum inhibited the migration of vascular endothelial cells (VECs) and bone marrow-derived mesenchymal stem cells, and exogenous perlecan added to the culture medium promoted the migration of these cell types. The migration of other cell types was inhibited or was not promoted by exogenous perlecan. Cell proliferation was measured using a water-soluble tetrazolium dye. When cells were cultured at low densities, perlecan blocking inhibited the proliferation of VECs, and exogenous perlecan promoted the proliferation of keratinocytes. In contrast, the proliferation of fibroblasts, pre-adipocytes and vascular smooth muscle cells cultured at low densities was inhibited by exogenous perlecan. When cells were cultured at high densities, perlecan blocking promoted the proliferation of most cell types, with the exception of skeletal system-derived cells (chondrocytes and osteoblasts), which were inhibited by exogenous perlecan. Our results provide an overview of the multiple functions of perlecan in various cell types, and implicate a potential role of perlecan to inhibit undesirable activities, such as fibrosis, obesity and intimal hyperplasia.
DOI: 10.6084/m9.figshare.5128819.v1
title: Supplementary Material for: Phase I Dose-Escalation and Pharmacokinetic Study of Intravenous Aflibercept in Combination with Docetaxel, Cisplatin, and 5-Fluorouracil in Patients with Advanced Solid Malignancies

description: <b><i>Purpose:</i></b> This phase I study (EudraCT No. 2006-001177-25) investigated aflibercept, a vascular endothelial growth factor decoy receptor protein (VEGF Trap), in combination with docetaxel, cisplatin, and 5-fluorouracil in patients with advanced solid tumors. <b><i>Patients and Methods:</i></b> Patients received 2, 4, or 6 mg/kg of intravenous aflibercept with docetaxel 75 mg/m<sup>2</sup>, cisplatin 75 mg/m<sup>2</sup>, and 5-fluorouracil 750 mg/m<sup>2</sup> in 3-week cycles until disease progression or unacceptable toxicity. Primary objectives were to evaluate dose-limiting toxicities (DLTs) during cycle 1 and to determine the recommended phase II dose. Pharmacokinetics, tolerability, and antitumor activity were also investigated. <b><i>Results:</i></b> Forty-four patients were enrolled and treated (29 patients in a dose-escalation phase and 15 patients in an expansion cohort). Following three cases of febrile neutropenia in patients receiving aflibercept at 4 mg/kg, the protocol was amended to allow earlier granulocyte colony-stimulating factor support (from day 6) and prophylactic use of ciprofloxacin. Subsequently, there were two DLTs: febrile neutropenia (2 mg/kg) and grade 4 pulmonary embolism (6 mg/kg). An excess of free over VEGF-bound aflibercept was observed at 6 mg/kg. The most frequent grade 3/4 adverse events (AEs) were neutropenia (54.5%), lymphopenia (47.7%), and stomatitis (38.6%). AEs associated with VEGF blockade (any grade) included epistaxis (61.4%), dysphonia (40.9%), hypertension (38.6%), and proteinuria (11.4%). There were 15 partial responses, including 9 in patients with gastroesophageal cancers. Thirteen patients had stable disease. <b><i>Conclusion:</i></b> Aflibercept 6 mg/kg administered every 3 weeks in combination with docetaxel, cisplatin, and 5- fluorouracil is the recommended dose for further clinical development based on tolerability, pharmacokinetics, and antitumor activity.
DOI: 10.6084/m9.figshare.5128813
title: Supplementary Material for: Comparison of Safety and Efficacy of Different Models of Target Vessel Regional Chemotherapy for Gastric Cancer with Liver Metastases

description: <b><i>Background/Aims:</i></b> We previously demonstrated the safety and efficacy of low-dose, short-interval target vessel regional chemotherapy (TVRC<sup>LDSI</sup>) delivered through the hepatic artery with transarterial embolization (TAE) in patients with advanced gastric cancer (AGC). The present study aimed to compare the efficacy of TAE + TVRC<sup>LDSI</sup> with that of standard TAE + TVRC in AGC patients with liver metastases who failed to respond to first- or second-line systemic chemotherapy. <b><i>Methods:</i></b> This study recruited a total of 58 GC patients with liver metastases after failure of first- or second-line systemic chemotherapy. Twenty-eight patients were assigned to the TAE + TVRC<sup>LDSI</sup> group and 30 patients to the TAE + TVRC group. The primary end point was overall survival (OS<sup>TVRC</sup>), which was defined as the time from the initiation of TVRC until the last follow-up or death. <b><i>Results:</i></b> OS<sup>TVRC</sup>, time to progression (TTP) until appearance of intra- and extrahepatic metastases, and overall TTP and treatment periods in the TAE + TVRC<sup>LDSI</sup> group were all significantly longer than in the TAE + TVRC group (all p &lt; 0.001). <b><i>Conclusion:</i></b> TAE + TVRC<sup>LDSI</sup> had a higher efficacy and safety, which was reflected by OS rates, progression-free survival rates, longer duration of treatment and milder side effects compared to standard TAE + TVRC.
DOI: 10.6084/m9.figshare.5128807
title: Supplementary Material for: Risk and Protective Factors for Small Intestine Neuroendocrine Tumors: A Prospective Case-Control Study

description: <b><i>Background:</i></b> The incidence of small intestine neuroendocrine tumors (SI-NETs) is increasing, but few studies have investigated risk factors for their occurrence, suggesting that family history (FH) of any cancer, smoking and previous cholecystectomy are associated with an increased risk. Such studies investigated small series or examined cancer registries without direct interviews. <b><i>Aim:</i></b> We therefore aimed at clarifying risk and protective factors for the occurrence of sporadic SI-NETs. <b><i>Subjects and Methods:</i></b> We performed a multicenter case-control study. Patients with a histologic diagnosis of SI-NETs were prospectively evaluated, excluding familial syndromes. Controls with non-neoplastic/non-chronic disorders seen at gastrointestinal outpatients clinics were matched for sex and age (4:1). All subjects were directly interviewed by means of a specific questionnaire on potential risk and protective factors. Cases and controls were compared by Fisher's test or Student's t test for categorical or continuous variables. Explanatory variables were analyzed by simple logistic regression analysis. A multiple logistic regression analysis was performed with an Enter model; p &lt; 0.05 was considered significant. <b><i>Results:</i></b> 215 SI-NET patients and 860 controls were enrolled. FH of colorectal cancer (CRC) (8.8 vs. 5.0%) and breast cancer (10.2 vs. 4.8%), heavy smoking (24.7 vs. 14.8%) and drinking &gt;21 alcohol units per week (7.4 vs. 3.8%) were all significantly more frequent in SI-NET patients than in controls. Multivariate analysis showed that FH of CRC (OR 2.23, 95% CI 1.29-3.84, p = 0.003), FH of breast cancer (OR 2.05, 95% CI 1.13-3.69, p = 0.01) and smoking (OR 1.47, 95% CI 1.07-2.03, p = 0.01) and in particular heavy smoking (OR 1.94, 95% CI 1.29-3.84, p = 0.0008) were associated with an increased risk for carcinoid occurrence, while use of aspirin can be considered a protective factor (OR 0.20, 95% CI 0.06-0.65, p = 0.008). <b><i>Conclusion:</i></b> FH of colorectal and breast cancer as well as smoking seem to be risk factors for the development of SI-NETs, while use of aspirin might be a protective factor. These factors partially overlap with those associated with CRC, but are different from those previously associated with pancreatic neuroendocrine tumors. These findings may suggest that the mechanisms of carcinogenesis for endocrine cells in different sites can be specific and similar to those of their exocrine counterparts.
DOI: 10.6084/m9.figshare.5128816.v1
title: Supplementary Material for: Perlecan Diversely Regulates the Migration and Proliferation of Distinct Cell Types in vitro

description: Perlecan is a multifunctional component of the extracellular matrix. It shows different effects on distinct cell types, and therefore it is thought to show potential for therapies targeting multiple cell types. However, the full range of multifunctionality of perlecan remains to be elucidated. We cultured various cell types, which were derived from epithelial/endothelial, connective and muscle tissues, in the presence of either antiserum against perlecan or exogenous perlecan, and examined the effects of perlecan on cell migration and proliferation. Cell migration was determined using a scratch assay. Blocking of perlecan by anti-perlecan antiserum inhibited the migration of vascular endothelial cells (VECs) and bone marrow-derived mesenchymal stem cells, and exogenous perlecan added to the culture medium promoted the migration of these cell types. The migration of other cell types was inhibited or was not promoted by exogenous perlecan. Cell proliferation was measured using a water-soluble tetrazolium dye. When cells were cultured at low densities, perlecan blocking inhibited the proliferation of VECs, and exogenous perlecan promoted the proliferation of keratinocytes. In contrast, the proliferation of fibroblasts, pre-adipocytes and vascular smooth muscle cells cultured at low densities was inhibited by exogenous perlecan. When cells were cultured at high densities, perlecan blocking promoted the proliferation of most cell types, with the exception of skeletal system-derived cells (chondrocytes and osteoblasts), which were inhibited by exogenous perlecan. Our results provide an overview of the multiple functions of perlecan in various cell types, and implicate a potential role of perlecan to inhibit undesirable activities, such as fibrosis, obesity and intimal hyperplasia.
DOI: 10.6084/m9.figshare.5128798
title: Supplementary Material for: An Aggregate of Four Anthrax Cases during the Dry Summer of 2011 in Epirus, Greece

description: <b><i>Background:</i></b> Human anthrax is currently a sporadic disease in Europe, without significant regional clustering. <b><i>Objective:</i></b> To report an unexpected aggregate of anthrax cases and correlate local climatic factors with yearly anthrax admissions. <b><i>Methods:</i></b> Clinical description of a geographical-temporal anthrax aggregate, correlation of disease admissions with local weather data in the period 2001-2014 and literature reports of anthrax clusters from Europe in the last 20 years. <b><i>Results:</i></b> We identified 5 cases, all cutaneous: an unexpected aggregate of 4 cases in mid-summer 2011 (including a probable human-to-human transmission) and a sporadic case in August 2005, all in relatively dry periods (p &lt; 0.05). Remarkably, 3/6 reports of human anthrax aggregates from Europe were observed in Balkan Peninsula countries in the year 2011. <b><i>Conclusion:</i></b> In the light of the predicted climatic change, unexpected anthrax aggregates during dry periods in southern Europe underscore the risk of future anthrax re-emergence on this continent.
DOI: 10.6084/m9.figshare.5128804
title: Supplementary Material for: Fermentative Cyclohexane Carboxylate Formation in <b><i>Syntrophus aciditrophicus</i></b>

description: Short-chain fatty acids such as acetic, propionic, butyric or lactic acids are typical primary fermentation products in the anaerobic feeding chain. Fifteen years ago, a novel fermentation type was discovered in the obligately anaerobic Deltaproteobacterium <i>Syntrophus aciditrophicus</i>. During fermentative growth with crotonate and/or benzoate, acetate is formed in the oxidative branch and cyclohexane carboxylate in the reductive branch. In both cases cyclohexa-1,5-diene-1-carboxyl-CoA (Ch1,5CoA) is a central intermediate that is either formed by a class II benzoyl-CoA reductase (fermentation of benzoate) or by reverse reactions of the benzoyl-CoA degradation pathway (fermentation of crotonate). Here, we summarize the current knowledge of the enzymology involved in fermentations yielding cyclohexane carboxylate as an excreted product. The characteristic enzymes involved are two acyl-CoA dehydrogenases specifically acting on Ch1,5CoA and cyclohex-1-ene-1-carboxyl-CoA. Both enzymes are also employed during the syntrophic growth of <i>S. aciditrophicus</i> with cyclohexane carboxylate as the carbon source in coculture with a methanogen. An investigation of anabolic pathways in <i>S. aciditrophicus</i> revealed a rather unusual pathway for glutamate synthesis involving a <i>Re</i>-citrate synthase. Future work has to address the unresolved question concerning which components are involved in reoxidation of the NADH formed in the oxidative branch of the unique cyclohexane carboxylate fermentation pathway in <i>S. aciditrophicus</i>.
DOI: 10.6084/m9.figshare.5128801
title: Supplementary Material for: A Novel Mixture Model to Estimate the Time to Drug Effect Onset and Its Association with Covariates

description: <b><i>Objective:</i></b> Drugs take effect at different times in different individuals. Consequently, researchers seek to examine how the timing of the biological response to drugs may be affected by factors such as gender, genotypes, age, or baseline symptom scores. <b><i>Methods:</i></b> Typically, studies measure symptoms immediately after the initiation of drug treatment and then at a sequence of later time points. In this study, we develop a statistical mixture model for analyzing such longitudinal data. Our method estimates the onset of drug effect and assesses the association between the probability distribution of the onset times and possible contributing factors. Our mixture model treats the timing of onset as missing for each individual but restricts it, for simplicity, to two possible onset points, early or late. To estimate the model, we use an expectation-maximization-based approach and provide the general formulas of the variance and covariance matrix for the estimated parameters. <b><i>Results:</i></b> We evaluate the model's overall utility and performance via simulation studies. In addition, we illustrate its use by application to longitudinal data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. The algorithm identified age and anxiety status as significant factors in affecting the onset distribution of citalopram (Celexa).
DOI: 10.6084/m9.figshare.5128795
title: Supplementary Material for: DAPHNE: A New Tool for the Assessment of the Behavioral Variant of Frontotemporal Dementia

description: <b><i>Background:</i></b> The diagnosis of behavioral variant of frontotemporal dementia (bvFTD) relies primarily on clinical features and remains challenging. The specificity of the recently revised criteria can be disappointing, justifying development of new clinical tools. <b><i>Objective:</i></b> We produced a behavioral inventory named DAPHNE. This scale (adapted from Rascovsky's criteria) explores six domains: disinhibition, apathy, perseverations, hyperorality, personal neglect and loss of empathy. It is composed of ten items (five answer categories). The aim was (1) to assess the validity and reliability of DAPHNE and (2) to evaluate its contribution in differentiating patients. <b><i>Methods:</i></b> Two scores were computed: DAPHNE-6 (screening) from the six domains and DAPHNE-40 (diagnosis) from the ten items. Reliability and reproducibility were assessed. External validity was studied with the Frontal Behavioral Inventory (FBI) and the Frontotemporal Behavioral Scale (FBS). Finally, the diagnostic performance of DAPHNE was compared to revised criteria, FBI and FBS. <b><i>Results:</i></b> DAPHNE was administered to the caregivers of 89 patients, 36 with bvFTD, 22 with Alzheimer's disease, 15 with progressive supranuclear palsy and 16 with bipolar disorder. Reliability and reproducibility were excellent, as was external validity. DAPHNE-6 allowed bvFTD diagnosis (score ≥4) with a sensitivity of 92%, while DAPHNE-40 (score ≥15) had a specificity of 92%. <b><i>Conclusion:</i></b> We demonstrate excellent psychometric features for DAPHNE. This quick tool could help for both diagnosing and screening bvFTD.
DOI: 10.6084/m9.figshare.5128798.v1
title: Supplementary Material for: An Aggregate of Four Anthrax Cases during the Dry Summer of 2011 in Epirus, Greece

description: <b><i>Background:</i></b> Human anthrax is currently a sporadic disease in Europe, without significant regional clustering. <b><i>Objective:</i></b> To report an unexpected aggregate of anthrax cases and correlate local climatic factors with yearly anthrax admissions. <b><i>Methods:</i></b> Clinical description of a geographical-temporal anthrax aggregate, correlation of disease admissions with local weather data in the period 2001-2014 and literature reports of anthrax clusters from Europe in the last 20 years. <b><i>Results:</i></b> We identified 5 cases, all cutaneous: an unexpected aggregate of 4 cases in mid-summer 2011 (including a probable human-to-human transmission) and a sporadic case in August 2005, all in relatively dry periods (p &lt; 0.05). Remarkably, 3/6 reports of human anthrax aggregates from Europe were observed in Balkan Peninsula countries in the year 2011. <b><i>Conclusion:</i></b> In the light of the predicted climatic change, unexpected anthrax aggregates during dry periods in southern Europe underscore the risk of future anthrax re-emergence on this continent.
DOI: 10.6084/m9.figshare.5128789
title: Supplementary Material for: Endotoxin Tolerance Inhibits Lyn and c-Src Phosphorylation and Association with Toll-Like Receptor 4 but Increases Expression and Activity of Protein Phosphatases

description: Endotoxin tolerance protects the host by limiting excessive 'cytokine storm' during sepsis, but compromises the ability to counteract infections in septic shock survivors. It reprograms Toll-like receptor (TLR) 4 responses by attenuating the expression of proinflammatory cytokines without suppressing anti-inflammatory and antimicrobial mediators, but the mechanisms of reprogramming remain unclear. In this study, we demonstrate that the induction of endotoxin tolerance in human monocytes, THP-1 and MonoMac-6 cells inhibited lipopolysaccharide (LPS)-mediated phosphorylation of Lyn, c-Src and their recruitment to TLR4, but increased total protein phosphatase (PP) activity and the expression of protein tyrosine phosphatase (PTP) 1B, PP2A, PTP nonreceptor type (PTPN) 22 and mitogen-activated protein kinase phosphatase (MKP)-1. Chemical PP inhibitors, okadaic acid, dephostatin and cantharidic acid markedly decreased or completely abolished LPS tolerance, indicating the importance of phosphatases in endotoxin tolerization. Overexpression of PTPN22 decreased LPS-mediated nuclear factor (NF)-κB activation, p38 phosphorylation and CXCL8 gene expression, while PTPN22 ablation upregulated LPS-induced p65 NF-κB and p38 phosphorylation and the expression of TNF-a and pro-IL-1ß mRNA, indicating PTPN22 as an inhibitor of TLR4 signaling. Thus, LPS tolerance interferes with TLR4 signaling by inhibiting Lyn and c-Src phosphorylation and their recruitment to TLR4, while increasing the phosphatase activity and expression of PP2A, PTPN22, PTP1B and MKP1.
DOI: 10.6084/m9.figshare.5128792
title: Supplementary Material for: Oxidized Docosahexaenoic Acid Species and Lipid Peroxidation Products Increase Amyloidogenic Amyloid Precursor Protein Processing

description: One of the main characteristics of Alzheimer's disease (AD) is the β-amyloid peptide (Aβ) generated by β- and γ-secretase processing of the amyloid precursor protein (APP). Previously it has been demonstrated that polyunsaturated fatty acids (PUFAs), especially docosahexaenoic acid (DHA), are associated with a reduced risk of AD caused by decreased Aβ production. However, in epidemiological studies and nutritional approaches, the outcomes of DHA-dependent treatment were partially controversial. PUFAs are very susceptible to reactive oxygen species and lipid peroxidation, which are increased during disease pathology. In line with published results, lipid peroxidation was elevated in human postmortem AD brains; especially 4-hydroxy-nonenal (HNE) was increased. To investigate whether lipid peroxidation is only a consequence or might also influence the processes leading to AD, we analyzed 7 different oxidized lipid species including 5 oxidized DHA derivatives and the lipid peroxidation products of ω-3 and ω-6 PUFAs, HNE and 4-hydroxy-hexenal, in human neuroblastoma cells and mouse mixed cortical neurons. In the presence of oxidized lipids Aβ and soluble β-secreted APP levels were elevated, whereas soluble α-secreted APP was decreased, suggesting a shift from the nonamyloidogenic to the amyloidogenic pathway of APP processing. Furthermore, β- and γ-secretase activity was increased by oxidized lipids via increased gene expression and additionally by a direct effect on β-secretase activity. Importantly, only 1% oxidized DHA was sufficient to revert the protective effect of DHA and to significantly increase Aβ production. Therefore, our results emphasize the need to prevent DHA from oxidation in nutritional approaches and might help explain the divergent results of clinical DHA studies.
DOI: 10.6084/m9.figshare.5128804.v1
title: Supplementary Material for: Fermentative Cyclohexane Carboxylate Formation in <b><i>Syntrophus aciditrophicus</i></b>

description: Short-chain fatty acids such as acetic, propionic, butyric or lactic acids are typical primary fermentation products in the anaerobic feeding chain. Fifteen years ago, a novel fermentation type was discovered in the obligately anaerobic Deltaproteobacterium <i>Syntrophus aciditrophicus</i>. During fermentative growth with crotonate and/or benzoate, acetate is formed in the oxidative branch and cyclohexane carboxylate in the reductive branch. In both cases cyclohexa-1,5-diene-1-carboxyl-CoA (Ch1,5CoA) is a central intermediate that is either formed by a class II benzoyl-CoA reductase (fermentation of benzoate) or by reverse reactions of the benzoyl-CoA degradation pathway (fermentation of crotonate). Here, we summarize the current knowledge of the enzymology involved in fermentations yielding cyclohexane carboxylate as an excreted product. The characteristic enzymes involved are two acyl-CoA dehydrogenases specifically acting on Ch1,5CoA and cyclohex-1-ene-1-carboxyl-CoA. Both enzymes are also employed during the syntrophic growth of <i>S. aciditrophicus</i> with cyclohexane carboxylate as the carbon source in coculture with a methanogen. An investigation of anabolic pathways in <i>S. aciditrophicus</i> revealed a rather unusual pathway for glutamate synthesis involving a <i>Re</i>-citrate synthase. Future work has to address the unresolved question concerning which components are involved in reoxidation of the NADH formed in the oxidative branch of the unique cyclohexane carboxylate fermentation pathway in <i>S. aciditrophicus</i>.