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901.
Giovanni Ianiro Roberto Delogu Rosalia Graffeo Maurizio Sanguinetti Lucia Fiore Franco M. Ruggeri 《Emerging infectious diseases》2014,20(11):1906-1910
Infection with a rare G3P[19] rotavirus A strain was identified in an immunosuppressed patient in Italy. The strain showed a P[19] viral protein 4 gene and a complete AU-1–like genomic constellation. Phylogenetic analyses showed high nucleotide identity between this strain and G3P[19] rotavirus A strains from Asia, indicating possible reassortment events. 相似文献
902.
Preclinical models of human cancers are indispensable in the drug discovery and development process for new cancer drugs, small molecules and biologics. They are however imperfect facsimiles of human cancers given the genetic and epigenetic heterogeneity of the latter and the multiplicity of dysregulated survival and growth-regulatory pathways that characterize this spectrum of diseases. This review discusses pre-clinical tumor models – traditional ectopic xenografts, orthotopic xenografts, genetically engineered tumor models, primary human tumorgrafts, and various multi-stage carcinogen-induced tumor models – their advantages, limitations, physiological and pathological relevance. Collectively, these animal models represent a portfolio of test systems that should be utilized at specific stages in the drug discovery process in a pragmatic and hierarchical manner of increasing complexity, physiological relevance, and clinical predictability of the human response. Additionally, evaluating the efficacy of novel therapeutic agents emerging from drug discovery programs in a variety of pre-clinical models can better mimic the heterogeneity of human cancers and also aid in establishing dose levels, dose regimens and drug combinations for use in clinical trials. Nonetheless, despite the sophistication and physiological relevance of these human cancer models (e.g., genetically engineered tumor models and primary human tumografts), the ultimate proof of concept for efficacy and safety of novel oncology therapeutics lies in humans. The judicious interpretation and extrapolation of data derived from these models to humans, and a correspondingly greater emphasis placed on translational medical research in early stage clinical trials, are essential to improve on the current clinical attrition rates for novel oncology therapeutic agents. 相似文献
903.
S. Cannavo F. Ferrau O. R. Cotta S. Saitta V. Barresi M. T. Cristani A. Saija R. M. Ruggeri F. Trimarchi S. Gangemi 《Pituitary》2014,17(1):76-80
Cytokines’ involvement in tumorigenesis has been hypothesized. Interleukin-22 (IL-22) is implicated in proliferative and anti-apoptotic pathways via its receptor IL-22R. Its role in pituitary adenomas has never been investigated. Twenty-seven patients with pituitary macroadenomas (PA, 21 males, mean age 53.8 ± 14.4 years) and 30 healthy controls (19 males, mean age 50.4 ± 8.4 years) were enrolled. Out of 27 PA patients, 17 had a non-functioning tumour (NFPA) and 10 a PRL-secreting adenoma (PRL-oma). Serum IL-22 levels were measured in both patients and controls. Immunohistochemical (IHC) tumoral IL-22R expression was evaluated in 10 patients with NFPA and 4 with PRL-oma. IL-22 levels were significantly higher in PA patients than in controls [32.47 (11.29–70.12) vs. 5.58 (0.19–21.46) pg/mL, p < 0.0001] but did not correlate with tumor maximum diameter and were not associated to pituitary function impairment. PRL-oma patients had significantly higher IL-22 levels than NFPA patients [37.18 (14.82–70.12) vs. 21.29 (11.29–56) pg/mL, p = 0.039]. IHC revealed a strong IL-22R staining in 100 % of PRL-omas and 60 % of NFPAs. We provide the first evidence of increased serum IL-22 levels in patients with pituitary macroadenoma, especially in PRL-omas, regardless of tumor size and/or degree of pituitary function impairment. We also demonstrated the expression of IL22R in all PRL-omas and in 60 % of NFPAs. 相似文献
904.
Signaling through GP Ib-IX-V activates alpha IIb beta 3 independently of other receptors 总被引:9,自引:5,他引:9 下载免费PDF全文
Platelet adhesion to von Willebrand factor (VWF) activates alpha IIb beta 3, a prerequisite for thrombus formation. However, it is unclear whether the primary VWF receptor, glycoprotein (GP) Ib-IX-V, mediates alpha IIb beta 3 activation directly or through other signaling proteins physically associated with it (eg, FcR gamma-chain), possibly with the contribution of other agonist receptors and of VWF signaling through alpha IIb beta 3. To resolve this question, human and GP Ibalpha transgenic mouse platelets were plated on dimeric VWF A1 domain (dA1VWF), which engages only GP Ib-IX-V, in the presence of inhibitors of other agonist receptors. Platelet adhesion to dA1VWF induced Src kinase-dependent tyrosine phosphorylation of the FcR gamma-chain and the adapter molecule, ADAP, and triggered intracellular Ca(2+) oscillations and alpha IIb beta 3 activation. Inhibition of Ca(2+) oscillations with BAPTA-AM prevented alpha IIb beta 3 activation but not tyrosine phosphorylation. Pharmacologic inhibition of protein kinase C (PKC) or phosphatidylinositol 3-kinase (PI 3-kinase) prevented alpha IIb beta 3 activation but not Ca(2+) oscillations. Inhibition of Src with 2 distinct compounds blocked all responses downstream of GP Ib-IX-V under static or flow conditions. However, dA1VWF-induced responses were reduced only slightly in GP Ibalpha transgenic platelets lacking FcR gamma-chain. These data establish that GP Ib-IX-V itself can signal to activate alpha IIb beta 3, through sequential actions of Src kinases, Ca(2+) oscillations, and PI 3-kinase/PKC. 相似文献
905.
Ruggeri RM Villari D Simone A Scarfi R Attard M Orlandi F Barresi G Trimarchi F Trovato M Benvenga S 《Journal of endocrinological investigation》2002,25(11):959-966
Data on the expression of interleukin 6 (IL-6)/interleukin 6 receptor (IL-6R) in thyroid nodules is scarce. Based on our recent data of CD30 ligand (CD30L)/CD30 receptor (CD30) in these nodules and on the knowledge that this signal stimulates IL-6 production in non-thyroid neoplasms, we wanted to evaluate the immunocytochemical expression of these 2 ligand/receptor systems in a large archival series of paraffin-embedded specimens. These specimens included 6 normal thyroids and 130 thyroid nodules. Co-expression of IL-6 and IL-6R in the epithelial (follicular) cells was observed solely in CD30L/CD30 positive nodules: 5/15 (33%) oncocytic adenomas; 6/30 (20%) follicular adenomas which belonged to 2 variants (4/4 microfollicular toxic and 2/2 hyalinizing trabecular); 9/30 (30%) papillary thyroid cancers (PTC), all belonging to the conventional variant. In PTC the proportion of tumor epithelial cells that were IL6 positive was inversely correlated with the pTNM staging (r=-0.549, p=0.01). All 15 follicular cancers (FTC), all 6 anaplastic cancers (ATC) were IL-6/lL-6R negative; 14/15 FTC and 5/6 ATC were CD30L/CD30 negative. In another oncocytic adenoma, another 4 conventional PTC and another 7 non-conventional PTC CD30L/CD30 expression was associated to expression of IL-6 only. IL-6 staining associated to absent expression of CD30L and CD30 was observed in 7 follicular adenomas (all belonging to variants different from toxic and hyalinizing trabecular), 2 oncocytic adenomas, 5 of the 30 colloid nodules and 2 normal thyroids. Of the 6 tumors arising from the parafollicular C cells (medullary thyroid cancer, MTC), all 3 that had metastasized were CD30L/CD30/IL-6 positive and IL-6R negative; only IL-6 expression was lost in both the local and distant metastases. This finding matched the loss of IL-6 expression in one PTC metastasis. All 3 non-metastasized MTC were IL-6/IL-6R negative, and 1/3 was CD30L positive/CD30 negative. We conclude that only in a subset of both benign and malignant thyroid nodules the IL-6/IL-6R signal could be induced by the CD30L/CD30. IL-6 expression is related with aggressiveness in both PTC and MTC. In the normal thyroid tissue, colloid nodules, and another subset of benign and malignant thyroid nodules, IL-6 expression is under control of signals other than CD30L/CD30. 相似文献
906.
Distinct abnormalities in the interaction of purified types IIA and IIB von Willebrand factor with the two platelet binding sites, glycoprotein complexes Ib-IX and IIb-IIIa. 总被引:5,自引:3,他引:5 下载免费PDF全文
L De Marco M Mazzucato D De Roia A Casonato A B Federici A Girolami Z M Ruggeri 《The Journal of clinical investigation》1990,86(3):785-792
We have studied the interaction of the congenitally abnormal type IIA and IIB von Willebrand factor (vWF) molecules, both lacking the larger multimeric forms, with the two vWF binding sites on platelets, the glycoprotein (GP) Ib-IX and GP IIb-IIIa complexes. Variant as well as normal (N) vWF were purified from plasma. Estimates for binding of subunit molecules per platelet at saturation (Bmax) and dissociation constant in moles/liter (Kd), respectively, were obtained from binding isotherms of 125I-labeled vWF, with the following results. In the presence of ristocetin (binding to GP Ib-IX): N, 25,693 and 0.5 x 10(-8); IIA, both parameters not measurable; IIB, 17,708 and 0.87 x 10(-8). After thrombin stimulation (binding to GP IIb-IIIa): N, 17,059 and 1.12 x 10(-8); IIA, 23,751 and 4.87 x 10(-8); IIB, 19,890 and 2.52 x 10(-8). Distinct experiments based on measuring the ability of the variant species (from the same patients and one additional IIB patient) to inhibit the binding of normal 125I-vWF to platelets gave results in agreement with those reported above. Other studies showed that only IIB vWF bound to platelets in the absence of any mediating substance (Kd = 5.21 x 10(-8) mol/liter and Bmax = 9,599 subunits per platelet) and induced aggregation at a concentration of 10 micrograms/ml (3.6 x 10(-8) M). Thus, IIB vWF binds to GP Ib-IX with high affinity and induces platelet aggregation, whether with or without ristocetin, in spite of the absence of larger multimers. In contrast, the binding of IIA vWF to GP Ib-IX occurs with very decreased affinity, and this defective function may result from specific structural abnormalities rather than just being a reflection of the absence of larger multimeric forms. Both IIA and IIB vWF exhibit decreased affinity for GP IIb-IIIa. In this case, the extent of the defect correlates with the absence of larger multimers. 相似文献
907.
Optimization of coronary sinus lead placement targeted to the longest right‐to‐left delay in patients undergoing cardiac resynchronization therapy: The Optimal Pacing SITE 2 (OPSITE 2) acute study and protocol 下载免费PDF全文
Daniele Oddone MD Diana Solari MD René Nangah MD Giuseppe Arena MD Roberto Mureddu MD Davide Giorgi MD Nadir Sitta MD Nicola Bottoni MD Gaetano Senatore MD Marzia Giaccardi MD Massimo Giammaria MD Sakis Themistoclakis MD Mattia Laffi MD Eliana Cipolla Eng Fabio Di Lorenzo Eng Romina Carpi Eng Michele Brignole MD 《Pacing and clinical electrophysiology : PACE》2017,40(12):1350-1357
908.
Laura Avanzino Alessia Raffo Elisa Pelosin Carla Ogliastro Roberta Marchese Piero Ruggeri Giovanni Abbruzzese 《The European journal of neuroscience》2014,40(3):2581-2588
Mirror visual feedback (MVF) therapy has been demonstrated to be successful in neurorehabilitation, probably inducing neuroplasticity changes in the primary motor cortex (M1). However, it is not known whether MVF training influences the hemispheric balance between the M1s. This topic is of extreme relevance when MVF training is applied to stroke rehabilitation, as the competitive interaction between the two hemispheres induces abnormal interhemispheric inhibition (IHI) that weakens motor function in stroke patients. In the present study, we evaluated, in a group of healthy subjects, the effect of motor training and MVF training on the excitability of the two M1s and the IHI between M1s. The IHI from the ‘active’ M1 to the opposite M1 (where ‘active’ means the M1 contralateral to the moving hand in the motor training and the M1 of the seen hand in the MVF training) increased, after training, in both the experimental conditions. Only after motor training did we observe an increase in the excitability of the active M1. Our findings show that training based on MVF may influence the excitability of the transcallosal pathway and support its use in disorders where abnormal IHI is a potential target, such as stroke, where an imbalance between the affected and unaffected M1s has been documented. 相似文献
909.
Franco Valenza Lorenzo Rosso Silvia Coppola Sara Froio Alessandro Palleschi Davide Tosi Paolo Mendogni Valentina Salice Giulia M. Ruggeri Jacopo Fumagalli Alessandro Villa Mario Nosotti Luigi Santambrogio Luciano Gattinoni 《Transplant international》2014,27(6):553-561
This paper describes the initial clinical experience of ex vivo lung perfusion (EVLP) at the Fondazione Ca’ Granda in Milan between January 2011 and May 2013. EVLP was considered if donor PaO2/FiO2 was below 300 mmHg or if lung function was doubtful. Donors with massive lung contusion, aspiration, purulent secretions, pneumonia, or sepsis were excluded. EVLP was run with a low‐flow, open atrium and low hematocrit technique. Thirty‐five lung transplants from brain death donors were performed, seven of which after EVLP. EVLP donors were older (54 ± 9 years vs. 40 ± 15 years, EVLP versus Standard, P < 0.05), had lower PaO2/FiO2 (264 ± 78 mmHg vs. 453 ± 119 mmHg, P < 0.05), and more chest X‐ray abnormalities (P < 0.05). EVLP recipients were more often admitted to intensive care unit as urgent cases (57% vs. 18%, P = 0.05); lung allocation score at transplantation was higher (79 [40–84] vs. 39 [36–46], P < 0.05). After transplantation, primary graft dysfunction (PGD72 grade 3, 32% vs. 28%, EVLP versus Standard, P = 1), mortality at 30 days (0% vs. 0%, P = 1), and overall survival (71% vs. 86%, EVLP versus Standard P = 0.27) were not different between groups. EVLP enabled a 20% increase in available donor organs and resulted in successful transplants with lungs that would have otherwise been rejected (ClinicalTrials.gov number: NCT01967953). 相似文献
910.
Jennifer L. Strauss Jennifer B. Zervakis Karen M. Stechuchak Maren K. Olsen Jeffrey Swanson Marvin S. Swartz Morris Weinberger Christine E. Marx Patrick S. Calhoun Daniel W. Bradford Marian I. Butterfield Eugene Z. Oddone 《Community mental health journal》2013,49(4):457-465
Consumers’ satisfaction with inpatient mental health care is recognized as a key quality indicator that prospectively predicts functional and clinical outcomes. Coercive treatment experience is a frequently cited source of dissatisfaction with inpatient care, yet more research is needed to understand the factors that influence consumers’ perceptions of coercion and its effects on satisfaction, including potential “downstream” effects of past coercive events on current treatment satisfaction. The current study examined associations between objective and subjective indices of coercive treatments and patients’ satisfaction with care in a psychiatric inpatient sample (N = 240). Lower satisfaction ratings were independently associated with three coercive treatment variables: current involuntary admission, perceived coercion during current admission, and self-reported history of being refused a requested medication. Albeit preliminary, these results document associations between patients’ satisfaction ratings and their subjective experiences of coercion during both current and prior hospitalizations. 相似文献