Biomedical subjects

Mauro Ferrari

Publications and source records attributed to Mauro Ferrari.

At least 19 recordsLinked to original sources

PubMed2006

Polymorphic analysis of the matrix metalloproteinase-9 gene and susceptibility to sporadic abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) has a multifactorial aetiology and the importance of genetic components is getting increasing interest. Alteration in the structure of the vascular extracellular matrix has been described in AAA. Matrix metalloproteinases (MMPs) degrade extracellular matrix proteins which alter the vessel wall stability. We evaluated two different polymorphisms, a CA repeat and a cytosine to thymidine transition in the promoter sequence of MMP-9 gene for frequency in 146 patients with AAA. We compared the results with those of 156 healthy subjects. No difference was found in the allelic distribution of either polymorphisms. We therefore found no evidence that MMP-9 is a marker of susceptibility for AAA.

Adult↗

PubMed2006

Physicochemically modified silicon as a substrate for protein microarrays.

Reverse phase protein microarrays (RPMA) enable high throughput screening of posttranslational modifications of important signaling proteins within diseased cells. One limitation of protein-based molecular profiling is the lack of a PCR-like intrinsic amplification system for proteins. Enhancement of protein microarray sensitivities is an important goal, especially because many molecular targets within patient tissues are of low abundance. The ideal array substrate will have a high protein-binding affinity and low intrinsic signal. To date, nitrocellulose-coated glass has provided an effective substrate for protein binding in the microarray format when using chromogenic detection systems. As fluorescent systems, such as quantum dots, are explored as potential reporter agents, the intrinsic fluorescent properties of nitrocellulose-coated glass slides limit the ability to image microarrays for extended periods of time where increases in net sensitivity can be attained. Silicon, with low intrinsic autofluorescence, is being explored as a potential microarray surface. Native silicon has low binding potential. Through titrated reactive ion etching (RIE), varying surface areas have been created on silicon in order to enhance protein binding. Further, via chemical modification, reactive groups have been added to the surfaces for comparison of relative protein binding. Using this combinatorial method of surface roughening and surface coating, 3-aminopropyltriethoxysilane (APTES) and mercaptopropyltrimethoxysilane (MPTMS) treatments were shown to transform native silicon into a protein-binding substrate comparable to nitrocellulose.

Adsorption↗

PubMed2006

Duodenal duplication cyst causing severe pancreatitis: imaging findings and pathological correlation.

We here report a case of a 18-year-old man with a history of recurrent abdominal pain and a previous episode of severe acute pancreatitis. Abdominal ultrasonography, contrast enhanced multislice computer tomography, endoscopic retrograde cholangiopancreatography, endoscopic ultrasonography and magnetic resonance imaging demonstrated a cystic mass lesion. Only on delayed phase magnetic resonance images after Gadolinium-BOPTA injection, it was possible to demonstrate the lesionos relationship with the biliary tree, differentiating the lesion from intraluminal duodenal diverticulum, and to achieve the diagnosis of duodenal duplication cyst, a recognized rare cause of acute pancreatitis. The diagnosis was confirmed by histology.

Adolescent↗

PubMed2006

Nanotechnologies for biomolecular detection and medical diagnostics.

Nanotechnology-based platforms for the high-throughput, multiplexed detection of proteins and nucleic acids in heretofore unattainable abundance ranges promise to bring substantial advances in molecular medicine. The emerging approaches reviewed in this article, with reference to their diagnostic potential, include nanotextured surfaces for proteomics, a two-particle sandwich assay for the biological amplification of low-concentration biomolecular signals, and silicon-based nanostructures for the transduction of molecular binding into electrical and mechanical signals, respectively.

Biopolymers↗

PubMed2006

Selective binding and enrichment for low-molecular weight biomarker molecules in human plasma after exposure to nanoporous silica particles.

The present manuscript describes a biomarker capturing strategy based on nanoporous silica particles. The method is shown to enrich the yield of species in the low-molecular weight proteome (LMWP), allowing detection of small peptides in the low-nanomolar range. Plasma samples were exposed to the silica particles, and the captured molecular species were profiled using MALDI-TOF. Mass spectra of the silica-treated human plasma samples showed a significant enrichment in MALDI-TOF protein profiles in the LMWP. Preliminary results indicated good level of reproducibility in plasma profiles with CVs on peak heights ranging from 6.3 to 14.7%. The MALDI-TOF signature changed significantly when the characteristics of the nanoporous silica were altered. The facile sample pretreatment before MS analysis, coupled to the potential for tailoring the surface properties of silica supports, hold promise for improving the recovery of low-abundance serum biomarkers.

Biomarkers↗

PubMed2006

Multiscale modeling of protein transport in silicon membrane nanochannels. Part 1. Derivation of molecular parameters from computer simulations.

We report in this account our efforts in the development of a novel multiscale simulation tool for integrated nanosystem design, analysis and optimization based on a three-tiered modeling approach consisting of (i) molecular models, (ii) atomistic molecular dynamics simulations, and (iii) dynamical models of protein transport at the continuum scale. In this work we used molecular simulations for the analysis of lysozyme adsorption on a pure silicon surface. The molecular modeling procedures adopted allowed (a) to elucidate the specific mechanisms of interaction between the biopolymer and the silicon surface, and (b) to derive molecular energetic and structural parameters to be employed in the formulation of a mathematical model of diffusion through silicon-based nanochannel membranes, thus filling the existing gap between the nano--and the macroscale.

Adsorption↗

PubMed2006

Multiscale modeling of protein transport in silicon membrane nanochannels. Part 2. From molecular parameters to a predictive continuum diffusion model.

Transport and surface interactions of proteins in nanopore membranes play a key role in many processes of biomedical importance. Although the use of porous materials provides a large surface-to-volume ratio, the efficiency of the operations is often determined by transport behavior, and this is complicated by the fact that transport paths (i.e., the pores) are frequently of molecular dimensions. Under these conditions, a protein diffusion can be slower than predicted from Fick law. The main contribution of this paper is the development of a mathematical model of this phenomenon, whose parameters are computed via molecular modeling, as described Part 1. Our multiscale modeling methodology, validated by using experimental results related to the diffusion of lysozyme molecules, constitutes an "ab initio" recipe, for which no experimental data are needed to predict the protein release, and can be tailored in principle to match any different protein and any different surface, thus filling gap between the nano and the macroscale.

Computer Simulation↗

PubMed2006

Laparoscopy-assisted abdominal aortic aneurysm repair: early and middle-term results of a consecutive series of 122 cases.

BACKGROUND: Endoaneurysmorrhaphy with intraluminal graft placement, described by Creech, is the gold standard for abdominal aortic aneurysm (AAA) repair. Endovascular aneurysm repair has gained popularity for its minimal invasiveness and satisfying short-term results, but there are still many concerns about the long-term success of the procedure. Since 1998, laparoscopic surgery has been proposed for AAA treatment. The potential benefits of a minimally invasive procedure reproducing the endoaneurysmorrhaphy results over time have been advocated. In our experience, hand-assisted laparoscopic surgery (HALS) has been routinely used for the open-surgery transperitoneal/retroperitoneal approach and for endovascular aneurysm repair. After 4 years, we are able to define the early and middle-term results of such laparoscopic-assisted treatment. METHODS: From October 2000 to March 2004, 604 consecutive nonurgent AAAs were treated at our institution. Of these, 122 (20.2%) were treated by HALS. Exclusion criteria for HALS were hostile abdomen (previous major abdominal or aortic surgery), bilateral diffuse common iliac and/or hypogastric aneurysms, massive aortoiliac calcifications, and severe cardiac (ejection fraction <35%) and respiratory (P(O2) <60 mm Hg or carbon dioxide >50 mm Hg) insufficiency. Juxtarenal and proximal iliac aneurysms were not a contraindication, nor was obesity. In all patients, we performed a minilaparotomy (7-8 cm) both for laparoscopic hand-assisted dissection and for endoaneurysmorrhaphy. All perioperative data were prospectively recorded. Follow-up consisted of ultrasonography and clinical evaluation after 6 and 12 months and then every year after surgery. RESULTS: The mean laparoscopic and total operative times were respectively 64 +/- 32 minutes and 257 +/- 70 minutes, the mean aortic cross-clamping time was 76 +/- 26 minutes, and the mean autotransfused blood volume was 1136 +/- 711 mL. The overall mortality and morbidity were respectively 0% and 12.2%. Morbidity was surgery related in only two cases (bleeding from an ipogastric artery lesion and a leg graft thrombosis). The mean intensive care unit stay was 14.3 +/- 13 hours. Oral food intake was resumed after 27.4 +/- 15 hours, and patients were discharged after a mean of 4.4 +/- 1.7 days. Operative times were not affected by obesity, suprarenal aortic cross-clamping, or aneurysm size. Both concomitant iliac aneurysms and bifurcated graft implantation (related to longer vascular reconstruction) involved significantly longer operative times. The learning curve of the procedure (comparing the first 30 patients with the last 92 patients) led to significantly shorter endoscopic, cross-clamping, and total operative times (P = .000). The mean follow-up was 28.6 +/- 16 months. Three incisional hernias and one case of bowel occlusion were detected. All these cases (3.4%) required laparoscopic treatment. CONCLUSIONS: The HALS technique is a safe and minimally invasive treatment for AAA; it is useful for limiting the need for conventional open surgery and reducing the length of hospital stay. Despite the lack of randomized studies, HALS seems to be associated with a better postoperative course than standard open surgery. HALS can also be considered as an equivalent of a well-established procedure and as a bridge between open and total laparoscopic surgery.

Aged↗

PubMed2006

Nanoporous surfaces as harvesting agents for mass spectrometric analysis of peptides in human plasma.

Silica-based nanoporous surfaces have been developed in order to capture low molecular weight peptides from human plasma. Harvested peptides were subjected to mass spectrometric analysis by using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) as a means of detecting and assessing the bound molecules. Peptide profiles consisting of about 70 peaks in the range 800-10,000 m/z were generated. The method could allow detection of small peptides at ng/mL concentration levels, either in standard solutions or in plasma. The same molecular cutoff effect was observed for mixtures of standard proteins and peptides incubated with silicon-based nanoporous surfaces.

Blood Proteins↗

PubMed2006

Controlled-release microchips.

Efficient drug delivery remains an important challenge in medicine: continuous release of therapeutic agents over extended time periods in accordance with a predetermined temporal profile; local delivery at a constant rate to the tumour microenvironment to overcome much of the systemic toxicity and to improve antitumour efficacy; improved ease of administration, and increasing patient compliance required are some of the unmet needs of the present drug delivery technology. Microfabrication technology has enabled the development of novel controlled-release microchips with capabilities not present in the current treatment modalities. In this review, the current status and future prospects of different types of controlled-release microchips are summarised and analysed with reference to microneedle-based microchips, as well as providing an in-depth focus on microreservoir-based and nanoporous microchips.

Animals↗

PubMed2006

Mathematical modeling of cancer progression and response to chemotherapy.

The complex, constantly evolving and multifaceted nature of cancer has made it difficult to identify unique molecular and pathophysiological signatures for each disease variant, consequently hindering development of effective therapies. Mathematical modeling and computer simulation are tools that can provide a robust framework to better understand cancer progression and response to chemotherapy. Successful therapeutic agents must overcome biological barriers occurring at multiple space and time scales and still reach targets at sufficient concentrations. A multiscale computer simulator founded on the integration of experimental data and mathematical models can provide valuable insights into these processes and establish a technology platform for analyzing the effectiveness of chemotherapeutic drugs, with the potential to cost-effectively and efficiently screen drug candidates during the drug-development process.

Antineoplastic Agents↗

PubMed2005

Morphologic instability and cancer invasion.

PURPOSE: A solid tumor embedded in host tissue is a three-dimensional arrangement of cells and extracellular matrix that acts as a sink of oxygen and cell nutrients, thus establishing diffusional gradients. This and variations in vascular density and blood flow typically produce intratumoral regions of hypoxia and acidosis, and may result in spatially heterogeneous cell proliferation and migration. Here, we formulate the hypothesis that through these mechanisms, microenvironmental substrate gradients may drive morphologic instability with separation of cell clusters from the tumor edge and infiltration into surrounding normal tissue. EXPERIMENTAL DESIGN: We used computer simulations and in vitro experiments. RESULTS: We provide evidence that morphologic instability could be suppressed in vivo by spatially homogeneous oxygen and nutrient supply because normoxic conditions act both by decreasing gradients and increasing cell adhesion and, therefore, the mechanical forces that maintain a well-defined tumor boundary. A properly working tumor microvasculature can help maintain compact noninfiltrating tumor morphologies by minimizing oxygen and nutrient gradients. In contrast, antiangiogenic therapy, by increasing microenvironmental heterogeneity, may promote morphologic instability, leading to invasive patterns even under conditions in which the overall tumor mass shrinks. CONCLUSIONS: We conclude that therapeutic strategies focused solely on reduction of vascular density may paradoxically increase invasive behavior. This theoretical model accounts for the highly variable outcome of antiangiogenic therapy in multiple clinical trials. We propose that antiangiogenic strategies will be more consistently successful when aimed at "normalizing" the vasculature and when combined with therapies that increase cell adhesion so that morphologic instability is suppressed and compact, noninvasive tumor morphologies are enforced.

Antineoplastic Agents↗

PubMed2005

Dynamic model of biomolecular diffusion through two-dimensional nanochannels.

The molecular diffusion dynamics in unconstrained cases has been studied thoroughly during the last two centuries, leading to the well-known Fick's diffusion laws and Stokes-Einstein equation. More recently, a new impulse to the study of this topic has been provided by the necessity of understanding the behavior of solute particles in the presence of environmental constraints of size comparable to the molecular dimensions. In this work, we investigate the diffusion kinetics of biomolecules, such as bovine serum albumin, interferon, and lysozyme, through microfabricated silicon membranes, having pores of nanometric size in only one dimension, in the range from few to tens of nanometers (the other dimensions are in the mum range). Experimental results show that the diffusion profiles, in some cases, deviate substantially from those predicted by Fick's laws. In light of these results, a new diffusion mathematical model is proposed, which can reasonably explain the phenomenon and, at the same time, recovers the classical diffusion laws in the unconstrained case. Moreover, a physical description, derived from van der Waals equation of state, is presented, and it is compared with the results obtained by the mathematical model.

Animals↗

PubMed2005

Tailoring width of microfabricated nanochannels to solute size can be used to control diffusion kinetics.

Top-down microfabrication techniques were used to create silicon-based membranes consisting of arrays of uniform channels having a width as small as 7 nm. The measurement of diffusion kinetics of solutes across these membranes under sink conditions reveals non-Fickian behavior as the nanopore width approaches the hydrodynamic diameter of the solute. Zero-order diffusion of interferon is observed at channel width of 20 nm, and the same phenomenon occurs with albumin and 13-nm-wide channels, whereas Fickian diffusion kinetics is seen at 26 nm and larger pore sizes. A prototypical drug delivery device is described that is fitted with a 13-nm nanopore membrane and loaded with radio-labeled BSA. Following subcutaneous implantation in rats, diffusion from the device provided prolonged levels of BSA in the blood. Such a nonmechanical device offers important advantages in drug delivery applications, including zero-order release and high loading capacity.

Animals↗

PubMed2005

Release of biologically functional interferon-alpha from a nanochannel delivery system.

Metastatic melanoma lesions often are unresectable due to their size and/or location near critical structures. These lesions represent a significant challenge for the oncologist, because radiation therapy and chemotherapy are infrequently successful in halting tumor growth. Of primary concern is the fact that these lesions are usually painful and present a cosmetic dilemma. We hypothesized that the development of a silicon-based nano-device capable of delivering antitumor compounds (e.g. immune modulators), locally, at a constant rate, to the tumor microenvironment could avoid the toxicity of systemic administration and the inconvenience of frequent clinic visits for local injections. Because of its diminutive size, such a device could be implanted using a minimally invasive procedure in close proximity to unresectable melanoma lesions. The current report uses interferon alpha-2b (IFN-alpha) as a model antitumor agent, since it is commonly used in the treatment of malignant melanoma and metastatic renal cell carcinoma. In this system, IFN-alpha is delivered directly to the tumor microenvironment by a novel nanochannel delivery system (nDS) that is capable of zero order release of small molecules. We have demonstrated that the IFN-alpha released from the nDS is functionally active on both host immune cells and a human melanoma cell line in vitro. This drug delivery platform could be used to develop alternative strategies for the treatment of unresectable tumors.

Antineoplastic Agents↗

PubMed2005

Nanovector therapeutics.

An ideal injected therapeutic drug would travel through the vasculature, reach the intended target at full concentration, and there act selectively on diseased cells and tissues only, without creating undesired side effects. Unfortunately, even the best current therapies fail to attain this ideal behavior, by a wide margin. A primary reason is the fact that the target recognition abilities of the current therapeutics molecules are quite limited. Furthermore, the natural defenses of the body present a sequence of formidable obstacles on the drug's pathway to the intended lesion. Requiring any molecule to have sufficient therapeutic efficacy, target recognition specificity, as well as all of the tools required to bypass multiple biological barriers is probably unrealistic. A different approach is to decouple the problem (i.e. employ the drug molecules for their therapeutic action only, and deliver them to the intended site by vectors that can be preferentially concentrated at desired body locations through the concurrent action of multiple targeting mechanisms). These vectors must also be large enough to comprise all the requirements for the evasion of the body defenses, while still sufficiently small so as not to create undesired blockages of even the smallest of blood vessels - and thus, by definition, nanotechnological.

Animals↗

PubMed2005

Type II lumbar endoleaks: hemodynamic differentiation by contrast-enhanced ultrasound scanning and influence on aneurysm enlargement after endovascular aneurysm repair.

OBJECTIVE: The objective of this study was to differentiate type II lumbar endoleaks on the basis of dynamic features identified by contrast-enhanced ultrasound scanning (CUS) and to evaluate the role of this differentiation in detecting abdominal aortic aneurysm (AAA) enlargement > or =1 mL/mo. METHODS: Eighteen male patients (mean age, 71.8 years) with type II lumbar endoleak suspected at CUS underwent computed tomography angiography (CTA) and digital subtraction angiography (DSA). On CTA, AAA volumes and endoleak visualization and volume were assessed. At CUS, performed after a bolus of 1.5 to 2.4 mL of a second generation blood pool contrast agent, the following parameters were evaluated: presence of contrast material within the aneurysmal sac (endoleak), delay of endoleak detection (wash-in) and disappearance (washout) from the beginning of contrast injection, visualization of inflow and outflow vessels, and presence of cavity filling. Statistical analysis was performed regarding endoleak features at CUS, endoleak detection at CTA, and rate of AAA enlargement. RESULTS: DSA confirmed all the endoleaks. Mean +/- standard deviation wash-in and washout times were 121.9 +/- 132.6 and 337.2 +/- 193.7 seconds, respectively; a significant relation was observed between these two parameters (P < .01, analysis of variance). By Youden plots, endoleaks were classified as hyperdynamic when wash-in was <100 seconds (n = 10, 55.5%) and/or washout was <520 seconds (n = 13, 72.2%). A slower washout was associated with nonvisualized outflow (66.7%) and/or inflow arteries (66.7%) ( P < .05). Eight endoleaks (44.4%) were missed at CTA; it occurred in hypodynamic endoleaks, absence of detectable inflow or outflow vessels, and absence of cavity filling at CUS (P < .05). Overall mean AAA volume increase rate was 1.1 +/- 1.7 mL/mo. By multiple logistic regression model, the washout time > or = 520 seconds was the only independent predictor of AAA volume increase > or = 1 mL/mo (8 patients, 44.4%). CONCLUSION: Type II lumbar endoleaks show different hemodynamic features at CUS, which might influence the rate of aneurysm enlargement, addressing the need for treatment.

Aged↗

PubMed2005

Cancer nanotechnology: opportunities and challenges.

Nanotechnology is a multidisciplinary field, which covers a vast and diverse array of devices derived from engineering, biology, physics and chemistry. These devices include nanovectors for the targeted delivery of anticancer drugs and imaging contrast agents. Nanowires and nanocantilever arrays are among the leading approaches under development for the early detection of precancerous and malignant lesions from biological fluids. These and other nanodevices can provide essential breakthroughs in the fight against cancer.

Antineoplastic Agents↗