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Yves Boucher

Publications and source records attributed to Yves Boucher.

At least 19 recordsLinked to original sources
PubMed2006

Nicotine suppression of gustatory responses of neurons in the nucleus of the solitary tract.

This study investigated effects of nicotine applied to the tongue surface on responses of gustatory neurons in the nucleus of the solitary tract (NTS) in rats. In pentobarbital-anesthetized rats, single-unit recordings were made from NTS units responsive to one or more tastants (sucrose, NaCl, citric acid, monosodium glutamate, quinine). Application of nicotine (0.87, 8.7, or 600 mM) excited gustatory NTS units and significantly attenuated NTS unit responses to their preferred tastant in a dose-dependent manner. The depressant effect of nicotine was equivalent regardless of which tastant best excited the NTS unit. Nicotinic excitation of NTS units and depression of their tastant-evoked responses were both significantly attenuated by the nicotinic antagonist mecamylamine, which itself did not excite NTS units. In rats with bilateral trigeminal ganglionectomy, nicotine still excited nearly all NTS units but no longer depressed tastant-evoked responses. Nicotine did not elicit plasma extravasation when applied to the tongue. The results indicate that nicotine directly excites NTS units by gustatory nerves and inhibits their tastant-evoked responses by a nicotinic acetylcholine receptor-mediated excitation of trigeminal afferents that inhibit NTS units centrally.

Animals↗
PubMed2006

Degradation of fibrillar collagen in a human melanoma xenograft improves the efficacy of an oncolytic herpes simplex virus vector.

Oncolytic viral therapy provides a promising approach to treat certain human malignancies. These vectors improve on replication-deficient vectors by increasing the viral load within tumors through preferential viral replication within tumor cells. However, the inability to efficiently propagate throughout the entire tumor and infect cells distant from the injection site has limited the capacity of oncolytic viruses to achieve consistent therapeutic responses. Here we show that the spread of the oncolytic herpes simplex virus (HSV) vector MGH2 within the human melanoma Mu89 is limited by the fibrillar collagen in the extracellular matrix. This limitation seems to be size specific as nanoparticles of equivalent size to the virus distribute within tumors to the same extent whereas smaller particles distribute more widely. Due to limited viral penetration, tumor cells in inaccessible regions continue to grow, remaining out of the range of viral infection, and tumor eradication cannot be achieved. Matrix modification with bacterial collagenase coinjection results in a significant improvement in the initial range of viral distribution within the tumor. This results in an extended range of infected tumor cells and improved virus propagation, ultimately leading to enhanced therapeutic outcome. Thus, fibrillar collagen can be a formidable barrier to viral distribution and matrix-modifying treatments can significantly enhance the therapeutic response.

Animals↗
PubMed2006

Combined vascular endothelial growth factor-targeted therapy and radiotherapy for rectal cancer: theory and clinical practice.

Despite the routine use of adjuvant and neoadjuvant chemoradiotherapy, patients with advanced rectal tumors experience significant rates of treatment failure and disease recurrence. Resistance to radiation is a particular problem. Adding a vascular endothelial growth factor (VEGF)-targeted therapy may improve outcomes in these patients. Epidemiologic studies have shown that tumor expression of VEGF predicts disease recurrence and lower overall survival in patients treated with radiation. In tumor xenograft models in mice, VEGF-targeted agents increase the response to radiation, with a greater probability of tumor control and a greater delay in tumor growth. In addition to killing cancer cells indirectly by damaging tumor blood vessels (antivascular effect), VEGF-targeted therapy may sensitize tumors to radiation through two mechanisms: by normalizing the tumor vasculature, leading to greater tumor oxygenation, and thereby increasing the cytotoxicity of radiation to cancer cells, and by increasing the radiosensitivity of tumor-associated endothelial cells. In addition, anti-VEGF agents may inhibit the regrowth of tumors after radiation by decreasing the number of circulating endothelial cells and endothelial progenitor cells. A phase I dose-escalation study has shown the safety of bevacizumab at a dose of 5 mg/kg in combination with 5-fluorouracil and radiation in patients with rectal carcinoma, and has provided evidence of both vascular normalization and antivascular mechanisms. Phase II evaluation of bevacizumab in this setting is under way.

Animals↗
PubMed2006

Taste deficits related to dental deafferentation: an electrogustometric study in humans.

Dental treatments, the prevalence of which increases with age, can cause orofacial somatosensory deficits. In order to examine whether they may also affect taste sensitivity, electrogustometric thresholds were measured at 9 loci on the tongue surface in 391 healthy non-smoking, non-medicated subjects. Results showed that the greater the number of deafferented teeth, the higher the thresholds. Irrespective of age, subjects with more than 7 deafferented teeth exhibited significantly higher thresholds than subjects with fewer than 7 deafferented teeth. Conversely, across age groups, no statistical difference was observed among subjects with no, or few, deafferented teeth. Hence, a taste deficit, which was not correlated to aging, was observed. An association was noticed between the location of taste deficits and the location of deafferented teeth. Higher thresholds at anterior sites, with no possible traumatic injury relationship, suggested that neurophysiological convergence between dental somatosensory and taste pathways - possibly in the nucleus tractus solitarius - could be responsible for these relative decreases of taste sensitivity when dental afferences were lacking. Among trigeminal contributions, lingual nerve and inferior alveolar nerve may synergize taste.

Adult↗
PubMed2005

Lack of telopeptides in fibrillar collagen I promotes the invasion of a metastatic breast tumor cell line.

Defective fibrillar collagen polymerization in primary tumors has been correlated with increased metastasis. However, it is unclear how collagen organization influences tumor invasion. In this study, we show that collagen I polymerized without telopeptides (the flanking regions of collagen molecules) can differentially affect the three-dimensional migration of mammary carcinoma cells. MDA-MB-231 cells capable of proteolytic degradation and mesenchymal motion, invaded telopeptide-intact and telopeptide-free collagen gels to the same extent. In contrast, MDA-MB-435S cells, with typical features of amoeboid cells (poor collagenolytic activity, rounded cell morphology), were 5-fold more invasive in telopeptide-free than telopeptide-intact collagen. A fraction of the MDA-MB-435S cells that invaded telopeptide-intact or telopeptide-free collagen had a rounded morphology; however, in telopeptide-free collagen, a significant fraction of the cells switched from a rounded to elongated morphology (protrusion formation). The dynamic changes in cellular shape facilitated MDA-MB-435S locomotion through the narrow interfiber gaps, which were smaller than cell diameters. Based on the spherical morphology of MDA-MB-435S cells, we tested if the changes in cell shape and invasion were related to RhoA-ROCK activity; GTP-bound RhoA was measured in pull-down assays. RhoA activity was 1.8-fold higher for MDA-MB-435S cells seeded on telopeptide-free than telopeptide-intact collagen. Y27632 inhibition of ROCK, a Rho effector, significantly reduced the changes in cellular morphodynamics and the invasion of MDA-MB-435S cells but did not alter the invasion of MDA-MB-231 cells. Thus, the higher RhoA activity of MDA-MB-435S cells in telopeptide-free collagen enhances the changes in cellular morphodynamics associated with motility and invasion.

Animals↗
PubMed2005

Paclitaxel decreases the interstitial fluid pressure and improves oxygenation in breast cancers in patients treated with neoadjuvant chemotherapy: clinical implications.

PURPOSE: It has been hypothesized that tumors with high interstitial fluid pressure (IFP) and/or hypoxia respond poorly to chemotherapy (CT) because of poor drug delivery. Preclinical studies have shown that paclitaxel reduces the IFP and improves the oxygenation (pO(2)) of tumors. Our aim is to evaluate the IFP and pO(2) before and after neoadjuvant CT using sequential paclitaxel and doxorubicin in patients with breast cancer tumors of >/= 3 cm. PATIENTS AND METHODS: Patients were randomly assigned, according to an institutional review board-approved phase II protocol, to receive neoadjuvant sequential CT consisting of either four cycles of dose-dense doxorubicin at 60 mg/m(2) every 2 weeks followed by nine cycles of weekly paclitaxel at 80 mg/m(2) (group 1) or vice versa, with paclitaxel administered before doxorubicin (group 2). Patients were re-evaluated clinically and radiologically. The IFP (wick-in-needle technique) and pO(2) (Eppendorf) were measured in tumors at baseline and after completing the administration of the first and second drug. RESULTS: IFP and pO(2) were measured in 54 patients at baseline and after the first CT. Twenty-nine and 25 patients were randomly assigned to groups 1 and 2, respectively. Paclitaxel, when administered first, decreased the mean IFP by 36% (P = .02) and improved the tumor pO(2) by almost 100% (P = .003). In contrast, doxorubicin did not have a significant effect on either parameter. This difference was independent of the tumor size or response measured by ultrasound. CONCLUSION: Paclitaxel significantly decreased the IFP and increased the pO(2), whereas doxorubicin did not cause any significant changes. Tumor physiology could potentially be used to optimize the sequence of neoadjuvant CT in breast cancer.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors.

Elevated interstitial fluid pressure, a hallmark of solid tumors, can compromise the delivery of therapeutics to tumors. Here we show that blocking vascular endothelial growth factor (VEGF) signaling by DC101 (a VEGF-receptor-2 antibody) decreases interstitial fluid pressure, not by restoring lymphatic function, but by producing a morphologically and functionally "normalized" vascular network. We demonstrate that the normalization process prunes immature vessels and improves the integrity and function of the remaining vasculature by enhancing the perivascular cell and basement membrane coverage. We also show that DC101 induces a hydrostatic pressure gradient across the vascular wall, which leads to a deeper penetration of molecules into tumors. Thus, vascular normalization may contribute to the improved survival rates in tumor-bearing animals and in colorectal carcinoma patients treated with an anti-VEGF antibody in combination with cytotoxic therapies.

Animals↗
PubMed2004

Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer.

The effects of vascular endothelial growth factor (VEGF) blockade on the vascular biology of human tumors are not known. Here we show here that a single infusion of the VEGF-specific antibody bevacizumab decreases tumor perfusion, vascular volume, microvascular density, interstitial fluid pressure and the number of viable, circulating endothelial and progenitor cells, and increases the fraction of vessels with pericyte coverage in rectal carcinoma patients. These data indicate that VEGF blockade has a direct and rapid antivascular effect in human tumors.

Adenocarcinoma↗
PubMed2004

Two-photon fluorescence correlation microscopy reveals the two-phase nature of transport in tumors.

Transport parameters determine the access of drugs to tumors. However, technical difficulties preclude the measurement of these parameters deep inside living tissues. To this end, we adapted and further optimized two-photon fluorescence correlation microscopy (TPFCM) for in vivo measurement of transport parameters in tumors. TPFCM extends the detectable range of diffusion coefficients in tumors by one order of magnitude, and reveals both a fast and a slow component of diffusion. The ratio of these two components depends on molecular size and can be altered in vivo with hyaluronidase and collagenase. These studies indicate that TPFCM is a promising tool to dissect the barriers to drug delivery in tumors.

Animals↗
PubMed2004

Measurement of macromolecular diffusion coefficients in human tumors.

The diffusive transport of macromolecules in tumors is an important determinant of the delivery of many anticancer therapeutics. However, measurements of diffusive transport to date have only been performed in animal models. In this work, diffusion coefficients of BSA and IgM were measured in human tumor biopsies (cooled to 4-7 degrees C to prevent degradation) using fluorescence recovery after photobleaching. To quantify the effects of excision and cooling, the diffusion coefficient of BSA and IgM was measured in human tumor xenografts in situ and after cooling and excision. The change in diffusion coefficients before and after excision of xenografts was used to calculate in vivo diffusion coefficients in human tumors from ex vivo measurements. Using this approach, we obtained the first quantitative determinations of macromolecular diffusion coefficients in human tumors and find that the diffusion coefficients of BSA and IgM in human colon were adenocarcinomas higher than those in xenografts. This difference is consistent with lower collagen content in the accessible regions of these human tumors. These measurements allow the quantitative prediction of the diffusive transport of like-sized macromolecular therapeutics in human tumors. These measurements should help in modeling the transport of novel large MW therapeutics, and hence in estimating their distribution and efficacy in tumors.

Animals↗
PubMed2003

Irradiation reduces interstitial fluid transport and increases the collagen content in tumors.

PURPOSE: We have shown that the interstitial diffusion of large molecules is significantly hindered in tumors with high collagen levels. Because large therapeutic agents (e.g., monoclonal antibodies and viral vectors) will be combined with radiation or chemotherapy, it is significant to determine how cytotoxic therapies modify the transport and composition of the interstitial space in tumors. To test the hypothesis that radiation alters tumor interstitial transport, we measured tumor hydraulic conductivity (K) and hyaluronan and collagen type I levels after irradiation. EXPERIMENTAL DESIGN: K and the quantification of interstitial matrix components were determined in sections of s.c. implants of the human colon adenocarcinoma LS174T. K was measured on days 1 and 5 after 10 Gy of irradiation or on day 5 after 30 Gy of irradiation. RESULTS: Compared with control tumors, K decreased by approximately 12-fold after 10 or 30 Gy of irradiation on day 5. At 24 h after irradiation with 10 Gy, the decrease in K was not significant. Five days after 10 and 30 Gy of irradiation, the decrease in K was associated with significantly higher levels of collagen type I. The collagen type I content was not changed 24 h after irradiation with 10 Gy. Irradiation did not significantly increase hyaluronan levels in LS174T tumors. CONCLUSIONS: After irradiation, the decrease in K and increase in collagen type I levels could significantly hinder the convective movement and diffusion of large therapeutic agents in tumors.

Adenocarcinoma↗
PubMed2003

Trigeminal modulation of gustatory neurons in the nucleus of the solitary tract.

Electrophysiological methods were used to investigate the effects of trigeminal nerve stimulation or transection on responses of single gustatory neurons in the nucleus of the solitary tract (NTS) to tastants (NaCl, sucrose, citric acid, monosodium glutamate) in pentobarbital-anesthetized rats. Unilateral transection of the lingual nerve, or the mandibular branch of the trigeminal nerve, resulted in significant reductions (by 21 and 29%, respectively; P<0.01) in tastant-evoked responses, with no further effect following bilateral transection. Electrical stimulation of the central cut end of the mandibular nerve directly excited nine of 14 gustatory NTS units. For these units, central mandibular stimulation facilitated the tastant-evoked responses in six, depressed responses in three, and had no effect in five. Facilitation of tastant-evoked responses peaked 4 min after mandibular stimulation and recovered within 8 min. Electrical stimulation of the peripheral cut end of the mandibular nerve significantly reduced tastant-evoked responses in nine other NTS units, with a maximal reduction at 4 min post-stimulation followed by recovery. Stimulation of the superior cervical sympathetic ganglion did not affect NTS tastant-evoked responses. These results suggest the presence of complex central modulation of NTS neurons by trigeminal afferents, as well as a peripheral depressant effect on gustatory processing possibly mediated via neuropeptide release from trigeminal nerve endings in the tongue.

Action Potentials↗
PubMed2003

Dynamic imaging of collagen and its modulation in tumors in vivo using second-harmonic generation.

The content and structure of collagen is essential in governing the delivery of therapeutic molecules in tumors. Thus, simple histological staining of tumor tissue biopsies for collagen could be used to assess the accessibility of molecular therapeutics in tumors. Here we show that it is possible to optically image fibrillar collagen in tumors growing in mice using second-harmonic generation (SHG). Using this noninvasive technique, we estimated relative diffusive hindrance, quantified the dynamics of collagen modification after pharmacologic intervention and provided mechanistic insight into improved diffusive transport induced by the hormone relaxin. This technology could offer basic scientists and clinicians an enhanced ability to estimate the relative penetrabilities of molecular therapeutics.

Animals↗
PubMed2003

Suppression of central taste transmission by oral capsaicin.

Because intraoral capsaicin is reported to reduce the perceived intensity of certain taste qualities, we investigated whether it affects the central processing of gustatory information. The responses of gustatory neurons in the nucleus tractus solitarius (NTS) to tastant stimuli were recorded before and after lingual application of capsaicin in anesthetized rats. Thirty-four NTS units were characterized as responding best to sucrose (0.3 m), NaCl (0.1 m), citric acid (0.03 m), monosodium glutamate (0.2 m), or quinine (0.001 m). During lingual application of 330 microm capsaicin for 7 min, the firing rate increased for five units and decreased for four units; the remainder were unaffected. Immediately after capsaicin, responses to each tastant were in nearly all cases depressed (mean, 61.5% of control), followed by recovery in most cases. NTS tastant-evoked unit responses were unaffected by lingual application of vehicle (5% ethanol). Capsaicin elicited an equivalent reduction (to 64.5%) in tastant-evoked responses of nine additional NTS units recorded in rats with bilateral trigeminal ganglionectomy, arguing against a trigeminally mediated central effect. Furthermore, capsaicin elicited a puncate pattern of plasma extravasation in the tongue that matched the distribution of fungiform papillae. These results support a peripheral site of capsaicin suppression of taste possibly via direct or indirect effects on taste transduction or taste receptor cell excitability. The depressant effect of capsaicin on gustatory transmission might underlie its ability to reduce the perceived intensity of some taste qualities.

Administration, Oral↗
PubMed2003

Solid stress generated by spheroid growth estimated using a linear poroelasticity model.

The unchecked growth of a solid tumor produces solid stress, causing deformation of the surrounding tissue. This stress can result in clinical complications, especially in confined environments such as the brain, and may also be responsible for pathophysiological anomalies such as the collapse of blood and lymphatic vessels. High stress levels may also inhibit further cell division within tumors. Unfortunately, little is known about the dynamics of stress accumulation in tumors or its effects on cell biology. We present a mathematical model for tumor growth in a confined, elastic environment such as living tissue. The model, developed from theories of thermal expansion using the current configuration of the material element, allows the stresses within the growing tumor and the surrounding medium to be calculated. The experimental observation that confining environments limit the growth of tumor spheroids to less than the limit imposed by nutrient diffusion is incorporated into the model using a stress dependent rate for tumor growth. The model is validated against experiments for MU89 tumor spheroid growth in Type VII agarose gel. Using the mathematical model and the experimental evidence we show that the tumor cell size is reduced by solid stress inside the tumor spheroid. This leads to the interesting possibility that cell size could be a direct indicator of solid stress level inside the tumors in clinical setting.

Animals↗