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Biomedical subjects

François Martin

Publications and source records attributed to François Martin.

At least 19 recordsLinked to original sources
PubMed2006

Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients.

CD4+CD25+ regulatory T cells are involved in the prevention of autoimmune diseases and in tumor-induced tolerance. We previously demonstrated in tumor-bearing rodents that one injection of cyclophosphamide could significantly decrease both numbers and suppressive functions of regulatory T cells, facilitating vaccine-induced tumor rejection. In humans, iterative low dosing of cyclophosphamide, referred to as "metronomic" therapy, has recently been used in patients with advanced chemotherapy resistant cancers with the aim of reducing tumor angiogenesis. Here we show that oral administration of metronomic cyclophosphamide in advanced cancer patients induces a profound and selective reduction of circulating regulatory T cells, associated with a suppression of their inhibitory functions on conventional T cells and NK cells leading to a restoration of peripheral T cell proliferation and innate killing activities. Therefore, metronomic regimen of cyclophosphamide does not only affect tumor angiogenesis but also strongly curtails immunosuppressive regulatory T cells, favoring a better control of tumor progression. Altogether these data support cyclophosphamide regimen as a valuable treatment for reducing tumor-induced immune tolerance before setting to work anticancer immunotherapy.

Adult↗
PubMed2006

Perceived importance and integration of the human-animal bond in private veterinary practice.

OBJECTIVE: To determine perceptions of the human-animal bond (HAB) among veterinarians in private practice and evaluate how these veterinarians incorporate the HAB in their practices. DESIGN: Survey. SAMPLE POPULATION: 1,602 veterinarians in private practice in Washington state. PROCEDURE: Participants were contacted and asked to complete a survey. RESULTS: Response rate was 26% (415/1,602). Most respondents agreed that veterinarians will be more successful if they recognize and facilitate the HAB, that facilitating the HAB was important to their practices, that they actively evaluated the degree of bonding between clients and their animals, and that the bonding between a client and his or her animal affected the way they practiced medicine. However, > 50% of respondents did not train veterinary technicians and front office staff members in the HAB or encourage veterinary technicians or front office staff members to learn about the HAB. Fifty-one percent of respondents offered few or no HAB resources to clients. When asked to quantify the importance of 10 nontechnical skills associated with private veterinary practice, respondents ranked communication skills, ethical reasoning, and business management first, second, and third; the HAB was ranked fifth. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that for veterinarians in private practice in Washington state, there is a dichotomy between how important they consider the HAB to be in their practice and the degree to which they facilitate the HAB with regard to communication, training, and client resources. More research on the HAB is necessary to better understand what the HAB encompasses and its implications for private practitioners.

Animal Technicians↗
PubMed2006

A novel dendritic cell subset involved in tumor immunosurveillance.

The interferon (IFN)-gamma-induced TRAIL effector mechanism is a vital component of cancer immunosurveillance by natural killer (NK) cells in mice. Here we show that the main source of IFN-gamma is not the conventional NK cell but a subset of B220(+)Ly6C(-) dendritic cells, which are atypical insofar as they express NK cell-surface molecules. Upon contact with a variety of tumor cells that are poorly recognized by NK cells, B220(+)NK1.1(+) dendritic cells secrete high levels of IFN-gamma and mediate TRAIL-dependent lysis of tumor cells. Adoptive transfer of these IFN-producing killer dendritic cells (IKDCs) into tumor-bearing Rag2(-/-)Il2rg(-/-) mice prevented tumor outgrowth, whereas transfer of conventional NK cells did not. In conclusion, we identified IKDCs as pivotal sensors and effectors of the innate antitumor immune response.

Adoptive Transfer↗
PubMed2006

Apoptotic, necrotic, or fused tumor cells: an equivalent source of antigen for dendritic cell loading.

The identification of the most efficient strategy for tumor antigen loading of dendritic cells (DCs) remains a challenge in cancer immunotherapy protocols. Autologous dead tumor cells have been demonstrated to constitute an acceptable source of multiple tumor-associated antigens (TAA) to pulse DCs. However the optimal approach for inducing cell death that would lead to effective endocytosis and activation of DCs remains controversial. In this study we have induced and defined 3 distinct mechanisms of tumor cell death (apoptosis, necrosis and fusion-mediated cell death), and investigated their differential effects on DCs. Bone marrow-derived DCs demonstrated comparable uptake of primary apoptotic, necrotic, or fused dead tumor cells. Furthermore, the distinct modes of cancer cell death had analogous potential in activating the transcription factors NF-kappaB and STAT1 and in maturing DCs, resulting in an equally effective stimulation of immune T cells. The current study therefore provides further informations on the use of dead whole tumor cells as antigen sources for effective active anti-cancer immunotherapy.

Animals↗
PubMed2005

CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor-beta-dependent manner.

Tumor growth promotes the expansion of CD4+CD25+ regulatory T (T reg) cells that counteract T cell-mediated immune responses. An inverse correlation between natural killer (NK) cell activation and T reg cell expansion in tumor-bearing patients, shown here, prompted us to address the role of T reg cells in controlling innate antitumor immunity. Our experiments indicate that human T reg cells expressed membrane-bound transforming growth factor (TGF)-beta, which directly inhibited NK cell effector functions and down-regulated NKG2D receptors on the NK cell surface. Adoptive transfer of wild-type T reg cells but not TGF-beta-/- T reg cells into nude mice suppressed NK cell-mediated cytotoxicity, reduced NKG2D receptor expression, and accelerated the growth of tumors that are normally controlled by NK cells. Conversely, the depletion of mouse T reg cells exacerbated NK cell proliferation and cytotoxicity in vivo. Human NK cell-mediated tumor recognition could also be restored by depletion of T reg cells from tumor-infiltrating lymphocytes. These findings support a role for T reg cells in blunting the NK cell arm of the innate immune system.

Animals↗
PubMed2005

Tumor cells convert immature myeloid dendritic cells into TGF-beta-secreting cells inducing CD4+CD25+ regulatory T cell proliferation.

The mechanisms through which regulatory T cells accumulate in lymphoid organs of tumor-bearing hosts remain elusive. Our experiments indicate that the accumulation of CD4+CD25+ regulatory T cells (T reg cells) expressing FoxP3 and exhibiting immunosuppressive function originates from the proliferation of naturally occurring CD25+ T cells and requires signaling through transforming growth factor (TGF)-beta receptor II. During tumor progression, a subset of dendritic cells (DCs) exhibiting a myeloid immature phenotype is recruited to draining lymph nodes. This DC subset selectively promotes the proliferation of T reg cells in a TGF-beta-dependent manner in mice and rats. Tumor cells are necessary and sufficient to convert DCs into regulatory cells that secrete bioactive TGF-beta and stimulate T reg cell proliferation. In conclusion, tumor expansion can stimulate T reg cells via a specific DC subset.

Animals↗
PubMed2005

Perceptions of the human-animal bond in veterinary education of veterinarians in Washington State: structured versus experiential learning.

RATIONALE FOR THE STUDY: The purpose of this research was to describe Washington private practitioners' beliefs about how the Human-Animal Bond (HAB) should be addressed in DVM curricula and continuing education. METHODOLOGY: 1,602 Washington veterinarians in private practice were asked to participate in an online survey that addressed the importance of HAB and of DVM/post-DVM HAB education. RESULTS AND CONCLUSIONS: The response rate was 25.9% (415/1,602). Eighty-one percent (334/412) of respondents indicated that the HAB was important to their decisions to become veterinarians. The HAB was more important to the most recent graduates than to earliest graduates and to females than to males. Forty-four percent (184/415) of respondents considered mentoring to be the best way to learn about the HAB while in veterinary school. Of the 40% (165/415) of respondents who indicated that their veterinary schools offered structured learning on the HAB, 89% (145/163) said they had participated in it. Seven percent (29/415) indicated that entry-level veterinarians were very prepared to identify and facilitate the HAB, while 54% (224/415) said that they were somewhat prepared. Only 32% (131/415) had participated in any HAB structured learning since having started practicing, and the earliest graduates were twice as likely to have participated as the most recent graduates. More than half (55%, 223/407) disagreed or strongly disagreed that post-DVM, the best way to learn about the HAB is through structured learning. However, 83% (342/414) agreed that continuing-education credits should be given for HAB classes. Eighty-six percent (358/414) supported additional HAB research. Ninety-seven percent (402/414) agreed that the best way to learn about the HAB is through experience. These results suggest that veterinarians do not value HAB structured learning as much as experiential learning and that they are not very confident in recent graduates' abilities regarding the HAB. We propose HAB structured learning in the first three years of DVM education, complemented by the incorporation of the HAB into clinical rotations and post-DVM continuing education.

Adult↗
PubMed2004

Compositional changes in cement-stabilized waste during leach tests--comparison of SEM/EDX data with predictions from geochemical speciation modeling.

Cement-based stabilization/solidification (s/s) is a widely used treatment process for hazardous wastes containing toxic metals. The treated waste consists of a complex mixture of several solid phases produced by cement hydration reactions. Understanding and predicting the effects of leaching on these individual phases is essential for assessing the long-term immobilization of metal contaminants in s/s waste exposed to rain and groundwater. In this paper, particles of crushed Portland cement doped with copper, lead, and zinc nitrates were leached with nitric acid solutions maintained at constant pH in the range pH 4-7. Changes in solid composition at the microscopic scale were measured by scanning electron microscopy and energy dispersive X-ray spectrometry (SEM/EDX). The geochemical equilibrium model SOLTEQ-B, which accounts for the incongruent solubility behavior of calcium silicate hydrate, was used to simulate the compositional changes in the hydration gel for increasing extents of leaching. Measured concentrations of calcium, silicon, and sulfur were successfully predicted at all extents of leaching. Aluminum, lead, and zinc concentrations were also in good agreement with model predictions, except in the remineralization zones that form when metals solubilized in the outer regions of the s/s waste particles diffuse toward the interior and reprecipitate at higher pH. Copper was less accurately modeled at high extents of leaching. Accounting for the incorporation of contaminant metals into the cement hydration gel (in opposition to assuming the presence of individual metal hydroxides) is crucial for successfully predicting contaminant metal concentrations in the hydration gel at low and intermediate extents of leaching.

Journal Article↗
PubMed2004

Factors associated with client, staff, and student satisfaction regarding small animal euthanasia procedures at a veterinary teaching hospital.

OBJECTIVE: To identify factors influencing satisfaction with procedures for small animal euthanasia and to compare the relative importance of those factors among clients, staff, and students at a veterinary teaching hospital. DESIGN: Survey. SAMPLE POPULATION: 18 nonclinical hospital staff members, 13 clinical staff members, 10 veterinary technicians, 19 veterinary students, and 91 clients. PROCEDURE: Participants were asked to complete a survey that was designed to assess satisfaction with various aspects of the euthanasia procedure. RESULTS: Overall response rate was 48% (151/313). Respondents most strongly agreed with the statements that clients should have the option to be present, that having a private place was important, and that employees should be trained to attend to the emotional needs of the client. When asked to place factors in order of importance, those that were ranked the highest included compassionate and caring attitudes of the hospital employees, the option for the client to be present during the euthanasia, and the client being informed and well prepared. CONCLUSIONS AND CLINICAL RELEVANCE: Overall, all groups (nonclinical staff, clinical staff, veterinary technicians, veterinary students, and clients) identified the same factors as being important in the euthanasia of a pet. Results may help facilitate healthy euthanasia experiences.

Animals↗
PubMed2004

Comparison of measurements of the outer scale of turbulence by three different techniques.

We have made simultaneous and nearly simultaneous measurements of L0, the outer scale of turbulence, at the Palomar Observatory by using three techniques: angle-of-arrival covariance measurements with the Generalized Seeing Monitor (GSM), differential-image-motion measurements with the adaptive-optics system on the Hale 5-m telescope, and fringe speed measurements with the Palomar Testbed Interferometer (PTI). The three techniques give consistent results, an outer scale of approximately 10-20 m, despite the fact that the spatial scales of the three instruments vary from 1 m for the GSM to 100 m for the PTI.

Journal Article↗
PubMed2004

CD4+CD25+ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative.

We investigated the mechanisms of immune tolerance raised by tumors by comparing immunogenic and tolerogenic tumor cell clones isolated from a rat colon carcinoma. When injected into syngeneichosts, the immunogenic REGb cells yield tumors that are rejected, while the tolerogenic PROb cells yield progressive tumors and inhibit the regression of REGb tumors. We show here that PROb tumor volume is correlated with an expansion of CD4(+)CD25(+) regulatory T lymphocytes in lymphoid tissues. These cells delay in vivo the rejection of REGb tumors and inhibit in vitro T cell-mediated immune responses against REGb cells through a mechanism that requires cell contact between effector and regulatory T cells and involves TGF-beta. While total T cells fromPROb tumor-bearing rats yield no apparent anti-tumor immune response, depletion of CD25(+) T cells restores this reactivity. A single administration of cyclophosphamide depletes CD4(+)CD25(+) T cells in PROb tumor-bearing animals, delays the growth of PROb tumors, and cures rats bearing established PROb tumors when followed by an immunotherapy which has no curative effect when administered alone. These results demonstrate the role of CD4(+)CD25(+) regulatory T cells in tumor-induced immune tolerance and the interest of regulatory T cell depletion to sensitize established tumors to immunotherapy.

Animals↗
PubMed2003

Freshly isolated bone marrow cells induce death of various carcinoma cell lines.

In some carcinomas such as digestive tract carcinomas, bone marrow infiltration by tumor cells is a frequent event but usually remains a micrometastatic disease and rarely induces overt bone lesions. The mechanisms responsible for the control of these metastases in the bone marrow remain poorly known. We show that freshly isolated bone marrow cells from human, murine and rat origin rapidly kill a wide range of syngeneic or xenogeneic carcinoma cell lines in culture. Further analysis of this cytotoxic process in the rat indicated that neither resident bone marrow macrophages nor NK cells were responsible for this cytotoxic effect that was restricted to a subpopulation of bone marrow cells expressing CD90 (Thy-1), a marker of hemopoietic precursors. The tumoricidal activity of these cells did not require long-term culture nor addition of exogenous cytokines or growth factors. A subset of CD90+ cells that rapidly differentiates into CD163(ED2)-expressing macrophages was observed to be responsible for tumor cell killing. These macrophages induced a non-apoptotic death of tumor cells, a process that required both a direct interaction with the tumor cell and nitric oxide (NO) production through the activation of inducible nitric oxide-synthase (iNOS). This ability of pluripotent hemopoietic stem cells to rapidly differentiate into macrophages capable of killing invasive tumor cells may account for the limited expansion of micrometastases of some carcinomas in the bone marrow.

Animals↗
PubMed2003

Intradermal injection, as opposed to subcutaneous injection, enhances immunogenicity and suppresses tumorigenicity of tumor cells.

Tumor cell immunogenicity depends heavily upon the microenvironment in which the cells grow. We have compared the tumorigenicity and immunogenicity of the same tumor cells when injected either into the dermis, a tissue containing numerous dendritic cells (DCs), or s.c., at a site which contains only few DCs. After s.c. injection, progressive tumors were constantly obtained, whereas most intradermal injections did not give rise to tumor and immunized animals against additional challenge. We present evidence that the high density of DCs at dermal sites facilitates the capture of tumor antigens and that local inflammation induces maturation of the DCs and their migration into draining lymph nodes.

Adenocarcinoma↗
PubMed2003

Importance of the human-animal bond for pre-veterinary, first-year, and fourth-year veterinary students in relation to their career choice.

RATIONALE FOR THE STUDY: The Human-Animal Bond (HAB) is a construct that has received increased attention in the field of veterinary medicine. However, it remains unclear how important the HAB is to veterinary students and how it may be related to their career choice. METHODOLOGY: Questionnaires were administered to 146 veterinary students. A variety of variables was assessed, including sex, year of study, career choice, surgery track, and "farm" versus "city" upbringings. RESULTS AND CONCLUSIONS: Overall, students consider the HAB to be an important and valuable construct, one that was influential in their decision to become veterinarians. However, the HAB's importance seems to decrease as students progress in school. Also, students aspiring to food animal careers seem to attach less value to some aspects of the HAB. Females attached more importance to the role HAB plays in their lives than did males; those on "alternative" surgery track assigned more significance to the role of the HAB in veterinary medicine than did those on the "traditional" surgery track. Students also reported that they believe the HAB should be addressed in veterinary curricula.

Adult↗
PubMed2002

An atypical caspase-independent death pathway for an immunogenic cancer cell line.

REGb cell line, a highly immunogenic tumor cell variant isolated from a rat colon cancer, yields regressive tumors when injected into syngeneic hosts. We previously demonstrated that REGb tumor immunogenicity was related to the capacity of releasing dead cells in vivo. Also, in vitro, REGb cell monolayers release dead cells, especially when cultured in serum-free medium. In the current study, we show that the release of dead cells results from an atypical death process associating features of necrosis and apoptosis. In spite of features considered as hallmarks of caspase-dependent apoptosis, including chromatin fragmentation and DNA oligonucleosomal cleavage, caspases are not activated and caspase inhibitors are ineffective to prevent REGb cell death. In contrast with a number of other types of cell death, the spontaneous death of REGb cells in culture depends on de novo protein synthesis as this death is blocked by low doses of the mRNA translation inhibitor cycloheximide. This unusual mode of cell death that associates necrotic and apoptotic features could provide optimal conditions for triggering a specific immune response.

Amino Acid Chloromethyl Ketones↗
PubMed2002

HMG-CoA reductase inhibition and PPAR- alpha activation both inhibit cyclosporin A induced endothelin-1 secretion in cultured endothelial cells.

The use of cyclosporin A (CsA) in solid organ transplantation has been shown to be associated with the development of hypertension and nephrotoxicity. Several mechanisms, including endothelin (ET)-1-mediated systemic vasoconstriction, are considered to be responsible for CsA-induced hypertension. This study shows that: (i) incubation of CsA (1 microg) with bovine aortic endothelial cells leads to increased ET secretion by+40%; (ii) the use of compactin, the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor and fibric acid, the peroxisome-proliferator-activated receptor (PPAR)-alpha activator, inhibit the CsA-induced ET secretion to the level below the basal ET secretion, by -32% and -26% respectively; (iii) both inhibitions were reversed by the addition of mevalonate, suggesting communication between the HMG-CoA reductase product and PPAR-alpha pathway. The present findings may be of significant clinical relevance, since statins and fibrates beyond their hypolipidaemic action may represent a potential therapeutic tool in the treatment or prophylaxis of CsA-associated side effects. Furthermore, we suggest that the mevalonate metabolism would interfere with PPAR-alpha activity.

Animals↗