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Biomedical subjects

R A Lawrence

Publications and source records attributed to R A Lawrence.

At least 19 recordsLinked to original sources
PubMed2002

Efficient induction of apoptosis by ONYX-015 adenovirus in human colon cancer cell lines regardless of p53 status.

The ONYX-015 virus is a mutated adenovirus that in theory selectively replicates and induces cytolysis in tumor cells lacking functional p53. The present study investigated whether ONYX-015 viral infection alone or in combination with conventional chemotherapeutic agents could significantly increase apoptosis in human colon cancer cell lines, regardless of p53 status, compared to untreated cells. A pair of colon cancer cell lines that differ only in their p53 status (RKO with wild-type p53 and RKOp53 with deficient p53) was tested. Two chemotherapeutic agents, 5-fluorouracil (5-FU) and CPT-11, were tested in combination with ONYX-015. Final concentrations of these agents corresponded to peak plasma levels achievable in patients. ONYX-015 concentration was 10 p.f.u./cell. In RKO and RKOp53 cell lines, ONYX-015 viral infection alone or in combination with 5-FU or CPT-11 induced a significant increase in apoptosis compared to chemotherapeutic agents alone, regardless of p53 status. Moreover, the combination of ONYX-015 and chemotherapeutics induced more apoptosis than chemotherapeutics alone in the two colon cancer cell lines independently of their p53 status. We conclude that ONYX-015 virus infection alone or in combination with 5-FU or CPT-11 induced apoptosis in human colon cancer cell lines, independently of p53 status.

Adenoviridae↗
PubMed2001

Immunity to filarial nematodes.

Mosquito-borne filarial nematodes cause the severe, debilitating disease of human lymphatic filariasis. In areas endemic for this disease, differential responses range from putative immunity through asymptomatic microfilaraemic infection to chronic pathology. Current research in mouse models of infection is elucidating the immunological mechanisms that can lead to immunity against this disease. In this review, the importance of different immunological pathways are discussed in relation to their role in human disease and in terms of their ability to kill separate developmental stages of the filarial parasite.

Animals↗
PubMed2001

Milk banking: the influence of storage procedures and subsequent processing on immunologic components of human milk.

The immunoprotective constituents of human milk are stable when stored at room temperature for 8 hours, when stored at 0 degree-4 degrees C for three days, or when frozen at -20 degrees C for 12 months. They are also stable during pasteurization at 56 degrees C for 30 minutes. Sonification may reduce levels of sIgA and lysozyme and the ability of milk to inhibit growth of E coli. The number of cells in human milk is reduced by storage, freezing, pasteurizing, microwaving and sonification, and the functional capacity of surviving cells is also reduced.

Cold Temperature↗
PubMed2001

Given the benefits of breastfeeding, what contraindications exist?

Breastfeeding is not contraindicated in association with environmental hazards in the United States under ordinary circumstances. Unusual massive exposure should be assessed on an individual basis. In the face of any possible contraindication to breastfeeding, the tremendous benefits of being breastfed should be compared with the theoretic risk for the hazard involved and a decision made on an individual basis.

Adult↗
PubMed2001

Xenobiotics and breastfeeding.

Breastfeeding provides important benefits to mothers and infants and should be encouraged strongly as the optimal feeding choice for most infants. In assessing the effects of maternal medication on breastfeeding, clinicians must weigh the many benefits of breastfeeding for mothers and infants against the risk for exposing infants to a drug as it is present in breast milk. With regard to most medications, continued breastfeeding despite drug exposure is advantageous to mothers and infants.

Breast Feeding↗
PubMed2001

The role of lactation specialists. A guide for physicians.

Breastfeeding support is a team event. The physician works with many health care professionals to provide complete care to the perinatal patient, including working with nurses trained in prenatal care, labor, delivery, and postpartum and newborn care, and working with midwives who provide prenatal care, labor, and delivery for the normal, uncomplicated patient. The pediatrician is part of this team and interacts with all of these players and with the office or clinic staff who provide follow-up, newborn, and child care.

Allied Health Personnel↗
PubMed2001

Lymphatic filariasis: parallels between the immunology of infection in humans and mice.

Mouse models of Brugia infection have provided much useful quantitative and qualitative information on the immune response elicited by different life cycle stages of filarial worms. Many parallels exist between the immune response in the mouse and the infected human and in this review we highlight areas of topical interest, including the induction of specific cytokine responses and their role in immunomodulation and protective immunity. These studies have reinforced the concept that different life cycle stages of filarial parasites each have their own mechanism of modulating responses so that potentially inflammatory IFN-gamma responses are downregulated. While the precise mechanisms of protective immunity remain to be defined, studies in the mouse have suggested novel pathways, including a possible role for granulocytes.

Animals↗
PubMed2001

Neuropeptide receptor status in human tumor cell lines.

Tumor types expressing a neuroendocrine phenotype secrete neuropeptides with paracrine or autocrine growth factor activity. The efficacy of these paracrine or autocrine loops depends on the expression of specific receptors on tumor cells. Once specific receptors are identified, specific neuropeptide antagonists disrupting paracrine and autocrine loops could be potential treatments in neuropeptide-secreting tumors. In the present study, 11 human tumor cell lines representing astrocytoma, lymphoma, and pancreatic, prostate, lung and colon carcinomas were examined for expression of five different neuropeptide receptors (cholecystokinin, neurotensin, vasopressin, tachykinine substance P and cannabinoid) using RT-PCR and radioligand binding. The presence of various neuropeptide receptors in different human cancer cell lines supports development of new antitumor treatments based on disruption of neuropeptide autocrine growth pathways.

Cell Division↗
PubMed2001

Effects of calorie restriction on polymicrobial peritonitis induced by cecum ligation and puncture in young C57BL/6 mice.

Calorie restriction (CR) is known to prolong the life span and maintain an active immune function in aged mice, but it is still not known if rodents under CR can respond optimally to bacterial infection. We report here on the influence of CR on the response of peritoneal macrophages to lipopolysaccharide, splenic NF-kappaB and NF-interleukin-6 (IL-6) activities, and mortality in polymicrobial sepsis induced by cecal ligation and puncture (CLP). Macrophages from 6-month-old C57BL/6 mice on a calorie-restricted diet were less responsive to lipopolysaccharide, as evidenced by lower levels of IL-12 and IL-6 protein and mRNA expression. Furthermore, in vitro lipopolysaccharide-stimulated macrophages from mice under CR also expressed decreased lipopolysaccharide receptor CD14 levels as well as Toll-like receptor 2 (TLR2) and TLR4 mRNA levels. In addition, the phagocytic capacity and class II (I-A(b)) expression of macrophages were also found to be significantly lower in mice under CR. Mice under CR died earlier (P < 0.005) after sepsis induced by CLP, which appeared to be a result of increased levels in serum of the proinflammatory cytokines tumor necrosis factor alpha and IL-6 and splenic NF-kappaB and NF-IL-6 activation 4 h after CLP. However, mice under CR survived significantly (P < 0.005) longer than mice fed ad libitum when injected with paraquat, a free radical-inducing agent. These data suggest that young mice under CR may be protected against oxidative stress but may have delayed maturation of macrophage function and increased susceptibility to bacterial infection.

Aging↗
PubMed2000

The serpin secreted by Brugia malayi microfilariae, Bm-SPN-2, elicits strong, but short-lived, immune responses in mice and humans.

Understanding the basic immunology of an infectious disease requires insight into the pattern of T cell reactivity and specificity. Although lymphatic filariasis is a major tropical disease, the predominant T cell Ags of filarial species such as Brugia malayi are still undefined. We have now identified a prominent T cell Ag from B. malayi microfilariae (Mf) as Bm-SPN-2, a serpin secreted exclusively by this stage. Mf-infected mice mounted strong, but short-lived, Bm-SPN-2-specific Th1 responses, measured by in vitro production of IFN-gamma, but not IL-4 or IL-5, 14 days postinfection. By day 35, responsiveness to Bm-SPN-2 was lost despite enhanced reactivity to whole Mf extract. Single immunization with Mf extract also stimulated typical Th1 reactions to Bm-SPN-2, but IgG1 Ab responses dominated after repeated immunizations. Human patients displayed potent humoral responses to Bm-SPN-2 in both IgG1 and IgG4 subclasses. Thus, 100% (20 of 20) of the microfilaremic (MF(+)) patients bore IgG4 responses to Bm-SPN-2, while only 30% of endemic normal subjects were similarly positive. Following chemotherapy, Bm-SPN-2-specific Abs disappeared in 12 of 13 MF(+) patients, although the majority remained seropositive for whole parasite extract. PBMC from most, but not all, endemic subjects were induced to secrete IFN-gamma when stimulated with Bm-SPN-2. These findings demonstrate that Bm-SPN-2 is recognized by both murine and human T and B cells and indicate that their responses are under relatively stringent temporal control. This study also provides the first example of a stage-specific secreted molecule that acts as a major T cell Ag from filarial parasites and is a prime candidate for a serodiagnostic probe.

Animals↗
PubMed2000

Requirements for in vivo IFN-gamma induction by live microfilariae of the parasitic nematode, Brugia malayi.

Lymphatic filariasis caused by the parasitic nematode, Brugia malayi, is a chronic human disease immunologically characterized by stimulation of Th2 cells and reduced antigen-specific T cell responses. Single stage intra-peritoneal infections with infective larvae (L3) or adult nematodes induce Th2 cells, while the microfilarial stage (Mf) stimulates IFN-gamma and Mf-specific IgG1, IgG2a, IgG2b, IgG3 and IgM, but not IgE. To investigate whether IFN-gamma is elicited by live Mf in their natural site of infected, mice were infected intravenously. Intravenous infection had a striking effect on the response to Mf and high levels of IgE were induced even in the presence of IFN-gamma. Indeed IgE levels to Mf increased markedly with the number of immunizations, higher doses of Mf and prolonged exposure to Mf suggesting that under conditions of chronic antigen exposure, typical of human disease, Mf will stimulate high levels of IgE. The ability of Mf-induced IFN-gamma to modulate or regulate a pre-existing Th2 response, was investigated by infecting mice initially with adult male worms to induce a Th2 response, followed 14 days later by infection with Mf. Although Mf stimulated IFN-gamma in the presence of male adults, the antibody isotypes elicited did not reflect IFN-gamma induction and IgG1 and IgE dominated the response. Although it cannot be discounted that IFN-gamma induction by Mf may act locally as an inflammatory mediator or modulator of Th2 cells, these data suggest that Mf-stimulated IFN-gamma does not have a profound effect overall on progression of the Th2-dominated immune response to filarial infection.

Animals↗
PubMed2000

Breastfeeding: benefits, risks and alternatives.

Obstetricians play a major role in guiding the infant feeding choices of their pregnant patients. The world literature continues to swell with reports and studies of the short- and long-term benefits to both mother and infant of breastfeeding. These benefits include protection against acute illnesses, long-term health protection, the psychological relationship and even savings in health care costs.

Breast Feeding↗
PubMed1999

Effects of cationic porphyrins as G-quadruplex interactive agents in human tumor cells.

A series of cationic porphyrins has been identified as G-quadruplex interactive agents (QIAs) that stabilize telomeric G-quadruplex DNA and thereby inhibit human telomerase; 50% inhibition of telomerase activity was achieved in HeLa cell-free extract at porphyrin concentrations in the range < or = 50 microM. Cytotoxicity of the porphyrins in vitro was assessed in normal human cells (fibroblast and breast) and human tumor cells representing models selected for high telomerase activity and short telomeres (breast carcinoma, prostate, and lymphoma). In general, the cytotoxicity (EC50, effective concentration for 50% inhibition of cell proliferation) against normal and tumor cells was > 50 microM. The porphyrins were readily absorbed into tumor cell nuclei in culture. Inhibition of telomerase activity in MCF7 cells by subcytotoxic concentrations of TMPyP4 showed time and concentration dependence at 1-100 microM TMPyP4 over 15 days in culture (10 population doubling times). The inhibition of telomerase activity was paralleled by a cell growth arrest in G2-M. These results suggest that relevant biological effects of porphyrins can be achieved at concentrations that do not have general cytotoxic effects on cells. Moreover, the data support the concept that a rational, structure-based approach is possible to design novel telomere-interactive agents with application to a selective and specific anticancer therapy.

Antineoplastic Agents↗