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Biomedical subjects

Sarah Cox

Publications and source records attributed to Sarah Cox.

7 recordsLinked to original sources
PubMed2003

HIV-related lung cancer in the era of highly active antiretroviral therapy.

OBJECTIVES: To address the impact of highly active antiretroviral therapy (HAART) on the incidence and outcome of patients with HIV-related lung cancer. DESIGN AND SUBJECTS: Patients with HIV-related lung cancer were identified from a prospective HIV data base of 8400 patients diagnosed between 1986 and 2001. Patients diagnosed with HIV-related lung cancer before 1996 were in the pre-HAART cohort whereas the remainder were in the post-HAART cohort. METHODS: The incidence of HIV-related lung cancer in the pre- and post-HAART cohorts was compared with the age and sex-matched population of south east England. Clinicopathological features, treatments and outcomes were also recorded. RESULTS: The incidence of HIV-related lung cancer increased from 0.8 (95% CI 0.2-3.2)/10(5) patient-years follow-up in the pre-HAART era to 6.7 (95% CI 3.1-13.9)/10(5) patient-years follow-up in the post-HAART era. The age and sex-matched incidence of lung cancer in south east England was 0.75 (95% CI 0.63-0.87)/10(5) patient-years, suggesting that HIV-related lung cancer only occurred more frequently in the post-HAART era (relative risk 8.93, 95% CI 4.92-19.98). The patient characteristics and outcomes were similar in the pre- and post-HAART eras, although the time interval between testing HIV positive and developing HIV-related lung cancer was longer in post-HAART patients. CONCLUSION: In this study HIV-related lung cancer occurred more frequently in the post-HAART era, when compared with the HIV-negative population. Unfortunately, the outcome of these patients remains poor despite HAART.

Antiretroviral Therapy, Highly Active↗
PubMed2003

Regulation of alpha(1)-adrenoceptor-linked phosphoinositide metabolism in cultured glia: involvement of protein phosphatases and kinases.

Noradrenaline-stimulated phosphoinositide breakdown in cultured glia was found to be mediated by alpha(1A)-adrenoceptors. The alpha(1A)-selective agonist A61603 was as effective as noradrenaline in eliciting 3H-inositol phosphate (IP) accumulation but was approximately 50-fold more potent. In addition, the use of selective antagonists revealed a clear rank order of potency in the ability of these drugs to reverse the effect of noradrenaline on phosphoinositide breakdown: RS17053 (alpha(1A)-selective) >>AH11110A (alpha(1B)-selective)>BMY7378 (alpha(1D)-selective). Pre-treatment of cultured glia with the protein phosphatase inhibitor okadaic acid resulted in a concentration- and time-dependent reduction in noradrenaline-evoked 3H-IP accumulation. This effect was mimicked by, but was not additive with, a phorbol ester, was reversed by protein kinase C (PKC) inhibitors and was not evident in cells which had been PKC depleted. The ability of cell extracts to dephosphorylate radiolabelled glycogen phosphorylase revealed the presence of the phosphatases PP1 and PP2A in almost equal abundance. Okadaic acid pre-treatment of intact cultures elicited a marked reduction in total phosphatase activity, particularly that mediated by PP2A. We also determined the effect of okadaic acid pre-treatment on PKC and cyclic AMP-dependent protein kinase (PKA) activities in these cells. PKC and PKA activities in cell extracts were assessed by determining the incorporation of 32P into histone and kemptide, respectively. Okadaic acid elicited increases in both Ca(2+)-dependent and Ca(2+)-independent PKC activity; in addition, increases in both initial and total PKA activities were also recorded. The effect of okadaic acid on noradrenaline-stimulated 3H-IP accumulation were not, however, mimicked by either forskolin or 8-bromo-cyclic AMP, suggesting that this event is not regulated by PKA. Our data point to roles for both PKC and PP2A in the regulation of alpha(1A)-adrenoceptor-linked phosphoinositide metabolism in cultured cortical glia.

Adrenergic alpha-Agonists↗
PubMed2002

Synthesis and evaluation of indenopyrazoles as cyclin-dependent kinase inhibitors. 2. Probing the indeno ring substituent pattern.

We disclose a novel series of indenopyrazole-based cyclin-dependent kinase (CDK) inhibitors. Kinetic experiments confirmed our initial molecular modeling studies that the compounds are competitive with respect to adenosine 5'-triphosphate (ATP) and bind in the kinase ATP pocket. A unique combination of active pharmacophores led us to a series of semicarbazide-based inhibitors that are highly potent against CDK2 and CDK4 while maintaining selectivity against other relevant serine/threonine kinases. These compounds were active against a transformed human colon cancer cell line (HCT116) while maintaining an acceptable margin of activity against a normal fibroblast cell line. The compounds were found to be highly protein bound in our cell-based assay with the exception of 11k, which maintained a reasonable level of activity in the presence of human plasma proteins.

Antineoplastic Agents↗
PubMed2002

Synthesis and evaluation of indenopyrazoles as cyclin-dependent kinase inhibitors. 3. Structure activity relationships at C3(1,2).

The identification of indeno[1,2-c]pyrazol-4-ones as inhibitors of cyclin-dependent kinases (CDKs) has led to the discovery of a series of novel and potent compounds. Herein, we report the effects of substitutions at C3 of the indeno[1,2-c]pyrazol-4-one core with alkyls, heterocycles, and substituted phenyls. Substitutions at the para position of the phenyl ring at C3 were generally well-tolerated; however, larger groups were generally inactive. For alkyls directly attached to C3, longer chain substituents were not tolerated; however, shorter alkyl groups and cyclic alkyls were acceptable. In general, the heterocycles at C3 gave the most potent analogues. One such heterocycle, 24j, was examined in detail and was determined to have a biological profile consistent with CDK inhibition. An X-ray crystal structure of one of the alkyl compounds, 13q, complexed with CDK2 was determined and showed the inhibitor residing in the adenosine 5'-triphosphate pocket of the enzyme.

Antineoplastic Agents↗
PubMed2002

Heterogeneity of chondroitin sulfate glycosaminoglycan localization during early development of the striped bass (Morone saxatilis).

Recent studies have suggested important functions for proteoglycan-associated chondroitin sulfate glycosaminoglycans (GAGs) during embryonic and larval development in numerous organisms, including the teleost. Little is known, however, about the specific distribution of different chondroitin sulfate GAGs during early development. The present study utilized immunohistochemistry to localize chondroitin sulfate GAG antigens during development of the striped bass (Morone saxatilis). Immunoreagents utilized were monoclonal antibodies (MAbs) TC2, d1C4, and CS-56, which recognize, respectively, native epitopes on glycosaminoglycan chains enriched in chondroitin-4-, chondroitin-6-, and both chondroitin-4- and -6-sulfate. Little or no immunoreactivity was observed in gastrulating embryos at 18 hr postfertilization with any MAb tested. By 24 hr (8 somites), the CS-56 epitope was localized around the notochord. At hatching (48 hr) and early larval (72 hr) stages, d1C4 and CS-56 antigens codistributed in some sites (e.g., the notochord and myosepta), but a striking heterogeneity of chondroitin sulfate GAG localization was observed in other developing tissues, including the eye and specific subsets of basement membrane. At these latter time points, TC2 reacted primarily with the extracellular matrix of the developing heart, particularly the ventricular and conotruncal segments. Heterogeneous patterning of these chondroitin sulfate GAG epitopes suggests dynamic regulation of proteoglycan function during critical morphogenetic events in early development of the striped bass.

Animals↗
PubMed1999

Lymphatic Mapping and Sentinel Lymph Node Biopsy.

The status of the regional nodal basin remains the most important prognostic indicator of survival. The current standard of care for the management of invasive breast cancer is the complete removal of the tumor, with documentation of negative margins by either mastectomy or lumpectomy, followed by complete axillary lymph node dissection. Data suggest that complete lymph node dissection (CLND) provides better local control of the disease and may actually offer a survival advantage. Lymphatic mapping and sentinel lymph node (SLN) biopsy are clearly changing this long-held paradigm and have the potential to change the standard of surgical care of the breast cancer patient. The purpose of this report is to describe the lymphatic mapping experience at the H. Lee Moffitt Cancer Center and Research Institute. From April 1994 to January 1999, 1,147 consecutive breast cancer patients were enrolled in an institutional review board-approved lymphatic mapping protocol. Lymphatic mapping was performed using Tc99m-labeled sulfur colloid and isosulfan blue dye. An SLN was defined as any blue node and/or any hot node with ex vivo radioactivity counts >/=10 times an excised non-SLN or in situ radioactivity counts >/=3 times the background counts. Lymphatic mapping was successful in identifying the SLN in 1,098 of 1,147 (95.7%) cases. In the first 186 patients, all of whom underwent CLND following SLN biopsy, one false-negative biopsy was encountered for a false-negative rate of 0.83%. The method of diagnosis (excisional versus minimally invasive) does not appear to impact on lymphatic mapping. Tumor size, however, is directly related to the probability of axillary lymph node involvement. Advances in technology and the development of minimally invasive surgical techniques have heralded a new era in surgery. Lymphatic mapping and SLN biopsy may actually prove to be a more accurate method of identifying metastases to the axilla by allowing a more focused pathologic examination of the axillary node(s) at highest risk for metastasis. With adequate training, this technique can be readily implemented as a valuable tool in the surgical treatment of breast cancer.

Journal Article↗