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Biomedical subjects

K Fife

Publications and source records attributed to K Fife.

At least 19 recordsLinked to original sources
PubMed2001

Signaling to the nucleus by an L-type calcium channel-calmodulin complex through the MAP kinase pathway.

Increases in the intracellular concentration of calcium ([Ca2+]i) activate various signaling pathways that lead to the expression of genes that are essential for dendritic development, neuronal survival, and synaptic plasticity. The mode of Ca2+ entry into a neuron plays a key role in determining which signaling pathways are activated and thus specifies the cellular response to Ca2+. Ca2+ influx through L-type voltage-activated channels (LTCs) is particularly effective at activating transcription factors such as CREB and MEF-2. We developed a functional knock-in technique to investigate the features of LTCs that specifically couple them to the signaling pathways that regulate gene expression. We found that an isoleucine-glutamine ("IQ") motif in the carboxyl terminus of the LTC that binds Ca2+-calmodulin (CaM) is critical for conveying the Ca2+ signal to the nucleus. Ca2+-CaM binding to the LTC was necessary for activation of the Ras/mitogen-activated protein kinase (MAPK) pathway, which conveys local Ca2+ signals from the mouth of the LTC to the nucleus. CaM functions as a local Ca2+ sensor at the mouth of the LTC that activates the MAPK pathway and leads to the stimulation of genes that are essential for neuronal survival and plasticity.

Amino Acid Motifs↗
PubMed2001

Lymph-node metastases in patients with melanoma: what is the optimum management?

Lymph-node metastasis is an indicator of poor prognosis for patients with melanoma. The management of regional nodes is controversial, with continuing debate about whether surgery or radiotherapy of positive lymph nodes improves long-term survival or whether nodal involvement is merely a marker of aggressive disease. However, there is general agreement that systemic chemotherapy is rarely an effective form of management. This review therefore considers surgical and radiotherapeutic aspects of lymph-node management in patients with melanoma. We discuss regional control and survival after lymph-node surgery in retrospective series, randomised trials of elective lymph-node dissection, the role of 'sentinel' lymph-node biopsy, radiobiology and radiotherapy fractionation issues in melanoma treatment, retrospective studies of adjuvant nodal radiotherapy, and finally, randomised trials of adjuvant radiotherapy after lymph-node dissection.

Combined Modality Therapy↗
PubMed2001

Current issues in the biology of AIDS-related lymphoma.

Three important issues have been the focus of much recent attention in the biology of AIDS-related lymphomas. The altered epidemiology in the era of highly active antiretroviral therapy, the role of herpesviruses including human herpesvirus 8 and the molecular genetics of HIV-associated T-cell lymphomas. These topics are covered in this article and their potential application to the clinical management of AIDS-related lymphomas are discussed.

Antiretroviral Therapy, Highly Active↗
PubMed2000

Continued lamivudine versus delavirdine in combination with indinavir and zidovudine or stavudine in lamivudine-experienced patients: results of Adult AIDS Clinical Trials Group protocol 370.

OBJECTIVE: To compare the virologic activity of continued lamivudine (3TC) versus a switch to delavirdine (DLV) when initiating protease inhibitor therapy in nucleoside-experienced patients. DESIGN: Randomized, open-label, multi-center study. SETTING: Adult AIDS clinical trials units. PATIENTS: Protease and non-nucleoside reverse transcriptase inhibitor-naive patients who had received 3TC plus zidovudine (ZDV), stavudine (d4T), or didanosine (ddl) for at least 24 weeks. INTERVENTIONS: Patients with plasma HIV-1 RNA levels > 500 copies/ml who previously received d4T + 3TC or ddI + 3TC were randomized to ZDV + 3TC + indinavir (IDV) or ZDV + DLV + IDV. MAIN OUTCOME MEASURES: Primary endpoints were the proportion of patients with plasma HIV-1 RNA levels < or = 200 copies/ml at 24 weeks, and occurrence of serious adverse events. The proportion of patients with plasma HIV-1 RNA levels < or = 200 copies/ml at week 48 was a secondary endpoint. RESULTS: At week 24, 58% of subjects in the ZDV + 3TC + IDV arm and 73% in the ZDV + DLV + IDV arm had plasma HIV-1 RNA levels < or = 200 copies/ml (P = 0.29). At week 48, plasma HIV-1 RNA levels were < or = 200 copies/ml in 48% and 83%, respectively (P = 0.007). Rash and hyperbilirubinemia occurred more frequently in the DLV arm than in the 3TC arm. Steady-state plasma IDV levels were higher among patients in the DLV arm as compared with the 3TC arm. CONCLUSIONS: Substituting DLV for 3TC when adding IDV improved virologic outcome in nucleoside-experienced patients. This result might be explained, in part, by the positive effect of DLV on IDV pharmacokinetics.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Treatment of HIV-associated invasive anal cancer with combined chemoradiation.

There is an increased frequency of invasive anal cancer in HIV-seropositive men. Early treatment strategies in this patient group employed reduced dosages of chemotherapy or radiotherapy alone to reduce toxicity. Since 1989 we have used combined modality treatment consisting of chemotherapy 5-fluorouracil (5-FU) and mitomycin C, and concomitant radical radiotherapy to the pelvis (38-51 Gy in 20-30 fractions), with most patients receiving a perineal boost (10-18 Gy). 12 homosexual HIV-positive men have been treated. The median CD4 count at diagnosis of anal cancer was 209 cells/microl (range: 29-380 cells/microl), 5 had prior AIDS defining diagnoses. No patients had metastatic disease. Complete remissions were obtained in 9/11 evaluable patients and in 1 further patient following surgery. 2 patients relapsed both within 6 months of diagnosis. At a median follow-up of 4.8 years (range: 0.4-10 years), 4 patients have died (2 from anal cancer, 1 from treatment-related consequences and 1 from opportunistic infection in remission). Actuarial 2-year survival is 60% (95% confidence interval (CI): 29-91%). Grade 3 haematological toxicity was recorded in 3 patients, grade 4 and 5 gastrointestinal toxicity in 1 patient each and grade 3 skin toxicity in 1 patient. Radical chemoradiation may be given safely at conventional doses in HIV-positive patients, with a high complete response rate.

Adult↗
PubMed2000

Weekly alternating combination chemotherapy for good prognosis AIDS-related lymphoma.

Early studies reported that the major adverse prognostic factors in AIDS-related non-Hodgkin's lymphoma (ARL) are low CD4 cell count, prior AIDS defining diagnosis and poor performance status. Since 1989 we have adopted a prognosis-stratified approach for ARL. In this study, we identified a group of good prognosis patients. These patients with one or no adverse prognostic factors were treated with alternating weekly chemotherapy using the bleomycin, etoposide, vincristine, methotrexate, prednisolone/cyclophosphamide, doxorubicin (BEMOP/CA) schedule (Bower M, Block C, Gulliford T, et al. Cancer Chemother Pharmacol 1995, 38, 106-109). Modifications to the regimen with the aim of reducing toxicity were a briefer duration (12 weeks) and the addition of prophylaxis against pneumocystis and mycobacteria. Intrathecal methotrexate was administrated fortnightly to patients with Burkitt's histology, meningeal involvement or base of skull disease. 30 patients were treated, including 5 with prior AIDS, 3 with ECOG status 3 and 1 with CD4 <100/microl. The mean age was 40 (range 22-60 years), the median CD4 cell count at ARL diagnosis was 262/microl (range 44-588/microl). The International non-Hodgkin's lymphoma (NHL) prognostic factors project classifications were low risk 8 (maximum 5.4 years) (27%), low-intermediate risk 6 (20%), high-intermediate risk 11 (37%) and high risk 5 (17%). The median follow-up was 2.1 years. 3 patients withdrew from treatment within 2 weeks due to toxicity, 2 patients died within 2 weeks of starting chemotherapy. The major toxicity was myelosuppression with 14 patients developing grade 4 neutropenia. The 2-year overall survival rate is 46% (95% confidence interval (CI)=27-65%), and lymphoma-specific survival at 2 years is 59% (95% CI: 40-78%). For selected patients with good prognosis ARL 12 weeks BEMOP/CA therapy produces good overall survival at 2 years.

Adult↗
PubMed1999

Highly active anti-retroviral therapy (HAART) prolongs time to treatment failure in Kaposi's sarcoma.

OBJECTIVE: To evaluate the impact of highly active antiretroviral therapy (HAART) on Kaposi's sarcoma. DESIGN: Retrospective study of patients who had received systemic or local treatment for AIDS-related Kaposi's sarcoma who subsequently commenced HAART. METHODS: Case note review to determine time to treatment failure for Kaposi's sarcoma before and after starting HAART. Time to treatment failure was calculated from the end of last therapy to the start of the next new treatment for Kaposi's sarcoma. RESULTS: The cohort contained 78 patients. Only 38% had good risk Kaposi's sarcoma (stage T0I0) at presentation. The median time to treatment failure before starting HAART was 0.5 years. Initial HAART therapy was three or more drugs including a protease inhibitor for 38 (49%), three or more drugs without a protease inhibitor for 27 (35%) and a two-drug protease combination for 13 (16%). The median follow-up after starting HAART was 12 months (range, 0.5-52 months) and anti-Kaposi's sarcoma treatment has been required for 24 (31%) patients. The median time to treatment failure for Kaposi's sarcoma from the start of HAART is 1.7 years. This is statistically longer than the time to treatment failure for the same cohort of patients before they started HAART (log rank chi2 = 16.5, P < 0.0001). The serum HIV RNA viral load (VL) at the time of Kaposi's sarcoma progression revealed virological failure of HAART (defined as VL > 5000 copies/ml) in 14 of 24 (58%) and good control (VL < 200 copies/ml) in five of 24 (21%). CONCLUSION: HAART is associated with prolonged time to treatment failure in Kaposi's sarcoma. Progression of Kaposi's sarcoma while on HAART is not necessarily associated with virological failure as determined by rising viral RNA titre.

Adult↗
PubMed1999

Lamivudine in combination with zidovudine, stavudine, or didanosine in patients with HIV-1 infection. A randomized, double-blind, placebo-controlled trial. National Institute of Allergy and Infectious Disease AIDS Clinical Trials Group Protocol 306 Investigators.

OBJECTIVE: To study the antiviral activity of lamivudine (3TC) plus zidovudine (ZDV), didanosine (ddl), or stavudine (d4T). DESIGN: Randomized, placebo-controlled, partially double-blinded multicenter study. SETTING: Adult AIDS Clinical Trials Units. PATIENTS: Treatment-naive HIV-infected adults with 200-600x10(6) CD4 T lymphocytes/l. INTERVENTIONS: Patients were openly randomized to a d4T or a ddl limb, then randomized in a blinded manner to receive: d4T (80 mg/day), d4T plus 3TC (300 mg/day), or ZDV (600 mg/day) plus 3TC, with matching placebos; or ddl (400 mg/day), ddl plus 3TC (300 mg/day), or ZDV (600 mg/day) plus 3TC, with matching placebos. After 24 weeks 3TC was added for patients assigned to the monotherapy arms. MAIN OUTCOME MEASURE: The reduction in plasma HIV-1 RNA level at weeks 24 and 48. RESULTS: Two hundred ninety-nine patients were enrolled. After 24 weeks the mean reduction in plasma HIV-1 RNA copies/ml from baseline was 0.49 log10 (d4T monotherapy) versus 1.03 log10 (d4T plus 3TC; P = 0.001), and 0.68 log10 (ddl monotherapy) versus 0.82 log10 (ddl plus 3TC; P>0.22). After 48 weeks the mean reduction was 1.08 log10 (d4T plus 3TC) versus 1.01 log10 (ZDV plus 3TC) in the d4T limb (P = 0.66), and 0.94 log10 (ddl plus 3TC) versus 0.88 log10 (ZDV plus 3TC; P = 0.70) in the ddl limb. CONCLUSIONS: 3TC added significantly to the virologic effects of d4T, but not ddl, in treatment-naive patients. 3TC plus d4T produced virologic changes comparable to those of 3TC plus ZDV. These results support the use of 3TC with either ZDV or d4 as a component of initial combination antiretroviral therapy.

Adult↗
PubMed1999

Treatment outcome in presumed and confirmed AIDS-related primary cerebral lymphoma.

A retrospective analysis identified 38 HIV seropositive patients with a diagnosis of presumed (n = 26) or confirmed (n = 12) primary cerebral lymphoma (PCNSL). All patients had failed to respond to empirical antitoxoplasma therapy and the clinical diagnosis of PCNSL was confirmed by brain biopsy (n = 4), cerebrospinal fluid (CSF) examination for Epstein-Barr virus (EBV) by PCR (n = 7) or postmortem examination (n = 1). There was no difference in the age, performance status, CD4 counts, antiretroviral usage or interval since first HIV serodiagnosis between patients with presumed or confirmed PCNSL. 16 patients received either radiotherapy (n = 14) or chemotherapy (n = 2). Patients with confirmed or presumptive PCNSL were equally likely to receive treatment. The median overall survival, which was measured from the end of unsuccessful antitoxoplasma therapy, was 1.2 months for the whole cohort. There was no difference in overall survival between patients with presumptive (median 0.8 months) and confirmed (median 1.3 months) PCNSL (logrank P = 0.69). This suggests that there may be little value in positively diagnosing PCNSL in the current diagnostic algorithm. Recent improvements in outcome have been reported with systemic chemotherapy in HIV-PCNSL and may influence the need for earlier definitive diagnosis in the future.

Adult↗
PubMed1999

Genital warts and their treatment.

Genital warts are manifestations of a common viral sexually transmitted disease (STD) that are often diagnosed and treated with a variety of clinical specialties. Unlike for other STDs, there is a general lack of a well-established treatment algorithm for the management of external genital warts. This, coupled with a wide variety of treatments and clinical settings, makes the development of a simple algorithm virtually impossible. In this review what is known and not known about current treatments and case management will be discussed.

Condylomata Acuminata↗
PubMed1998

Endothelial cell transfection with cationic liposomes and herpes simplex-thymidine kinase mediated killing.

Endothelial cells are a promising target for cancer gene therapy because neoangiogenesis is vital for the supply of oxygen and nutrients to solid tumours. However, endothelial cells have been reported to be difficult to transfect. We demonstrate high rates of transfection with the reporter gene pSV40 beta gal using DC-Chol/DOPE cationic liposomes and lower rates with the novel polyamine cationic liposomes ACHx/DC-Chol/DOPE and ACO/DC-Chol/DOPE. Endothelial cells transfected with HSV-thymidine kinase using DC-Chol/DOPE demonstrated 3 log10 increased cytotoxicity compared with controls when exposed to the prodrug ganciclovir, thereby demonstrating significant biological effect.

Cations↗
PubMed1998

Activity of thalidomide in AIDS-related Kaposi's sarcoma and correlation with HHV8 titre.

A phase II study of thalidomide was conducted to evaluate its efficacy and toxicity in the treatment of cutaneous AIDS-related Kaposi's sarcoma (AIDS-KS). To evaluate whether clinical response is correlated with titre of human herpesvirus 8 (HHV8) DNA in peripheral blood, levels were determined by serial end-point dilution at enrolment and 4-6 weeks later. Seventeen male HIV-seropositive patients with histopathologically diagnosed KS were treated with thalidomide 100mg orally once nightly for 8 weeks. Response evaluation was performed using AIDS Clinical Trials Group (ACTG) criteria and analysis was by intention to treat. Six of 17 patients achieved a partial response (35%: 95% confidence interval 10-61%). Eight patients withdrew (6 owing to toxicity, one to early progression and one to non-compliance). HHV8 DNA load decreased by at least 3log10 to undetectable levels in 3 of the 5 virologically assessable partial responders. This preliminary study demonstrates that thalidomide has activity in the treatment of AIDS-KS and that clinical response is associated with a reduction of HHV8 DNA titre in peripheral blood.

AIDS-Related Opportunistic Infections↗
PubMed1997

Isolation and characterization of Exodus-2, a novel C-C chemokine with a unique 37-amino acid carboxyl-terminal extension.

Chemokines are a group of small, homologous proteins that regulate leukocyte migration, hemopoiesis, and HIV-1 absorption. We report here the cloning and characterization of a novel murine and human C-C chemokine termed Exodus-2 for its similarity to Exodus-1/MIP-3alpha/LARC, and its chemotactic ability. This novel chemokine has a unique 36 or 37 (murine and human, respectively) amino acid carboxyl-terminal extension not seen in any other chemokine family member. Purified recombinant Exodus-2 was found to have two activities classically associated with chemokines: inhibiting hemopoiesis and stimulating chemotaxis. However, Exodus-2 also had unusual characteristics for C-C chemokines. It selectively stimulated the chemotaxis of T-lymphocytes and was preferentially expressed in lymph node tissue. The combination of these characteristics may be a functional correlate for the unique carboxyl-terminal structure of Exodus-2.

Amino Acid Sequence↗
PubMed1997

Cloning and characterization of exodus, a novel beta-chemokine.

Chemokines are a family of related proteins that regulate leukocyte infiltration into inflamed tissue. Some chemokines such as MIP-1 alpha also inhibit hematopoietic progenitor cell proliferation. Recently, three chemokines, MIP-1 alpha, MIP-1 beta, and RANTES, have been found to significantly decrease human immunodeficiency virus production from infected T cells. We report here the cloning and characterization of a novel human chemokine termed Exodus for its chemotactic properties. This novel chemokine is distantly related to other chemokines (28% homology with MIP-1 alpha) and shares several biological activities. Exodus is expressed preferentially in lymphocytes and monocytes, and its expression is markedly upregulated by mediators of inflammation such as tumor necrosis factor or lipopolysaccharide. Purified synthetic Exodus was found to inhibit proliferation of myeloid progenitors in colony formation assays. Exodus also stimulated chemotaxis of peripheral blood mononuclear cells. The sequence homology, expression, and biological activity indicate that Exodus represents a novel divergent beta-chemokine.

Amino Acid Sequence↗
PubMed1997

Phase II trial of 13-cis-retinoic acid for poor risk HIV-associated Kaposi's sarcoma.

Fifteen men with HIV-associated Kaposi's sarcoma (KS) and poor risk disease according to the TIS staging were enrolled in a phase II trial of oral 13-cis-retinoic acid. The median CD4 cell count was 95 cells/microl (range 7-260) and 6 had prior AIDS-defining opportunistic infections. One patient was withdrawn on account of cutaneous toxicity. Evaluation was by AIDS Clinical Trials Group (ACTG)1 defined assessment. One patient achieved a partial response and remains on treatment in partial remission. Thus the overall response rate is 7% (95% confidence interval 0-23%). A further 5 patients had stable disease (38%: 95% confidence interval 7-64%). The overall low activity, considerable toxicity and limited cosmetic benefit even in responding patients limits the value of this approach in KS. However, this treatment strategy may be more rewarding in early good risk KS.

AIDS-Related Opportunistic Infections↗
PubMed1996

Chemotherapy for ovarian germ cell tumours.

59 patients were treated for newly diagnosed metastatic ovarian germ cell tumours with POMB/ACE chemotherapy (which contains cisplatinum, vincristine, methotrexate, bleomycin, actinomycin D, cyclophosphamide and etoposide). The median follow-up was 7.7 years. The 3 year survival is 87.8% (95% confidence interval 76.9-93.9%) and no relapses occurred more than 3 years after treatment. 4 (7%) patients had primary drug resistance to POMB/ACE and 4 (7%) have relapsed. One patient in complete remission developed secondary acute myeloid leukaemia after receiving a total of 1.3 g/m2 etoposide. 6 of 12 (50%) patients referred at relapse were salvaged by POMB/ACE. 14 of 33 (42%) women (> 18 years old) have had successful pregnancies after fertility conserving surgery and chemotherapy with no congenital abnormalities reported. The POMB/ACE regimen is as efficacious as other published regimens for ovarian germ cell tumours (OGCT) and balances a low incidence of life-threatening toxicity with a high success rate.

Adolescent↗