Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Regulation through phosphorylation is a characteristic of signalling pathways and the lymphocyte kinase Lck (p56lck) both performs phosphorylation and is affected by it. Lck is a Src-family tyrosine kinase expressed in T lymphocytes, where it participates in the cellular immune response. Like all Src homologues, it comprises SH3, SH2 and kinase domains. Lck associates through its distinctive amino-terminal segment with the cytoplasmic tails of either T-cell co-receptor, CD4 or CD8-alpha. Activated Lck phosphorylates T-cell receptor zeta-chains, which then recruit the ZAP70 kinase to promote T-cell activation. Lck is activated by autophosphorylation at Tyr 394 in the activation loop and it is inactive when Tyr 505 near the carboxy terminus is phosphorylated and interacts with its own SH2 domain. Here we report the crystal structure of the Lck tyrosine kinase domain (LCKK) in its activated state at 1.7 A resolution. The structure reveals how a phosphoryl group at Tyr 394 generates a competent active site. Comparisons with other kinase structures indicate that tyrosine phophophorylation and ligand binding may in general elicit two distinct hinge-like movements between the kinase subdomains. From modelling studies, we suggest a basis for inhibition by phosphorylation at Tyr 505.
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PMID:Structural basis for activation of human lymphocyte kinase Lck upon tyrosine phosphorylation. 894 79

Utilizing a prospective study of health service activity for HIV/AIDS, 2 estimates of hospital costs of care analysed with reference to gender, risk activity, immunological and clinical staging (1987 definition of AIDS) were undertaken. Utilizing combined costs per life year (based on hospital and hospice activity but not primary and community care) the ratio of costs for CD4 < 200 and CD4 > 200 was for most risk groups between 2-5:1 whilst for AIDS: pre-AIDS it was between 3.6-8.3:1 except for homosexuals where it was 12.6:1. A comparison of the standard hospital costs for infectious diseases with the published accounts for clinical AIDS care in Lothian suggests a 3-4-fold underestimate in the costs of providing a comprehensive health care service.
Int J STD AIDS 1997 Jan
PMID:The cost of health care for HIV-positive patients. 904 82

We measured plasma levels of all the antioxidant-micronutrients in subjects with HIV infection and controls. Plasma levels of all the carotenoids, including lutein, cryptoxanthin, lycopene, alpha-carotene and beta-carotene as well as vitamins A, C and E and cholesterol were assayed in 35 subjects with HIV infection and 38 controls. We found a significant depletion of all the carotenoids (P < 0.001) and vitamin C (P < 0.01) and cholesterol (P < 0.001) but not vitamins A or E in HIV-infected subjects. Further analysis of the HIV-infected subjects revealed that plasma levels of 4 of the groups of carotenoids and cholesterol were correlated with CD4 count but that beta-carotene and vitamins A, C and E were not. These results are reviewed in the light of the published literature and we conclude that these abnormalities of antioxidant-micronutrients are likely to reflect a metabolic phenomenon associated with HIV infection. However, an additional contribution to these deficiencies from malabsorption later in HIV disease cannot be ruled out.
Int J STD AIDS
PMID:Antioxidant-micronutrients and HIV infection. 911 64

A prospective study of health service and hospice resource utilization (average length of stay or ALOS, discharge rate, bed day use, outpatient consultation) analysed with reference to gender, risk activity, immunological and clinical staging (1987 definition of AIDS) for the financial year 1992-93 was undertaken at the Regional Infectious Disease Unit (RIDU), City Hospital, Edinburgh, Scotland where 72% of 513 patients were infected via injection drug use. Not surprising therefore overall, drug users were the heaviest users of the inpatient facilities (74% of the discharges and 65% of the bed days) although homosexuals had the highest discharge rate (114 per 100 person years) and rate of bed day use (1654 days per 100 person years). Immunodeficiency (CD4 count < 200 cells/ul) and a clinical diagnosis of AIDS were both associated with greater inpatient and outpatient resource use compared to those without immunodeficiency (CD4 count > or = 200 CD4 cells/ul) or AIDS. Gender effects were complex; the ALOS for women was increased for all risk groups whatever the CD4 count whilst there was no consistent trend of more resource use for women by risk group. Drug users were the heaviest overall users of the local hospice (84% of all admissions, 83% of the bed days and a discharge rate of 76.4 per 100 person years), more than double the rates experienced by the other risk groups. Thus both clinical and immunological staging (AIDS or a CD4 count < 200 cells/ul) were associated with increased resource use in HIV infection and estimates of resource use for AIDS need to be increased by around one-third to take into account hospice use. Despite the preponderance of drug users in Edinburgh, comparisons with other centres did not reveal increased resource use.
Int J STD AIDS 1997 Apr
PMID:Hospital and hospice resource use of HIV-positive patients in Edinburgh. 914 56

Although much is known about the activation, proliferation, and function of CD4(+) T cells, little is known about how they survive as resting T cells in animals. Resting T cells have a half-life in animals of more than a week; however, when they are removed from animals and placed in tissue culture their half-life falls to approximately 24 h. In this paper, we show that the survival of resting T cells in vitro is promoted by two cytokines, interleukins 4 and 7 (IL-4, IL-7). They may do this in part by maintaining levels of survival-promoting proteins such as Bcl-2 in the cells, because the levels of Bcl-2 and Bcl-Xl in resting T cells fall rapidly after the cells are isolated from animals, and are maintained by culture in IL-4. Because the IL-4 receptor is known to signal through the JAK1 and JAK3/Stat6 pathway, we tested whether Stat6 was required for IL-4- dependent T cell survival. Surprisingly, we found that IL-4 rescued T cells from apoptosis in what appeared to be a Stat6-independent manner. These results demonstrate that the survival of resting T cells is an active process that can be affected by signals delivered by cytokines and also suggest that the IL-4 receptor on resting T cells may use a novel signaling pathway to facilitate T cell viability.
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PMID:Interleukin 4 (IL-4) or IL-7 prevents the death of resting T cells: stat6 is probably not required for the effect of IL-4. 922 62

Measurement of the CD4 lymphocyte count is widely used as a prognostic marker and guide for the institution of antiretroviral therapy in patients infected with HIV (human immunodeficiency virus). CD4 counts are known to fluctuate with strenuous physical activity and diurnal variation but there is no information on the effects of rest or normal daily activity. We investigated the effects of rest on the absolute CD4 lymphocyte count in 20 healthy laboratory workers. Blood samples were obtained in 20 subjects upon arrival in the laboratory (CD4 0), following 30 and 60 min rest (CD4 30 and CD4 60 respectively) and 8 h into a normal working day (CD4 8). A significant decrease in the CD4 lymphocyte count was observed following 60 min rest; mean CD4 count at 0 min 1060 x 10(6)/L, mean CD4 count at 60 min 660 x 10(6)/L (P = 0.0017). These results demonstrate a significant effect of rest on CD4 lymphocyte counts in healthy volunteers. This biological variation may be important in HIV-infected patients and needs to be addressed by further studies.
Int J STD AIDS 1997 Jul
PMID:Decrease in CD4 lymphocyte counts with rest; implications for the monitoring of HIV infection. 922 88

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.
Int J STD AIDS 1997 Aug
PMID:Phase II trial of 13-cis-retinoic acid for poor risk HIV-associated Kaposi's sarcoma. 925 1

To determine the association between trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis for Pneumocystis carinii pneumonia and risk of bacterial infections in persons with AIDS, we abstracted hospital records from 6496 adult admissions to 42 hospitals in western Washington state. Of these admissions, 570 involved 637 bacterial infections diagnosed among patients who had been prescribed prophylactic TMP-SMX or aerosolized pentamidine. Cases [admissions with bacteraemia, bacterial pneumonia, acute or chronic sinusitis, or urinary tract infection (UTI)] were compared to controls (admissions not associated with any of the 5 bacterial infections). After adjusting for CD4 lymphocyte count and presence of P. carinii pneumonia, TMP-SMX prophylaxis, relative to aerosolized pentamidine prophylaxis, was associated with a reduced risk of bacteraemia (adjusted OR = 0.5; 95% CI, 0.2-1.0; P = 0.04), bacterial pneumonia (adjusted OR = 0.5; 95% CI, 0.3-0.8; P = 0.01), acute sinusitis (adjusted OR = 0.5; 95% CI, 0.2-1.3; P = 0.2), chronic sinusitis (adjusted OR = 0.3; 95% CI, 0.1-0.7; P = 0.01), and UTI (adjusted OR = 0.5; 95% CI, 0.2-1.2; P = 0.1), and all 5 bacterial infections combined (adjusted OR = 0.6; 95% CI, 0.5-0.8; P < 0.001).
Int J STD AIDS 1997 Sep
PMID:Bacterial infections in adult patients hospitalized with AIDS: case-control study of prophylactic efficacy of trimethoprim-sulfamethoxazole versus aerosolized pentamidine. 929 45

Mutations of the Janus family kinase JAK3 have been found to be responsible for autosomal recessive severe combined immunodeficiency (SCID) in humans. We report here the analysis of four new unrelated patients affected by JAK3-deficient SCID. The genetic defects were heterogeneous and included a large intragenic deletion as well as different point mutations, leading to missense substitutions, early stop codons, or splicing defects. We performed a series of studies of the biochemical events induced by cytokines on lymphoblastoid B-cell lines obtained from these patients. Abnormalities in tyrosine phosphorylation of JAK3 in response to interleukin-2 (IL-2) and IL-4 were present in all patients. Accordingly, IL-2-mediated phosphorylation of STAT5 was also absent or barely detectable. On the contrary, in all cases, we could show reduced but clear phosphorylation of STAT6 upon IL-4 stimulation. In one patient carrying a single amino acid change (Glu481Gly) in the JH3 domain of JAK3, we observed partially conserved IL-2 responses resulting in reduced but detectable levels of JAK3 and STAT5 phosphorylation. Interestingly, the patient bearing this mutation developed a substantial number of circulating CD4(+)/CD45RO+ activated T lymphocytes that were functionally impaired. In two cases, patients' cells expressed JAK3 proteins with mutations in the JH2 pseudo-kinase domain. A single cysteine to arginine substitution (Cys759Arg) in this region resulted in high basal levels of constitutive JAK3 tyrosine phosphorylation unresponsive to either downregulation by serum starvation or cytokine-mediated upregulation. The characterization of the genetic defects and biochemical abnormalities in these JAK3-deficient patients will help define the role of JAK3 in the ontogeny of a competent immune system and may lead to a better understanding of the JAK3 functional domains.
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PMID:Structural and functional basis for JAK3-deficient severe combined immunodeficiency. 935 68

The association between genetic instability in repetitive DNA domains and cancer has been reported in different types of malignancies. In this work we perform a comparative study of 29 gastric tumors with paired normal tissue using seven tetra-(FES/FPS, VWA31/A, HTPO, TH01, MBPB) and pentanucleotide (CD4, TP53) STR polymorphic markers regarding loss of heterozygosity and replication error status. Furthermore, we compare the gene frequencies obtained in normal tissue from patients with those of a normal control population from the same area, looking for allele associations between any of these polymorphic loci and gastric cancer risk. The results have shown that FES/FPS and TP53 present the higher rates of somatic instability. The observed results for TP53 are in accordance with those previously reported in gastric carcinogenesis, while instability of FES/FPS is for the first time reported in this tumor type. Our data suggest that different loci show different rates of instability and/or loss of heterozygosity and do not seem to consist of a result of an RER+ phenotype affecting several genomic repetitive domains. Furthermore, the instability in markers TH01, MBPB, TP53, and FES was generally detected in genotypes involving alleles with a high number of repeats. Comparing gene frequencies in patients and normal controls, no significant differences were found, although longer alleles are consistently more frequent in patients for the markers MBPB, TH01, and CD4.
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PMID:Tetra- and pentanucleotide short tandem repeat instability in gastric cancer. 937 35


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