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)

Our objective was to understand the circumstances surrounding HIV testing among recent HIV seroconverters (n=80) compared to HIV-negative controls (n=106) in Ontario, Canada using self-reported interview data. Diagnosis of symptomatic primary HIV infection (SPHI) was defined as diagnosis by the participant's physician. Testing in response to symptoms was reported by 42% of seroconverters vs 12% of controls. More controls than seroconverters tested in response to risk behaviour (70% vs 50%) or from a desire to know their status (34% vs 12%). Among seroconverters, 76% reported 'flu-like' illness during the time period of infection, 66% had symptoms consistent with SPHI, and 35% reported a physician's diagnosis of SPHI. Compared to seroconverters with undiagnosed SPHI, more of those diagnosed with SPHI had rash (odds ratio=4.5). SPHI plays a significant role in HIV testing and subsequent early diagnosis in this population. More seroconversions could be diagnosed with better patient and physician awareness of its symptoms.
Int J STD AIDS 2003 Sep
PMID:Symptomatic primary HIV infection or risk experiences? Circumstances surrounding HIV testing and diagnosis among recent seroconverters. 1451 96

Transforming growth factor beta (TGF-beta) inhibits myogenesis and associated gene expression. We previously reported that the TGF-beta signaling effector Smad3 mediates this inhibition, by interfering with the assembly of myogenic bHLH transcription factor heterodimers on E-box sequences in the regulatory regions of muscle-specific genes. We now show that TGF-beta-activated Smad3 suppresses the function of MEF2, a second class of essential myogenic factors. TGF-beta signaling through Smad3 represses myogenin expression independently of E-boxes, and prevents a tethered MyoD-E47 dimer to activate transcription indirectly through MEF2-binding sites. In addition, Smad3 interacts with MEF2C, which requires its MADS domain, and disrupts its association with the SRC-family coactivator GRIP-1, thus diminishing the transcription activity of MEF2C. Consistent with this physical displacement, TGF-beta signaling blocks the GRIP-1-induced redistribution of MEF2C to discrete nuclear subdomains in 10T1/2 cells, and the recruitment of GRIP-1 to the myogenin promoter in differentiating myoblasts. These findings indicate that the TGF-beta/Smad3 pathway targets two critical components of the myogenic transcription machinery to inhibit terminal differentiation.
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PMID:TGF-beta-activated Smad3 represses MEF2-dependent transcription in myogenic differentiation. 1504 54

Kinetics of BCR-ABL transcript elimination and its prognostic implications on relapse were analyzed in patients with chronic myeloid leukemia (CML) after reduced intensity hematopoietic cell transplantation (HCT). In all, 19 CML patients were conditioned with 2 Gy total-body irradiation in combination with (n=14) or without (n=3) fludarabine 3 x 30 mg/m(2) (Flu) or 4.5 Gy total lymphoid irradiation (TLI) with Flu and OKT3 3 x 5 mg (n=2) and were treated with cyclosporine (CSP) and mycophenolate mofetil after allogeneic HCT. BCR-ABL transcripts were analyzed by nested RT-PCR and Taqman((R)) RT-PCR on days +28, +56 and +84 after HCT and were evaluated for their association with relapse. Of the 19 patients, 14 achieved sustained remissions of which six had a negative RT-PCR 28 days after HCT. Five patients relapsed +41, +54, +57, +136 and +234 days after HCT. Predictors for relapse were advanced disease stage (P=0.02) and slow reduction of BCR-ABL transcripts at day 28 (P=0.006) and day 56 (P=0.047) post-transplant. We conclude that a complete clearance of BCR-ABL transcripts is achievable within 4 weeks from HCT even after minimal conditioning and that early kinetics of BCR-ABL transcripts significantly correlate with the probability of hematological relapse.
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PMID:BCR-ABL transcripts are early predictors for hematological relapse in chronic myeloid leukemia after hematopoietic cell transplantation with reduced intensity conditioning. 1524 37

Our objective was to investigate demographic, behavioural, and psychosocial correlates of negative intent to receive a hypothetical AIDS vaccine. A cross-sectional survey was conducted of 278 adults from three populations: gay men, African-American women, and persons who used illicit drugs (including injectable drugs). Twenty percent of the sample expressed negative intent. In controlled analyses, negative intent was significantly more likely among people reporting they had not had sex (past year) (P = 0.01), people who reported they worried about 'problems' that could be caused by an AIDS vaccine (P = 0.006), and those never diagnosed with a sexually transmitted disease (P = 0.04). Finally, although significance was marginal, persons reporting they had not had a flu vaccination in the past five years were about 1.9 times more likely to have negative intent (P = 0.055). Among this demographically diverse sample, behavioural and psychosocial (rather than demographic measures) were associated with negative intent to receive an AIDS vaccine.
Int J STD AIDS 2004 Aug
PMID:Correlates of negative intent to receive an AIDS vaccine: an exploratory study. 1530 67

Surfactant protein D is a pattern recognition molecule that plays diverse roles in immune regulation and anti-microbial host defense. Its interactions with known ligands are calcium-dependent and involve binding to the trimeric, C-type carbohydrate recognition domain. Surfactant protein D preferentially binds to glucose and related sugars. However, CL-43, a bovine serum lectin, which evolved through duplication of the surfactant protein D gene in ruminants, prefers mannose and mannose-rich polysaccharides. Surfactant protein D is characterized by two relatively conserved motifs at the binding face, along the edges of the shallow carbohydrate-binding groove. For CL-43, sequence alignments demonstrate a basic insertion, Arg-Ala-Lys (RAK), immediately N-terminal to the first motif. We hypothesized that this insertion contributes to the differences in saccharide selectivity and host defense function and compared the activities of recombinant trimeric neck + carbohydrate recognition domains of human surfactant protein D (NCRD) with CL-43 (RCL-43-NCRD) and selected NCRD mutants. Insertion of the CL-43 RAK sequence or a control Ala-Ala-Ala sequence (AAA) into the corresponding position in NCRD increased the efficiency of binding to mannan and changed the inhibitory potencies of competing saccharides to more closely resemble those of CL-43. In addition, RAK resembled CL-43 in its greater capacity to inhibit the infectivity of influenza A virus and to increase uptake of influenza by neutrophils.
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PMID:Ligand specificity of human surfactant protein D: expression of a mutant trimeric collectin that shows enhanced interactions with influenza A virus. 1571 Oct 12

The NR4A1-3 (Nur77, NURR1 and NOR-1) subfamily of nuclear hormone receptors (NRs) has been implicated in Parkinson's disease, schizophrenia, manic depression, atherogenesis, Alzheimer's disease, rheumatoid arthritis, cancer and apoptosis. This has driven investigations into the mechanism of action, and the identification of small molecule regulators, that may provide the platform for pharmaceutical and therapeutic exploitation. Recently, we found that the purine antimetabolite 6-Mercaptopurine (6-MP), which is widely used as an anti-neoplastic and anti-inflammatory drug, modulated the NR4A1-3 subfamily. Interestingly, the agonist-mediated activation did not involve modulation of primary coactivators' (e.g. p300 and SRC-2/GRIP-1) activity and/or recruitment. However, the role of the subsequently recruited coactivators, for example CARM-1 and TRAP220, in 6-MP-mediated activation of the NR4A1-3 subfamily remains obscure. In this study we demonstrate that 6-MP modulates the activity of the coactivator TRAP220 in a dose-dependent manner. Moreover, we demonstrate that TRAP220 potentiates NOR-1-mediated transactivation, and interacts with the NR4A1-3 subgroup in an AF-1-dependent manner in a cellular context. The region of TRAP220 that mediated 6-MP activation and NR4A interaction was delimited to amino acids 1-800, and operates independently of the critical PKC and PKA phosphorylation sites. Interestingly, TRAP220 expression does not increase the relative induction by 6-MP, however the absolute level of NOR-1-mediated trans-activation is increased. This study demonstrates that 6-MP modulates the activity of the NR4A subgroup, and the coactivator TRAP220.
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PMID:TRAP220 is modulated by the antineoplastic agent 6-Mercaptopurine, and mediates the activation of the NR4A subgroup of nuclear receptors. 1595 51

ZnS nanocrystal, a class of wide-gap semiconductors, has shown interesting optical, electrical, and optoelectric properties via quantum confinement. For those applications, phase controls of ZnS nanocrystals and nanowires were critical to tune their physical properties to the appropriate ones. The wurtzite ZnS nanocrystal growth at room temperature is the useful fabrication; however, the most stable ZnS structure in nanoscale is the zinc blende (cubic) structure, and scientists have just begun exploring the room-temperature synthesis of the wurtzite (hexagonal) structure of ZnS nanocrystals. In this report, we applied the Zn finger-like peptides as templates to control the phase of ZnS nanocrystals to the wurtzite structure at room temperature. The peptide nanotubes, consisting of a 20 amino acids (VAL-CYS-ALA-THR-CYS-GLU-GLN-ILE-ALA-ASP-SER-GLN-HIS-ARG-SER-HIS-ARG-GLN-MET-VAL, M1 peptide) synthesized based on the peptide motif of the Influenza Virus Matrix Protein M1, could grow the wurtzite ZnS nanocrystals on the nanotube templates in solution. In the M1 protein, the unfolding process of the helical peptide motif via pH change creates a linker region between N- and C-terminated helical domains that contains a Zn finger-like Cys2His2 motif. Because the higher pH increases the uptake of Zn ions in the Cys2His2 motif of the M1 peptide by unfolding more helical domains, the pH change can essentially control the size and the number of the nucleation sites in the M1 peptides to grow ZnS nanocrystals with desired phases. Here we optimized the nucleation sites in the M1 peptides by unfolding them via pH change to obtain highly monodisperse and crystalline wurtzite ZnS nanocrystals on the template nanotubes at room temperature. This type of peptide-induced biomineralization technique will provide a clean and reproducible method to produce semiconductor nanotubes due to its efficient nanocrystal formation, and the band gaps of resulting nanotubes can also be tuned simply by phase control of ZnS nanocrystal coatings via the optimization of the unfolding peptide structures.
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PMID:Room-temperature Wurtzite ZnS nanocrystal growth on Zn finger-like peptide nanotubes by controlling their unfolding peptide structures. 1628 68

Systemic sclerosis (scleroderma, SSc) is an autoimmune, connective tissue disorder that is characterized by impaired vascular function, increased oxidative stress, inflammation of internal organs, and impaired angiogenesis. Tight skin mice (Tsk(-/+)) have a defect in fibrillin-1, resulting in replication of many of the myocardial and vascular features seen in humans with SSc. D-4F is an apolipoprotein A-I (apoA-I) mimetic that improves vascular function in diverse diseases such as hypercholesterolemia, influenza, and sickle cell disease. Tsk(-/+) mice were treated with either phosphate-buffered saline (PBS) or D-4F (1 mg.kg(-1).day(-1) for 6-8 wk). Acetylcholine and flow-induced vasodilation were examined in facialis arteries. Proinflammatory HDL (p-HDL) in murine and human plasma samples was determined by the cell-free assay. Angiostatin levels in murine and human plasma samples were determined by Western blot analysis. Hearts were examined for changes in angiostatin and autoantibodies against oxidized phosphotidylcholine (ox-PC). Angiogenic potential in thin sections of murine hearts was assessed by an in vitro vascular endothelial growth factor (VEGF)-induced endothelial cell (EC) tube formation assay. D-4F improved endothelium-, endothelial nitric oxide synthase-dependent, and flow-mediated vasodilation in Tsk(-/+) mice. Tsk(-/+) mice had higher plasma p-HDL and angiostatin levels than C57BL/6 mice, as did SSc patients compared with healthy control subjects. Tsk(-/+) mice also had higher triglycerides than C57BL/6 mice. D-4F reduced p-HDL, angiostatin, and triglycerides in the plasma of Tsk(-/+) mice. Tsk(-/+) hearts contained notably higher levels of angiostatin and autoantibodies against ox-PC than those of control hearts. D-4F ablated angiostatin in Tsk(-/+) hearts and reduced autoantibodies against ox-PC by >50% when compared with hearts from untreated Tsk(-/+) mice. Angiogenic potential in Tsk(-/+) hearts was increased only when the Tsk(-/+) mice were treated with D-4F (1 mg.kg(-1).day(-1), 6-8 wk), and cultured sections of hearts from the D-4F-treated Tsk(-/+) mice were incubated with D-4F (10 microg/ml, 5-7 days). Failure to treat the thin sections of hearts and Tsk(-/+) mice with D-4F resulted in loss of VEGF-induced EC tube formation. D-4F improves vascular function, decreases myocardial inflammation, and restores angiogenic potential in the hearts of Tsk(-/+) mice. As SSc patients have increased plasma p-HDL and angiostatin levels similar to the Tsk(-/+) mice, D-4F may be effective at treating vascular complications in patients with SSc.
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PMID:Effects of D-4F on vasodilation, oxidative stress, angiostatin, myocardial inflammation, and angiogenic potential in tight-skin mice. 1749 20

Since the implementation of highly active antiretroviral therapy in HIV-infected children, response to scheduled vaccines may determinate future morbidity and mortality. The aims of this study have been to describe the current vaccine coverage, vaccine safety and concordance with vaccine recommendations of the 68 HIV-infected children and adolescents followed up in our Unit. Forty-four percent of the children received at least one dose of the oral polio vaccine (OPV). Only 9.1% needed and received a second set of hepatitis B virus immunization because of low vaccine response. Only 14.7% were vaccinated against varicella. Coverages of 82.3% and 100% have been reached with the 23-valent and the 7-valent pneumococcal vaccines, respectively. Meningococcal conjugated vaccine uptake was moderate (80.8%). Influenza annual vaccination coverage was poor: only 22.7% had well-documented yearly vaccines. In our experience, vaccine coverage is lower in those vaccines administered in primary care centres compared with the immunizations given at the hospital. OPV administration did not cause any adverse effect in the children or in their families. Vaccine coverage in HIV-infected children was suboptimal.
Int J STD AIDS 2007 May
PMID:HIV-infected children vaccination coverage and safety in a Western European cohort: a retrospective study. 1752 1

Although the importance of the progesterone receptor (PR) to female reproductive and mammary gland biology is firmly established, the coregulators selectively co-opted by PR in these systems have not been clearly delineated. A selective gene-knockout approach applied to the mouse, which abrogates gene function only in cell types that express PR, recently disclosed steroid receptor coactivator 2 (SRC-2, also known as TIF-2 or GRIP-1) to be an indispensable coregulator for uterine and mammary gland responses that require progesterone. Uterine cells positive for PR (but devoid of SRC-2) were found to be incapable of facilitating embryo implantation, a necessary first step toward the establishment of the materno-fetal interface. Importantly, such an implantation defect is not exhibited by knockouts for SRC-1 or SRC-3, underscoring the unique coregulator importance of SRC-2 in peri-implantation biology. Moreover, despite normal levels of PR, SRC-1 and SRC-3, progesterone-dependent branching morphogenesis and alveologenesis fails to occur in the murine mammary gland in the absence of SRC-2, thereby establishing a critical coregulator role for SRC-2 in signaling cascades that mediate progesterone-induced mammary epithelial proliferation. Finally, the recent detection of SRC-2 in the human endometrium and breast suggests that this coregulator may represent a new clinical target for the future management of female reproductive health and/or breast cancer.
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PMID:Steroid receptor coactivator 2 is required for female fertility and mammary morphogenesis: insights from the mouse, relevance to the human. 1817 19


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