Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.16.2 (PCP)
 3,761 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Specific interventions to prevent mother-to-child transmission (MTCT) include antiretroviral therapy, elective caesarean section and avoidance of breastfeeding. Rates of MTCT below 1-2% are now achievable in developed country settings. However, although the vast majority of infants born to HIV infected mothers are protected from acquisition of infection, most are exposed to antiretroviral drugs for which there is only limited information on toxicity. Increasing use of complex and potent combinations of antiretroviral drugs in pregnancy, particularly during the period of organogenesis, has raised many questions relating to pregnancy outcome and safety issues for the exposed children, both in the short and longer term. A shorter duration of pregnancy has been reported to be associated with taking protease inhibitors in pregnancy, particularly prolonged and early use, but this has been an inconsistent finding. Risk of congenital abnormalities may be increased with exposure to specific antiretroviral drugs, such as efavirenz, and certain combinations of Pneumonia Pneumocystis Carinii (PCP) prophylaxis and antiretroviral drugs, but there is no evidence of an excess of congenital malformations associated with exposure to zidovudine prophylaxis. Although data from observational studies and follow-up of children enrolled in clinical trials have not shown uninfected, zidovudine-exposed children to be at increased risk of adverse events including cancer in the short- to medium-term, the possibility that they may be at risk of cancer at older ages cannot be excluded. Concerns regarding mitochondrial dysfunction in children with foetal/neonatal exposure to zidovudine have arisen following a report from France of eight uninfected children with mitochondrial dysfunction, of whom two died. However, there is limited additional evidence of clinically evident mitochondrial disease in children exposed to antiretroviral therapy in utero or neonatally, and the absence of any excess mortality in large observational cohort studies of children born to HIV infected women and exposed to antiretroviral drugs is reassuring.
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PMID:Antenatal and neonatal antiretroviral therapy in HIV-infected women and their infants: a review of safety issues. 1501 May 53

Pneumocystis infection in humans was originally described in 1942. The organism was initially thought to be a protozoan, but more recent data suggest that it is more closely related to the fungi. Patients with cellular immune deficiencies are at risk for the development of symptomatic Pneumocystis infection. Populations at risk also include patients with hematologic and nonhematologic malignancies, hematopoietic stem cell transplant recipients, solid-organ recipients, and patients receiving immunosuppressive therapies for connective tissue disorders and vasculitides. Trimethoprim-sulfamethoxazole is the agent of choice for prophylaxis against Pneumocystis unless a clear contraindication is identified. Other options include pentamidine, dapsone, dapsone-pyrimethamine, and atovaquone. The risk for PCP varies based on individual immune defects, regional differences, and immunosuppressive regimens. Prophylactic strategies must be linked to an ongoing assessment of the patient's risk for disease.
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PMID:Prevention of infection due to Pneumocystis spp. in human immunodeficiency virus-negative immunocompromised patients. 1548 47

Acute venous thromboembolism (VTE) is a common and potentially fatal complication that frequently occurs in cancer patients. Few data are currently available about the optimal management of this category of high-risk patients. In clinical practice, physicians have to deal with many problems related to cancer patients with acute VTE. For instance, cancer patients with deep vein thrombosis (DVT) are frequently admitted to the hospital since their high rate of recurrent thrombotic events and/or bleeding-related therapy; however, most of them would prefer alternatives to prolonged hospitalisation. Then, it is not clearly whether data coming from a non-cancer population (such as that regarding the use of D-dimer test and/or pre-test clinical probability [PCP]), can be reliable applied in cancer patients. Finally, scanty information is present on the feasibility of the "home-treatment program" for DVT in this category of high-risk patients. In our review we present data on a population of cancer patients evaluated at the Emergency Care in whom we have evaluated: 1) the diagnostic accuracy of PCP and D-dimer test; 2) the safety and efficacy of low molecular weight heparins (LMWH) as "protective anticoagulation" in case of deferred imaging for VTE and 3) the safety and efficacy of home treatment.
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PMID:Managing cancer patients with acute venous thromboembolism: exploring safe alternatives to hospitalisation. 1549 86

The signaling pathway mediated by Wingless-type (Wnt) proteins is highly conserved in evolution. This pivotal pathway is known to regulate cell fate decisions, cell proliferation, morphology, migration, apoptosis, differentiation and stem cell self-renewal. It currently includes the canonical or Wnt/beta-catenin pathway in which Wnt proteins bind to 'frizzled' receptors, which leads to downstream activation of gene transcription by beta-catenin. Second, the noncanonical or beta-catenin-independent pathways are now known to be mediated by three possible mechanisms: (1) the Wnt/Ca(2+) pathway, (2) the Wnt/G protein signaling pathway, and (3) the Wnt/PCP or planar cell polarity pathway. Wnt signaling is implicated at several stages of mammary gland growth and differentiation, and possibly in the involution of mammary gland following lactation. Recent evidence suggests the role of Wnt signaling in human breast cancer involves elevated levels of nuclear and/or cytoplasmic beta-catenin using immunohistochemistry, overexpression or downregulation of specific Wnt proteins, overexpression of CKII and sFRP4, downregulation of WIF-1 and sFRP1, as well as amplification of DVL-1. Further research is required to determine how Wnt signaling is involved in the development of different histological types of breast cancer and whether it promotes the viability of cancer stem cells or not.
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PMID:Wnt signaling pathway in mammary gland development and carcinogenesis. 1731 92

Pneumocystis jiroveci (formerly carinii) pneumonia (PCP) is a serious opportunistic infection in children and adolescents with cancer. It was the most common cause of death among children receiving chemotherapy prior to the inclusion of PCP prophylaxis as part of standard care for children with leukemia. The incidence of PCP has decreased significantly since initiation of prophylaxis; however, breakthrough cases continue to occur. Hematologic malignancies, brain tumors necessitating prolonged corticosteroid therapy, hematopoietic stem cell transplantation, prolonged neutropenia, and lymphopenia are the most important risk factors for PCP in children not infected with HIV. Of children with leukemia, 15-20% may develop PCP in the absence of prophylaxis. Infection with P. jiroveci occurs early in life in most individuals. However, clinically apparent disease occurs almost exclusively in immunocompromised persons. Dyspnea, cough, hypoxia, and fever are the most common presenting symptoms of PCP. Chest radiography and high-resolution CT scans of the chest demonstrate a characteristic ground-glass pattern. Induced sputum analysis and bronchoalveolar lavage are the diagnostic procedures of choice. Gomori's methenamine-silver stain, Geimsa or Wright's stain, and monoclonal immunofluorescent antibody stains are most commonly used to make a diagnosis. However, identification of P. jiroveci DNA using polymerase chain reaction assays in bronchoalveolar lavage fluid is more sensitive. Trimethoprim-sulfamethoxazole (TMP-SMZ; cotrimoxazole) is the recommended drug for the treatment of PCP. Patients who are intolerant of TMP-SMZ or who have not responded to treatment after 5-7 days of therapy with TMP-SMZ should be treated with pentamidine. A short course of corticosteroids is recommended for moderate to severe cases of PCP within the first 72 hours after diagnosis. Mutations in the dihydropteroate synthetase gene may confer resistance to TMP-SMZ; however, the clinical relevance of these mutations is not well established. TMP-SMZ is the most commonly used agent for prophylaxis. Myelosuppression is the most important adverse effect of TMP-SMZ and the most frequent cause for choosing alternative prophylactic agents in children undergoing chemotherapy. Alternative agents for chemoprophylaxis include dapsone, aerosolized pentamidine, and atovaquone. Alternative prophylactic agents must be used in patients developing myelosuppression secondary to TMP-SMZ or dapsone.
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PMID:Management of Pneumocystis jiroveci pneumonia in children receiving chemotherapy. 1792 2

In recent years, clusters of Pneumocystis jirovecii (formerly Pneumocystis carinii) pneumonia (PCP) among immunocompromised individuals have been reported. Mostly, the source of infections was suspected to be within the clinical settings when transplant recipients and PCP patients shared hospital facilities. We report on a cluster of 16 renal transplant recipients positive for P. jirovecii. None of them received anti-Pneumocystis prophylaxis prior to P. jirovecii detection. Epidemiological studies revealed that 15 of them had received kidney transplants at a German university hospital and attended the same inpatient and outpatient clinic from January through September 2006. Multilocus sequence typing (MLST) was performed on the following genes: ITS1, beta-tub, 26S, and mt26S. P. jirovecii DNA was available from 14 patients and showed identical MLST types among these renal transplant recipients. Surprisingly, one patient who was treated at a different nephrological center and reported no personal contact with patients from the renal transplantation cluster harbored an identical P. jirovecii MLST type. Three HIV-positive patients and one bone-marrow-transplanted hematologic malignancy patient--treated at different medical centers--were used as controls, and different MLST types were revealed. Interestingly, in three of the four previously described regions, new alleles were detected, and one new polymorphism was observed in the mt26S region. The epidemiological data and the genotyping results strongly suggest a nosocomial patient-to-patient transmission of P. jirovecii as the predominant transmission route. Therefore, strict segregation and isolation of P. jirovecii-positive/suspected patients in clinical settings seems warranted.
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PMID:Molecular evidence of nosocomial Pneumocystis jirovecii transmission among 16 patients after kidney transplantation. 1821 17

Cu-induced oxidative damage is associated with cancer, diabetes, neurodegenerative and age related diseases. The quest for Cu-chelators as potential antioxidants spans the past decades. Yet, biocompatible Cu-chelators that do not alter the normal metal-ion homeostasis are still lacking. Here, we explored the potential of natural and synthetic nucleotides and inorganic phosphates as inhibitors of the Cu(I)/(II)-induced ()OH formation via either the Fenton or Haber-Weiss mechanisms. For this purpose, we studied by ESR the modulation of Cu-induced ()OH production, from the decomposition of H(2)O(2), by nucleotides and phosphates. ATP inhibited both Cu(I) and Cu(II) catalyzed reactions (IC(50) 0.11 and 0.04mM, respectively). Likewise, adenosine 5'-beta,gamma-methylene triphosphate (AMP-PCP), adenosine 5'-O-(3-thiotriphosphate) (ATP-gamma-S), ADP and tripolyphosphate were identified as good inhibitors. However, AMP and adenosine were poor inhibitors in the Cu(I)-H(2)O(2) system, IC(50) ca. 1.2mM, and radical enhancers in the Cu(II)-H(2)O(2) system. The best antioxidant was adenosine 5'-[beta,gamma-imino] triphosphate (AMP-PNP) (IC(50) 0.05mM at Cu(I)-H(2)O(2) system) which was 15 times more active than the known antioxidant Trolox. ATP and analogues inhibit Cu-induced ()OH formation through an ion chelation rather than a scavenging mechanism. Two phosphate groups are required for making active Fenton-reaction inhibitors. Nucleotides and phosphates triggered a biphasic modulation of the Haber-Weiss reaction, but a monophasic inhibition of the Fenton reaction. We conclude that nucleotides at sub mM concentrations can prevent Cu-induced OH radical formation from H(2)O(2), and hence may possibly prevent oxidative damage.
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PMID:Can nucleotides prevent Cu-induced oxidative damage? 1825 54

Extracts from saffron, the dried stigmata from Crocus sativus L., are being used more and more in preclinical and clinical trials for the treatment of cancer and depression. Because of the known quality problems of saffron, HPLC methods on RP(18) 2.5 microm and monolithic RP(18) material have been developed and validated for quality control including the quantification of crocins 1 to 5, crocetin, picrocrocin and the degradation products, the CIS-crocins. Additionally, a GC-MS method has allowed detection and quantification of the volatile compounds from the pentane extract of saffron. Both systems together allowed the comprehensive characterisation of saffron herbal material and extracts for clinical/preclinical trials. For effective preparation of the respective reference standards, a fast centrifugal partition chromatography (FCPC) method was developed allowing the quick isolation of crocins 1, 2, 5 and picrocrocin in good yields. Using these chromatographic methods and the reference standards, a representative survey of saffron from the global market indicated a high variability of quality, especially concerning the amounts of volatile compounds in saffron samples. A specification for high-quality saffron of >20% crocins, >6% picrocrocin and not less than 0.3% of volatiles, calculated as sum of safranal, isophorone and ketoisophorone, was developed. Because no detailed pharmacological studies are available to explain the clinical effects of saffron for the treatment of cancer and depression, receptor binding studies were performed. Saffron extracts and crocetin had a clear binding capacity at the PCP binding side of the NMDA receptor and at the sigma(1) receptor, while the crocins and picrocrocin were not effective. These data could give biochemical support for the above-mentioned pharmacological effects of saffron.
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PMID:Quality and functionality of saffron: quality control, species assortment and affinity of extract and isolated saffron compounds to NMDA and sigma1 (sigma-1) receptors. 1849 83

Wnt signaling plays an important role in cancer. Signaling is initiated by binding of Wnt ligands to Frizzled cell surface receptors and results in signaling via one of three pathways, the canonical Wnt pathway, which is the best characterized in both normal tissues and in cancer, and two non-canonical Wnt pathways, the Ca(2+)-dependent and the PCP pathways. Canonical Wnt signaling results in beta-catenin accumulation in the cytoplasm, translocation into the nucleus and activation of transcription of Wnt target genes including the c-Myc oncogene. Some cancer types, including colorectal cancer, have mutations in APC and Axin, which are involved in beta-catenin phosphorylation, such that the canonical pathway is constitutively active. Few studies have investigated the role non-canonical Wnt signaling in cancer, or of Wnt signaling on tumor stromal cells. Wnt overexpression is observed in tumor stroma, as is overexpression of the Wnt pathway inhibitors, secreted Frizzled-related proteins and Dickkopf proteins. Interactions between epithelial cells and stromal cells have been observed to activate Wnt signaling in both cell types. Wnt signaling is also observed in tumor blood vessels and is likely to be activated by signals from tumor cells. Current cancer therapies focus on interfering with canonical Wnt signaling in the tumor cells. Future therapeutic targets for interfering with Wnt signaling include cell surface receptors such as the RYK and Ror2 receptors and secreted signaling molecules, which mediate signaling between cancer cells and the stromal environment.
Curr Cancer Drug Targets 2008 Sep
PMID:Importance of Wnt signaling in the tumor stroma microenvironment. 1878 92

Cell identity and tissue morphogenesis are tightly orchestrated during organogenesis, but the mechanisms regulating this are poorly understood. We show that interactions between Wnt11 and the secreted Wnt antagonist secreted frizzled-related protein 5 (Sfrp5) coordinate cell fate and morphogenesis during Xenopus foregut development. sfrp5 is expressed in the surface cells of the foregut epithelium, whereas wnt11 is expressed in the underlying deep endoderm. Depletion of Sfrp5 results in reduced foregut gene expression and hypoplastic liver and ventral pancreatic buds. In addition, the ventral foregut cells lose adhesion and fail to form a polarized epithelium. We show that the cell fate and epithelial defects are due to inappropriate Wnt/beta-catenin and Wnt/PCP signaling, respectively, both mediated by Wnt11. We provide evidence that Sfrp5 locally inhibits Wnt11 to maintain early foregut identity and to allow an epithelium to form over a mass of tissue undergoing Wnt-mediated cell movements. This novel mechanism coordinating canonical and noncanonical Wnt signaling may have broad implications for organogenesis and cancer.
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PMID:Sfrp5 coordinates foregut specification and morphogenesis by antagonizing both canonical and noncanonical Wnt11 signaling. 1898 81


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