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)

Acquired sideroblastic anemia with unilineage dysplasia (WHO RARS) is a clonal stem cell disorder characterized by erythroid dysplasia, mitochondrial accumulation of mitochondrial ferritin, defective erythroid maturation and anemia. A fraction of these patients also show elevated platelet counts; since 2001 this has been defined as RARS with marked thrombocytosis (RARS-T). It has recently been described that around half of RARS-T patients, along with a small subset of other MDS and mixed myelodysplastic/ myeloproliferative disorders, carry the JAK2 mutation, and that MPL mutations are found in single patients. Clinically, RARS-T patients show features of both RARS, essential thrombocythmia (ET) and to some extent also myelofibrosis. However, the degree of anemia and overall survival is more similar to RARS than myeloproliferative disorders. The occurrence of JAK2 mutations and features of ET in RARS is too frequent to be the result of chance only, and it is possible that this link may provide a key to an increased understanding of the genetic abnormalities causing ring sideroblast formation.
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PMID:The role of JAK2 mutations in RARS and other MDS. 1907 58

The purpose of this study was to evaluate the immune status of women with stage I-III breast cancer after receiving external beam radiotherapy (RT). Fourteen stage I-III, estrogen or progesterone receptor-positive or-negative (FER/PR +\-), postsurgical breast cancer patients undergoing a standard course of chemotherapy and radiation were studied. Complete blood counts (CBC) with differential, phagocytic activity, natural killer (NK) cell functional activity, and tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma cytokine activity were measured immediately before and for the six weeks following the completion of radiation therapy. Fatigue levels after completion of RT were measured using the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale. Nonparametric statistical methods (Wilcoxon rank and Spearman correlations) were used to analyze the data. Compared with postchemotherapy, following the completion of RT, these breast cancer patients showed lymphopenia, low functional activity of natural killer lymphocytes, decreased monocyte phagocytic activity, and decreased TNF-alpha production but no neutropenia, no anemia, and no change in interferon-gamma production. Lymphocyte count did not return to normal by the end of the 6-week post-RT observation period. The severity of lymphopenia and low natural killer cell activity was related to RT area but not radiation dose. Patients did not report significant fatigue levels for the 6 weeks after completing RT. Significant decreases in the numbers and functions of cells from both the innate and adaptive immune system were detected following a standard course of radiation therapy for the treatment of breast cancer. Immune deficits in lymphocyte populations and TNF-alpha production, should they persist, may have consequences for immune response to residual or recurrent malignancy following completion of conventional treatment. The use of adjunctive immune therapies which target these specific defects may be warranted in the post-treatment period.
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PMID:Immune defects in breast cancer patients after radiotherapy. 1908 68

Both the 2001 World Health Organisation (WHO) classification of haematopoietic neoplasms and the 2008 WHO classification revision include a distinctive diagnostic category, refractory anaemia with ring sideroblasts and thrombocytosis (RARS-T), to describe those rare patients who have both >or=15% ring sideroblasts and a sustained elevated platelet count. Recently, it has become clear that patients meeting WHO criteria for RARS-T have clonal JAK2(V617F) and MPL(W515) mutations at a similar rate to essential thrombocythaemia (ET). Given that the provisional classification of RARS-T as a myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap syndrome, rather than as a form of MPN (i.e., ET), rests principally upon the presence of ring sideroblasts, which are a non-specific morphological finding, these new molecular results prompt reconsideration of the necessity for a distinctive RARS-T category. Here we review the historical developments that led up the definition of RARS-T as a disease entity, and we discuss conceptual understanding of RARS-T and arguments against continued use of RARS-T as a separate diagnostic category.
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PMID:Is refractory anaemia with ring sideroblasts and thrombocytosis (RARS-T) a necessary or useful diagnostic category? 1912 Mar 70

PTPN11, which encodes the tyrosine phosphatase SHP2, is mutated in approximately 35% of patients with juvenile myelomonocytic leukemia (JMML) and at a lower incidence in other neoplasms. To model JMML pathogenesis, we generated knockin mice that conditionally express the leukemia-associated mutant Ptpn11(D61Y). Expression of Ptpn11(D61Y) in all hematopoietic cells evokes a fatal myeloproliferative disorder (MPD), featuring leukocytosis, anemia, hepatosplenomegaly, and factor-independent colony formation by bone marrow (BM) and spleen cells. The Lin(-)Sca1(+)cKit(+) (LSK) compartment is expanded and "right-shifted," accompanied by increased stem cell factor (SCF)-evoked colony formation and Erk and Akt activation. However, repopulating activity is decreased in diseased mice, and mice that do engraft with Ptpn11(D61Y) stem cells fail to develop MPD. Ptpn11(D61Y) common myeloid progenitors (CMPs) and granulocyte-monocyte progenitors (GMPs) produce cytokine-independent colonies in a cell-autonomous manner and demonstrate elevated Erk and Stat5 activation in response to granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulation. Ptpn11(D61Y) megakaryocyte-erythrocyte progenitors (MEPs) yield increased numbers of erythrocyte burst-forming units (BFU-Es), but MEPs and erythrocyte-committed progenitors (EPs) produce fewer erythrocyte colony-forming units (CFU-Es), indicating defective erythroid differentiation. Our studies provide a mouse model for Ptpn11-evoked MPD and show that this disease results from cell-autonomous and distinct lineage-specific effects of mutant Ptpn11 on multiple stages of hematopoiesis.
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PMID:Leukemogenic Ptpn11 causes fatal myeloproliferative disorder via cell-autonomous effects on multiple stages of hematopoiesis. 1917 68

It can be difficult to establish the clinical significance of the isolation of non-tuberculous mycobacteria (NTM) from the sputum of HIV-infected patients. In this observational study, we have investigated factors associated with having NTM infection. During the period of the study, 10 patients had NTM infection and 14 had NTM colonization. Factors associated with having NTM infections were: CD4 lymphocyte count <50 cells/mL (odds ratio [OR] 10; 95% confidence interval [CI] 1.4-69.3), haemoglobin <11 g/dL (OR 7.2; 95% CI 1.08-47.9), weight loss (OR 9; 95% CI 1.3-63.9), duration of symptoms for more than a month (OR 54; 95% CI 4.2-692.5), the presence of acid fast bacilli (AFB) in sputum (OR 30.3; 95% CI 2.6-348.9) and repeated positive NTM cultures in other sputum samples (OR 4.3; 95% CI 1.6-11.7). In conclusion, we must suspect NTM infection in patients with long-standing symptoms, anaemia, low CD4 lymphocyte count, several positive sputum cultures and when AFB are seen.
Int J STD AIDS 2009 Mar
PMID:Non-tuberculous mycobacteria in the sputum of HIV-infected patients: infection or colonization? 1925 69

Iron metabolism has been implicated in carcinogenesis and several studies assessed the potential role of genetic variants of proteins involved in iron metabolism (HFE C282Y, TFR S142G) in different malignancies. Few reports addressed this issue with relation to chronic myeloproliferative disorders (CMPD). The aims of our study were (a) to examine the potential associations of CMPD development with genetic modifiers of iron metabolism in a large cohort of CMPD patients; (b) to examine associations of genetic variants of proteins involved in iron metabolism; and acquired JAK2 V617F mutation with clinical characteristics of CMPD. HFE C282Y was genotyped in 328 CMPD patients and 996 blood donors as controls, HFE H63D, and TFR S142G were tested in CMPD patients and 171 first time blood donors. JAK2 V617F mutation was tested in CMPD patients and in 122 repeated blood donors. Decreased C282Y allele frequency (allele frequency+/-95% confidence interval) was found in the CMPD group (1.8%+/-1.0%) compared with controls (3.4%+/-0.8%; P=0.048). TFR S142G allele frequency was reduced among V617F-negative CMPD patients (34.8%+/-7.6%) compared with controls (47.8%+/-5.4%; P=0.02). The frequency of JAK2 V617F was 75.9% (249 of 328) in the CMPD group. At presentation, elevated hemoglobin levels were found in V617F-positive patients compared with V617F-negative counterparts (P<0.000). Vascular complications (26.6% versus 15.2%; P=0.039) as well as female gender (57.4% versus 41.8%; P=0.019) were more common in V617F-positive patients. We found that HFE C282Y might be associated with a protective role against CMPD. Because chronic iron deficiency or latent anemia may trigger disease susceptibility for CMPD, HFE C282Y positivity may be a genetic factor influencing this effect.
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PMID:HFE C282Y mutation as a genetic modifier influencing disease susceptibility for chronic myeloproliferative disease. 1925 83

JAK2-inhibitors rapidly reduce spleen enlargement and clinical symptoms in persons with myelofibrosis but have little, if any, effect on the WBC, anemia, decreased platelets or bone marrow fibrosis. Also, JAK2-inhibitors are active in persons with and without the JAK2-mutation. Based on these and other data we suggest that the predominant effect of JAK2-inhibitors in persons with myelofibrosis is on normal rather than the abnormal clones.
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PMID:Hypothesis: how do JAK2-inhibitors work in myelofibrosis. 1945 Aug 78

The prevalence rate of lower gastrointestinal bleeding in patients with AIDS is around 2.6%. A 42-year-old woman with AIDS (CD(4) count 9/microL) and recently treated for disseminated histoplasmosis presented to the emergency room with melena, severe anaemia and fever. A colonoscopy showed an umbilicated colonic nodule mimicking a carcinoma of the colon. The biopsy showed intracytoplasmic microorganisms compatible with Histoplasma capsulatum. She had poor compliance to the itraconazole when discharge on previous admission. Despite the fact that colonic histoplasmosis is uncommon, the mortality rate is around 8% and clinicians should be aware of the clinical presentation of histoplasmosis when recur, especially in patients not taking the itraconazole for long-term treatment.
Int J STD AIDS 2009 Jun
PMID:Recurrent histoplasmosis in AIDS mimicking a colonic carcinoma. 1945 33

Anaemia accelerates disease progression and increases mortality among HIV-infected individuals. Few studies have characterized this problem in developing countries. Haemoglobin values of adults presenting to an HIV tertiary care center in India between 1996 and 2007 were collected (n = 6996). Multivariate logistic regression analysis was performed to examine associations among anaemia, HIV progression and co-morbidities. Overall, anaemia prevalence was 41%. Twenty percent of patients with CD4 counts >500 cells/microL were anaemic, compared with 64% of those with CD4 counts <100 cells/microL (P < 0.001). In multivariate analysis, CD4 count <100 cells/microL (odds ratio [OR]:5.0, confidence interval [CI]:4.0-6.3), underweight body mass index (OR:4.8, CI:3.6-6.5), female gender (OR:3.1, CI:2.8-3.6) and tuberculosis (TB) (OR:1.6, CI:1.4-1.8) were significantly associated with anaemia. In this setting, management of anaemia should focus on antiretroviral therapy, nutritional supplementation and TB control. The high anaemia prevalence among patients meeting criteria for antiretroviral therapy highlights the need for increased access to non-zidovudine nucleoside reverse transcriptase inhibitors in developing countries.
Int J STD AIDS 2009 Jul
PMID:Factors associated with anaemia in HIV-infected individuals in southern India. 1954 92

A total of 186 patients with primary myelofibrosis (PMF) were genotyped for JAK2V617F at diagnosis aimed at analyzing the correlation of mutational status and mutated allele burden with outcome variables, including time to anemia, leukocytosis, leukopenia, thrombocytopenia, massive splenomegaly, leukemia, and with overall survival. A total of 127 JAK2V617F-mutated patients (68% of whole series) were divided in quartiles of V617F allele burden. After a median follow-up of 17.2 months, 23 patients died, 15 because of leukemia. A JAK2V617F mutated status did not impact on the rate of leukemia transformation or overall survival. Patients in the lower quartile had shorter time to anemia and leukopenia and did not progress to large splenomegaly. Furthermore, survival was significantly reduced in the lower quartile compared with upper quartiles and JAK2 wild-type patients. In multivariate analysis, factors associated with reduced survival were age, a blast count more than 1%, and a JAK2V617F burden within first quartile. Causes of death in the lower quartile were represented mainly by systemic infections. We conclude that a low JAK2V617F allele burden at diagnosis is preferentially associated with a myelodepletive rather than myeloproliferative phenotype and represents an independent factor associated with shortened survival in patients with PMF.
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PMID:Identification of patients with poorer survival in primary myelofibrosis based on the burden of JAK2V617F mutated allele. 1954 88


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