Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Studies have shown that BIRC7, a new member of inhibitor of the apoptosis protein family, is expressed in fetal tissues and most solid tumors in humans. However, there are no reported data concerning BIRC7 expression in lymphomas. We investigated the expression of BIRC7, survivin, Bcl-2, Bax, p53 and p170 proteins in 167 cases of non-Hodgkin's lymphoma (NHL) and 10 cases of non-specific lymphadenitis by tissue microarray-based immunohistochemistry. BIRC7 mRNA in three cell lines and 16 cases of NHL were detected by reverse transcriptase-polymerase chain reaction. BIRC7 protein was exhibited in the cytoplasm of cells in 25 (31%) of 80 cases of B-NHLs, 32 (37%) of 87 cases of T-NHLs, and none in non-specific lymphadenitis. The positive rate of BIRC7 was lower than that of survivin in almost all types of NHL with no significant differences, and similar to that of Bcl-2, Bax or p53. There was no correlation of protein expression between BIRC7 and any other detected markers, except p170 in T-NHL (P < 0.001). BIRC7 expression did not correlate with clinic pathologic factors such as sex, age, stage and grade, but overexpression of BIRC7 was positively correlated with aggression of NHL cells (P < 0.05). BIRC7 mRNA expressed in six (38%) of 16 cases of NHLs. BIRC7 mRNA expression was approximately consistent with BIRC7 protein in NHL. Our results indicate that the BIRC7 gene might play a role in the development and aggression of NHL and that the inhibition of BIRC7 expression may be important in NHL treatment.
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PMID:Expression of BIRC7 protein and mRNA in non-Hodgkin's lymphoma. 1684 Feb 3

Apoptosis is an inducible suicide program that occurs in all phases of multicellular as well as in protozoa life and gains more and more importance in all medical disciplines. It is required for normal ontogenesis, organ and tissue remodeling, function of the immune system, prevention of inappropriate cellular proliferation and of survival of inappropriate mutations. Thereby apoptosis represents the key event which guarantees differentiation and maintenance of homeostasis. Terminal differentiation seems to be a special form of apoptosis. Dysregulated apoptosis is associated with various pathological conditions, including inflammation, and cancer. Acanthosis, the hallmark of psoriatic skin, is an example for diminished epidermal apoptosis. Defects in termination of inflammatory reactions occur in atopic dermatitis. Lupus erythematosus may arise due to disturbed apoptosis on several check points of the apoptosis cascade. Experimental evidence suggests a role for Bcl-2 and CD95L in the inhibition of programmed cell death in UV-induced skin cancer or malignant melanoma cells. Thus, it leads to survival of malignant cell clones. The slow growth of basal cell carcinomas is due to an increased apoptosis to mitosis ratio. Spontaneous regression of tumors is associated with increased apoptotic rates. Malignant melanoma cells characteristically show different anti-apoptotic strategies which underscore its aggressive behavior and its refractory towards classic therapeutic regimens. Additionally, induction of apoptosis in tumor infiltrating immune cells seems to be a strategy by which the tumor escapes from an immunological attack (tumor counter-attack). Since apoptosis is either absent or altered under pathological conditions therapeutic procedures should correct this. Established therapies like dithranol, vitanin-D3 analogs, low-dose methotrexate, induce apoptosis. Future treatment regimens like vaccine and gene therapy are designed to selectively induce apoptosis. Therefore, pharmacological agents and therapeutic strategies interfering with disrupted apoptosis regulation could improve the therapeutic arsenal in the future.
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PMID:Apoptosis in physiological and pathological skin: implications for therapy. 1690 Jun 61

Bcl-2 overexpression is an important mechanism underlying the aggressive behavior of prostate cancer cells and their resistance to radio- or chemotherapy. HA14-1, a recently discovered organic Bcl-2 inhibitor, potently induces apoptosis in various human cancer cells. Sequential exposure of radioresistant LNCaP (wild-type (wt) p53), LNCaP/Bcl-2 (wt p53) and PC3 (mutant p53) prostate cancer cells to a minimally cytotoxic concentration of 10 microM HA14-1 for 1 h followed by 1-6 Gy gamma radiation, resulted in a highly synergistic (combination index <1.0) induction of cell death as determined by an apoptosis assay at 72 h, and a clonogenicity assay at 12 days, after the initial treatment. The reverse treatment sequence did not cause a synergistic induction of cell death. When compared to individual treatments, cell death induced by the combined treatment was associated with dramatically increased reactive oxygen species (ROS) generation, c-Jun N-terminal kinase (JNK) activation, Bcl-2 phosphorylation, cytochrome c release, caspase-3 activation and DNA fragmentation. Exposure to either 200 microg/ml of the antioxidant alpha-tocopherol or 10 microM JNK inhibitor SP600125 before the combined treatment resulted in decreased activation of JNK and caspase-3 as well as decreased DNA fragmentation. However, treatment with the pancaspase inhibitor carbobenzoxyl-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone before the combined treatment inhibited apoptosis without affecting JNK activation, and this inhibitory effect was enhanced in the presence of alpha-tocopherol or SP600125. Taken together, our results indicate that HA14-1 potently sensitizes radioresistant LNCaP and PC3 cells to gamma radiation, regardless of the status of p53. ROS and JNK are important early signals that trigger both caspase-dependent and -independent cell death pathways and contribute to the apoptotic synergy induced by the combined treatments.
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PMID:Overcoming the radioresistance of prostate cancer cells with a novel Bcl-2 inhibitor. 1690 21

Intravascular large B-cell lymphoma (IVLBCL) is pathologically distinct with a broad clinical spectrum and immunophenotypic heterogeneity. A series of 96 patients with IVLBCL (median age, 67 years; range, 41-85 years; 50 men) was reviewed. Anemia/thrombocytopenia (84%), hepatosplenomegaly (77%), B symptoms (76%), bone marrow involvement (75%), and hemophagocytosis (61%) were frequently observed. The International Prognostic Index score was high or high-intermediate in 92%. For 62 patients receiving anthracycline-based chemotherapies, median survival was 13 months. CD5, CD10, Bcl-6, MUM1, and Bcl-2 were positive in 38%, 13%, 26%, 95%, and 91% of tumors, respectively. All 59 CD10- IVLBCL cases examined were nongerminal center B-cell type because they lacked the Bcl-6+MUM1- immunophenotype. CD5 positivity was associated with a higher prevalence of marrow/blood involvement and thrombocytopenia and a lower frequency of neurologic abnormalities among patients with CD10-IVLBCL. Compared with 97 cases of de novo CD5+CD10-diffuse LBCL, 31 cases of CD5+CD10-IVLBCL exhibited higher frequencies of poor prognostic parameters, except age. Multivariate analysis in IVLBCL revealed that a lack of anthracycline-based chemotherapies (P<.001, hazard ratio [HR]: 9.256), age older than 60 years (P=.012, HR: 2.459), and thrombocytopenia less than 100x10(9)/L (P=.012, HR: 2.427) were independently unfavorable prognostic factors; CD5 positivity was not. Beyond immunophenotypic diversity, IVLBCL constitutes a unique group with aggressive behavior.
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PMID:Intravascular large B-cell lymphoma (IVLBCL): a clinicopathologic study of 96 cases with special reference to the immunophenotypic heterogeneity of CD5. 1698 83

We studied 29 cases of basal cell carcinoma of the prostate including what others call adenoid cystic carcinoma of the prostate. Patients' age ranged from 42 to 89 (mean 69) years. The most common methods of diagnosis was transurethral resection (TURP) (n=29) and needle biopsy (n=9). In 28/29 cases, slides were reviewed and 24 (86%) cases showed more than 1 pattern: adenoid cysticlike (AC-P) pattern and small solid nests with peripheral palisading were the most predominant patterns, each seen in 18 cases (64%). Other patterns included: basal cell hyperplasialike in 9 cases (32%); small tubules occasionally lined by a hyaline rim in 9 cases (32%), with 4 of these cases also demonstrating intermingling cords of cells; and large solid nests in 8 cases (28.5%), 5 of which had central necrosis. Fourteen cases of small nests and tubules were centrally lined by eosinophilic cells. Desmoplasia was noted in 20 (71%) cases. Infiltration around benign glands was seen in 10 (36%) cases, with predominantly small nests and AC-P. Invasion of thick muscle bundles of the bladder neck was seen in 10 of 21 TURP cases. Perineural invasion was noted in 3 cases with AC-P and 1 case of small basaloid nests. Perineural and vascular invasion was seen in 2 basal cell carcinomas with large basaloid nests. Mitoses ranged from 0 to 60/10 hpf (mean=4). bcl2 was diffusely positive in 22/24 (92%) cases. Ki67 ranged from 2% to 80% (mean=23%). Ki67 > or =20% was seen in 13 (56.5%) cases, including all patterns except small solid nests. Basal cell markers (HMWCK, p63) either: (1) highlighted multiple layers of cells in 15/25 (60%) cases with sparing of the inner most luminal layer; (2) labeled just the outermost layers in 6/25 (24%) cases; or (3) reacted with only a few scattered cells in 4/25 (16%) cases (3 with large solid nests with central necrosis, 1 with tubules and cords). Seven patients had RP with: 5/7 showing extraprostatic extension with 1/5 also showing seminal vesicle involvement and 2/5 also with a positive margin; 1/7 having organ confined disease; and 1/7 showing no residual disease. An additional 11 cases showed extraprostatic extension on TURP with bladder neck invasion (n=10) or periprostatic adipose tissue invasion (n=1). Of 29 (65.5%) cases, 19 had follow-up > 1 year with a mean of 4.3 years (1 to 19 y). Of 19 (77%) cases, 14 had no evidence of disease after 1 to 19 (mean 5.8) years. Of 19 patients, 4 locally recurred with 2 after TURP, 1 after enucleation, and 1 after RP. Metastases developed in 4/29 patients: 1 in lung, 1 in lung and liver, 1 in lung, bone and liver, 1 in penile urethra. Basal cell carcinomas are rare tumors with a broad morphologic spectrum. These tumors predominantly show an indolent course with local infiltrative behavior. A small subset behaves aggressively with local recurrences and distant metastases. The most common morphology among those with an aggressive behavior is large solid nests more often with central necrosis, high Ki67%, and less staining with basal cell markers.
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PMID:Basal cell carcinoma of the prostate: a clinicopathologic study of 29 cases. 1746 Apr 52

Odontogenic keratocyst (OKC) has an aggressive clinical course and a high tendency toward recurrence, while orthokeratinized odontogenic cyst has different characteristics and does not show aggressive behavior. Bax and bcl-2 are two important anti-apoptotic and pro-apoptotic factors of the bcl-2 family. The different outcomes of theses two cysts could be related to these apopto-proteins. Twenty-eight cases of OKC and nine cases of orthokeratinized odontogenic cyst (OOC) were stained for bax and bcl-2 proteins. Immunoreactivity for bcl-2 was detected in the basal layer of OKCs, while OOCs were completely negative in the basal layer (P<0.001). Bcl-2 expression in the whole thickness of OKCs was also significantly higher than in OOCs (P<0.001). Bax expression did not show any statistically significant difference between the two cysts (P=0.077). The different behaviors of these cysts are compatible with their immunohistochemical view. Lower expression of bcl-2 in OOC ends in less aggressiveness and a lower tendency toward recurrence. Bax seems to play no significant role by itself; however, the bcl-2/bax ratio is probably a determinant factor for different outcomes.
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PMID:Evaluation of bax and bcl-2 expression in odontogenic keratocysts and orthokeratinized odontogenic cysts: A comparison of two cysts. 1936 40

Accumulating evidence indicates that oxidative stress is involved in the physiopathology of liver fibrogenesis. However, amid the global context of hepatic oxidative stress, the specific role of hepatocyte mitochondrial dysfunction in the fibrogenic process is still unknown. The aim of this study was to determine whether a targeted protection of hepatocytes against mitochondrial dysfunction could modulate fibrosis progression. We induced liver fibrogenesis by chronic carbon tetrachloride treatment (3 or 6 weeks of biweekly injections) in transgenic mice expressing Bcl-2 in their hepatocytes or in normal control mice. Analyses of mitochondrial DNA, respiratory chain complexes, and lipid peroxidation showed that Bcl-2 transgenic animals were protected against mitochondrial dysfunction and oxidative stress resulting from carbon tetrachloride injury. Picrosirius red staining, alpha-smooth muscle actin immunohistochemistry, and real-time PCR for transforming growth factor-beta and collagen alpha-I revealed that Bcl-2 transgenic mice presented reduced fibrosis at early stages of fibrogenesis. However, at later stages increased nonmitochondrial/nonhepatocytic oxidative stress eventually overcame the capacity of Bcl-2 overexpression to prevent the fibrotic process. In conclusion, we demonstrate for the first time that specific protection against hepatocyte mitochondrial dysfunction plays a preventive role in early stages of fibrogenesis, delaying its onset. However, with the persistence of the aggression, this protection is no longer sufficient to impede fibrosis progression.
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PMID:Protection against hepatocyte mitochondrial dysfunction delays fibrosis progression in mice. 1980 50

The purpose of this study was to evaluate whether 2-methoxyestradiol (2-ME(2)), a promising anticancer agent, modulates Barrett's esophageal adenocarcinoma (BEAC) cell growth and behavior through a cellular pathway involving beta-catenin in partnership with E-cadherin, which seems to play a critical role in the induction of antitumor responses in cancer cells. We found that 2-ME(2) markedly reduced the BEAC cell proliferation through regulating apoptotic machinery such as Bcl-2 and Bax. It may nullify the aggressive behavior of the cells by reducing the migratory behavior. Expressions of beta-catenin and E-cadherin and binding of these two proteins is activated in a 2-ME(2)-dependent fashion in Bic-1 cells. Moreover, overexpressions of these two proteins may be due to the stabilization of these proteins by 2-ME(2). We found that 2-ME(2)-induced antimigratory effects are mediated through the beta-catenin-E-cadherin signaling pathways. In view of these results, we determined whether 2-ME(2) reduces BEAC tumor growth. Administration of 2-ME2 significantly decreased the growth of BEAC cells xenografted on the flank of nude mice. The evidence presented points out that the effect of 2-ME(2) on beta-catenin-orchestrated signal transduction plausibly plays a multifaceted functional role to inhibit the proliferation and cell migration of 2-ME(2)-treated malignant cells and it could be a potential candidate in novel treatment strategies for Barrett's esophageal adenocarcinoma.
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PMID:2-methoxyestradiol inhibits Barrett's esophageal adenocarcinoma growth and differentiation through differential regulation of the beta-catenin-E-cadherin axis. 2019 89

Basal cell carcinoma is a very common malignant skin tumor that rarely metastasizes but is often locally aggressive. In a number of studies conducted by different investigators, Bcl2, beta-catenin, cyclin D1, hMSH2, and alpha-smooth muscle actin have been reported to have potential for predicting basal cell carcinoma aggressiveness. However, these reports were inconclusive and sometimes contradictory. We therefore studied the expression and topographic locations (tumor versus stroma) of all these gene products in a group of clinically proven aggressive basal cell carcinomas (n = 30) and randomly selected control cases of nonaggressive basal cell carcinomas (n = 33). The results were subjected to statistical analysis with Mann-Whitney test and logistic regression. The accuracy of the resulting significant discriminating criteria was further tested using the omnibus tests of model coefficients. With multivariate analysis, differential expression of Bcl-2, beta-catenin, and cyclin D1 was not significantly different between aggressive and nonaggressive tumors. hMSH2 expression was up-regulated in the aggressive tumors (P = .005). Alpha-smooth muscle actin was expressed by tumor cells in both study groups, but stromal expression of alpha-smooth muscle actin was restricted to the aggressive tumors and highly predictive of aggressive behavior (P < .001; accuracy, 87%). Logistic regression combining the expression of alpha-smooth muscle actin and hMSH2 yielded a predictive model with 97% accuracy (P < .001). These data show conclusively that aggressive basal cell carcinomas express alpha-smooth muscle actin in the stroma, whereas nonaggressive basal cell carcinomas express alpha-smooth muscle actin in the tumor cells, and that stromal expression of alpha-smooth muscle actin is an accurate, reliable, and easy to use marker of aggressiveness in basal cell carcinomas and can be used in clinical practice for surgical therapeutic decisions.
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PMID:Stromal expression of actin is a marker of aggressiveness in basal cell carcinoma. 2038 Nov 22

Most patients with myelodysplastic syndrome (MDS) are classified at diagnosis as having a low/INT-I or INT-II/high risk disease, based on the classical International Prognostic Scoring System (IPSS) criteria. The low/INT-I risk patients are usually managed mildly with supportive care, including red blood cell (RBC) transfusions, erythroid stimulating agents (ESAs), other cytokines (G-CSF, platelet stimulating agents), as well as thalidomide and lenalidomide. Some patients receive immunosuppressive therapy, and iron chelation is indicated in iron overloaded patients. Aggressive approach (hypomethylating agents, chemotherapy and stem cell transplantation) is usually not applied in such patients. Occasionally, we observe a "low risk" patient with rapid progression of disease and poor outcome. Can we identify demographic, clinical, laboratory, cellular-biological and/or molecular parameters that can predict "poor prognostic features" (PPF) in "low risk" MDS patients? Clinical and laboratory parameters have been reported to be associated with poor prognosis, in addition to the known "classical" IPSS criteria. These include older age, male gender, poor performance status, co-morbidities, degree of anemia, low absolute neutrophile count (ANC) and platelet counts, RBC transfusion requirements, high serum ferritin, high LDH, bone marrow (BM) fibrosis, increased number of BM CD34+ cells and multi-lineage dysplasia. Certain immunophenotypes (low CD11b, high HLA-Dr, CD34, CD13 and CD45), clonal granulocytes, multiple chromosomal abnormalities, chromosomal instability, short telomeres and high telomerase activity were also reported as PPF. Studies of apoptosis identified Bcl-2 expression and high caspase 3 as PPF, while the reports on survivin expression have been confusing. Recent exciting data suggest that methylation of p15 INK4b and of CTNNA1 (in 5q-), high level of methylation of other genes, absence of the TET2 mutation, down regulation of the lymphoid enhancer binding factor 1 (LEF1), mutation of the polycomb-associated gene ASXL1 and a specific 6-gene signature in gene expression profiling - are all associated with poor prognosis in MDS. Do we have data suggesting a different treatment for "low risk" MDS patients displaying PPF? Two teams, the combined Nordic-Italian and the GFM groups have reported an improved survival with ESAs. The GFM has achieved prolonged survival with iron chelation. Recently, encouraging data with survival advantage in azacitidine-treated patients have been published, including a few INT-I patients. Finally, data suggest that low/INT-I MDS patients who undergo stem cell transplantation (SCT0 do better than INT-II/high risk patients). In summary, some patients, classified as "low risk MDS" carry PPF. An appropriate therapeutic approach is indicated. Future updated classifications and prospective trials may lead to a better outcome.
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PMID:The lower risk MDS patient at risk of rapid progression. 2057 98


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