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

Primary biliary cirrhosis is characterized by the immune-mediated, progressive destruction of interlobular bile ducts. Lymphoid cells migrate into the biliary epithelial layer through integrin alpha(4)/fibronectin interaction and are responsible for chronic destructive cholangitis. The bile ducts express intercellular adhesion molecule-1 (ICAM-1) and vascular cellular adhesion molecule-1 (VCAM-1), and infiltrating lymphocytes express LFA1 and VLA4, facilitating their interaction. Epithelioid granulomas contain foamy cells ingesting biliary lipids, and CD1d was detectable in epithelioid granulomas, suggesting that the biliary substance(s) which are leaked is a trigger for chronic destructive cholangitis. Apoptotic biliary destruction is brought about by antigen-specific and non-specific reactions. Shrunken biliary epithelial cells with pyknotic nuclei positive for terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelling (TUNEL) may reflect apoptotic processes. Increased expression of caspase-3 and -8 with DNA fragmentation factor on the bile ducts may reflect molecular events during apoptosis, and down-regulation of Bcl-2 of biliary epithelial cells seems to facilitate apoptosis. Multiple factors, particularly the Fas system, are stimuli of apoptosis. Anoikis with decreased biliary expression of integrin 6, a ligand for laminin, may also be involved in biliary epithelial apoptosis.
Baillieres Best Pract Res Clin Gastroenterol 2000 Aug
PMID:Destruction of bile ducts in primary biliary cirrhosis. 1097 14

The heterogeneity of acute myeloid leukemia (AML) has been established by many new insights into the diagnosis, pathogenesis, clinical manifestations, treatment, and prognosis of patients with AML. Morphology remains the foundation for the diagnosis. However, additional diagnostic studies, including immunophenotyping, cytogenetic evaluation, and molecular genetic studies, are necessary to develop treatments because specific subtypes of AML can now be approached with targeted therapy. Acute promyelocytic leukemia (APL), defined by a single molecular abnormality, is now treated with specific targeted therapy, all-trans retinoic acid (ATRA), and this subtype of AML is now highly curable. Currently, a number of agents have been explored in AML, including anti-CD33 antibodies and immunoconjugate drugs, inhibitors of multidrug resistance proteins, farnesyl transferase inhibitors, tyrosine kinase inhibitors, anti-Bcl-2 transcription agents, and inhibitors of mammalian target of rapamycin (mTOR). New alkylating agents, and purine analogs such as Cloretazine and clofarabine, affect DNA and ribonucleoside reductases, respectively. These agents have shown promise in small studies. Large phase III studies will address whether these are effective in inducing complete responses. Combining targeted agents with chemotherapy may improve the response rates. The plan for the future is to find therapeutic strategies that are specific for patients based on the specific biology of the disease. Future studies will investigate combinations of targeted therapies with each other and with chemotherapies to maximize the inhibition of multiple pathways present in AML. Additionally, evaluation of the identified prognostic factors and gene mutations will enable further pathologic classification of patients with AML.
Best Pract Res Clin Haematol 2006
PMID:New agents for the treatment of acute myeloid leukemia. 1651 28

Bestrophin 3 (Best-3) is expressed in a variety of tissues, such as cardiac, smooth muscle and renal tissues, and it is highly expressed in rat basilar arterial smooth muscle cells (BASMCs). Lee et al. (Biochim Biophys Acta 1823:1864-1876, 2012) reported that Best-3 prevented apoptotic cell death induced by endoplasmic reticulum stress. In the present study, we used small interference RNA (siRNA) and bestrophin 3 cDNA transfection strategy to investigate whether Best-3 can provide a protective effect on apoptosis induced by hydrogen peroxide (H2O2) in BASMCs and studied the underlying mechanisms. We found that silencing of Best-3 with siRNA resulted in an increased H2O2-induced apoptosis and a decreased cell viability, whereas overexpression of Best-3 significantly prevented the apoptotic cell death and increased the cell viability. Overexpression of Best-3 could stabilize the mitochondrial membrane potential, increase the ratio of Bcl-2/Bax, and decrease cytochrome c release and caspase-3 activation. In contrast, silencing of Best-3 produced the opposite effects. Our present data strongly suggest that Best-3 inhibits apoptosis induced by H2O2 in BASMCs through mitochondria dependent pathway.
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PMID:Mitochondria dependent pathway is involved in the protective effect of bestrophin-3 on hydrogen peroxide-induced apoptosis in basilar artery smooth muscle cells. 2346 20

Treatment of patients with chronic lymphocytic leukemia and other B cell malignancies is evolving very rapidly. We have observed the quick transition during the last couple of years, from chemo-immunotherapy based treatments to oral targeted therapies based on B cell receptor signaling and Bcl-2 inhibitors, as well as the increasing use of second generation glyco-engineered antibodies. The next wave of revolution in the treatment for this conditions is approaching and it will be based on strategies that harness the power of the immune system to fight cancer. In the center of this biotechnological revolution is cellular engineering, the field that had made possible to redirect the immune system effector cells to achieve a more effective and targeted adoptive cellular therapy. In this chapter, we will review the historical context of these scientific developments, the most recent basic and clinical research in the field and some opinions regarding the future of adoptive cellular therapy in CLL and other B cell malignancies.
Best Pract Res Clin Haematol 2016 03
PMID:Adoptive cellular therapy for chronic lymphocytic leukemia and B cell malignancies. CARs and more. 2774 68

Despite the availability of novel targeted agents, TP53 defects remain the most important adverse prognostic factor in chronic lymphocytic leukemia (CLL). Detection of deletion of TP53 locus (17p deletion) by fluorescent in situ hybridization (FISH) has become standard and performed prior to every line of treatment as the incidence dramatically increases as relapses occur. As monoallelic mutations of TP53 equally affect outcome, novel methods are being developed to improve detection of TP53 defects and include next-generation sequencing (NGS) and functional assays. TP53 defects highly affect outcome of immunochemotherapy but also alter response durations of tyrosine kinase inhibitors. Although BCR-targeting agents and Bcl-2-inhibitos have achieved durable responses in some patients with TP53 defects, long-term follow-up is currently lacking. In this review biological and clinical consequences of TP53 dysfunction as well as applicability of currently available methods to detect TP53 defects are described. In addition, proposed novel therapeutic strategies specifically for patients with TP53 dysfunction are discussed. In summary, the only curative treatment option for TP53-defective CLL is still allogeneic hematopoietic stem cell transplantation. Other treatment strategies such as rationale combinations of agents with different (TP53 independent) targets, including kinase inhibitors and inhibitors of anti-apoptotic molecules but also immunomodulatory agents need to be further explored.
Best Pract Res Clin Haematol 2016 03
PMID:TP53 dysfunction in CLL: Implications for prognosis and treatment. 2774 75

Follicular lymphoma is one of the most common non-Hodgkin's lymphomas. Although current frontline regimens are associated with high response rates, most patients still relapse. When progression is discovered, re-establishing the diagnosis and ruling out transformation in paramount. The outcomes following relapse have been improving due to the activity and increasing availability of novel agents with various mechanisms of action. Despite these advances, single agent activity is limited and the disease remains incurable in the majority of cases. Examples of drug classes with promising activity in relapsed disease include anti-CD20 monoclonal antibodies, immunomodulatory drugs (IMiDs), small molecule tyrosine kinase inhibitors, bcl2 inhibitors, epigenetic modifiers, conjugated antibodies, and checkpoint inhibitors. Many drugs in each class are associated with unique, variable and often surprising toxicity profiles. Combination studies are currently underway with novel-novel combinations and with traditional chemotherapy regimens. This overview will discuss the results of several recent studies exploring activity of novel drugs in relapsed follicular lymphoma.
Best Pract Res Clin Haematol 2018 03
PMID:Novel agents for relapsed and refractory follicular lymphoma. 2945 65