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Cancer
Published in Sally Robinson, Priorities for Health Promotion and Public Health, 2021
Bone marrow produces red blood cells, platelets and white blood cells. Blood cells begin life as immature stem cells inside the marrow. Lymphoid stem cells develop into white blood cells called lymphocytes. Myeloid stem cells develop into white blood cells (monocytes and granulocytes), red blood cells and platelets. A mutation in the stem cells will cause the production of abnormal blood cells. These do not form tumours but accumulate in the blood stream. Leukaemia is cancer of white blood cells. Acute forms develop very quickly, and chronic forms develop slowly. Acute myeloid leukaemia starts with immature, abnormal myeloid blood cells in the bone marrow (Figure 14.2)Acute lymphoblastic leukaemia starts with immature, abnormal lymphocytes in the bone marrowChronic lymphocytic leukaemia starts with almost mature, abnormal lymphocytesChronic myeloid leukaemia starts with almost mature, abnormal granulocytes
Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Many cases are now known in which specific kinases are mutated in cancer cells. For example, a mutation of the protein kinase Abl (i.e., the cytoplasmic tyrosine kinase Bcr-Abl, which is constitutively active) is the main cause of Chronic Myeloid Leukemia (CML); it is present in virtually all cases of CML and is used as a diagnostic feature for this disease. It is also present in 15–30% of cases of adult acute lymphoblastic leukemia (ALL). This mutation was used as the basis for the design of inhibitors such as imatinib (Gleevec™). Other examples include mutations of the EGFR and B-RAF kinases which allowed the development of gefitinib (IressaTM) for lung cancer and vemurafenib (ZelborafTM) for melanoma, respectively.
On patients’ difficulties in understanding medical risks and the aims of clinical risk communication
Published in Ulrik Kihlbom, Mats G. Hansson, Silke Schicktanz, Ethical, Social and Psychological Impacts of Genomic Risk Communication, 2020
Leukaemia is a group of cancers in the myeloid and lymphoid blood cells. In haematological malignancies, the presence of specific somatic mutations has also extensively been used to stratify patients into risk categories that might benefit from risk-adapted treatment, particularly consolidation treatments with autologous or allogeneic haematopoietic stem cell transplantations – i.e. bone marrow transplantation. Clearly, the clinical context of risk communication and consultation with leukaemia patients is very complex. Depending on age, specific mutations and phase in the illness trajectory, many of these patients face complex treatment options that involve different and very severe kinds of risks, especially for leukaemia patients facing a bone marrow transplantation. These decisions should consider both short-term and long-term adverse effects as well as the patient’s own attitudes towards risks and counselling. These effects, including life-threatening infections, severe chronic graft-versus-host diseases, and late malignancies, require successfully managing the challenge of communicating risk to already vulnerable patients.
An update on the safety of olaparib for treating ovarian cancer
Published in Expert Opinion on Drug Safety, 2022
Kelsi Cottrell, Caroline L. Clark, Richard T. Penson
While the immediate toxicities related to olaparib can be well-known, the long-term effects of this drug are relatively unstudied. Long-term effects of PARP inhibitor treatment are primarily thought to be secondary-myelodysplastic syndrome (MLS) and acute myeloid leukemia (AML) and these conditions were actively solicited during the overall survival follow-up periods in SOLO-2 and SOLO-1 trials [7,21,23]. In patients with solid tumors, such as those with ovarian cancer, these conditions may remain latent for 10–15 years [24]. Myelodysplastic syndromes are a group of myeloid cell disorders that present as peripheral blood cytopenias and have the potential to escalate to AML [25]. AML occurs when bone marrow becomes genetically damaged, resulting in the overproduction of immature myeloid cells that, with healthy origins, would continue to differentiate into mature types of white blood cells, but due to their underlying genetic injury, instead stagnate at an unfinished point in their development and overcrowd the circulatory system [25]. The magnitude of risk of these two conditions was underappreciated in previous trials, with 8% of patients on olaparib contracting MLS/AML in the SOLO-2 trial and 7% of patients on niraparib contracting MLS/AML in the NOVA trial [26].
Study on hypoxia-inducible factor and its roles in immune system
Published in Immunological Medicine, 2021
Ali Asghar Kiani, Hossein Elyasi, Shadiyeh Ghoreyshi, Negar Nouri, Ali Safarzadeh, Amirhossein Nafari
Glycolytic enzymes play important roles in TH17 cells and Treg cell metabolisms and can be regulated by HIF-1α. HIF1-α dependent glycolytic pathway expression was observed in developing TH17 Cells, but lack of HIF1α improves Treg cell differentiation and potentiates mice to be protected against neuroinflammation. Bacterial infection promotes HIF1-α expression in normoxic conditions. It is demonstrated that HIF-1α loss in myeloid cells of mice reduces the ability of the immune system to inhibit infections. Myeloid cells act as the most important cells in innate immunity. HIF-1α regulates the glycolytic capacity of myeloid cells, and knockdown of it results in the disturbance of myeloid cell function [107]. HIF-1α can be upregulated in macrophages when an organ is deprived of oxygen, and overexpression of HIF-1α potentiates macrophages phagocytosis. Th1 cytokines upregulate HIF-1α, while HIF-2α will be upregulated by Th1 cytokines in macrophages, and isoforms of HIF-2α play important roles in NO homeostasis by macrophages. NO causes apoptosis, growth, and proper functioning of immune cells such as macrophages and demonstrated protective activity against inflammation in autoimmunity. HIF-1α can induce IFN-γ by binding to its promoter and improve immune responses such as presenting antigens and cytokines produced by T cells. It is elucidated that HIF-1α regulates neutrophil survival in the hypoxic condition through targeting of NF-κB [108,109].
Nutritional Indexes as Predictors of Survival and Their Genomic Implications in Gastric Cancer Patients
Published in Nutrition and Cancer, 2021
Yesennia Sánchez, Felipe Vaca-Paniagua, Luis Herrera, Luis Oñate, Roberto Herrera-Goepfert, Guiselle Navarro-Martínez, Dennis Cerrato, Clara Díaz-Velázquez, Ericka Marel Quezada, Claudia García-Cuellar, Diddier Prada
The FBXW7 gene codes for an E3 ubiquitin ligase that targets different oncogene protein products; hence FBXW7 is considered a tumor suppressor gene (29). The loss of this gene has been associated with poor prognosis in gastric cancer patients, as well as poor response to neoadjuvant chemotherapy (30). In the case of TET2, it was mutated in almost 3% of the TCGA cohort (10). These genes, FBXW7 and TET2, have been classified as tumor suppressor genes because of their role in DNA demethylation by methylcytosine oxidation. Their mutations have been mainly reported in myeloid leukemia. In gastric cancer, it has been shown that TET2 inhibits gastric cancer cell growth by upregulating the long non-coding RNA ANRIL and increasing the expression of P15, p16, and p14 proteins (31).