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Myelodysplastic Syndromes
Published in Wojciech Gorczyca, Atlas of Differential Diagnosis in Neoplastic Hematopathology, 2014
Outside the context of MDS, ring sideroblasts are seen in other myeloid malignancies, especially myeloproliferative neoplasms or mixed myelodysplastic/myeloproliferative disorders. Sideroblastic anemia can be seen secondary to the toxic effects of alcohol, lead, and drugs (isoniazid), or can be due to copper or pyridoxine deficiency. Ring sideroblasts are also seen in congenital sideroblastic anemias associated with germline mutations of ALAS2, ABCB7, and SLC25A38 genes (among others). In patients with mutations, red blood cells are microcytic. In primary myelofibrosis (PMF), presence of SRSF2 mutations may be associated with ring sideroblasts.
Ataxia Telangiectasia
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Differential diagnoses for AT include ataxia with oculomotor apraxia type 1 (AOA1 or aprataxin deficiency; childhood-onset ataxia), ataxia with oculomotor apraxia type 2 (AOA2 or senataxin deficiency; childhood-onset ataxia, elevated serum AFP concentration), autosomal recessive spinocerebellar ataxia 9 (SCAR9; childhood-onset ataxia, CoQ10 deficiency), infantile-onset spinocerebellar ataxia (IOSCA, childhood-onset ataxia, due to biallelic pathogenic variants in TWNK or C10orf2), sensory ataxic neuropathy with dysarthria and ophthalmoplegia (SANDO, childhood-onset ataxia; due to biallelic pathogenic variants in POLG), X-linked sideroblastic anemia and ataxia (childhood-onset ataxia; due to mutation in ABCB7), microcephaly, seizures, and developmental delay (MCSZ, early seizures and microcephaly, due to biallelic pathogenic variants in PNKP [polynucleotide kinase phosphatase]), Nijmegen breakage syndrome [intellectual impairment and microcephaly; autosomal recessive inheritance; biallelic pathogenic variants in NBN (nibrin); t(7;14) translocation], Mre11 deficiency [ataxia, normal serum AFP concentration; autosomal recessive inheritance; biallelic pathogenic variants in MRE11; t(7;14) translocation], or RAD50 deficiency [microcephaly, developmental delay, mild spasticity, non-progressive ataxia, T cell ALL (Ph+); autosomal recessive inheritance; biallelic pathogenic variants in RAD50; heterozygous NBN pathogenic variant; t(7;14) translocation], RNF168 deficiency (RIDDLE [radiosensitivity, immunodeficiency, dysmorphic features, and learning difficulties] syndrome; ataxia and telangiectasia, growth retardation, microcephaly, immunodeficiency, elevated serum AFP; autosomal recessive inheritance; due to biallelic pathogenic variants in RNF168), cerebral palsy (CP, non-progressive disorder of motor function due to malformation or early damage to the brain; distinctive regional or diffuse spasticity, absence of AT-related laboratory abnormalities), congenital ocular motor apraxia (COMA; delayed development of visual saccades), Friedreich ataxia (FA or FRDA, a common autosomal recessive cerebellar ataxia; ataxia typically appearing between 10 and 15 years of age, absence of telangiectasia and oculomotor apraxia, early absence of tendon reflexes, normal AFP, frequent scoliosis, abnormal EKG features) [1,22].
Improving mitochondrial function in preclinical models of heart failure: therapeutic targets for future clinical therapies?
Published in Expert Opinion on Therapeutic Targets, 2023
Anna Gorący, Jakub Rosik, Joanna Szostak, Bartosz Szostak, Szymon Retfiński, Filip Machaj, Andrzej Pawlik
A potential target for therapy in HF is ATP-binding cassette (ABC) transporters. These are transmembrane proteins that are also present in the cardiac mitochondria [165]. They are responsible for transporting substances from inside and outside the organelles, allowing them to function properly [166]. Dysfunction of ABC probably leads to reduced electron transport chain complex activity, increased amounts of reactive oxygen species and mitochondrial biogenesis and dynamics disruption [167]. In animal model studies, it has been shown that prolonged pressure overload of cardiomyocytes leads to a deficiency of the mitochondrial ATP-binding cassette transporter ABCB7 in the hypertrophied heart, which is associated with changes in mitochondrial function and dynamics. It has been noted that ABCB7 is involved in regulating mitochondrial iron homeostasis, autophagy and that its overexpression reduces the production of hypertrophy markers in cardiomyocytes [168]. Another study noted that ABCB8 reduction in the mouse heart, leads to mitochondrial iron accumulation, increased ROS production and cardiomyopathy [169]. Considering the number of proteins in this group, they represent an interesting therapeutic target for heart failure therapy [167].
A novel tumor-homing TRAIL variant eradicates tumor xenografts of refractory colorectal cancer cells in combination with tumor cell-targeted photodynamic therapy
Published in Drug Delivery, 2022
Zhao Li, Tianshan She, Hao Yang, Tao Su, Qiuxiao Shi, Ze Tao, Yanru Feng, Fen Yang, Jingqiu Cheng, Xiaofeng Lu
The chemotherapeutic MDR of cancer cells is predominantly attributed to overexpressed chemical efflux pumps, such as ABC transporters. To investigate the expression of ABC transporters in tumor tissues derived from CRC patients, public RNA-seq data obtained from TCGA and GTEx were analyzed by GEPIA. As shown in Figure 1(A) and Supplementary Figure S1, bioinformatics analysis demonstrated that the tumor tissue levels of ABC transporters, including ABCB1, ABCB7, ABCC1, ABCC2, ABCC3, ABCC4, ABCC6, ABCC10, ABCC11, and ABCG1, were significantly higher than those in normal tissues, suggesting the MDR of CRC cells. In fact, cytotoxicity assays revealed that CRC cells, such as COLO205, HCT116, LS174T, and HT29, showed resistance (IC50 > 1000 nM) to all tested chemical drugs, including cisplatin, vincristine, doxorubicin, and bortezomib (Figure 1(B)). Interestingly, bioinformatics analysis also demonstrated that death receptors, including DR4 and DR5, were overexpressed in CRC tumor tissues (Figure 1(A)), suggesting the potential of TRAIL as an anticancer agent for CRC. In fact, TRAIL showed robustly (ICs50 < 10 nM) cytotoxicity in CRC cells, including COLO205, HCT116, and LS174T cells overexpressing DR5 and/or DR4 (Figure 1(C, D)), indicating that TRAIL might overcome the chemotherapeutic MDR of CRC cells. Nevertheless, due to the low expression of death receptors, some CRC cells, such as HT29, showed moderate resistance (IC50s > 50 nM) to TRAIL (Figure 1(C, D)), suggesting the need to improve the cytotoxicity of TRAIL in these cells.
Heme metabolism as a therapeutic target against protozoan parasites
Published in Journal of Drug Targeting, 2019
Guilherme Curty Lechuga, Mirian C. S. Pereira, Saulo C. Bourguignon
ATP-binding cassette transporters (ABC transporters) are another superfamily of proteins implicated in the heme uptake process [33]. These proteins can move inorganic ions, metals, peptides, steroids, nucleosides, sugars and many other small molecules across the cell’s surface membrane [34]. In Leishmania donovani, the intracellular heme transporter, LABCG5, modulates parasite growth. Downregulation of this protein inhibits parasite proliferation but this effect is reversed when heme is available [35]. Recently, it was also described a Leishmania major ABC transporter (LmABCB3), which is similar to human ABCB7 (29.3% sequence identity), but has a unique N-terminal extension with a metal binding site required for the proper localisation in mitochondria. LmABCB3 is required for mitochondrial heme synthesis and maturation of cytosolic iron-sulfur clusters. The removal of LmABCB3 allele reduced promastigote proliferation and affected intracellular amastigote replication. Also, in a murine model of cutaneous leishmaniasis, LmABCB3+/− infected mice showed minimal footpad inflammation [36].