Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute lymphoblastic leukemia (ALL) is currently treated with an intense regimen of chemotherapy yielding cure rates near 80%. However, additional changes using available drugs are unlikely to provide significant improvement in survival. New therapies are warranted given the risk of severe therapy-associated toxicities including infertility, organ damage, and secondary malignancy. Here, we report ectopic expression of the receptor tyrosine kinase Mer in pediatric B-cell ALL. Inhibition of Mer prevented Erk 1/2 activation, increased the sensitivity of B-ALL cells to cytotoxic agents in vitro by promoting apoptosis, and delayed disease onset in a mouse model of leukemia. In addition, we discovered cross-talk between the Mer and mammalian target of rapamycin (mTOR) signaling pathways. Our results identify Mer as a novel therapeutic target in ALL and suggest that inhibitors of Mer will interact synergistically with currently used therapies. This strategy may allow for dose reduction resulting in decreased toxicity and increased survival rates. Mer is aberrantly expressed in numerous other malignancies suggesting that this approach may have broad applications.
 ...
PMID:Mer receptor tyrosine kinase is a novel therapeutic target in pediatric B-cell acute lymphoblastic leukemia. 2275 64

The human endometrium is receptive for implantation of a blastocyst for only 4-5 days in each menstrual cycle. Failure of implantation is a major reason for infertility in women and the inability to achieve endometrial receptivity is responsible for much of the failure of reproductive technologies. Endometrial receptivity requires changes in the uterine luminal and glandular cells, particularly in terms of their secretory capacity and altered expression of adhesion molecules. In parallel with these changes, decidualisation (differentiation) of the endometrial stroma is initiated in women during the receptive phase, regardless of the presence of a blastocyst. Increased leucocyte numbers are also important. The microenvironments provided by the endometrium during the receptive phase and that support implantation are highly complex and constantly changing as implantation progresses. The present review provides a comprehensive overview of the cellular and molecular events of human implantation. It also summarises work from our laboratories emphasising the functional importance of proprotein convertase 6, along with key cytokines (interleukin-11, leukaemia inhibitory factor, activin A) and chemokines (including CX3CL1 and CCL14), during implantation. Of particular importance is how these mediators contribute to receptivity and how they are disturbed in infertile women. Factors that are critical for uterine receptivity may also be manipulated to provide new contraceptive strategies for women.
 ...
PMID:Society for Reproductive Biology Founders' Lecture 2009. Preparing fertile soil: the importance of endometrial receptivity. 1969 96

The ability of embryonic germinal cells (EG) to differentiate into primordial germinal cells (PGCs) and later into gametes during early developmental stages is a perfect model to address our hypothesis about cancer and infertility. This protocol shows how to isolate primordial germinal cells from developing gonads in 10.5-11.5 days post coitum (dpc) mouse embryos. Developing gonadal ridges from mouse embryos (C57BL6J) were dissociated by mechanical disruption with collagenase, then plated in a mouse embryo fibroblast feeder layer (MEF-CF1) that was previously mitotically inactivated with mitomycin C in the presence of knockout media and supplemented with Leukemia Inhibitor Factor (LIF), basic Fibroblast Growth Factor (bFGF), and Stem Cell Factor (SCF). Using these optimized methods for PCG identification, isolation, and establishment of culture conditions permits long term cultures of EG cells for more than 40 days. The embryonic germinal cell lines showed embryonic phenotype and expression of common used markers of the pluripotent state. Isolation and derivation of germinal cells in culture provide a tool to understand their development in vitro and offer the opportunity to monitor cumulative damage at genetic and epigenetic levels after exposure to oxidative stress.
 ...
PMID:Isolation and derivation of mouse embryonic germinal cells. 1985 Dec 76

The results on relapse rate and disease progression of available drugs for multiple sclerosis are shown, as well as their most relevant side effects. Results from pivotal and long-term follow-up studies support the efficacy and safety of interferons and glatiramer acetate. The treatment with mitoxantrone is limited by the occurrence of infertility, cardiotoxicy and leukaemia. Efficacy and tolerability of natalizumab are undisputable, compared to other drugs. Risks related to its treatment are PML, opportunistic infections, hepatotoxicity, melanoma, and their occurrence needs to be more exactly assessed by post-marketing surveillance. The principles of induction versus escalating therapy are also discussed. The final therapeutic decision is based on the evaluation of the disease state and prognosis, based on clinical and instrumental measures, and on the safety/efficacy profile of each treatment.
 ...
PMID:Treatment of multiple sclerosis: role of natalizumab. 1988 65

Mitoxantrone (MTX) is a synthetic antineoplastic cytotoxic drug, active both on proliferative and non-proliferative cells. The efficacy of MTX has been suggested by many open-label or observational studies and demonstrated in four randomized controlled clinical trials (RCTs). It is indicated for reducing neurological disability and the frequency of clinical relapses in patients with progressive relapsing and worsening relapsing-remitting MS patients. The short-term most frequent adverse events observed in RCTs have been nausea/vomiting, alopecia, an increased risk of urinary and respiratory tract infections, phlebitis, transitory leukopenia, amenorrhea in female patients and infertility. However, the most serious risks of the drug are represented by potential cardiotoxicity and leukaemia, whose incidence seems to be higher than previously reported. Therefore, all potential serious adverse events should be carefully considered against the potential relevant benefits of MTX treatment on every single MS patient.
 ...
PMID:Mitoxantrone: benefits and risks in multiple sclerosis patients. 1988 68

The improved survival rates among patients with haematological malignancies, such as lymphoma and leukaemia, are shifting areas of focus towards understanding and preventing treatment-induced sequelae. Of these, infertility is one of the most devastating consequences for patients with reproductive potential. The degree of treatment-induced gonadal dysfunction depends on age and gender-related differences, the type and dosage of chemotherapy used and the field and cumulative dose of abdomino-pelvic irradiation. There is also the interesting phenomenon of reduced pre-treatment fertility among male lymphoma patients. At present, the only established methods of fertility preservation are cryopreservation of sperm, oocytes and embryos, as well as gonadal shielding and transposition of ovaries during irradiation. Several other methods, such as cryopreservation and subsequent transplantation of gonadal tissue and the gonadoprotective role of hormonal suppression, are under investigation. Pre-pubertal patients present a unique constellation of fertility considerations, especially as embryo and sperm cryopreservation are not applicable to this age group.
 ...
PMID:Fertility considerations and preservation in haemato-oncology patients undergoing treatment. 2139 73

With increasing numbers of survivors from cancer at a young age, the issue of fertility preservation has assumed greater importance. This review describes normal ovarian and testicular function and summarizes what is known about the effect of chemotherapy and radiotherapy on the gonads and uterus. All young patients with cancer or leukemia should have their fertility prognosis discussed before the initiation of treatment. Sperm and embryo cryopreservation should be considered standard practice and be widely available for those at significant risk of infertility. For prepubertal girls, ovarian tissue cryopreservation should be considered if the risk of premature menopause is high, but for the prepubertal boy there are no established techniques in current practice.
 ...
PMID:Oncofertility and preservation of reproductive capacity in children and young adults. 2152 50

Fanconi anaemia (FA) is a rare recessive disorder marked by developmental abnormalities, bone marrow failure, and a high risk for the development of leukaemia and solid tumours. The inactivation of FA genes, in particular FANCF, has also been documented in sporadic tumours in non-FA patients. To study whether there is a causal relationship between FA pathway defects and tumour development, we have generated a mouse model with a targeted disruption of the FA core complex gene Fancf. Fancf-deficient mouse embryonic fibroblasts displayed a phenotype typical for FA cells: they showed an aberrant response to DNA cross-linking agents as manifested by G(2) arrest, chromosomal aberrations, reduced survival, and an inability to monoubiquitinate FANCD2. Fancf homozygous mice were viable, born following a normal Mendelian distribution, and showed no growth retardation or developmental abnormalities. The gonads of Fancf mutant mice functioned abnormally, showing compromised follicle development and spermatogenesis as has been observed in other FA mouse models and in FA patients. In a cohort of Fancf-deficient mice, we observed decreased overall survival and increased tumour incidence. Notably, in seven female mice, six ovarian tumours developed: five granulosa cell tumours and one luteoma. One mouse had developed tumours in both ovaries. High-resolution array comparative genomic hybridization (aCGH) on these tumours suggests that the increased incidence of ovarian tumours correlates with the infertility in Fancf-deficient mice and the genomic instability characteristic of FA pathway deficiency.
 ...
PMID:Fancf-deficient mice are prone to develop ovarian tumours. 2191 57

Fanconi anemia (FA) is a human disease of bone marrow failure, leukemia, squamous cell carcinoma, and developmental anomalies, including hypogonadism and infertility. Bone marrow transplants improve hematopoietic phenotypes but do not prevent other cancers. FA arises from mutation in any of the 15 FANC genes that cooperate to repair double stranded DNA breaks by homologous recombination. Zebrafish has a single ortholog of each human FANC gene and unexpectedly, mutations in at least two of them (fancl and fancd1(brca2)) lead to female-to-male sex reversal. Investigations show that, as in human, zebrafish fanc genes are required for genome stability and for suppressing apoptosis in tissue culture cells, in embryos treated with DNA damaging agents, and in meiotic germ cells. The sex reversal phenotype requires the action of Tp53 (p53), an activator of apoptosis. These results suggest that in normal sex determination, zebrafish oocytes passing through meiosis signal the gonadal soma to maintain expression of aromatase, an enzyme that converts androgen to estrogen, thereby feminizing the gonad and the individual. According to this model, normal male and female zebrafish differ in genetic factors that control the strength of the late meiotic oocyte-derived signal, probably by regulating the number of meiotic oocytes, which environmental factors can also alter. Transcripts from fancd1(brca2) localize at the animal pole of the zebrafish oocyte cytoplasm and are required for normal oocyte nuclear architecture, for normal embryonic development, and for preventing ovarian tumors. Embryonic DNA repair and sex reversal phenotypes provide assays for the screening of small molecule libraries for therapeutic substances for FA.
 ...
PMID:The role of Fanconi anemia/BRCA genes in zebrafish sex determination. 2195 43

Alterations in androgen levels lead to reproductive defects in both males and females, including hypogonadotropic hypogonadism, anovulation, and infertility. Androgens have been shown to down-regulate GnRH mRNA levels through an androgen receptor (AR)-dependent mechanism. Here, we investigate how androgen regulates expression from the GnRH regulatory region in the GT1-7 cell line, a model of GnRH neurons. A synthetic androgen, R1881, repressed transcription from the GnRH promoter (GnRH-P) in an AR-dependent manner, and liganded AR associated with the chromatin at the GnRH-P in live GT1-7 cells. The three known octamer-binding transcription factor-1 (Oct-1) binding sites in GnRH-P were required for AR-mediated repression, although other sequences were also involved. Although a multimer of the consensus Oct-1 binding site was not repressed, a multimer of the cluster of Oct-1, Pre-B cell leukemia transcription factor (Pbx)/Prep, and NK2 homeobox 1 (Nkx2.1) binding sites, found at -106/-91 in GnRH-P, was sufficient for repression. In fact, overexpression of any of these factors disrupted the androgen response, indicating that a balance of factors in this tripartite complex is required for AR repression. AR bound to this region in EMSA, indicating a direct interaction of AR with DNA or with other transcription factors bound to GnRH-P at this sequence. Collectively, our data demonstrate that GnRH transcription is repressed by AR via multiple sequences in GnRH-P, including three Oct-1 binding sites, and that this repression requires the complex interaction of several transcription factors.
 ...
PMID:Androgen receptor repression of GnRH gene transcription. 2207 52


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>