Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The early reactions of the eye to radiation are conjunctivitis and, with higher doses, corneal damage. The inflammatory reactions are transient and remit within a few weeks after the end of radiotherapy. Doses above 60 Gy can produce corneal ulcerations with the risk of perforation and loss of the eye. The most frequent late reaction of the eye is cataract of the lens. The tolerance dose (about 5 Gy) is extremely low and the latent period varies from 6 months to 3 years. The lens in children has a much lower tolerance. The increasing potential for optical support and ophthalmic surgery over recent decades has reduced the fear of this complication. The most severe late complications are retinopathy (RR) and neuropathy of the optic nerve (RON), both of which are caused by radiation-induced microangiopathy. Visual loss is very frequent and complete blindness is seen with high doses in the range of 50-60 Gy. The latent period of these injuries varies widely from 1 month to 15 years, but they usually occur within 3 years of treatment. Conflicting frequencies are reported in the literature. Beyond 30 Gy, usually no RR is seen. However, the lowest recorded dose producing RR is 11 Gy. In the high dose range of 60-70 Gy RR and RON are found in 10%-100% of patients. There is a great need for prospective trials to estimate the true risk to patients with nasopharyngeal, maxillo-ethmoidal, and orbital tumors, pituitary adenomas, and tumors of the salivary glands. To minimize complications of radiotherapy to the eyes daily fractions should be reduced to 1.7-1.8Gy.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Eye sequelae following external irradiation. 836 92

Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant disorder caused by mutation in the transthyretin gene. The most common mutation is substitution of valine for methionine at position 30 (MET30). Liver transplantation (LT) is the preferred treatment. After LT, although many patients show stabilization or improvement in the disease, adverse outcomes have been reported in those who have malnutrition, long-standing disease, and non-MET (NMET) mutations at position 30. Our aim is to compare survival and outcome of symptoms associated with FAP after LT in patients with MET30 and NMET30 mutations. Medical records of all patients who underwent LT for amyloidosis at our institution were reviewed to obtain demographic information and clinical features, such as severity of neuropathy, diarrhea, orthostatic hypotension, and posterior wall or ventricle septal thickness before and after LT. Fifteen patients underwent LT for amyloidosis at our institution between 1990 and 2000 (MET30, n = 5; NMET30, n = 7; hereditary amyloidosis, n = 2; primary amyloidosis, AL type, n = 1). Patients with hereditary and primary amyloidosis were excluded from analysis. One- and 3-year survival rates after LT in MET30 patients were 100%. Before LT, five of five patients had sensorimotor neuropathy; five of five patients had diarrhea, and four of five patients had orthostatic hypotension. After LT, improvement or stabilization of neuropathy was seen in two of five patients; of diarrheal symptoms, in three of five patients; and of orthostatic hypotension, in three of four patients. One- and 3-year survival rates after LT in NMET30 patients were 100% and 85.7%, respectively. Before LT, six of seven patients had sensorimotor neuropathy, six of seven patients had diarrhea, and five of seven patients had orthostatic hypotension. After LT in this group, improvement or stabilization of neuropathy was seen in two of six patients; of diarrhea, in six of six patients; and of orthostatic hypotension, in five of five patients. Before LT, posterior wall and/or ventricle septal thickness was increased in two of five MET patients and seven of seven NMET patients. Five of seven NMET30 patients (71.4%) who received a combined liver and heart transplant had stabilization, and two patients in the NMET group and one patient in the MET group had progression of heart disease. Outcomes for LT for patients with FAP with MET or NMET mutations were similar. Earlier LT for patients with FAP with MET30 or NMET30 mutation would improve outcomes after LT.
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PMID:Outcome of liver transplantation for familial amyloidotic polyneuropathy. 1462 27

Background. - Trastuzumab is known as an active agent in HER2/neu overexpressing advanced breast cancer. In the prospective study we investigated efficacy, safety and toxicity of trastuzumab and paclitaxel in advanced breast cancer progressing on previous therapy. Patients and methods. - Seventeen patients with histologically confirmed disease were accrued. Inclusion criteria were as follows: Karnofsky performance status >/= 60 %, age < 75, pretreatment with at least two regimens; HER2/neu by immunohistochemistry 3+ or 2+, adequate organ function. Trastuzumab was given 4 mg/kg i.v. as a loading dose followed by 2mg/kg i.v. weekly. Paclitaxel was given 80 mg/m2 i.v. weekly. Both drugs were given until disease progression or unacceptable toxicity. We assessed the response rate (RR), the time to progression (TTP), the overall survival (OS) and toxicity. Results. RR in the intent to treat population was 59 % (10 out of 17), including 2 complete responses. In the median follow up of 4,3 years median TTP was 9 month and median OS 23 month. In total 710 cycles including 528 full dose cycles of trastuzumab and paclitaxel were administered. One patient developed hypersensitivity reaction after the first trastuzumab infusion and discontinued from study. Trastuzumab infusion related pyretic reaction was observed in 6 patients. Left ventricular ejection fraction decline occurred in 2 patients (grade 2 and grade 3). Five patients experienced grade 3 neuropathy. Hematological toxicity was very modest: 1 episode of grade 4 neutropenia and grade 3 anemia. Other grade 3/4 toxicity: 4 episodes of grade 3 infection without neutropenia, grade 3 elevation of liver function tests in 1 patient, 1 episode of grade 3 hyperglycemia, and 1 episode of grade 3 weight gain. Other grade 3 or 4 toxicity was not detected. Conclusion. - Trastuzumab and paclitaxel have shown activity and good tolerability in HER-2/neu overexpressing advanced breast cancer patients.
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PMID:4-years results of weekly trastuzumab and paclitaxel in the treatment of women with HER2/neu overexpressing advanced breast cancer: single institution prospective study. 1558 95

A phase II trial was designed to evaluate the effectiveness of docetaxel/cisplatin as primary or neoadjuvant chemotherapy of locally advanced breast carcinoma (LABC). Patients with newly diagnosed breast cancers > or = 5 cm in size by palpation were treated with docetaxel/cisplatin, both at 70 mg/m2 intravenously every 21 days for 4 courses. Upon completion of chemotherapy, all patients underwent modified radical mastectomy with axillary nodal dissection. Pathologic complete response (pCR) was defined as absence of any invasive carcinoma in the breast. Standard AC (doxorubicin/cyclophosphamide) at 60 mg/m2 and 600 mg/m2, respectively, for 4 cycles was given as adjuvant therapy to maximally eradicate occult distant disease. Between March 1998 and October 2001, 57 women were entered onto this trial, 28 (49%) with inoperable T4 and inflammatory cancers. Pretreatment median tumor size was 9 cm. Thirty-six patients (63%) had estrogen receptor-positive tumors and 10 patients (18%) had tumors with HER2 overexpression. All tumors became operable after neoadjuvant chemotherapy. Pathologic complete response in the breast was achieved in 15 patients (26%) and pCR in the breast and the axilla was achieved in 11 patients (20%). All neoadjuvant chemotherapy courses were administered at full doses without treatment delays caused by toxicity. The most common side effects were hyperglycemia, anemia, and mild neuropathy. The results of this study suggest that the docetaxel/cisplatin combination can be an effective and well-tolerated induction treatment of LABC, even in very large mostly HER2-nonoverexpressing tumors.
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PMID:Docetaxel and cisplatin as primary chemotherapy for treatment of locally advanced breast cancers. 1558 76

Complications of diabetes mellitus within the nervous system are peripheral and central neuropathy. In peripheral neuropathy, defects in neurofilament and microtubules have been demonstrated. In this study, we examined the effects of insulin deficiency within the brain in insulin knockout mice (I-/-). The I-/- exhibited hyperphosphorylation of tau, at threonine 231, and neurofilament. In addition, we showed hyperphosphorylation of c-Jun N-terminal kinase (JNK) and glycogen synthase kinase 3 beta (GSK-3 beta) at serine 9. Extracellular signal-regulated kinase 1 (ERK 1) showed decrease in phosphorylation, whereas ERK 2 showed no changes. Ultrastructural examination demonstrated swollen mitochondria, endoplasmic reticulum, and Golgi apparatus, and dispersion of the nuclear chromatin. Microtubules showed decrease in the number of intermicrotubule bridges and neurofilament presented as bunches. Thus, lack of insulin brain stimulation induces JNK hyperphosphorylation followed by hyperphosphorylation of tau and neurofilament, and ultrastructural cellular damage, that over time may induce decrease in cognition and learning disabilities.
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PMID:The effect of insulin deficiency on tau and neurofilament in the insulin knockout mouse. 1603 5

This study investigates whether the immediate early gene (IEG) products c-Fos and c-Jun are activated in vivo in monkeys with experimental glaucoma, and in vitro in cultured human ONH astrocytes exposed to hydrostatic pressure (HP). Three Rhesus monkeys with mild glaucomatous damage (mean intraocular pressure (IOP) 27 +/- 1.3 mm Hg approximately 42 weeks) and three with moderate glaucomatous damage (mean IOP 44 +/- 6.7% mm Hg approximately 11 weeks) were used for this study; the contralateral eye served as normal control (mean IOP 18.6 +/- 1.7 mm Hg). ONH tissues were stained with GFAP, DAPI, and c-Jun or c-Fos, and transcription factor positive and negative nuclei were counted to determine nuclear localization. Cultured human normal and glaucomatous ONH astrocytes exposed to elevated HP served as the in vitro model of elevated pressure. Activation and nuclear localization of c-Fos and c-Jun increased significantly in the monkeys with elevated IOP. These data correlated with axonal loss, reactive astrocytes, and remodeling of the optic disc. Cultured human ONH astrocytes showed increased nuclear localization of c-Fos and c-Jun under exposure to HP. Immunohistochemistry demonstrated that the upstream regulators of c-Fos and c-Jun, ERK-MAPK and MAPKp38 localized to the nuclei of ONH astrocytes in monkeys with experimental glaucoma. Taken together, these results demonstrate c-Fos and c-Jun activation in ONH astrocytes in vivo and in vitro, and that activation of both transcription factors is associated with ERK and MAPKp38 activation in experimental glaucoma, suggesting that activation of transcription factors may participate in the induction and maintenance of the reactive astrocyte phenotype in glaucomatous optic neuropathy.
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PMID:Long-term activation of c-Fos and c-Jun in optic nerve head astrocytes in experimental ocular hypertension in monkeys and after exposure to elevated pressure in vitro. 1608 Oct 55

Sub-lethal concentrations of the organophosphate phenyl saligenin phosphate (PSP) inhibited the outgrowth of axon-like processes in differentiating mouse N2a neuroblastoma cells (IC(50) 2.5 microM). A transient rise in the phosphorylation state of neurofilament heavy chain (NFH) was detected on Western blots of cell extracts treated with 2.5 microM PSP for 4 h compared to untreated controls, as determined by a relative increase in reactivity with monoclonal antibody Ta51 (anti-phosphorylated NFH) compared to N52 (anti-total NFH). However, cross-reactivity of PSP-treated cell extracts was lower than that of untreated controls after 24 h exposure, as indicated by decreased reactivity with both antibodies. Indirect immunofluorescence analysis with these antibodies revealed the appearance of neurofilament aggregates in the cell bodies of treated cells and reduced axonal staining compared to controls. By contrast, there was no significant change in reactivity with anti-alpha-tubulin antibody B512 at either time point. The activation state of the MAP kinase ERK 1/2 increased significantly after PSP treatment compared to controls, particularly at 4 h, as indicated by increased reactivity with monoclonal antibody E-4 (anti-phosphorylated MAP kinase) but not with polyclonal antibody K-23 (anti-total MAP kinase). The observed early changes were concomitant with almost complete inhibition of the activity of neuropathy target esterase (NTE), one of the proposed early molecular targets in organophosphate-induced delayed neuropathy (OPIDN).
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PMID:Inhibition of neurite outgrowth in differentiating mouse N2a neuroblastoma cells by phenyl saligenin phosphate: effects on MAP kinase (ERK 1/2) activation, neurofilament heavy chain phosphorylation and neuropathy target esterase activity. 1649 76

We have identified a consanguineous family from Morocco segregating autosomal recessive congenital progressive hearing loss (ARNSHL) and retinal degeneration. Detailed clinical investigation of the six siblings revealed combined severe cone-rod dystrophy (CORD) and severe/profound hearing impairment in two of them, while there is isolated CORD in three and nonsyndromic profound hearing loss in one. We therefore assumed a partial overlap of two nonsyndromic autosomal recessive conditions instead of a monogenic syndrome and performed genomewide linkage analysis. The disease loci were mapped to chromosome 2q31.1-2q32.1 for ARNSHL and to 2q13-2q14.1 for CORD, respectively. The retinal phenotype was shown to be due to homozygosity for a novel splice site mutation, c.2189+1G>T, in the retinitis pigmentosa gene MERTK. The ARNSHL interval comprised the DFNB59 locus. The DFNB59 gene has been identified recently, and two missense mutations (p.R183W and p.T54I) have been shown to cause auditory neuropathy in both humans and transgenic mice. Mutation screening in the DFNB59 gene in our family revealed homozygosity for a 1-bp insertion in exon 2 (c.113_114insT), predicting a truncated protein of 47 amino acids, in all three hearing impaired subjects. This is the first description of biallelic putative loss-of-function of the DFNB59 gene. Detailed audiological investigation clearly indicated hair cell dysfunction and, in contrast to cases reported previously, excluded auditory neuropathy. We show that besides otoferlin (OTOF), DFNB59 is the second known gene in which mutations can result in these two distinct forms of hearing impairment. Moreover, all patients in our family with homozygosity for the DFNB59 mutation display central vestibular dysfunction.
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PMID:Truncating mutation of the DFNB59 gene causes cochlear hearing impairment and central vestibular dysfunction. 1730 63

A high concentration of glutamate in the vitreous body and optic nerves of the eyes activates N-methyl-D-aspartate (NMDA) receptors and is toxic to retina ganglion cells (RGCs) in glaucomatous patients. Aloe-emodin sulfates/glucuronides (s/g), the major metabolites of aloe-emodin, was found to be effective in decreasing NMDA-induced apoptosis in RGCs. In order to elucidate the mechanisms, an in vitro optic neuropathy model adding NMDA to N18 RGCs was used in this study. The phosphorylation level of extra-cellular signal-regulated kinase1/2 (ERK1/2), c-Jun N-terminal kinase (JNK) and p38 kinase (cytokines-suppressive antiinflammatory drug binding protein kinase) were measured by western blotting and luciferase reporter assay. The results showed that aloe-emodin metabolites significantly decreased the activation of three major mitogen-activated protein (MAP) kinase pathways and the activation of downstream genes in nucleus induced by NMDA, which were verified by the addition of the respective inhibitors. Comparing the effect of the inhibitors of the three MAP kinase pathways, the ERK pathway was found to be the major route of aloe-emodin metabolites in decreasing the apoptosis of NMDA-treated RGCs. Besides, cfos rather then cjun was the target downstream gene. Aloe-emodin emodin metabolites could regulate the phosphorylation of ERK kinases and it was a promising candidate for NMDA-induced apoptosis of RGCs.
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PMID:Aloe-emodin suppressed NMDA-induced apoptosis of retinal ganglion cells through regulation of ERK phosphorylation. 1766 29

TNFalpha is involved in the generation of hyperalgesia in pathological states such as neuropathy and inflammation. The pronociceptive action of TNFalpha may be mediated at least in part by activation of the TRPV1 receptor which transduces heat stimuli in primary nociceptive afferents and mediates thermal hyperalgesia. In the present study, we investigated in cultured dorsal root ganglion (DRG) neurones, the somata of primary afferent fibres, whether TNFalpha increases TRPV1 receptor expression. We found that long-term exposure of DRG neurones of both rat and mouse to TNFalpha significantly increased the proportion of DRG neurones expressing TRPV1 receptor-like immunoreactivity. This TNFalpha effect was abolished in mice DRG neurones when DRG cultures were obtained from tnfr1/2-/- and tnfr1-/-, but not from tnfr2-/- mice. Furthermore, we found that activation of ERK but not of p38 kinase or cyclooxygenases is critically involved in the TNFalpha-induced increase of TRPV1 receptor expression.
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PMID:The cytokine TNFalpha increases the proportion of DRG neurones expressing the TRPV1 receptor via the TNFR1 receptor and ERK activation. 1785 Oct 89


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