Fassil B Mesfin

A peptide derived from α-fetoprotein prevents the growth of estrogen-dependent human breast cancers sensitive and resistant to tamoxifen

An 8-mer peptide (EMTOVNOG) derived from α-fetoprotein was compared with tamoxifen for activity against growth of human breast cancer xenografts implanted in immune-deficient mice. Both peptide and tamoxifen prevented growth of estrogen-receptor-positive MCF-7 and T47D human breast cancer xenografts. A subline of MCF-7, made resistant to tamoxifen by a 6-month exposure to this drug in culture, was found to be resistant to tamoxifen in vivo. Peptide completely prevented the xenograft growth of this tamoxifen-resistant subline of MCF-7. Neither peptide nor tamoxifen was effective in slowing the xenograft growth of the estrogen-receptor-negative MDA-MB-231 human breast cancer. A worrisome side effect of tamoxifen is its hypertrophic effect on the uterus. In this study, tamoxifen was shown to stimulate the growth of the immature mouse uterus in vivo, and the peptide significantly inhibited tamoxifens uterotrophic effect. The mechanism of action of peptide is different from that of tamoxifen in that the peptide does not interfere with the binding of [3H]estradiol to the estrogen receptor. In conclusion, α-fetoprotein-derived peptide appears to be a novel agent that interferes with the growth of tamoxifen-sensitive as well as tamoxifen-resistant estrogen-receptor-positive human breast cancers; it inhibits the uterotrophic side effect of tamoxifen and, thus, it may be useful in combination with or in place of tamoxifen for treatment of estrogen-receptor-positive human breast cancers.

Alpha-fetoprotein-derived antiestrotrophic octapeptide.

Alpha-fetoprotein (AFP) is a major serum protein produced during fetal development. Experimental findings suggest that AFP has antiestrotrophic activity and that it can be developed as a therapeutic agent to treat existing estrogen-dependent breast cancer or to prevent premalignant foci from developing into breast cancer. The antiestrotrophic activity of AFP was reported to be localized to a peptide consisting of amino acids 447-480, a 34-mer peptide termed P447. A series of parsings and substitutions of amino acids in the P447 sequence was intended to identify the shortest analog which retained antiestrotrophic activity. Peptides related to P447 were generated using solid phase peptide synthesis. Several shorter peptides, including an 8-mer called P472-2 (amino acids 472-479, peptide sequence EMTPVNPG), retained activity, whereas peptides shorter than eight amino acid residues were inactive. The dose-related antiestrotrophic activity of AFP-derived peptides was determined in an immature mouse uterine growth assay that measures their ability to inhibit estradiol-stimulated uterine growth. In this assay, the maximal inhibitory activities exhibited by peptide P472-2 (49%), by peptide P447 (45%), and by intact AFP (35-45%) were comparable. The octapeptide P472-2 was also active against estradiol-stimulated growth of T47D human breast cancer cells in culture. These data suggest that peptide P472-2 is the minimal sequence in AFP, which retains the antiestrotrophic activity found with the full-length molecule. The synthetic nature and defined structure of this 8-mer peptide suggest that it can be developed into a new drug which opposes the action of estrogen, perhaps including the promotional effects of estradiol in the development of human breast cancer.

Epidural Hematoma After Tympanomastoidectomy and Bone-Anchored Hearing Aid (BAHA) Placement: Case Report

BACKGROUND AND IMPORTANCE:Epidural hematoma (EDH) has never been reported as a complication after placement of a bone-anchored hearing aid (BAHA). To our knowledge, this is the first case report of an EDH after placement of a BAHA. CLINICAL PRESENTATION:We report the case of a 15-year-old girl with an EDH after placement of a BAHA. Initially, she presented with a history of right ear conductive hearing loss and had a tympanomastoidectomy and placement of a BAHA at an outpatient surgical facility. Postoperatively, the patient was transferred to the postoperative care unit in stable neurological condition but was subsequently noted to be lethargic with dilated, nonreactive pupils and extensor posturing. A computed tomography scan revealed a large right temporal EDH with midline shift. She was then taken to the operating room emergently for craniotomy and evacuation of the EDH. After evacuation, she was admitted to the pediatric intensive care unit and slowly emerged from her coma with supportive care. She was discharged to inpatient rehabilitation and has made a good recovery. CONCLUSION:This report emphasizes the need for a high index of suspicion of this rare, but life-threatening complication of an EDH after the placement of a BAHA.

Low pressure traumatic epidural hematoma in a child with a prior hemispherectomy: Case report

A 2½-year-old male child with a prior history of a left anatomic hemispherectomy to treat refractory epilepsy fell down two steps, striking his head on the ipsilateral side of the hemispherectomy. He presented with non-consolable crying and emesis. CT scan of the head demonstrated a left frontal epidural hematoma beneath the site of his prior craniectomy. The patient was initially treated by close observation. However, due to an increase in the hematoma from 29.5 to 49.3 ml over a 12-hour period along with the patients lack of clinical improvement, surgical evacuation was performed. Intraoperatively, the source of the hemorrhage was found to be the skull fracture. Postoperatively, he returned to his neurologic baseline and was discharged home on postoperative day 3.

Abstract 562: Multi-Kinase Inhibitor: AFPep inhibits the growth and invasion of U87 glioblastoma cells through inhibition of FAK, MAPK, and PKC

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL INTRODUCTION: Glioblastomas are the most frequent tumors of the central nervous system. Patients with a diagnosis of glioblastomas have poor prognosis, and new therapeutic agents are in demand for management of this disease. Here, we report on a novel multi-protein kinase inhibitor, AFPep, with regard to its effects on the growth, invasion, and localization in U87 cells. METHODS: Proliferation/Invasion Assay: Cells were seeded into wells of plastic tissue culture plates and treated with various concentrations of AFPep. Crystal violet method was used to determine cell numbers. The Matrigel chemoinvasion assay was used to determine the effect of AFPep on U87 cell invasion. During Xenograft growth assay, U87 cells were solidified in fibrin clot and implanted under the kidney capsule of severe combined immunodeficient (SCID) mice. Various doses of AFPep were administrated i.p and tumor growth was monitored during survival laparotomy. Localization assay was performed by utilizing fluorescent-labeled AFPep. Multi-immunoblotting Assay was performed using Kinexus, the KinetworksTM methodology to screen for protein kinase expression profile in GBM before and after AFPep treatment. RESULTS: AFPep inhibited the growth of U87 cells in culture with it is maximal effect at 10−7 M. Higher concentrations of AFPep (10−6M to 10−4M) inhibited the invasion of U87 cells in a dose dependent manner. Treatment of SCID mice bearing U87 xenografts with 4 mg/Kg/day AFPep resulted in a 50% inhibition of tumor growth. Further, AFPep-Bodipy appeared to be localized in mitochondria and interferes with phosphorylation of FAK, MAPK, and c-kit. CONCLUSION: AFPep has an inhibitory effect on U87 cells. All studies to date have shown no toxicity. As such AFPep is expected to be tolerated and may be a new agent for the treatment of malignant glioblastomas Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 562. doi:10.1158/1538-7445.AM2011-562