Biomedical subjects

Eyas M Hattab

Publications and source records attributed to Eyas M Hattab.

10 recordsLinked to original sources

PubMed2007

Repression of cyclin D1 as a target for germ cell tumors.

Metastatic germ cell tumors (GCT) are curable, however GCTs refractory to cisplatin-based chemotherapy have a poor prognosis. This study explores D-type cyclins as molecular targets in GCTs because all-trans-retinoic acid (RA)-mediated differentiation of the human embryonal carcinoma (EC) cell line NT2/D1 is associated with G1 cell cycle arrest and proteasomal degradation of cyclin D1. RA effects on D-type cyclins are compared in human EC cells that are RA sensitive or dually RA and cisplatin resistant (NT2/D1-R1) and in clinical GCTs that have both EC and mature teratoma components. Notably, GCT differentiation was associated with reduced cyclin D1 but increased cyclin D3 expression. RA was shown here to repress cyclin D1 through a transcriptional mechanism in addition to causing its degradation. The siRNA-mediated repression of individual cyclin D species resulted in growth inhibition in both RA sensitive and resistant EC cells. Only repression of cyclin D1 occurred in vitro and when clinical GCTs mature, implicating cyclin D1 as a molecular therapeutic target. To confirm this, the EGFR-tyrosine kinase inhibitor, Erlotinib, was used to repress cyclin D1. This inhibited proliferation in RA and cisplatin sensitive and resistant EC cells. Taken together, these findings implicate cyclin D1 targeting agents for the treatment of GCTs.

Antineoplastic Agents↗

PubMed2006

Impaired growth and neurological abnormalities in branched-chain alpha-keto acid dehydrogenase kinase-deficient mice.

The BCKDH (branched-chain alpha-keto acid dehydrogenase complex) catalyses the rate-limiting step in the oxidation of BCAAs (branched-chain amino acids). Activity of the complex is regulated by a specific kinase, BDK (BCKDH kinase), which causes inactivation, and a phosphatase, BDP (BCKDH phosphatase), which causes activation. In the present study, the effect of the disruption of the BDK gene on growth and development of mice was investigated. BCKDH activity was much greater in most tissues of BDK-/- mice. This occurred in part because the E1 component of the complex cannot be phosphorylated due to the absence of BDK and also because greater than normal amounts of the E1 component were present in tissues of BDK-/- mice. Lack of control of BCKDH activity resulted in markedly lower blood and tissue levels of the BCAAs in BDK-/- mice. At 12 weeks of age, BDK-/- mice were 15% smaller than wild-type mice and their fur lacked normal lustre. Brain, muscle and adipose tissue weights were reduced, whereas weights of the liver and kidney were greater. Neurological abnormalities were apparent by hind limb flexion throughout life and epileptic seizures after 6-7 months of age. Inhibition of protein synthesis in the brain due to hyperphosphorylation of eIF2alpha (eukaryotic translation initiation factor 2alpha) might contribute to the neurological abnormalities seen in BDK-/- mice. BDK-/- mice show significant improvement in growth and appearance when fed a high protein diet, suggesting that higher amounts of dietary BCAA can partially compensate for increased oxidation in BDK-/- mice. Disruption of the BDK gene establishes that regulation of BCKDH by phosphorylation is critically important for the regulation of oxidative disposal of BCAAs. The phenotype of the BDK-/- mice demonstrates the importance of tight regulation of oxidative disposal of BCAAs for normal growth and neurological function.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗

PubMed2006

Primary testicular diffuse large B-cell lymphoma belongs to the nongerminal center B-cell-like subgroup: A study of 18 cases.

The most common type of primary testicular lymphoma is diffuse large B-cell type, which has the potential for aggressive clinical behavior. Diffuse large B-cell lymphoma can be further subclassified into two major prognostic categories: germinal center B-cell-like and nongerminal center B-cell-like. Such distinction is made possible using the immunohistochemical expression of CD10, Bcl-6 and MUM1. The aim of this study was to stratify primary testicular lymphoma of the diffuse large B-cell type according to this scheme. Immunohistochemical stains for CD10, Bcl-6 and MUM1 were performed on 18 cases of primary testicular lymphoma of diffuse large B-cell type. Subclassification was carried out as previously described where CD10 and/or Bcl-6 positivity and negativity for MUM1 were considered indicative of germinal center B-cell-like type and the opposite expression as nongerminal center B-cell-like type. The proliferative activity was determined using immunostaining with the Ki-67 antibody. Of 18 cases, 16 (89%) were found to belong to the nongerminal center B-cell-like type. Two cases (11%) were classified as germinal center B-cell-like type; one had a CD10-positive, Bcl-6-positive and MUM1-negative profile, and the other was CD10 negative, Bcl-6 positive and MUM1 negative. The former occurred in a 38-year-old patient who was human immunodeficiency virus positive. All the cases expressed high proliferative activity (> or =50% Ki-67 labeling). We conclude that most (89%) primary testicular lymphomas of the diffuse large B-cell type belong to the nongerminal center B-cell-like subgroup and have high proliferative activity.

Adult↗

PubMed2006

Tertiary Gleason pattern 5 is a powerful predictor of biochemical relapse in patients with Gleason score 7 prostatic adenocarcinoma.

PURPOSE: In radical prostatectomy specimens Gleason score 7 is among the most commonly assigned scores for prostate carcinoma accounting for 30% to 50% of cases. Gleason score 7 is different from other more differentiated prostate carcinomas (tumors of Gleason scores 5 and 6) with a significantly worse outcome and higher rate of recurrence. Nonetheless, Gleason score 7 tumors are heterogeneous. In this study we examined the differences in clinical outcome between primary Gleason grade 3 and 4 tumors in patients who underwent radical prostatectomy, and determined the influence of tertiary Gleason pattern 5 on patient outcome. MATERIALS AND METHODS: A total of 504 patients underwent radical prostatectomy for prostate cancer and 228 of the patients (45%) had a Gleason score of 7. Cases were analyzed for a variety of clinical and pathological parameters. The influence of primary Gleason pattern and tertiary Gleason pattern 5 on patient outcome was assessed in the Cox regression model. RESULTS: Among 228 patients with Gleason score 7 prostatic adenocarcinoma, 91 (40%) had a primary Gleason pattern 4 and 137 (60%) had primary Gleason pattern 3. Patients of the former group were more likely to have a higher pathological stage (p = 0.003), more likely to have PSA recurrence (p = 0.02) and more likely to have a tertiary Gleason pattern 5 (p <0.0001). A total of 37 (41%) patients with primary Gleason 4 had a tertiary Gleason pattern 5, whereas only 13 (9%) patients with primary Gleason 3 had a tertiary Gleason pattern 5. In the Cox regression model controlling for tumor stage and surgical margin status, the primary Gleason pattern was not an independent predictor of PSA recurrence (p = 0.80), whereas the presence of tertiary Gleason pattern 5 was a significant predictor of PSA recurrence (hazard ratio 2.10, 95% CI 1.24-3.55, p = 0.006). Five-year PSA recurrence-free survival was 70% for patients without a tertiary Gleason pattern 5 compared to 19% for those patients with a tertiary Gleason pattern 5. CONCLUSIONS: Among patients with Gleason score 7, primary Gleason grade 4 indicates a likelihood of higher tumor stage and higher probability of PSA recurrence than does primary pattern 3. However, it does not independently predict a worse outcome after controlling for other known prognostic parameters associated with disease progression. Regardless of whether the primary Gleason pattern is 3 or 4, a tertiary Gleason pattern 5 is the strongest predictor of a worse outcome in patients with Gleason grade 7 prostatic adenocarcinoma. Therefore, tertiary pattern 5 should be reported in radical prostatectomy specimens.

Adenocarcinoma↗

PubMed2006

Chromosome 12p abnormalities in dysgerminoma of the ovary: a FISH analysis.

Dysgerminoma is the most common malignant ovarian germ cell tumor and shares histological and immunophenotypical features with its testicular counterpart, seminoma. Chromosome 12p abnormalities are genetic hallmarks of testicular seminomas. Little is known about these genetic changes in dysgerminoma. We performed dual color fluorescence in situ hybridization (FISH) analyses with a centromeric alpha-satellite probe for chromosome 12 and a subtelomeric probe for 12p on paraffin-embedded tissue sections from 21 dysgerminomas and two gonadoblastomas. Chromosome 12p abnormalities were detected in 81% of dysgerminomas. In all, 57% of cases had only isochromosome 12p and 5% had only 12p overrepresentation. In all, 19% had both isochrome 12p and 12p overrepresentation. Gonadoblastomas were negative for isochromosome 12p or 12p overrepresentation. Chromosome 12p abnormalities are common in dysgerminoma of the ovary. FISH analyses for chromosome 12p abnormalities may be a useful diagnostic adjunct for confirming the diagnosis of dysgerminoma and for distinguishing it from nongerm cell malignancies that enter into the differential diagnosis.

Adolescent↗

PubMed2006

Temporal arteritis presenting with gastrointestinal symptoms in a middle aged man.

Giant cell arteritis, also known as temporal arteritis, is a vasculitis of unknown etiology that classically involves the wall of the large to medium size. We are reporting a case of a young onset temporal arteritis presenting with gastrointestinal symptoms. The patient was a 48-year-old male who presented with a 2-week history of fever, diffuse abdominal pain, and malaise. He underwent a laparoscopic cholecystectomy after findings of elevated bilirubin and alkaline phosphatase as well as suspicion of porcelain gallbladder on ultrasound (or computed tomography scan). The patient subsequently developed painless, intermittent vision loss and unilateral headaches. A work-up included temporal artery biopsy, which showed marked lymphocytic infiltrate in the arterial wall consistent with temporal arteritis. The presentation of temporal arteritis may be atypical. We are reporting a case of temporal arteritis at a young age presenting mainly with gastrointestinal symptoms.

Adrenal Cortex Hormones↗

PubMed2005

Expression of CD117 (c-kit) receptor in dysgerminoma of the ovary: diagnostic and therapeutic implications.

The proto-oncogene c-kit encodes a tyrosine kinase receptor, c-kit (CD117), which has been implicated in the development of a number of human malignancies. While the preferential expression of this protein has been well documented in testicular seminomas, there is little data concerning its expression in dysgerminomas of the ovary. We examined the expression of c-kit in 30 cases of ovarian dysgerminomas using immunohistohemical staining with a polyclonal anti-CD117 antibody. Staining was graded in a semiquantitative manner as follows: negative (no staining), 1+(1-10% staining), 2+(10-29% staining), 3+(30-50% staining), or 4+ (>50% staining). Of the 30 cases examined, 26 (87%) demonstrated immunoreactivity for CD117. In total, 10 (33%) demonstrated 4+ staining; 9 (30%) demonstrated 3+staining; 3 (10%) demonstrated 2+staining; 4 (13%) demonstrated 1+staining; and 4 (13%) demonstrated no staining. In conclusion, CD117 immunoreactivity was detected in 87% of ovarian dysgerminomas, a finding that correlates with previously reported frequencies of CD117 expression in seminomas (78-100%). Thus, antibodies to c-kit may be a useful diagnostic marker for ovarian dysgerminoma. Although the prognosis of patients with dysgerminoma is generally good, this receptor could potentially serve as a target for site-specific immunotherapy as an alternative and/or complement to conventional treatment options.

Adolescent↗

PubMed2005

OCT4 immunohistochemistry is superior to placental alkaline phosphatase (PLAP) in the diagnosis of central nervous system germinoma.

OCT4 is an 18-kDa POU-domain transcription factor encoded by the POU5F1 gene. Also known as OCT3, OTF3, and POU5F1, OCT4 is involved in the initiation, maintenance, and differentiation of pluripotent and germline cells during normal development. It is expressed in mouse and human embryonic stem and germ cells but absent from all differentiated somatic cell types in vitro and in vivo. OCT4 has been detected in primary testicular germ cell tumors with pluripotent potential: seminoma and embryonal carcinoma. We investigated: 1) whether a similar pattern of expression is present in primary intracranial germinomas; and 2) how OCT4 compares with placental alkaline phosphatase (PLAP) in terms of specificity and sensitivity as a potential diagnostic tool. We examined histologic sections from 25 cases of germinoma in which paraffin blocks with sufficient material were available. All cases were reviewed and sections from 32 different blocks were obtained and immunostained for OCT4 and PLAP. Additionally, 49 primary and metastatic brain tumors that may be potentially confused with germinoma, either clinically or histologically, were investigated for OCT4 expression. All but one germinoma were pure (ie, lacking other germ cell components). Intense and often diffuse nuclear staining was detected in 100% of germinomas. PLAP immunoreactivity was detected in 23 of 25 cases and was absent in the remaining 2 cases. The intensity of OCT4 immunostaining was significantly better than that of PLAP. None of the 49 control cases, which included glioblastoma multiforme, pineoblastoma, pituitary adenoma, malignant lymphoma, metastatic melanoma, capillary hemangioblastoma, meningioma, schwannoma, and a variety of metastatic carcinomas showed immunoreactivity for OCT4. Our study demonstrates that OCT4 is a highly specific and sensitive immunohistochemical marker for primary intracranial germinomas. OCT4 should be part of immunoperoxidase staining panels in which germinoma enters the differential diagnosis.

Alkaline Phosphatase↗

PubMed2003

Small bowel tumors.

Primary tumors of the small bowel are rare, and their clinical presentation is nonspecific. Consequently, preoperative diagnosis remains the exception rather than the rule. Although the small intestine makes up 75% of the length and 90% of the surface area of the gastrointestinal tract, small bowel tumors make up approximately 3% of all malignant gastrointestinal neoplasms. Primary neoplasms of the small intestine are notorious for their insidious presentation and vague symptoms, including abdominal pain, anorexia, and weight loss. These nonspecific symptoms, coupled with the lack of physical findings, often cause a significant delay in reaching a diagnosis. Because the small bowel has been a relatively inaccessible area to standard endoscopic techniques, contrast radiography has been regarded historically as the gold standard diagnostic modality. The management of primary malignant small bowel tumors is invariably surgical. However, adjuvant chemotherapy and radiotherapy may be warranted, depending on the type of tumor.

Diagnosis, Differential↗

PubMed2003

Astrocytic cytoplasmic inclusions within an epileptic focus in an otherwise neurologically intact patient.

A 17-year-old woman with intractable seizures since infancy underwent resection of an epileptic focus in the left frontal cortex. The cytoplasm of many cortical astrocytes contained amorphous eosinophilic inclusions, which ultrastructurally were non-membrane bound and consisted of densely packed osmiophilic material. Similar inclusions have previously been observed, at autopsy, in patients with unspecified mental retardation and various brain malformations. The present report is unique in that the inclusions were detected in the resected specimen of an epileptic focus. The patient is neurologically intact except for the seizures that presently are totally controlled by the surgery. The pathogenesis of these inclusions is unclear. The fact they occurred in an epileptic focus raises the possibility that prolonged seizures or its underlying precipitating factors may cause conglutination of an indeterminate element of the protoplasmic astrocytes resulting in inclusion formation.

Adolescent↗