Robert Gagel - Academia.edu (original) (raw)

Papers by Robert Gagel

Recent Results in Cancer Research, 2015

Two independent events-the identification of activating mutations of the RET proto-oncogene, a re... more Two independent events-the identification of activating mutations of the RET proto-oncogene, a receptor tyrosine kinase, in medullary thyroid carcinoma, and the recognition that small organic molecules could bind to and inhibit phosphorylation of signaling molecules, thereby inactivating the pathway-led to the recognition that kinase inhibitors could be used to treat medullary thyroid carcinoma (MTC). The introduction of these compounds into clinical practice has transformed the treatment of metastatic MTC and provided insight into the mechanisms by which RET causes C-cell transformation. This chapter will review the progress in this field over the past 7 years.

Molecular and cellular biology, 1999

Polypyrimidine tract-binding protein (PTB) is an abundant vertebrate hnRNP protein. PTB binding s... more Polypyrimidine tract-binding protein (PTB) is an abundant vertebrate hnRNP protein. PTB binding sites have been found within introns both upstream and downstream of alternative exons in a number of genes that are negatively controlled by the binding of PTB. We have previously reported that PTB binds to a pyrimidine tract within an RNA processing enhancer located adjacent to an alternative 3'-terminal exon within the gene coding for calcitonin and calcitonin gene-related peptide. The enhancer consists of a pyrimidine tract and CAG directly abutting on a 5' splice site sequence to form a pseudoexon. Here we show that the binding of PTB to the enhancer pyrimidine tract is functional in that exon inclusion increases when in vivo levels of PTB increase. This is the first example of positive regulation of exon inclusion by PTB. The binding of PTB was antagonistic to the binding of U2AF to the enhancer-located pyrimidine tract. Altering the enhancer pyrimidine tract to a consensus ...

Cancer research, Jan 15, 2000

Inherited mutations of the RET proto-oncogene are tumorigenic in patients with multiple endocrine... more Inherited mutations of the RET proto-oncogene are tumorigenic in patients with multiple endocrine neoplasia type 2 (MEN 2). However, it is not understood why only few of the affected cells in the target organs develop into tumors. Genetic analysis of nine pheochromocytomas from five unrelated patients with MEN 2 showed either duplication of the mutant RET allele in trisomy 10 or loss of the wild-type RET allele. Our results suggest a "second hit" causing a dominant effect of the mutant RET allele, through either duplication of the mutant allele or loss of the wild-type allele, as a possible mechanism for pheochromocytoma tumorigenesis in patients with MEN 2.

Molecular and cellular biology, 1998

Although considerable information is currently available about the factors involved in constituti... more Although considerable information is currently available about the factors involved in constitutive vertebrate polyadenylation, the factors and mechanisms involved in facilitating communication between polyadenylation and splicing are largely unknown. Even less is known about the regulation of polyadenylation in genes in which 3'-terminal exons are alternatively recognized. Here we demonstrate that an SR protein, SRp20, affects recognition of an alternative 3'-terminal exon via an effect on the efficiency of binding of a polyadenylation factor to an alternative polyadenylation site. The gene under study codes for the peptides calcitonin and calcitonin gene-related peptide. Its pre-mRNA is alternatively processed by the tissue-specific inclusion or exclusion of an embedded 3'-terminal exon, exon 4, via factors binding to an intronic enhancer element that contains both 3' and 5' splice site consensus sequence elements. In cell types that preferentially exclude exon...

Surgery, 1995

Surgical resection is the only potentially curative treatment for adrenal cortical carcinoma, yet... more Surgical resection is the only potentially curative treatment for adrenal cortical carcinoma, yet the value of extended resection, palliative resection, and tumor DNA analysis remains unclear. The records of 23 patients with adrenal cortical carcinoma who underwent primary surgical resection at our institution were retrospectively reviewed. Flow cytometric DNA analysis was performed on primary tumor tissue from 14 patients. Sixteen of 23 patients underwent complete resection. For these 16 patients the median follow-up was 43 months, the actuarial median survival was 46 months, and the actuarial 5-year survival rate was 46%. The seven patients who underwent incomplete resection all died of disease with a median survival of 8.5 months. Isolated local recurrence as the first site of failure occurred in two patients. Only completeness of resection (p = 0.004) and stage at presentation (p = 0.006) were significant prognostic indicators. None of the following predicted a poor prognosis in...

Current problems in surgery, 2008

Thyroid cancer, although relatively rare, is the most common endocrine malignancy, and there has ... more Thyroid cancer, although relatively rare, is the most common endocrine malignancy, and there has been a steady increase in its incidence over the past 15 to 20 years, particularly in developed countries. Among American women, the incidence rate of thyroid cancer has risen faster than that of all major cancers in the past decade; among American men, its incidence rate has risen faster than that of all but 2 major cancers. Although exposure to ionizing radiation and inherited RET mutations are wellestablished etiologic factors for nonmedullary and medullary thyroid cancers, respectively, the cause of most thyroid malignancies is unknown. However, evidence suggests that the dramatic rise in thyroid cancer incidence is attributable to greater detection of early papillary thyroid cancers and not to a true increase in disease incidence.

Current Rheumatology Reports, 2010

Cancer patients are at risk for adverse events involving bone. Metastasis of cancer to bone and p... more Cancer patients are at risk for adverse events involving bone. Metastasis of cancer to bone and primary bone tumors can compromise the integrity of bone. Various cancer therapies cause long-term skeletal disorders, particularly bone loss, osteomalacia, and avascular necrosis. Cancer therapies that include chemotherapy, glucocorticoids, hormonal agents, and newer targeted therapies can affect bone in several ways. With the improved effectiveness of cancer treatment, more cancer patients are surviving longer and may experience fractures as a long-term complication of bone loss. Prevention of bone loss through early detection and appropriate use of anti-osteoporosis treatment may decrease bone loss and fractures. This article reviews causative risk factors, mechanisms, and prevention and treatment strategies for cancer therapy-related bone loss in hematologic and specific solid malignancies.

Surgery, 1996

Bilateral pheochromocytomas are common in patients with multiple endocrine neoplasia type 2 (MEN ... more Bilateral pheochromocytomas are common in patients with multiple endocrine neoplasia type 2 (MEN 2) and von Hippel-Lindau disease (VHL). In an effort to avoid long-term steroid dependence and Addisonian crisis, we have performed cortical-sparing adrenalectomy in this patient population. Retrospective chart review was completed for patients with MEN 2- or VHL-related pheochromocytomas who underwent laparotomy at our institution for intended cortical-sparing adrenalectomy between June 1965 and March 1995. Fifteen patients (MEN 2A [10], MEN 2B [2], VHL [3]) underwent laparotomy for cortical-sparing adrenalectomy. None of the tumors were malignant. Cortical-sparing adrenalectomy was possible in 14 (93%). Thirteen of these 14 patients (93%) had normal postoperative plasma cortisol measurements and did not require steroid hormone supplementation. At a median follow-up of 138 months, two patients had died of metastatic medullary thyroid cancer, no patient had suffered Addisonian crisis, and three patients (21%) had recurrent pheochromocytomas (at 118, 176, and 324 months after operation). The remaining nine patients were alive without pheochromocytomas. Cortical-sparing adrenalectomy can be performed successfully in MEN 2 or VHL patients with bilateral pheochromocytomas, avoiding chronic steroid hormone replacement and the risk of Addisonian crisis in most patients. Long-term follow-up is necessary because recurrence may develop many years after operation.

Nerves that contain calcitonin gene-related peptide (CGRP) are components of the sensory nervous ... more Nerves that contain calcitonin gene-related peptide (CGRP) are components of the sensory nervous system. Although these afferent nerves have traditionally been thought to sense stimuli in the periphery and transmit the information centrally, they also have an efferent vasodilator function. Acute administration of a CGRP receptor antagonist increases the blood pressure (BP) in several models of hypertension, which indicates that

Current Osteoporosis Reports, 2007

Cancers of the breast and prostate are very common in the general population, with breast cancer ... more Cancers of the breast and prostate are very common in the general population, with breast cancer accounting worldwide for 23% of cancer cases in women and prostate cancer accounting for 12% of cases in men. During the past decade, the survival rates of patients with estrogen-dependent breast cancer and testosterone-dependent prostate cancer have improved. This improvement has been possible thanks to the introduction of hormone treatments that suppress the synthesis or antagonize the actions of gonadal steroids. However, estrogen and testosterone deficiencies are associated with excessive bone resorption that translates into damage of the bone microarchitecture, loss of bone mineral density, and predisposition to osteoporosis and fractures. Herein, we review the mechanisms of bone loss in breast and prostate cancer survivors, their clinical implications, and different available therapeutic modalities that may help to correct the damage of bone and prevent the development of fractures.

Molecular and Cellular Biology - MOL CELL BIOL, 1995

This report describes deletion and mutation analyses of a mini-gene construct to identify regulat... more This report describes deletion and mutation analyses of a mini-gene construct to identify regulatory sequences involved in the utilization of the calcitonin (CT)-specific terminal exon. Mutation of the splice site resulted in diminished utilization of the CT-specific terminal exon and increased skipping of the CT exon in both the mini-gene and in the natural CT/CGRP gene. 28 refs., 8 figs.

Thyroid, 2008

Cutaneous metastasis from thyroid cancer, especially medullary thyroid cancer (MTC) is rare. We r... more Cutaneous metastasis from thyroid cancer, especially medullary thyroid cancer (MTC) is rare. We report four patients with cutaneous metastases from sporadic MTC, three women and one man, aged 50 to 69 years. They presented different cutaneous lesions phenotypes. The first patient had a remote history of MTC and initial presentation of the recurrence was a rapidly progressing cutaneous lesion; on subsequent disease staging, widely metastatic disease was discovered. The other three patients developed cutaneous metastases in the presence of known distant metastases, indicating systemic spread of thyroid cancer. Definitive diagnosis of cutaneous metastases of MTC was made on biopsy of the lesions with cells that stained positive for neuroendocrine markers. Accurate diagnosis of cutaneous metastasis from MTC is important because it is a negative prognostic factor indicative of multisystemic disease. Thus, MTC metastases should be included in the differential diagnosis of erythematous maculopapular eruptions and nodular lesions of the skin, especially when these metastases occur in the upper part of the body and if the patient has a history of MTC. The appearing of cutaneous metastasis is a negative prognostic factor since all the patients here described died within one year from the diagnosis of cutaneous metastases.

The Endocrinologist, 1994

Page 1. Artide 002î-972X/94/700î-0095$3.00/0 The Endocrinologist Copyright © 1994 by Williams &am... more Page 1. Artide 002î-972X/94/700î-0095$3.00/0 The Endocrinologist Copyright © 1994 by Williams &. Wilkins Advances in Genetic Screening for Multiple Endocrine Neoplasia Type 2 and the Implications for Management of Children ...

Surgery, 1998

Fine-needle aspiration biopsy to identify adrenal metastasis from an occult primary malignancy ha... more Fine-needle aspiration biopsy to identify adrenal metastasis from an occult primary malignancy has been recommended as part of the evaluation of the patient who presents with an incidentally discovered adrenal mass. This recommendation was assessed by examining the frequency of adrenal involvement in patients with suspected unknown primary cancer. Data from 1715 patients referred for evaluation of suspected unknown primary cancer were retrospectively reviewed. Of 1639 patients found to have cancer, the adrenal gland was identified as a site of involvement at presentation in 95 (5.8%). Involvement was limited to the adrenal gland in 4 patients (0.2%). All 4 patients had large (> or = 6 cm) adrenal tumors, 3 of 4 had bilateral involvement, and all had symptoms that otherwise mandated evaluation for an occult malignancy; none had a true adrenal incidentaloma. Although cancer of an unknown primary site occasionally involves the adrenal gland, metastatic cancer presenting as a true adrenal incidentaloma is extremely rare. Therefore, in the absence of a history of prior malignancy or symptoms, physical examination findings, radiographic findings, or laboratory findings suggestive of an occult malignancy, we do not recommend fine-needle aspiration biopsy as part of the diagnostic evaluation of the patient who presents with a unilateral adrenal mass.

Surgery, 2001

The natural history of nonfunctioning islet cell carcinoma of the pancreas is poorly defined. We ... more The natural history of nonfunctioning islet cell carcinoma of the pancreas is poorly defined. We therefore reviewed our institutional experience during a period of 12 years to define more clearly the natural history of this disease as a basis for individual therapeutic recommendations. The records of all patients who had histologically or cytologically confirmed nonfunctioning islet cell carcinoma of the pancreas were retrospectively reviewed. Patients were grouped by extent of disease at diagnosis and by initial treatment. Survival distributions were estimated by Kaplan-Meier analysis. One hundred sixty-three patients with nonfunctioning islet cell carcinoma of the pancreas were identified. The overall median survival duration was 3.2 years. The median survival was 7.1 years in patients with localized disease who underwent a potentially curative resection and 5.2 years in those with locally advanced, unresectable, nonmetastatic disease (P = .04). Patients with metastatic disease that could not be resected had a median survival of 2.1 years. Patients with completely resected localized disease had a long median survival. Patients with nonmetastatic but unresectable locally advanced disease also had a surprisingly long median survival; major treatment-related morbidity may be hard to justify in this subgroup. The short median survival in patients with metastatic disease suggests that the frequent practice of observation in this patient subgroup needs to be reexamined and that continued investigation of regional and systemic therapies with novel agents is warranted.

Surgery, 2000

Size has been considered to be the single best predictor of malignancy in adrenal neoplasms that ... more Size has been considered to be the single best predictor of malignancy in adrenal neoplasms that have been identified incidentally. However, small adrenal cortical cancers have been reported from multiple centers. We retrospectively evaluated the value of tumor size and other clinical parameters in the prediction of the presence of adrenal malignancy. The records of 117 patients who underwent evaluation for tumors of the adrenal gland were reviewed. The median tumor size of the adrenal cortical carcinomas (n = 38 carcinomas) was 9.2 cm (range, 1.7-30 cm); 5 cancers (13.5%) were smaller than 5.0 cm. The median overall size of the benign tumors, excluding pheochromocytomas, was 4.0 cm (n = 38 carcinomas); 10 benign tumors (26%) were larger than 5.0 cm. The imaging features of 4 of 5 small adrenal cancers predicted malignancy; the remaining patients had hormonally functioning tumors. The imaging features of 7 of 10 large benign adrenal tumors predicted benign histologic features, including 5 of 5 myelolipomas. Although size remains a good predictor of the histologic features and clinical behavior of adrenal neoplasms, both small adrenal cortical cancers and large benign tumors occur with measurable frequency. High-quality imaging studies may be helpful in the identification of relatively small adrenal cancers and of characteristic benign lesions that may be selectively followed.

Nucleic Acids Research, 1992

Transcripts derived from the 6 exon CALC I gene are differentially processed in a tissue-specific... more Transcripts derived from the 6 exon CALC I gene are differentially processed in a tissue-specific fashion to include or exclude a calcitonin-specific exon 4. All cell types which transcribe a second calcitonin/CGRP gene, CALC II, exclude exon 4. Substitution of the first 30 nucleotides of CALC I exon 4 with analogous CALC II sequence was sufficient to prevent recognition of exon 4 in in vitro or in vivo RNA splicing systems. UV crosslinking detected a -66 kDa RNA-binding protein in HeLa nuclear extract which interacted with CALC I proximal exon sequence, but not CALC II or mutant sequences. UV crosslinking of this protein was inhibited by addition of nuclear extract from a cell type which normally causes exclusion of exon 4. These results identify an important regulatory element within exon 4 and support a model in which calcitonin production requires protein interaction with this sequence to facilitate exon recognition.