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

Papers by Robert Gagel

Hormone Research in Paediatrics, 1998

About 1–2% of melanoma patients develop hypercalcemia. We report hypercalcemia without bone metas... more About 1–2% of melanoma patients develop hypercalcemia. We report hypercalcemia without bone metastasis in a 46-year-old woman with advanced melanoma. The hypercalcemia was associated with elevated serum parathyroid hormone-related protein (PTHrP) levels. An even higher concentration (10 times the serum level) in pleural effusion caused by pleural metastases implied that the source of the increased circulating PTHrP was the melanoma. Immunohistochemical staining of paraffin sections, performed using a monoclonal antibody (9H7) against the peptide sequence 109–141 of human PTHrP, detected PTHrP in the cytoplasm and nucleoli of melanoma cells in an autopsy specimen but not in specimens from this patient prior to onset of hypercalcemia. Considering the evidence, it is very likely that PTHrP production by melanoma caused hypercalcemia in this patient.

Cancer, Jul 1, 1976

A 65‐year‐old man with hypergastrinemia associated with the Zollinger‐Ellison syndrome was found ... more A 65‐year‐old man with hypergastrinemia associated with the Zollinger‐Ellison syndrome was found to have a duodenal “carcinoid‐islet cell tumor.” Gastrin levels have remained normal for more than 1 year following total gastrectomy and removal of the duodenal tumor. Immunohistochemical studies for gastrin localization revealed positive staining of the tumor and of a population of non‐neoplastic G‐cells in the adjacent duodenal mucosa and Brunner's glands. These results support the hypothesis that gastrinomas may arise as primary tumors from duodenal G‐cells rather than from ectopic pancreatic tissue. “Carcinoid‐islet cell tumors,” like other tumors of APUD‐cell origin, may express dual biochemical functions in the form of polypeptide hormone and/or amine secretion. Their content of specific hormonal products may be predicted on the basis of sensitive histochemical and immunohistochemical techniques.

Nature Communications

Osteolytic destruction is a hallmark of multiple myeloma, resulting from activation of osteoclast... more Osteolytic destruction is a hallmark of multiple myeloma, resulting from activation of osteoclast-mediated bone resorption and reduction of osteoblast-mediated bone formation. However, the molecular mechanisms underlying the differentiation and activity of osteoclasts and osteoblasts within a myelomatous microenvironment remain unclear. Here, we demonstrate that the osteocyte-expressed major histocompatibility complex class II transactivator (CIITA) contributes to myeloma-induced bone lesions. CIITA upregulates the secretion of osteolytic cytokines from osteocytes through acetylation at histone 3 lysine 14 in the promoter of TNFSF11 (encoding RANKL) and SOST (encoding sclerostin), leading to enhanced osteoclastogenesis and decreased osteoblastogenesis. In turn, myeloma cell–secreted 2-deoxy-D-ribose, the product of thymidine catalyzed by the function of thymidine phosphorylase, upregulates CIITA expression in osteocytes through the STAT1/IRF1 signaling pathway. Our work thus broaden...

Definitions, 2020

Bisphosphonate-associated ONJ was defined as an area of exposed bone in the maxillofacial region ... more Bisphosphonate-associated ONJ was defined as an area of exposed bone in the maxillofacial region that did not heal within 8 wk after identification by a health care provider, in a patient who was receiving or had been exposed to a bisphosphonate and had not had radiation therapy to the craniofacial region.

Molecular Cancer Therapeutics, 2021

Gain-of-function point mutations in the receptor tyrosine kinase RET, a driver oncogene in medull... more Gain-of-function point mutations in the receptor tyrosine kinase RET, a driver oncogene in medullary thyroid carcinoma (MTC), prevent apoptosis through inhibition of ATF4, a critical transcriptional regulator of endoplasmic reticulum stress. However, the critical regulatory mechanisms driving RET-dependent oncogenesis remain elusive, and there is a clinical need to identify a transcriptional RET inhibitor. Here, we found that RET depletion decreased IGFBP2 and VEGFR2 mRNA and protein expression in MTC cells. IGFBP2 knockdown decreased cell survival and migration of MTC cells. In patients, IGFBP2 expression increased in metastatic MTC, and high IGFBP2 associated with poor overall survival. VEGFR2 protein levels were positively associated with RET expression in primary tumors, and VEGF-mediated increased cell viability was RET dependent. The small-molecule ONC201 treatment of MTC cells caused apoptotic cell death, decreased transcription of RET, VEGFR2, IGFBP2, increased mRNA levels o...

Molecular Cancer Research, 2018

Medullary thyroid carcinoma (MTC) originates from the C cells of the thyroid gland, which secrete... more Medullary thyroid carcinoma (MTC) originates from the C cells of the thyroid gland, which secrete calcitonin. Lymph node and distant metastases are frequently present at diagnosis. Activating mutations of RET, a driver oncogene in MTC that encodes a tyrosine kinase receptor, prevents apoptosis through inhibition of ATF4, a key transcriptional regulator of endoplasmic reticulum (ER) stress. We hypothesized that the combination of a tyrosine kinase inhibitor (TKI) and an ATF4 inducer promotes cell death by triggering catastrophic oxidative stress and apoptotic cell death. Here, we report that the ER-associated protein degradation (ERAD) inhibitor eeyarestatin sensitized MTC cells to the TKIs, sunitinib and vandetanib, thereby leading to synergistic upregulation of ATF4 expression, accumulation of reactive oxygen species, and subsequent cell death. Genome-wide analysis of ATF4 interaction sites by chromatin immunoprecipitation (ChIP) sequencing revealed that among ATF4 target genes was...

$Research paper thumbnail of Hip fracture trends in the United States, 2002 to 2015$

Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA, 2018

An analysis of United States (US) Medicare claims data from 2002 to 2015 for women aged ≥ 65 year... more An analysis of United States (US) Medicare claims data from 2002 to 2015 for women aged ≥ 65 years found that age-adjusted hip fracture rates for 2013, 2014, and 2015 were higher than projected, resulting in an estimated increase of more than 11,000 hip fractures. Hip fractures are a major public health concern due to high morbidity, mortality, and healthcare expenses. Previous studies have reported a decrease in the annual incidence of hip fractures in the US beginning in 1995, coincident with the introduction of modern diagnostic tools and therapeutic agents for osteoporosis. In recent years, there has been less bone density testing and fewer prescriptions for osteoporosis treatments. The large osteoporosis treatment gap raises concern of possible adverse effects on hip fracture rates. We assessed hip fracture incidence in the US to determine if the previous decline in hip fracture incidence continued. Using 2002 to 2015 Medicare Part A and Part B claims for women ≥ 65 years old, ...

Molecular and Cellular Biology, 1995

Regulation of calcitonin (CT)/calcitonin gene-related peptide (CGRP) RNA processing involves the ... more Regulation of calcitonin (CT)/calcitonin gene-related peptide (CGRP) RNA processing involves the use of alternative 3' terminal exons. In most tissues and cell lines, the CT terminal exon is recognized. In an attempt to define regulatory sequences involved in the utilization of the CT-specific terminal exon, we performed deletion and mutation analyses of a mini-gene construct that contains the CT terminal exon and mimics the CT processing choice in vivo. These studies identified a 127-nucleotide intron enhancer located approximately 150 nucleotides downstream of the CT exon poly(A) cleavage site that is required for recognition of the exon. The enhancer contains an essential and conserved 5' splice site sequence. 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. Other components of the intron enhancer modified utilization of the CT-specif...

Acta cytologica

1. Acta Cytol. 1995 Jul-Aug;39(4):831-2. Oncogenous osteomalacia: fine needle aspiration of a neo... more 1. Acta Cytol. 1995 Jul-Aug;39(4):831-2. Oncogenous osteomalacia: fine needle aspiration of a neoplasm with a unique endocrinologic presentation. Yu GH, Katz RL, Raymond AK, Gagel RF, Allison A, McCutcheon I. PMID: 7631565 [PubMed - indexed for MEDLINE]. ...

Henry Ford Hospital medical journal, 1989

Multiple endocrine neoplasia type 2A (MEN 2A) is a rare hereditary disease transmitted in familie... more Multiple endocrine neoplasia type 2A (MEN 2A) is a rare hereditary disease transmitted in families as an autosomal dominant trait. We have identified a family in which the expression of a rare autosomal dominant form of cutaneous lichen amyloidosis appears to cosegregate with MEN 2A. In this family the skin lesion presented as multiple infiltrated papules overlying well demarcated plaques over the scapular area (right or left). Immunohistochemical studies demonstrated amyloid which stained for keratin but not calcitonin. A total of 19 members were screened. Three members of the family have the characteristic skin lesion and MEN 2A; two additional members have MEN 2A but have not manifested observable skin changes of lichen amyloidosis. Another unrelated Italian family with a similar type of pruritic skin rash and MEN 2A has been reported recently. Although the initial skin biopsies were negative for amyloidosis, subsequent biopsy established the association of MEN 2A with amyloidosi...

Henry Ford Hospital medical journal, 1992

We have analyzed DNA marker typing data contributed by six independent groups to estimate the pai... more We have analyzed DNA marker typing data contributed by six independent groups to estimate the pairwise genetic distances between these markers and the locus for multiple endocrine neoplasia type 2A (MEN 2A). We used LIPED to calculate these distances for female, male, and sex-average linkage maps and to determine the corresponding LOD scores. The preliminary analyses of this large data set (89 MEN 2A families and five non-MEN 2A references families, with 1,934 total individuals) are reported here. These refined estimates of the genetic map in this region will aid in the assignment of presymptomatic diagnoses. This study clearly points out the limitation of pairwise linkage analysis in further refining the position of MEN2A in this small region of chromosome 10. Further refinement of the genetic map position of MEN2A will be best accomplished by finding, verifying, and accurately mapping crossovers in specific families.

Molecular Endocrinology, 1995

A CAMP-induced enhancer was previously mapped to nucleotides-255 to-85 of the calcitonin (CT) gen... more A CAMP-induced enhancer was previously mapped to nucleotides-255 to-85 of the calcitonin (CT) gene Y-flanking DNA. To determine the functional &-acting elements within this region, we transfected medullary thyroid carcinoma (MTC) cells with CT 5'-flanking DNA/GH fusion genes containing potential CAMP-responsive elements and assessed their transcriptional activities with and without CAMP. In CT-expressing MTC cells (the TT line), we identified by deletions and point mutations three transcriptionally active motifs: a CAMP-responsive element (CRE), TGACGTCA, at-253 to-248, and a hybrid site containing a CRE-like element (CREL; TGAC-CTCA,-189 to-182) adjacent to an equally transcriptionally active octamer (0) sequence (ATG-CAAAT,-181 to-154). These three motifs acted synergistically and their transcriptiohal activity was completely dependent on CAMP. In HeLa cells their synergistic activity was more constitutive than CAMP induced, whereas in CT-negative MTC cells (the RO-D81-1 line) these motifs were inactive. Gel mobility shift assays with antibodies against CRE-binding protein (CREB) and activating transcription factor 1 (ATF-1) showed that both CREB and ATF-1 interacted with the CRE in MTC cells, whereas in HeLa cells only ATF-1 bound to the CRE. Specific binding to the CREUO motif was detectable in extracts from tumors induced by injection of TT cells but not in extracts from any of the three cultured cell lines. We conclude that CAMP-induced transcription of the CT gene is modulated in a cell-specific manner by the CRE and the CREUO elements.

Molecular Endocrinology, 1994

Molecular Endocrinology, 1990

The pre-mRNA encoding calcitonin (CT) and CT gene-related peptide (CGRP) is differentially proces... more The pre-mRNA encoding calcitonin (CT) and CT gene-related peptide (CGRP) is differentially processed in a tissue-specific fashion to include exon 4 (which encodes CT) or exclude this exon and splice to exon 5 (which encodes CGRP). We have used a CT-specific in vitro RNA-processing system to identify c/s-acting sequences required to prevent splicing to exon 5. Deletion mapping demonstrated the presence of an element within the first 45 nucleotides of the CT-specific exon 4 that was required to suppress splicing to the CGRP-specific exon 5. This element was able to function in a completely heterologous system to suppress splicing when the CGRP exon was replaced with a constitutive viral exon. The element was unable to suppress splicing in the absence of a proximal CT-specific 3' splice site. Our results suggest that CT-specific splicing requires assisted recognition of its 3' splice site.

Journal of Neurosurgery: Spine, 2009

Phosphaturic mesenchymal tumors that cause the paraneoplastic syndrome known as oncogenic osteoma... more Phosphaturic mesenchymal tumors that cause the paraneoplastic syndrome known as oncogenic osteomalacia are rare. The authors report on the case of a 57-year-old man with a history of osteomalacia and in whom was diagnosed a thoracic spine tumor at the T-4 level. Complete tumor resection was accomplished. The histological diagnosis was phosphaturic mesenchymal tumor (mixed connective tissue variant). After lesion removal, the paraneoplastic syndrome resolved. At the 24-month follow-up, no recurrence of the disease was observed. The clinical presentation, surgical technique, and follow-up in this case were reviewed in detail.

The Journal of Clinical Endocrinology & Metabolism, 1996

Analysis of peripheral blood or tumor DNA samples from 101 patients with apparent sporadic medull... more Analysis of peripheral blood or tumor DNA samples from 101 patients with apparent sporadic medullary thyroid carcinoma (MTC) was performed to assess the frequency of RET proto-oncogene mutations in this patient population. Peripheral blood and/or tumor DNA was amplified by polymerase chain reaction. DNA sequence or restriction enzyme analysis was performed to detect mutations of RET proto-oncogene codons 609,611,618,620,634,768, and 918. Six of 101 patients with apparent sporadic MTC had peripheral blood DNA mutations more commonly associated with hereditary MTC. In 4 patients, these mutations led to the identification of previously un

Journal of Bone and Mineral Research, 2008

Introduction: Osteonecrosis of the jaw (ONJ) has been reported in patients treated with bisphosph... more Introduction: Osteonecrosis of the jaw (ONJ) has been reported in patients treated with bisphosphonates. The incidence and risk factors associated with this disorder have not been clearly defined.Materials and Methods: We conducted a retrospective analysis of 4019 patients treated with intravenous bisphosphonates between 1996 and 2004. Our goals were to estimate the frequency, understand the clinical presentation, and identify risk factors associated with ONJ development.Results: Sixteen of 1338 patients with breast cancer (1.2%) and 13 of 548 patients with multiple myeloma (2.4%) developed ONJ. The median dose and duration of treatment with pamidronate or zoledronic acid were significantly higher in patients with ONJ (p < 0.0001). Multivariate Cox proportional hazards regression analysis identified treatment with zoledronic acid (hazards ratio [HR], 15.01; 95% CI: 2.41–93.48; p = 0.0037), treatment with pamidronate followed by zoledronic acid (HR, 4.00; 95% CI: 0.86–18.70; p = 0...