tbuckley/cabot-search huggingface dataset:
Hypothalamic-Pituitary-Gonadal Dysfunction in Men Using Cimetidine
Authors: D. H. Van Thiel, J. S. Gavaler, William I. Smith, Gwendolyn Paul
Journal: New England Journal of Medicine (1979)

We studied the effect of cimetidine therapy (1200 mg per day by mouth for nine weeks) on the hypothalamic-pituitary-gonadal axis of seven men. There was a 43 per cent mean reduction in sperm count after therapy. The luteinizing hormone response to luteinizing hormone releasing factor was also reduced, and a statistically significnat rise in plasma testosterone occurred, although it was less than that before therapy. Gonadotropin responses to provocative clomiphene stimulation were inadequate when compared with those of controls. Cimetidine did not affect the responses of thyroid-stimulating hormone, prolactin, growth hormone and thyroxine to thyrotropin releasing factor. Caution is advisable in administration of cimetidine for prolonged periods to young men.
Molecular Defect of the Band 3 Protein in Southeast Asian Ovalocytosis
Authors: Shih-Chun Liu, Sen Zhai, Jiri Palek, David E. Golan, Dominick Amato, Khalid Hassan, George T. Nurse, Diro Babona, Theresa Coetzer, Petr Jarolim, Mahmood Zaik, Sarah Borwein
Journal: New England Journal of Medicine (1990)

Southeast Asian ovalocytosis is a form of hereditary elliptocytosis in which the red cells are rigid and resistant to malaria invasion. The underlying molecular defect is unknown.
FRI0301 A Phase I Pharmacokinetics TRIAL Comparing PF-06438179 (A Potential Biosimilar) and Infliximab in Healthy Volunteers (Reflections B537-01)
Authors: C. Udata, S.Y. Hua, D. Yin, S. Salts, X. Meng, M.I. Rehman
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> PF-06438179, a proposed biosimilar to infliximab, has an identical primary amino acid sequence and similar physicochemical, in vitro, and in vivo functional properties to infliximab. <h3>Objectives</h3> The Phase I study was designed to demonstrate pharmacokinetics (PK) similarity of PF-06438179 to infliximab sourced from the US (infliximab-US) and EU (infliximab-EU), and between infliximab-EU and infliximab-US. Safety was also evaluated. <h3>Methods</h3> In this double-blind trial (NCT01844804), 151 healthy volunteers, 18-55 years old were randomized 1:1:1 to one of 3 treatment groups, of which 146 received a single 10 mg/kg IV dose of PF-06438179 (n=49), infliximab-US (n=48), or infliximab-EU (n=49). All subjects provided informed consent. PK was evaluated over a period of 8 weeks and safety and immunogenicity were assessed up to 12 weeks. PK similarity for a given test-to-reference comparison was considered to be demonstrated if the 90% CI of the test-to-reference ratio of the area under curve from time 0 to the last time point (AUC<sub>T</sub>), from time 0 to infinity (AUC<sub>0–∞</sub>), and maximum concentration (C<sub>max</sub>) were within the 80.00% – 125.00% bioequivalence (BE) acceptance window. <h3>Results</h3> The baseline demographics for the 130 subjects evaluable for PK were similar among treatment groups. The 3 study drugs exhibited a similar PK profile, which is characterized by a rapid increase of serum drug concentration during infusion followed by a multi-phasic decline in drug concentrations (Figure). The 90% CI for the ratios of C<sub>max</sub>, AUC<sub>T</sub>, and AUC<sub>0–∞</sub> were within the BE acceptance window of 80.00–125.00% for the comparisons of PF-06438179 to infliximab-US or infliximab-EU, and infliximab-EU to infliximab-US. Similar number of subjects experienced AEs among all 3 treatment groups. Overall the frequency and type of AEs reported were similar across all three treatment groups, although the number of AEs was highest in the infliximab-US group. The 3 treatments had a comparable ADA profile with a somewhat lower incidence of ADA response in the PF-06438179 group. No infusion related reactions were reported. <h3>Conclusions</h3> This study demonstrates PK similarity of PF-06438179 to both infliximab-US and infliximab-EU and of infliximab-EU to infliximab-US. The 3 study drugs were generally safe and well-tolerated in this study. <h3>Disclosure of Interest</h3> C. Udata Employee of: Pfizer Inc, S. Hua Employee of: Pfizer Inc, D. Yin Employee of: Pfizer Inc, S. Salts Employee of: Pfizer Inc, X. Meng Employee of: Pfizer Inc, M. Rehman Employee of: Pfizer Inc <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.5377
Abstract 2720: Sym004, a novel anti-EGFR antibody mixture augments radiation response in human lung and head and neck cancer models
Authors: Shyhmin Huang, Eric A. Armstrong, Michael Kragh, Mikkel W. Pedersen, Paul M. Harari
Journal: Cancer Research (2012)

Abstract Sym004* is a newly developed EGFR targeting agent that is a mixture of two anti-EGFR antibodies directed against distinct epitopes on domain III of EGFR. In contrast to existing anti-EGFR antibodies, Sym004 induces rapid and efficient EGFR internalization and degradation. In the current study, we examine the capacity of Sym004 to augment radiation response in lung cancer and head and neck (H&amp;N) cancer model systems. We examined the anti-proliferative effect of Sym004 confirming 40∼60% growth inhibition by Sym004 across a variety of lung and H&amp;N cancer cell lines. Using clonogenic survival analysis, we identified that Sym004 potently increased cell kill by up to 10-fold following 9 Gy radiation exposure. Immunoblot analysis showed down-regulation of MAPK and AKT pathways, as well as changes in several key proteins involved in cell cycle progression, DNA damage repair and apoptosis. Flow cytometric analysis confirmed a significant increase of cells in S phase 24 hrs following 6 Gy radiation in control cells. However, treatment with Sym004 preceding radiation induced a significant G1 and G2 arrest accompanied by a reduction in S phase. Interestingly, we found a significant increase in apoptosis 48 hrs after radiation. These results suggest that Sym004 arguments radiation response via the induction of cell cycle arrest followed by the induction of apoptosis and cell death likely reflecting inhibitory effects on DNA damage repair. Finally, using single dose or fractionated radiation experiments in human tumor xenograft models, we found that the combination of Sym004 and radiation resulted in a significant delay in tumor regrowth and superior anti-tumor effects than treatment with drug or radiation alone. Taken together, these data reveal the strong capacity of Sym004 to augment radiation response in lung and H&amp;N cancers. The unique action mechanism of Sym004 warrants further investigation as a promising EGFR targeting agent combined with radiotherapy in cancer therapy. (*Pedersen et al., Cancer Res 70:588∼597, 2010) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2720. doi:1538-7445.AM2012-2720
Abstract 2031: A functional nuclear epidermal growth factor receptor, Src and Stat3 heteromeric complex in pancreatic cancer cells
Authors: David Paladino, Soumya Jaganathan, Peibin Yue, Jelena Bogdanovic, Qun Huo, James Turkson
Journal: Cancer Research (2011)

Abstract Pancreatic cancer is an extremely lethal malignancy whose prognosis has not improved appreciably in the last decade. The disease is usually diagnosed only after it has reached an advanced or metastatic state but even local, surgically resectable, tumors have a fairly poor prognosis. This is further complicated by the fact that little is known about the underlying mechanisms of pancreatic cancer, as evidenced by a lack of any efficacious targeted therapies. While hyperactive epidermal growth factor receptor (EGFR), Src tyrosine kinase and Signal Transducer and Activator of Transcription (Stat)3 have been detected in pancreatic cancer and implicated in the disease, the exact mechanisms by which they promote the disease phenotype are not well understood. We present evidence of a functional heteromeric complex of EGFR, c-Src and Stat3 that is detected at the plasma membrane and cytoplasm, and inside the nucleus of pancreatic cancer cells. The inhibition of c-Src, but not EGFR kinase, reduced the level of nuclear EGFR levels. Furthermore, the inhibition of Src or EGFR kinase alone decreased nuclear Stat3 levels, while the greatest decrease occurred upon the combined inhibition of EGFR and Src kinase activities. Significantly, evidence shows that the nuclear EGFR, Src and Stat3 complex functions as a transcriptional complex. Thus, the siRNA knockdown of EGFR or Src, or the pharmacological inhibition of aberrant Stat3 activity only moderately decreased c-Myc, iNOS, and VEGF expression. By contrast, the knockdown of EGFR or Src together with the inhibition of Stat3 activity strongly suppressed c-Myc expression in Panc-1 and Colo-357 cells. Chromatin immunoprecipitation (ChIP) studies further validated these findings and showed that the nuclear EGFR, Src, and Stat3 complex is bound to the c-Myc promoter. Taken together, these data identify a novel and functional heteromeric EGFR, Src, and Stat3 complex that promotes the induction of c-Myc in pancreatic cancer cells. Our study provides additional insight into the mechanisms by which hyperactive EGFR, Src and Stat3 pathway promotes the pancreatic cancer phenotype. 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 2031. doi:10.1158/1538-7445.AM2011-2031
TICAGRELOR VERSUS CLOPIDOGREL IN PATIENTS WITH ACUTE CORONARY SYNDROMES AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE: AN ANALYSIS FROM THE PLATELET INHIBITION AND PATIENT OUTCOMES (PLATO) TRIAL
Authors: Pontus Andell, Stefan James, Christopher Cannon, Derek Cyr, Anders Himmelmann, Steen Husted, Matyas Keltai, Sasha Koul, Anwar Santoso, Philippe Steg, Robert Storey, Lars Wallentin, David Erlinge
Journal: Journal of the American College of Cardiology (2015)
Programmed Cell Death 4 (PDCD4), a Novel Inhibitor of Leptin-Induced Breast Cancer Cell Invasion.
Authors: V. Gonzalez-Villasana, V. Gonzalez-Villasana, R. Nieves-Alicea, V. McMurtry, A. Tari, Y. Gutierrez-Puente
Journal: Cancer Research (2009)

Abstract Obesity is known to increase the risk of breast tumor development in post menopausal women. Leptin, an adipokine produced in high levels in obese individuals, has been found in breast tumors and been linked with increased incidence of breast cancer metastasis. Breast cancer metastasis is directly associated with breast cancer cell invasion. Previously we demonstrated that leptin increases breast cancer cell invasion. Here we determined whether PDCD4, a novel tumor suppressor, could block leptin-induced breast cancer cell invasion. In MCF-7 breast cancer cells overexpressing PDCD4 (MCF-7/PDCD4), leptin failed to induce invasion, in contrast to the parental MCF-7 cells, indicating that PDCD4 blocks leptin-induced breast cancer cell invasion. MCF-7/PDCD4 cells produced higher levels of the Tissue Inhibitor of Metalloproteinases-2 (TIMP-2) than the parental cells. Pretreatment of MCF-7/PDCD4 cells with TIMP-2 siRNA allowed leptin to induce the invasion of MCF-7/PDCD4 cells, thus indicating that knocking down TIMP-2 expression reversed the anti-invasive effects of PDCD4. The levels of phospho-ERK and phospho-STAT3 were higher in MCF-7/PDCD4 cells treated with leptin and TIMP-2 siRNA than in MCF-7/PDCD4 cells treated with leptin and non-silencing control siRNA. Yet the levels of phospho-JNK were similar in leptin-treated MCF-7/PDCD4 cells transfected with TIMP-2 siRNA or non-silencing control siRNA. Here we report the novel findings that PDCD4 increases TIMP-2 expression to block leptin-induced breast cancer cell invasion by suppressing ERK and STAT3 activities. Metastasis is the primary cause of breast cancer mortality. Novel therapeutic strategies aiming at enhancing PDCD4 expression in breast tumors may be able to stop obesity-related breast tumor progression and prolong patients' lives. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6153.
P4-07-17: Isolation of Highly Pure Circulating Tumor Cells (CTCs) from Metastatic Breast Cancer (MBC) Patients for Gene Expression Analysis.
Authors: MJ Magbanua, L Hauranieh, P Pendyala, E Sosa, J Scott, H Rugo, J Park
Journal: Cancer Research (2011)

Abstract Background: The paucity of information regarding the molecular nature of CTCs can be largely attributed to the difficulty of isolating these rare cells. As such, efforts on RNA profiling of CTCs have been limited to studies using immuno-enriched samples containing a high background of leukocytes. Methods: We developed a two-step process: immunomagnetic enrichment followed by fluorescence activated cell sorting (IE/FACS) to isolate CTCs away from leukocytes and performed expression analysis on a limited panel of genes. Magnetic beads coated with EpCAM mAb were used to enrich for tumor cells. Enriched samples were then subjected to FACS using fluorescently labeled mAbs to distinguish tumor cells (EpCAM+) from leukocytes (CD45+) during sorting. CTCs and matched leukocytes were isolated from 67 sequential patients with MBC. Total RNA from isolated 20–50 cells was reverse-transcribed into cDNA. Sixty four (64) CTC-related genes from previous published reports were chosen for expression analysis. cDNA of these genes were pre-amplified and analyzed in triplicate via Taqman®-based RT-PCR in a low density array format. Statistical analysis of gene expression data was performed using Realtime Statminer®. Results: Unsupervised hierarchical clustering analysis showed that CTCs clustered away from the leukocytes. Differential gene expression analysis revealed the up-regulation of several genes including EPCAM, MUC1, and KRT19 in CTCs (adjusted p &amp;lt;0.05). In addition, CTCs showed a significant down-regulation of the leukocyte-specific marker PTPRC (CD45) as well as CD44 and VIM, markers associated with stem cellness and epithelial to mesenchymal transition, respectively. Discussion: We demonstrate the feasibility of isolation and gene expression analysis of CTCs. Molecular profiling confirmed that isolated CTCs were highly pure with little or no evidence of leukocyte contamination. This approach can serve as a non-invasive source of tumor tissue for further molecular characterization of CTCs and for monitoring of therapeutic efficacy of targeted therapies in clinical trials. This study was supported by CALGB and BCRF. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-07-17.
Case 33-1990
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, Norman S. Nishioka, Susan S. Donnelly
Journal: New England Journal of Medicine (1990)

Presentation of CaseA 72-year-old woman was admitted to the hospital because of abdominal pain, nausea, and diarrhea.The patient was well until two days earlier, when crampy epigastric pain developed. She was seen at another hospital, where fluids were administered by vein, and she was sent home 12 hours later. The abdominal pain waxed and waned. On the day of admission the pain was more severe, and nausea and diarrhea developed; she came to this hospital.The patient was a native of China who had spent much of her life in Hong Kong and immigrated to the United States . . .
Abstract 1778: Nimotuzumab, a humanized antiepidermal growth factor receptor antibody, interacts with EGFRvIII
Authors: Maria L. Jaramillo, Suzanne Grothe, Jason Baardsnes, Myriam Banville, Beatrice Paul-Roc, Ilia A. Tikhomirov, Sean EL Thompson, Maureen O'Connor
Journal: Cancer Research (2010)

Abstract Introduction: Glioblastomas frequently overexpress a variant form of EGFR, called variant III (EGFRvIII), which has an in-frame deletion of an 801-bp sequence in the extracellular domain. EGFRvIII does not bind EGF ligand but exhibits constitutive kinase activity that results in enhanced transformation, reduced apoptosis, and resistance to therapy. Nimotuzumab (Nmab) is an EGFR-targeting antibody that has demonstrated encouraging results in early clinical trials treating adult and pediatric brain tumors. Here we present data characterizing the interaction of Nmab with EGFRvIII. Methods: Binding of Nmab to the extracellular domain of wtEGFR and EGFRvIII was first characterized by SPR biosensor analysis: Nmab was captured via its Fc domain and varying concentrations of EGFRvIII and EGFRwt were flowed. Flow cytometry analysis was subsequently performed using a parental U87MG glioblastoma cell line and derivatives which were engineered to overexpress either wtEGFR or EGFRvIII. Results: Nmab bound EGFRvIII and EGFRwt with similar affinity, which was in the 10−8 M range. This KD is consistent with the previously reported affinity constant of Nmab for EGFRwt (Telavera et al, 2009). Binding was further analyzed by flow cytometry. Nmab bound both EGFRwt and EGFRvIII expressed on the surface of parental U87MG, U87MG EGFRvIII and U87MG wtEGFR cells. Additional data concerning effects of Nmab on EGFRvIII expressing cell lines will be presented. Conclusion: Nmab binds to wtEGFR and EGFRvIII with similar affinity, which supports development of the antibody as a therapeutic for glioblastoma. In U87MG glioblastoma cells, synergistic activity of Nmab in combination with radiotherapy has been previously reported (Diaz Miqueli et al, 2009). Nmab is currently being tested in an advanced randomized study in the first line setting for the treatment of adult glioma. Nmab is being tested in combination with radiation plus temozolomide, vs radiation plus temozolomide alone, with preliminary results expected in the second half of 2010. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1778.
Case 25-2004
Authors: Janey S. Pratt, Susan Cummings, Deborah A. Vineberg, Fiona Graeme-Cook, Lee M. Kaplan
Journal: New England Journal of Medicine (2004)

A 49-year-old woman was evaluated for weight-loss surgery. She had been obese since late childhood, and her current body-mass index was 52. She had been unable to maintain weight loss by dieting and had both diabetes and hypertension. The multidisciplinary team discusses the surgical management of obesity.
1275 SERUM CHENODEOXYCHOLIC ACID, BMI AND TG ARE INDEPENDENTLY RELATED TO INSULIN-RESISTANCE IN BLOOD DONORS: AN INTERIM ANALYSIS OF AN ONGOING PROSPECTIVE STUDY
Authors: R. Arena, F. Azzaroli, P. Simoni, M. Montagnani, P. Cecinato, A. Lisotti, C. Colliva, C. Calvanese, F. Buonflglioli, G. Grande, A. Belardinelli, P. Pagliaro, A. Roda, G. Mazzella
Journal: Journal of Hepatology (2012)
Abstract 761: Comparison of different classes of CpG-ODNs to augment generation, proliferation and specific cytotoxicity of human epitope-peptide specific CTLs in vitro
Authors: Masahiro Katsuda, Makoto Iwahashi, Kenji Matsuda, Motoki Miyazawa, Mikihito Nakamori, Masaki Nakamura, Toshiyasu Ojima, Takeshi Iida, Keiji Hayata, Hiroki Yamaue
Journal: Cancer Research (2011)

Abstract Three distinct classes of CpG- oligonucleotides (ODN) (CpG-A, CpG-B and CpG-C) have been identified based on differences in their structures and immune effect. So far, CpG-B is only applied for clinical treatments; however, it is still unknown which of the different CpG-ODN classes is most useful as adjuvant of human cancer vaccine therapy. In the present study, we examined the activity of these 3 types of CpG-ODNs to enhance the induction of human peptide-specific CTLs. In addition, we elucidated the effect of CpG-ODNs on tumor antigen epitope peptide-specific CTL clones to investigate the adjuvant mechanism of CpG-ODNs on peptide vaccine therapy. Our data showed that PDC activated by CpG-ODNs augmented induction of peptide specific CTLs. Importantly, CpG-A is superior to CpG-B and CpG-C in augmenting the generation, proliferation and cytotoxic activity of human peptide specific CTLs in vitro. Moreover, type-1 IFNs produced by PBMCs that were stimulated with CpG-ODNs accelerated the proliferation of peptide-specific CTL clones, and also directly augmented the peptide specific cytotoxicity of CTL clones through the up regulation of Granzyme-B. These data showed that IFN-α might play an important role for CpG-ODNs to induce the adjuvant effects in peptide vaccine therapy. In addition, because CpG-A induced high amount of type-1 IFNs, CpG-A might be the superior candidate for vaccine adjuvant than CpG-B or CpG-C. 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 761. doi:10.1158/1538-7445.AM2011-761
Case 5-2013
Authors: Lori J. Wirth, Douglas S. Ross, Gregory W. Randolph, Mary Elizabeth Cunnane, Peter M. Sadow
Journal: New England Journal of Medicine (2013)

A 52-year-old woman was seen in the thyroid clinic of this hospital because of a mass in the neck. Imaging revealed abnormal cervical lymph nodes and two thyroid nodules with calcifications. A diagnostic procedure was performed.