tbuckley/cabot-search huggingface dataset:
Regulation of the tumor suppressor gene PAEP in the transition from serous borderline ovarian tumors to low-grade serous ovarian carcinomas.
Authors: E. R. King, Y. T. Tsang, Z. Zu, D. M. Gershenson, S. C. Mok, K. Wong
Journal: Journal of Clinical Oncology (2011)

5074 Background: Serous borderline ovarian tumors (SBOT) and low grade serous ovarian carcinomas (LG) form a molecular continuum, and SBOT may recur as LG. BRAF mutations are common in SBOT, but are rare in LG carcinomas. In an expression analysis comparing SBOT with and without BRAF mutations, BRAF mutation was correlated with upregulation of tumor suppressor genes, one of which was progestagen-associated endometrial protein (PAEP). Therefore, we sought to validate the overexpression of PAEP in SBOT as a possible mechanism of oncogene-induced senescence. Methods: Gene expression profiling of borderline tumors with BRAF and wild-type (wt) mutations was performed. Overexpression of PAEP in SBOT with BRAF mutations was validated by quantitative real-time polymerase chain reaction (qRT-PCR). Protein expression of PAEP was evaluated by immunohistochemistry (IHC) on SBOT and LG paraffin sections with and without known BRAF and KRAS mutations. Two LG cell lines (HOC-7, MPSC-1) were transduced with lentiviral PAEP, control, and EGFP plasmid constructs, and Western blot was performed to confirm successful transduction. The low-grade lines were treated with varying levels of PAEP-carrying lentiviral particles (0.007 to 0.07 MOI) and growth assays were performed. Results: In the expression analysis, 22 genes were significantly differentially expressed in BRAF-positive tumors, including PAEP (p<0.0001). This was confirmed by qRT-PCR on 13 SBOT samples; 7 with BRAF mutations, and 6 with wt BRAF. Mean mRNA expression of PAEP was 17-fold higher in SBOT with BRAF mutations than that of wt (p=0.0005). The protein expression of PAEP via IHC was also significantly higher in SBOT (n=9) versus LG (n=12, p=0.009); and in tumors with BRAF and KRAS mutations (n=17, n=11, respectively) versus wt (n=13, wt vs. KRAS p=0.013; wt vs. BRAF p=0.002). Cell growth was inhibited in a dose-response manner upon transient infection with PAEP-carrying lentiviral particles. Conclusions: PAEP is a secretory protein with anti-tumor growth effects, and is overexpressed in SBOT with BRAF mutations. Its downregulation in LG serous ovarian carcinoma may be implicated in the progression from SBOT to LG carcinoma.
Apoptotic Effects of Corticosteroids on Pure CD34+ Hematopoietic Stem Cells and Modulation of This Effect with Cytokines
Authors: Beyza Cetin, Serap Erdem Kuruca, Kadriye Akgun Dar, Sabriye Karadenizli, Ebru Gurel, Gulyuz Ozturk, Abdullah Yilmaz, Gunnur Deniz, Melek Yanasik
Journal: Blood (2010)
Abstract LB-176: Identification of mutations in histone modification genes in Hodgkin lymphoma
Authors: Winnie S. Liang, Bodour Salhia, Adrienne Helland, Shobana Sekar, Ignacio Garrido-Laguna, Michelle Fanale, Yasuhiro Oki, Jason R. Westin, R. Eric Davis, Funda Meric-Bernstam, Filip Janku
Journal: Cancer Research (2015)

Abstract Background: Understanding genetic aberrations in cancer has led to discoveries of new targets for cancer therapies. The genomic landscape of Hodgkin lymphoma (HL) has not been fully described. Methods: We performed targeted next generation sequencing (NGS) on 13 archival tumor samples from patients with relapsed/refractory HL treated in the phase I clinical trial with the mTOR inhibitor sirolimus and the HDAC inhibitor vorinostat using the Foundation One NGS panel (Foundation One, Foundation Medicine, MA). Subsequently, we performed whole exome and RNA sequencing on pre- and post-treatment tumor biopsies from 3 patients treated in the same study. Results: In archival samples from 13 HL patients tested using the Foundation One panel, a total of 21 gene aberrations across 13 genes were detected; 12 (92%) tumor samples had mutations in genes involved in immune response, apoptosis, and cell proliferation pathways (SOCS1, PIM1, MCL1, BRCA1, TP53, TNFAIP3, B2M, XPO1, BCL6) and 7 (54%) samples had mutations in DNA repair pathway genes (TP53, BRCA1, ATM, PIM1). In addition, whole exome and RNA sequencing of pre- and post-treatment tumor and germline (peripheral blood mononuclear cells) samples from HL patients treated with sirolimus and vorinostat (complete response, n = 1; stable disease for 3 months, n = 1; progression, n = 1) identified missense point mutations in key histone modification genes not included in the Foundation One panel, including HDAC8 (histone deacetylase 8), JMJD1C (jumonji domain containing 1C), and KDM2A (lysine-specific demethylase 2A) in the patient who progressed on therapy. This same patient additionally had a B2M missense mutation (M1R) affecting the same residue as the B2M event (M1I) identified in the archival cohort. Furthermore, there was a trend towards increased burden of molecular aberrations (median, 67 aberrations) in pre- and post- tumor samples of the patient who progressed compared to the other 2 patients (median, 6 aberrations), who did not progress. Conclusion: While analysis of additional HL specimens is needed, our data suggest that testing for molecular aberrations with NGS is feasible and somatic missense mutations in HDAC8, JMJD1C, and KDM2A may be associated with lack of clinical response to sirolimus and vorinostat. Citation Format: Winnie S. Liang, Bodour Salhia, Adrienne Helland, Shobana Sekar, Ignacio Garrido-Laguna, Michelle Fanale, Yasuhiro Oki, Jason R. Westin, R. Eric Davis, Funda Meric-Bernstam, Filip Janku. Identification of mutations in histone modification genes in Hodgkin lymphoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-176. doi:10.1158/1538-7445.AM2015-LB-176
The Effect of Donor Lymphocyte Infusion Dose on the Occurrence of Severe Life-Threatening Acute Graft-Versus-Host Disease Early after Reduced Intensity Conditioning T Cell Depleted Stem Cell Transplantation.
Authors: Peter A. Von Dem Borne, C.W.J. Ingrid Starrenburg, M. Floor Beaumont, Stijn J.M. Halkes, Erik W.A. Marijt, J.H. Frederik Falkenburg, Roelof Willemze
Journal: Blood (2008)
“I Haven't Time to Write”: Martha May Eliot and American Medical Education Reform
Authors: Deborah Levine
Journal: Annals of Internal Medicine (2016)

"We are up to our eyes in work. I have about 32 children tonight all with some contagious disease, if not two, and several very sick!" wrote Dr. Martha May Eliot to her parents in 1920, adding, "The hospital is full almost to overflowing and still they come." Eliot, who would go on to become an influential American pediatrician and public health authority, as well as the head of the Federal Children's Bureau, wrote her parents frequently during the course of her education at Radcliffe College (Cambridge, Massachusetts), Bryn Mawr College (Bryn Mawr, Pennsylvania), Johns Hopkins Medical School (Baltimore, Maryland), Peter Bent Brigham Hospital (Boston, Massachusetts), St. Louis Children's Hospital (St. Louis, Missouri), and Yale University Medical School (New Haven, Connecticut). Through these letters, she detailed her experience as a woman professional at elite institutions during a key transformative period in U.S. medicine. This article uses Eliot's collection of correspondence to shed light on physicians' experience of the increasingly rigorous training, testing, and licensing processes introduced in top medical schools and to offer insights into the history of women's medical education and experience in building careers as academic professionals during that time. Eliot's letters also illustrate how the newer, higher standards for medical graduates and postgraduates may have hastened—rather than hindered—the progress of some elite women in the medical profession. Today's physicians and medical educators, as well as those completing graduate training, will find much to draw on from the experience revealed by this rich epistolary archive.
Factors associated with type I and type II endometrial cancers in women with a germ-line mutation in a mismatch repair gene.
Authors: Y. C. Antill, A. K. Win, P. Webb, J. L. Hopper, S. Gallinger, N. M. Lindor, P. A. Newcomb, R. W. Haile, J. Church, L. Le Marchand, I. Winship, A. B. Spurdle, M. A. Jenkins
Journal: Journal of Clinical Oncology (2011)

1521 Background: Women with an inherited mutation in a mismatch repair (MMR) gene have a substantially increased risk of endometrial cancer (EC) during their lifetime. In the general population, risk factors are thought to differ between type I and type II EC, with type I tumors thought to be associated with hyper-estrogenic stimulation; the same is not well understood for mutation carriers. Methods: Using families recruited into the Colon Cancer Family Registry (CFR) with a known MMR germline mutation, we evaluated associations between age, menopausal status, body mass index (BMI), diabetes, hyperlipidaemia and cholecystectomy with EC for mutation carriers. Data was obtained from completed questionnaires with pathology reports attained to enable classification of tumors into type I and type II ECs. We then compared characteristics of the MMR carrier cases to that reported from population cohorts. Results: From 600 female carriers of a MMR mutation (244 MLH1, 299 MSH2, 38 MSH6 and 19 PMS2) recruited into the CFR, 140 cases of EC were reported (46MLH1, 77MSH2, 15MSH6 and 2 PMS2) with a mean age of 47.5 (standard deviation, SD 8.3) years. Pathology reports were available for 54 cases; 32 type I and 22 type II with mean age at diagnosis 49.3 (SD 7.4) and 49.0 (SD 8.4) yrs respectively (p=0.9).Overall mean BMI at diagnosis was 26.3 (SD 6.3) kg/m2 with no significant difference between type I and II cancers, 25.4 (SD 5.3) v 27.8 (SD 6.2) kg/m2 (p=0.3). No significant difference in diabetes, hyperlipidaemia or cholecystectomy was found between the two groups. When compared to a population based cohort, significant differences between mutation carrying cases and population cases were observed for both type I: mean diagnosis age; 49.3 (SD 7.4) v 60.0 (SD 17) yrs (p=0.0004), post-menopausal status; 56% v 80% (p=0.001) and BMI >25 kg/m2; 37% v 83% (p<0.001), and for Type II ECs; mean diagnosis age, 49.0 (SD 8.4) v 68.0 (SD 17.0) yrs (p<0.001) and post-menopausal status, 40% v 91% (p<0.001) but not for BMI >25kg/m2 55% v 69% (p=0.3). Conclusions: EC occurring in the presence of a germline MMR mutation appears not to be associated with factors traditionally associated with type I tumors for the general population.
Abstract 3943: Genetic abnormalites in hypoxia sensing regulators cause human pheochromocytoma/paraganglioma and plolycythemia syndrome
Authors: Chunzhang Yang, Herui Wang, Karel Pacak, Zhengping Zhuang
Journal: Cancer Research (2015)

Abstract Hypoxia inducible factors (HIFs) control the cellular response to hypoxia and when dysregulated, contribute to tumorigenesis. In the presence of oxygen, HIFs are strictly deactivated via EGLN/VHL/26S proteasome degradation mechanism. We identified that either gain-of-function mutations in HIF2A, or loss-of-function mutations in EGLN1/2, result in the multiple pheochromocytomas or paraganglioma associated with polycythemia. Mutation in HIF2A or EGLN1/2 cause compromised interaction of prolyl hydroxylase to HIF-α and lead to defects of HIF-α degradation. Stabilized HIF-α translocates into cell nucleus and function as a potent transcriptional factor, which induces constitutive transcriptional activation of hypoxia related genes, as well as pseudohypoxic change in cellular signaling and metabolism. Our finding provided direct evidence that genetic defect in intrinsic HIF-α and its regulatory proteins EGLN1/2 can be a key factor involved in the pathogenesis of this tumor-associated syndrome. Citation Format: Chunzhang Yang, Herui Wang, Karel Pacak, Zhengping Zhuang. Genetic abnormalites in hypoxia sensing regulators cause human pheochromocytoma/paraganglioma and plolycythemia syndrome. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3943. doi:10.1158/1538-7445.AM2015-3943
PTU-007 Developing minimally invasive resection techniques for colonic lesions – first report of the full thickness laparo-endoscopic excision procedure
Authors: C Fraser, P Sibbons, R Cahill, R Kennedy
Journal: Gut (2010)

<h3>Introduction</h3> Currently colonic lesions unsuitable for endoscopic resection are treated by segmental resection. However local full thickness excision alone may be sufficient and potentially would reduce immediate complications and subsequent morbidity. A novel technique is presented describing this. <h3>Methods</h3> With storyboard planning, the full thickness laparo-endoscopic excision (FLEX) concept evolved to entail initial endoscopic outlining of the lesion to be excised by circumferential argon plasma coagulation 1 cm from the lesion edge under synchronous laparoscopic control. Thereafter three separate brace bars are laparoscopically placed, transmurally around the lesion, from the intraperitoneal aspect 1 cm outside of the area circumscribed endoscopically and under direct endoscopic vision, with each one then being cinched to achieve inversion of the segment to be excised. The serosal aspect of the inversion site is oversewn laparoscopically in two layers to ensure security. A second endoscope is then passed transanally into the sigmoid colon to assist with intraluminal tissue traction. A full thickness excision of the hemi-circumferential fold that has been inverted into the bowel is then performed endoscopically. The feasibility and safety of this innovative approach was determined in a series of seven large White Landrace-Cross pigs with a sigmoid colonic pseudopolyp (created by endoscopic ink injection) as the target lesion. The first three procedures were used to standardise the technical components and steps and allow immediate assessment of technique competence by post-procedural laparotomy. The next four pigs underwent the same procedure with a post-procedural survival study, concluding with postmortem at 7–10 days to allow peritoneal and resection site scrutiny and bursting pressure assessment. <h3>Results</h3> The procedure was technically successful in every case without inducing inadvertent injury or bleeding. Median resected specimen diameter was 2.5 cm (range 2–3). Acute series post mortem examinations confirmed secure apposition without compromise of luminal diameter while all four survival animals thrived post-operatively. Late forensic laparotomy revealed neither sepsis nor complicated healing nor intraperitoneal adhesion formation. Lumen diameter was normal while bursting pressures of the colonic excision site were a median of 245 mm Hg (range 240–260). <h3>Conclusion</h3> This novel combined approach proved an effective and safe means of achieving full thickness resection of a site in the colon in this porcine series. While some components could be formatted in future for single port or natural orifice endoscopic working, the FLEX procedure is suitable for evaluation in clinical practice for selected patients.
The effect of intraperitoneal administration of clostridium perfringens enterotoxin on chemotherapy-resistant CD44+ human ovarian cancer stem cells in mice.
Authors: J. Varughese, F. Casagrande, E. Cocco, S. Bellone, C. E. Richter, M. Bellone, P. Todeschini, L. Carrara, F. Guzzo, E. Siegel, D. Silasi, M. Azodi, T. Rutherford, S. L. Pecorelli, P. E. Schwartz, A. Santin
Journal: Journal of Clinical Oncology (2011)

e13077 Background: Emerging evidence has suggested that the capability to sustain tumor formation, growth and chemotherapy-resistance in ovarian, as well as other human malignancies, exclusively resides in a small proportion of tumor cells termed cancer stem cells (CSCs). During the characterization of CD44+ ovarian CSCs, we found a high expression of the genes encoding for claudin-4. Because this tight junction protein is the natural high affinity receptor for Clostridium perfringens enterotoxin (CPE), we have extensively investigated the sensitivity of ovarian CSC to CPE treatment in vitro and in vivo. Methods: Real-time polymerase-chain-reaction and flow cytometry were used to evaluate claudin-3/-4 expression in ovarian CSCs. Small-interfering-RNA-knockdown experiments, and MTS-assays were used to evaluate CPE-induced cytotoxicity against ovarian CSC lines in vitro. C.B-17/SCID mice harboring ovarian CSC xenografts were used to evaluate CPE therapeutic activity in vivo. Results: CD44+ ovarian CSCs expressed claudin-4 gene at significantly higher levels than matched autologous CD44- ovarian cancer cells and, regardless of their higher resistance to chemotherapeutic agents, died within 1 hour after exposure to 1.0μg/ml of CPE in vitro. Conversely, small-interfering-RNA–mediated knockdown of claudin-3/-4 expression in CD44+ CSCs significantly protected CSCs from CPE-induced-cytotoxicity. Importantly, multiple intraperitoneal administrations of sublethal doses of CPE in mice harboring xenografts of chemotherapy resistant CD44+ ovarian CSCs had a significant inhibitory effect on tumor progression leading to the cure and/or long-term survival of all treated animals. Conclusions: CPE may represent an unconventional, potentially highly effective strategy to eradicate chemotherapy-resistant CSCs.
Analysis of Spontaneous Vs. Vaccine-Induced Antibody Responses Against Cancer-Testis Antigen MAGE-A3 in Cancer Patients
Authors: Yanran Cao, Sacha Gnjatic, Vincent G. Brichard, Tim Luetkens, Sebastian Kobold, Katrin Bartels, Nasser Altorki, Friedrich Haag, Gerd Ritter, Carsten Bokemeyer, Lloyd J Old, Nicolaus Kroeger, Djordje Atanackovic
Journal: Blood (2011)
An FDA Perspective on the Regulatory Implications of Complex Signatures to Predict Response to Targeted Therapies
Authors: Julia A. Beaver, Abraham Tzou, Gideon M. Blumenthal, Amy E. McKee, Geoffrey Kim, Richard Pazdur, Reena Philip
Journal: Clinical Cancer Research (2016)

As technologies evolve, and diagnostics move from detection of single biomarkers toward complex signatures, an increase in the clinical use and regulatory submission of complex signatures is anticipated. However, to date, no complex signatures have been approved as companion diagnostics. In this article, we will describe the potential benefit of complex signatures and their unique regulatory challenges, including analytic performance validation, complex signature simulation, and clinical performance evaluation. We also will review the potential regulatory pathways for clearance, approval, or acceptance of complex signatures by the FDA. These regulatory pathways include regulations applicable to in vitro diagnostic devices, including companion diagnostic devices, the potential for labeling as a complementary diagnostic, and the biomarker qualification program. Clin Cancer Res; 23(6); 1368-72. ©2016 AACR.
Pharmacokinetic (PK) and Pharmacodynamic (PD) Results of a Novel, First-in-Class Modulator of Eukaryotic Translation Initiation Factor 5A (eIF5A) in Patients (pts) with Relapsed or Refractory B-Cell Malignancies: Data from a Phase 1-2 Study
Authors: Alice S Bexon, Michael Craig, David S. Siegel, William Bensinger, Nicolas Novitzky, Andrew McDonald, Martin Gutierrez, Edward N. Libby, Frits van Rhee, Jeremy Heidel, John Thompson, Charles Barranco, Catherine A Taylor, Kathleen A. Donovan, Laurie L. Moon-Tasson, Leslie J. Browne, Michael R. Kurman, John A. Lust, Richard Dondero
Journal: Blood (2014)
Phase III randomized study of radiation and temozolomide versus radiation and nitrosourea therapy for anaplastic astrocytoma: results of NRG Oncology RTOG 9813
Authors: Susan Chang, Peixin Zhang, J. Gregory Cairncross, Mark R. Gilbert, Jean-Paul Bahary, Carol A. Dolinskas, Arnab Chakravarti, Kenneth D. Aldape, Erica H. Bell, David Schiff, Kurt Jaeckle, Paul D. Brown, Geoffrey R. Barger, Maria Werner-Wasik, Helen Shih, David Brachman, Marta Penas-Prado, H. Ian Robins, Karl Belanger, Christopher Schultz, Grant Hunter, Minesh Mehta
Journal: Neuro-Oncology (2016)

The primary objective of this study was to compare the overall survival (OS) of patients with anaplastic astrocytoma (AA) treated with radiotherapy (RT) and either temozolomide (TMZ) or a nitrosourea (NU). Secondary endpoints were time to tumor progression (TTP), toxicity, and the effect of IDH1 mutation status on clinical outcome.
240. Lenti-BMP2/GFP Gene Therapy Enhance the Chondrogenic and Osteogenic Differentiation of Human Muscle Derived Stem Cells In Vitro
Authors: Xueqin Gao, Ying Tang, Aiping Lu, Bing Wang, Xiaohong Bi, Guijin Lv, Johnny Huard
Journal: Molecular Therapy (2016)

Human muscle derived stem cells (hMDSCs) have been shown to be multipotent in vitro and can repair critical size bone defects as efficiently as human bone marrow stem cells, but require BMPs. In this study, we constructed a new lenti-BMP2/GFP vector and tested its ability to promote in vitro chondrogenesis and osteogenesis of the hMDSCs. Material and methods: 1. Lenti-BMP2/GFP was made by inserting human BMP2 gene up-stream of an eGFP tag gene in a Lenti-viral vector with a CMV promoter. 2. hMDSCs were isolated from skeletal muscle via the preplate technique. All 6 populations were transduced with the Lenti-BMP2/GFP virus, expanded and sorted via FACS based on GFP fluorescence. BMP2 secretion was measured using an R&D ELISA kit. 3. Osteogenesis:3D pellet cultures were used for osteogenic differentiation of non-transduced and Lenti-BMP2/GFP transduced hMDSCs. After 4 weeks, the cell pellets were fixed and scanned using VivaCT40 to detect mineralization. The pellets were embedded in NEG medium and snap frozen in liquid nitrogen, sectioned and von Kossa stained. Osteogenic differentiation was detected by staining for osteocalcin. 4. Chondrogenesis was performed on non-transduced and Lenti-BMP2/GFP transduced hMDSCs using a 3D pellet culture method. Cell pellets were cultured for 24 days in chondrogenic medium, embedded in freezing medium and cryosectioned. Alcian blue staining and Col2A1 immunohistochemistry was also performed. Raman Spectroscopy was used to quantify chondroitin sulphate and collagen. Results: 1. Lenti-BMP2/GFP transduction enhanced osteogenesis of the hMDSCs. BMP2 secretion levels of the sorted lenti-BMP2/GFP transduced cells are showed in Fig. 1A. MicroCT results of the lenti-BMP2/GFP transduced cells showed they had an increase in mineralized pellet volume (Fig. 1B, C). Von Kossa staining indicated that the non-transduced hMDSCs had variable brown-black mineralization while the lenti-BMP2/GFP transduced cells all showed stronger mineralization (Fig. 1D). Osteocalcin staining showed lenti-BMP2/GFP transduction enhanced osteogenic differentiation of the hMDSCs (Fig. 1E). 2. Lenti-BMP2/GFP transduction enhanced chondrogenesis of the hMDSCs. Alcian blue staining showed a significantly bluer chondrogenic matrix in the Lenti-BMP2/GFP transduced cell pellets compared to non-transduced hMDSCs (Fig2A and 2B). Raman Spectroscopy indicated the Lenti-BMP2/GFP transduced hMDSC exhibited higher amounts of chondroitin sulphate and collagen (Fig. 2C, D). Col2A1 staining showed more Col2A1 in the lenti-BMP2/GFP transduced hMDSCs compared to non-transduced hMDSCs (Fig. 2E). Conclusion: We found that all the Lenti-BMP2/GFP transduced hMDSCs showed enhanced osteogenesis and chonrogenesis compared to non-transduced cells. This in vitro study lays the foundation for using Lenti-BMP2/GFP gene transfer to repair bone and cartilage defects.