tbuckley/cabot-search huggingface dataset:
Uterine fibroid management: from the present to the future
Authors: Jacques Donnez, Marie-Madeleine Dolmans
Journal: Human Reproduction Update (2016)

Uterine fibroids (also known as leiomyomas or myomas) are the most common form of benign uterine tumors. Clinical presentations include abnormal bleeding, pelvic masses, pelvic pain, infertility, bulk symptoms and obstetric complications. Almost a third of women with leiomyomas will request treatment due to symptoms. Current management strategies mainly involve surgical interventions, but the choice of treatment is guided by patient's age and desire to preserve fertility or avoid 'radical' surgery such as hysterectomy. The management of uterine fibroids also depends on the number, size and location of the fibroids. Other surgical and non-surgical approaches include myomectomy by hysteroscopy, myomectomy by laparotomy or laparoscopy, uterine artery embolization and interventions performed under radiologic or ultrasound guidance to induce thermal ablation of the uterine fibroids. There are only a few randomized trials comparing various therapies for fibroids. Further investigations are required as there is a lack of concrete evidence of effectiveness and areas of uncertainty surrounding correct management according to symptoms. The economic impact of uterine fibroid management is significant and it is imperative that new treatments be developed to provide alternatives to surgical intervention. There is growing evidence of the crucial role of progesterone pathways in the pathophysiology of uterine fibroids due to the use of selective progesterone receptor modulators (SPRMs) such as ulipristal acetate (UPA). The efficacy of long-term intermittent use of UPA was recently demonstrated by randomized controlled studies. The need for alternatives to surgical intervention is very real, especially for women seeking to preserve their fertility. These options now exist, with SPRMs which are proven to treat fibroid symptoms effectively. Gynecologists now have new tools in their armamentarium, opening up novel strategies for the management of uterine fibroids.
Abstract LB-235: IGF-1R/mTOR blockade and mechanisms of resistance in Ewing sarcoma
Authors: Salah-Eddine LAMHAMEDI CHERRADI, Brian Menegaz, Vandhana Ramamoorthy, Joseph Ludwig
Journal: Cancer Research (2016)

Abstract Ewing sarcoma (ES), the second most common bone cancer in adolescents and young adults, is dependent upon the insulin-like growth factor receptor 1 (IGF-1R) and mammalian target of rapamycin (mTOR) cell-signaling axis for malignancy, survival, and metastasis. Therapies co-targeting IGF-1R and mTOR have demonstrated remarkable, although ephemeral, clinical responses in a subset of ES patients. However, the mechanisms of resistance and applicable strategies for overcoming drug resistance to IGF-1R/mTOR blockade are still undefined. To elucidate predominant mechanism(s) of acquired drug resistance, while identifying synergistic drug combinations that improve clinical efficacy, we generated ES cell lines resistant to IGF-1R or mTOR targeted therapy. Two small-molecule inhibitors of IGF-1R were chosen, NVP-ADW-742 (IGF-1R-selective) and OSI-906 (a dual IGF-1R/insulin receptor alpha [IR-α] inhibitor). Chronic ridaforolimus exposure led to mTOR-resistant ES cell lines. Reverse phase protein lysate arrays (RPPA) revealed proteomic changes linked to IGF-1R/mTOR resistance and selected proteins were validated using in vitro cell-based assays, xenografts, and human clinical samples. Novel mechanisms of resistance (MOR) occurred in NVP-ADW-742-, OSI-906-, and ridaforolimus-resistant cells. Of particular clinical relevance given OSI-906's ongoing phase 1b/2 clinical trials, the MOR varied depending upon whether IGF-1R or both IGF-1R and IR-α were targeted. Key proteomic alterations present in vitro also occurred in ES xenografts and human tumor specimens exposed to these agents. Novel synergistic drug combinations (e.g., inhibitors of Mnk and mTOR) were identified in vitro that are currently undergoing prospective validation. In conclusion, we discovered new druggable targets expressed by chemo-resistant ES cells, xenografts, and relapsed human tumors. Joint suppression of these newfound targets with IGF-1R or mTOR enhanced the antineoplastic effect of IGF-1R/mTOR blockade and suggests the need for in vivo validation. Citation Format: Salah-Eddine LAMHAMEDI CHERRADI, Brian Menegaz, Vandhana Ramamoorthy, Joseph Ludwig. IGF-1R/mTOR blockade and mechanisms of resistance in Ewing sarcoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-235.
Tolerability, efficacy and recommended phase II dose (RP2D) of tepotinib plus gefitinib in Asian patients with c-Met-positive/EGFR-mutant NSCLC: Phase Ib data.
Authors: Yi-Long Wu, Ross A. Soo, Dong-Wan Kim, James Chih-Hsin Yang, Uz M. Stammberger, Wenfeng Chen, Andreas Johne, Keunchil Park
Journal: Journal of Clinical Oncology (2016)

e20501 Background: Patients (pts) with NSCLC treated with EGFR inhibitors (EGFRi) ultimately develop resistance, often through c-Met activation. Dual EGFR and c-Met inhibition is therefore a rational option to treat c-Met+, EGFRi-resistant NSCLC. Tepotinib is a highly selective c-Met inhibitor with good tolerability and promising efficacy against solid tumors. This phase Ib trial examined tepotinib plus gefitinib in Asian pts with c-Met+/EGFR-mutant NSCLC. Methods: Asian adults were eligible if they had locally advanced/metastatic NSCLC, ECOG PS 0-1, EGFR mutation confirmed by Therascreen EGFR RGQ PCR (Qiagen), and c-Met positivity as determined by IHC using CONFIRM anti-c-Met mAb (SP44; Ventana/Roche). A 3+3 design was used with expansion at the RP2D. Pts received tepotinib 300 or 500 mg/day combined with gefitinib 250 mg/day (T300G250 or T500G250). The primary objective was to determine the RP2D of tepotinib in combination with gefitinib; secondary objectives included pharmacokinetics (PK), safety, and antitumor activity. Results: 18 pts were enrolled (median age 65 [41–78], male 8). Pts had received a median of 2 (1–8) prior regimens including an EGFR inhibitor. 6 received T300G250, 12 T500G250. No dose-limiting toxicities were observed, and tepotinib 500 mg/day was confirmed as the RP2D. T500G250 was associated with treatment-related grade ≥ 3 increased amylase (n = 2), increased lipase (2), neutropenia (1), and hyperglycemia (1). No evidence of cumulative toxicity was noted. The best overall response was partial response in 5/18 pts, 4 with IHC 3+ tumors, all treated with T500G250; 4/18 pts (IHC 2+, n = 3) had stable disease. PK were as expected based on historical comparisons. Conclusions: Tepotinib was well tolerated in combination with gefitinib; the RP2D of tepotinib for use in combination with gefitinib in NSCLC is 500 mg/kg/day. Data suggest an increased likelihood of response for IHC 3+ tumors and prolonged disease stabilization for IHC 2+ tumors. A phase II trial is randomizing ≈136 pts with T790M–/c-Met+ tumors who have failed first-line gefitinib to tepotinib + gefitinib or cisplatin/pemetrexed. Clinical trial information: NCT01982955.
Abstract 571: Pregnancy associated plasma protein A (PAPP-A) is a potential novel therapeutic target in Ewing sarcoma
Authors: Sabine Heitzeneder, John F. Shern, Javed Khan, Crystal L. Mackall
Journal: Cancer Research (2016)

Abstract Background: Ewing sarcoma (EWS) is the second most common bone malignancy in the pediatric population. Despite intensive treatment regimens, 5-year overall survival for patients with metastatic or relapsed disease is less than 20%, indicating a clear need for novel targeted therapies. The importance of IGF signaling in EWS is illustrated by activity of antagonistic targeting of IGF-1R in clinical trials, although this approach is plagued by rapid development of resistance. Pregnancy Associated Plasma Protein A (PAPP-A) anchors to cell surface proteoglycans and mediates metalloproteinase activity, that cleaves IGFs from IGFBP-4, IGFBP-2 and IGFBP-5, thus increasing local bioavailability of bioactive, free IGF. PAPP-A is expressed at high levels by placental trophoblasts, where it induces high levels of IGFs, which are required for fetal growth. Methods: In an attempt to identify novel targetable cell surface antigens in EWS, we performed ribosomal depleted RNA sequencing in 122 EWS samples (49 cell lines and 73 tumor samples) and 96 normal samples of variable tissues. Results: PAPP-A was identified as one of the top 5 membrane associated proteins overexpressed in EWS (&amp;gt; than 4-fold) compared to normal tissue (p = 3.89E-30). PAPP-A showed substantial expression in tumors (median log2FPKM = 3.933, n = 122) and minimal expression in normal tissue (median log2FPKM = -1.564, n = 96). We confirmed cell surface expression of PAPP-A by flow cytometry on 10 EWS cell lines tested, and identified PAPP-A in the supernatant of 12 EWS cell lines, measured by ELISA. Targeting the PAPP-A locus in the EWS cell line EW8 utilizing CRISPR/Cas9 completely abrogated PAPP-A secretion in single cell clones and significantly diminished bioactive IGF-1 levels in EWS cultures, while increasing IGF-1 bound to IGFBP-4, results which confirm absent PAPP-A metalloproteinase activity. Gene knockout of PAPP-A in EW8 resulted in decreased cell growth in vitro. Conclusions: We have identified PAPP-A as a novel potential cell surface target in Ewing sarcoma, characterized by high level tumor expression, limited normal tissue expression and biological significance in this tumor. Ongoing work is focused on studying growth of PAPP-A KO cell lines, and assessing whether PAPP-A neutralizing antibodies may mediate antitumor effects in EWS. Citation Format: Sabine Heitzeneder, John F. Shern, Javed Khan, Crystal L. Mackall. Pregnancy associated plasma protein A (PAPP-A) is a potential novel therapeutic target in Ewing sarcoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 571.
Implementation of the Affordable Care Act and Solid-Organ Transplantation Listings in the United States
Authors: Guilherme H. Oliveira, Sadeer G. Al-Kindi, Daniel I. Simon
Journal: JAMA Cardiology (2016)

This study uses UNOS data to compare listings for heart, liver, and kidney transplantation before and after implementation of the Affordable Care Act in states that did or did not adopt Medicaid expansion.
Case 12-1964
Authors: Richard Warren, Benjamin Castleman
Journal: New England Journal of Medicine (1964)

Presentation of Case*A forty-nine-year-old man entered the hospital because of abdominal swelling.Six years previously he was admitted to another hospital for a week because of vomiting; he stated that a diagnosis of obstructing duodenal ulcer was made, although he understood that it was not demonstrated on x-ray films. A short time later another physician informed him that he was jaundiced and prescribed an unknown medication, and the jaundice disappeared. Thereafter he remained well until a year before admission, when he experienced anorexia, progressive abdominal swelling and a change in his bowel habits from one formed stool to several . . .
MYC Expression Is Prognostic in Therapy Related Acute Myeloid Leukemia (AML) and AML with Myelodysplastic Syndrome (MDS)-Related Changes
Authors: Maro Ohanian, Uri Rozovski, Hagop M. Kantarjian, Sanam Loghavi, Yang O. Huh, Lynne Abruzzo, Guillermo Garcia-Manero, Farhad Ravandi, Michael Andreeff, Steven M. Kornblau, Gautam Borthakur, Martin Nguyen, Francesco Stingo, Peter Hu, Patricia Fox, L. Jeffrey Medeiros, Zeev Estrov, Carlos E. Bueso-Ramos, Jorge E. Cortes
Journal: Blood (2014)
Phase I/II Trial of the MEK1/2 Inhibitor Trametinib (GSK1120212) in Relapsed/Refractory Myeloid Malignancies: Evidence of Activity in Patients with RAS Mutation-Positive Disease
Authors: Gautam Borthakur, Leslie Popplewell, Michael Boyiadzis, James M. Foran, Uwe Platzbecker, Norbert Vey, Walter B. Roland, Rebecca L. Olin, Azra Raza, Aristotles Giagounidis, Oliver G. Ottmann, Aref Al-Kali, Elias J. Jabbour, Tapan M. Kadia, Guillermo Garcia-Manero, John W. Bauman, Yuehui Wu, Yuan Liu, Dan Schramek, John Z. Zhu, Paul Wissel, Hagop M. Kantarjian
Journal: Blood (2012)
Efficacy of Tumor Vaccines and Cellular Immunotherapies in Non–Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis
Authors: Floris Dammeijer, Lysanne A. Lievense, G.D. Marijn Veerman, Henk C. Hoogsteden, Joost P. Hegmans, Lidia R. Arends, Joachim G. Aerts
Journal: Journal of Clinical Oncology (2016)

Purpose Programmed cell death protein-1- checkpoint blockers have recently been approved as second-line treatment for advanced non–small-cell lung cancer (NSCLC). Unfortunately, only a subgroup of patients responds and shows long-term survival to these therapies. Tumor vaccines and cellular immunotherapies could synergize with checkpoint blockade, but which of these treatments is most efficacious is unknown. In this meta-analysis, we assessed the efficacy of tumor vaccination and cellular immunotherapy in NSCLC. Methods We searched for randomized controlled trials (RCTs) investigating cellular immunotherapy or vaccines in NSCLC. We used random effects models to analyze overall survival (OS) and progression-free survival (PFS), expressed as hazard ratios (HRs), and differences in time (months). The effect of immunotherapy type, disease stage, tumor histology, and concurrent chemotherapy was assessed using subgroup analysis and meta-regression. All procedures were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Results We identified 18 RCTs that matched our selection criteria; these included a total of 6,756 patients. Immunotherapy extended NSCLC survival and PFS, expressed as HR (OS: HR, 0.81, 95% CI, 0.70 to 0.94, P = .01; PFS: HR, 0.83, 95% CI, 0.72 to 0.95, P = .006) and month difference (OS: difference, 5.43 months, 95% CI, 3.20 to 7.65, P &lt; .005; PFS: difference, 3.24 months, 95% CI, 1.61 to 4.88, P &lt; .005). Cellular therapies outperformed tumor vaccines (OS as HR: P = .005, month difference: P &lt; .001; PFS as HR: P = .001, month difference: P = .004). There was a benefit of immunotherapy in low-stage compared with high-stage NSCLC and with concurrent administration of chemotherapy only in one of four outcome measures evaluated (PFS in months: P = .01 and PFS as HR: P = .031, respectively). There was no significant effect of tumor histology on survival or PFS. Conclusion Tumor vaccines and cellular immunotherapies enhanced OS and PFS in NSCLC. Cellular immunotherapy was found to be more effective than tumor vaccination. These findings have implications for future studies investigating combination immunotherapy in NSCLC.
A Novel beta-delta Globin Gene Fusion Leads to Over-Expression of Delta Globin Chain and a Mild Thalassemia Intermedia Phenotype When Co-Inherited with β0-Thalassemia.
Authors: Chi-Chiu So, Amy Y.Y. Chan, Stella T.Y. Tsang, Anselm C.W. Lee, Wing-Yan Au, Edmond ShiuKwan, Li-Chong Chan
Journal: Blood (2006)
Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension
Authors: Christophe Guignabert, Carole Phan, Andrei Seferian, Alice Huertas, Ly Tu, Raphaël Thuillet, Caroline Sattler, Morane Le Hiress, Yuichi Tamura, Etienne-Marie Jutant, Marie-Camille Chaumais, Stéphane Bouchet, Benjamin Manéglier, Mathieu Molimard, Philippe Rousselot, Olivier Sitbon, Gérald Simonneau, David Montani, Marc Humbert
Journal: Journal of Clinical Investigation (2016)

Pulmonary arterial hypertension (PAH) is a life-threatening disease that can be induced by dasatinib, a dual Src and BCR-ABL tyrosine kinase inhibitor that is used to treat chronic myelogenous leukemia (CML). Today, key questions remain regarding the mechanisms involved in the long-term development of dasatinib-induced PAH. Here, we demonstrated that chronic dasatinib therapy causes pulmonary endothelial damage in humans and rodents. We found that dasatinib treatment attenuated hypoxic pulmonary vasoconstriction responses and increased susceptibility to experimental pulmonary hypertension (PH) in rats, but these effects were absent in rats treated with imatinib, another BCR-ABL tyrosine kinase inhibitor. Furthermore, dasatinib treatment induced pulmonary endothelial cell apoptosis in a dose-dependent manner, while imatinib did not. Dasatinib treatment mediated endothelial cell dysfunction via increased production of ROS that was independent of Src family kinases. Consistent with these findings, we observed elevations in markers of endothelial dysfunction and vascular damage in the serum of CML patients who were treated with dasatinib, compared with CML patients treated with imatinib. Taken together, our findings indicate that dasatinib causes pulmonary vascular damage, induction of ER stress, and mitochondrial ROS production, which leads to increased susceptibility to PH development.
Abstract 1512: Functional validation of microRNA activity inferred by ActMiR in bladder cancer
Authors: Mireia Castillo-Martin, Ana Collazo Lorduy, EunJee Li, Jun Zhu
Journal: Cancer Research (2016)

Abstract Background: MicroRNAs (miRs) play a key role in cancer, both in tumorigenesis and tumor progression. In the past years, miR expression signatures have been reported as prognostic biomarkers in different tumor types including bladder cancer (BC). However, miR's expression does not always correlate with activity. We recently developed a novel computational method, named ActMiR, for explicitly inferring the activity of miRs based on the changes in expression levels of target genes. The main objective of this study was to validate the inferred miRs’ activity using BC as a model. Design: We applied ActMiR in 405 BC cases from The Cancer Genome Atlas (TCGA) database for which information from both mRNA and miR expression was available. Different BC cell lines (5637 and HT1376 for basal BC, SW780 and HT1197 for p53-like BC, and RT4 and RT112 for luminal BC) as well as the immortalized urothelial cell line [Human Urothelium cell (HUC)] were used to perform the in vitro functional validation. RNA was extracted from these cells basally and after inhibition of miR106-5p with specific anti-miR inhibitor (Taqman, Life Technologies); miR and target genes’ expression was assessed by qRT-PCR. Results: ActMir analyses revealed that a subset of 306 out of 1044 miRNAs were differentially expressed between tumor and normal samples at p-value&amp;lt;10-4. More importantly, at p-value&amp;lt;10-4, 155 out of 556 miRNAs were functionally active. From these, only four (miR106b, miR532, mir556, and mir134) were significantly differentially expressed, functionally active and showed prognostic significance. We chose to further analyze mir106b because it showed the biggest and most significant difference in activity between normal and cancer cells (p-value&amp;lt;2*10-11). As inferred by ActMir, mir106-5p was significantly overexpressed in all cancer cells when compared to HUC. Basal cells showed the highest fold increase (mean of 39; range: 31-47), followed by luminal (mean of 19; range: 5-32) and p53-like cells (mean of 8; range: 3-13). Inhibition of mir106b-5p was performed to assess whether the predicted target genes were consequently upregulated. Conclusion: Our results underscore the value of ActMir for inferring miR activity in BC from a systems biology perspective. It endorses ActMir as a promising tool for studying casual effects of miR activity on target genes, and ultimately for determining survival outcomes of BC patients. Citation Format: Mireia Castillo-Martin, Ana Collazo Lorduy, EunJee Li, Jun Zhu. Functional validation of microRNA activity inferred by ActMiR in bladder cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1512.
Abstract 2995: Mechanisms of high dose ascorbate inhibiting pancreatic cancer growth and metastasis
Authors: Qi Chen, Kishore Polireddy, Ruochen Dong, Ping Chen
Journal: Cancer Research (2016)

Abstract Purpose: High-dose intravenous ascorbate (IVC) bypasses bioavailability barriers of oral ingestion and provides pharmacologic concentrations in tissues, and exhibits pro-oxidant anti-cancer activities. In pancreatic cancer pre-clinical models, ascorbate has been shown to sensitize the tumor to the 1st line chemotherapeutic drug gemcitabine. Here, we investigated the possible mechanisms of actions of ascorbate on pancreatic cancer growth and metastasis. Methods Orthotopic pancreatic cancer mouse model was utilized for evaluation of the effects of ascorbate in inhibiting tumor growth and metastasis. Molecular biological approaches were used in investigation the mechanisms of these effects. Results In the orthotopic mouse tumor model, ascorbate treatment alone decreased pancreatic cancer growth and metastasis. Ascorbate treatment enhanced expressions of epithelial markers and suppressed expression of mesenchymal markers in pancreatic cancer cells. MMP-2 expression and activity were decreased dose-dependently. Tumor tissues from ascorbate-treated mice had markedly increased collagen and desmoplasia in the extracellular matrix. Such fibrosis was not seen in normal tissues from the same mouse. In addition, ascorbate decreased the protein level of deacetylase HDAC6, and inhibited activity of the deacetylase Sirt-2 through depletion of NAD+. As a result, ascorbate robustly increased α-tubulin acetylation in pancreatic cancer cells. Acetylation promoted tubulin polymerization and stabilization, mimicking the cellular outcome of paclitaxel, resulted in inhibition of cell motility and mitosis. Conclusion Pharmacological concentrations of ascorbate affected pancreatic tumor cells and the tumor microenvironment, led to inhibition of tumor growth and metastasis. Citation Format: Qi Chen, Kishore Polireddy, Ruochen Dong, Ping Chen. Mechanisms of high dose ascorbate inhibiting pancreatic cancer growth and metastasis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2995.