tbuckley/cabot-search huggingface dataset:
Abstract P2-05-08: p53 deficiency enhances metastatic potential of triple negative breast cancer by promoting growth in primary and metastatic sites
Authors: E Powell, J Shao, N Mistry, Y Yuan, T Tieu, K Decker, H-C Chen, S Cai, K-A Do, TP Heffernan, J Edwards, D Piwnica-Worms, H Piwnica-Worms
Journal: Cancer Research (2016)

Abstract TP53 is one of the most commonly mutated genes in human cancer. Mutation or loss of TP53 can occur during the early stages of oncogenesis or as a later event as tumors progress to more aggressive forms. We used a patient-derived xenograft (PDX) model of triple negative breast cancer (TNBC) to investigate how p53 deficiency contributes to metastasis. The PDX line was generated by engrafting the primary breast tumor of a patient with TP53 wild-type metastatic TNBC into the humanized mammary fat pad of NOD/SCID mice. Isogenic lines differing only in TP53 status were generated from this model by silencing p53. Here we demonstrate that the p53-proficient and -deficient tumors metastasized from the mouse mammary gland and colonized the lung, liver, bone, brain, and lymph nodes with similar frequency. p53-deficient tumors grew faster in both the primary and metastatic sites as a result of increased mitosis and decreased apoptosis. Circulating tumor cells (CTCs) are currently being evaluated in p53-proficient and –deficient PDX models. Gene expression profiling identified candidate genes with potential clinical relevance that may be responsible for increased tumor growth upon p53 loss in late stage tumors. This model is also being used to identify genes that promote breast cancer metastasis. To enrich for metastasis, metastatic subpopulations of tumor cells were isolated from lungs and serially passaged in vivo. This serial passaging enriched for metastasis to multiple secondary sites. A transcriptional signature of putative metastasis genes was generated and is being functionalized with high throughput screening in vivo. Citation Format: Powell E, Shao J, Mistry N, Yuan Y, Tieu T, Decker K, Chen H-C, Cai S, Do K-A, Heffernan TP, Edwards J, Piwnica-Worms D, Piwnica-Worms H. p53 deficiency enhances metastatic potential of triple negative breast cancer by promoting growth in primary and metastatic sites. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-05-08.
Heterogeneous Claudin-1 Expression in Human Liver
Authors: L. Mensa, S. Perez-del-Pulgar, X. Forns
Journal: Hepatology (2012)

We appreciate the observations made by Harris et al. regarding the differences in claudin-1 expression in human liver between the report by Reynolds et al.1 and our work.2 The main objective of our study was to assess the potential changes in tight junction proteins claudin-1 and occludin following hepatitis C virus (HCV) graft infection. We observed an increased expression of claudin-1 and occludin over time in HCV-infected patients. The increase in claudin-1 was particularly significant in individuals with cholestatic hepatitis. It is important to notice that when we applied very low threshold values to create a surface for quantification, it was almost impossible to discriminate basolateral claudin-1 staining from either unspecific staining or tissue autofluorescence. More restrictive thresholding guarantees the quantification of specific signal, although it should be noted that this is at the expense of decreased sensitivity. Thus, it is a possibility that we may have underestimated claudin-1 expression in the basolateral membrane because we quantified fluorescence intensity using a single threshold value. The detection of minor pools of basolateral claudin-1 is an interesting finding. Further studies are required to investigate the role of nonjunctional claudin-1 in HCV entry and the physiopathological consequences of increased levels of claudin-1 expression in HCV disease progression. L. Mensa B.Sc.*, S. Perez-del-Pulgar Ph.D.*, X. Forns M.D.*, * Liver Unit, Hospital Clínic, CIBERehd, IDIBAPS, Barcelona, Spain.
Phase 1 study of the BRAF inhibitor dabrafenib (D) with or without the MEK inhibitor trametinib (T) in combination with ipilimumab (Ipi) for V600E/K mutation–positive unresectable or metastatic melanoma (MM).
Authors: Igor Puzanov, Margaret K. Callahan, Gerald P Linette, Sapna Pradyuman Patel, Jason J. Luke, Jeffrey Alan Sosman, Jedd D. Wolchok, Omid Hamid, David R. Minor, Keith W. Orford, Bruce A. Hug, Bo Ma, Gemma M. Matthys, Axel Hoos
Journal: Journal of Clinical Oncology (2014)

2511 Background: D, T, and Ipi are each indicated for treatment of patients (pts) with MM (D+T in BRAF V600 mutation–positive MM). D and T can be safely combined and prolong progression-free survival compared with monotherapy. Combining D+T with the CTLA-4 antibody Ipi has the potential to improve treatment outcomes, but the safety profile is unknown. A recent report suggested caution in combining the BRAF inhibitor vemurafenib (V) with Ipi; V+Ipi resulted in G3 elevations of ALT in 6/10 pts leading to study discontinuation (NEJM2013 368; 14). The present study will characterize the safety of D±T+Ipi, select recommended phase 2 doses (RP2Ds), and report efficacy. Methods: Pts with stage IIIc/IV BRAF V600E /K mutation–positive MM and ≤1 prior treatments are eligible. Dose escalation occurs in cohorts of 3-6 pts followed by expansion (≤30 pts) at the RP2D. At data cutoff (Nov 8, 2013), 10 pts were enrolled: 4 received D+Ipi (doublet), 2 received D only (withdrawn before Ipi treatment), and 4 received D+T+Ipi (triplet). Results: Median age of the10 pts was 59.5 y (range, 32-75 y). Doublet: D 150 mg bid + Ipi 3 mg/kg q3w × 4 doses was well tolerated and selected as RP2D. No G3/4 ALT elevations or dose-limiting toxicities (DLTs) were observed. The most frequent adverse events (AEs; ≥2) were chills, fatigue, hand-foot syndrome, pyrexia, and maculopapular rash. Of 4 pts, 2 are ongoing and 2 stopped treatment (disease progression). Pts are currently being enrolled at this dose level in the expansion. Triplet: At current doses (D 100 mg bid/T 1 mg qd+Ipi 3 mg/kg q3w × 4), no G3/4 ALT elevations and 1 DLT (G3 colitis; associated with Ipi) occurred. The most frequent AEs (≥2) were pyrexia, chills, arthralgia, insomnia, and maculopapular rash. One pt had G4 renal insufficiency that reversed rapidly. Of 4 pts treated, 1 stopped treatment (DLT), and 3 are ongoing. Updated safety data and preliminary efficacy data will be presented for both cohorts. Conclusions: To date the combinations of D+Ipi and D+T+Ipi appear to be tolerable and have not been associated with significant hepatotoxicity in MM, suggesting differences between BRAF inhibitors when combined with Ipi. Clinical trial information: NCT01767454.
Medical Management of Primary Hypertension
Authors: Lot B. Page, James J. Sidd
Journal: New England Journal of Medicine (1972)

THE great importance of blood pressure as a predictor of longevity has long been recognized by insurance companies. From actuarial studies done in the early years of the 20th century, it appeared that both high and low blood pressures were associated with an increased risk of dying. However, as death rates due to infectious disease diminished, the relation between blood pressure and mortality emerged in sharpened focus. The Build and Blood Pressure Study of the Society of Actuaries in 1959,1 based on 3,900,000 policy holders and 102,000 deaths, showed that mortality ratios were more markedly affected by blood pressure than . . .
Biologic Characteristics of Transformed Rhesus Foreskin Cells Infected With Mason-Pfizer Monkey Virus 2 3
Authors: Donald L. Fine, Roman J. Pienta, Louise B. Malan, Mary T. Kubicek, David G. Bennett, John C. Landon, Marion G. Valerio, Donna M. West, David A. Fabrizio, Harish C. Chopra
Journal: JNCI Journal of the National Cancer Institute (1974)

Studies, including cytogenetic, immunofluorescence, infectivity, and tumorigenicity, were conducted to characterize 7 sublines of transformed rhesus foreskin cells chronically infected with Mason-Pfizer monkey virus (MPMV). These cell lines, referred to as MPfsl, released infectious MPMV and contained antigens common to MPMV-infected human lymphoblast (NC-37) and nontransformed MPMV-infected rhesus foreskin cells. Several of the MPfsl lines exhibited chromosomal changes typical of transformed cells and released interferon-like substances into the culture medium. MPfsl cells inoculated into newborn rhesus monkeys induced palpable nodules of donor cell origin at the sites of inoculation. Although these nodules were transient, explant cultures derived from the nodule biopsy specimens continued to release infectious virus; when subsequently reinoculated into other monkeys, these cultures induced nodules. These findings provide a convenient in vitro system for the study of MPMV and further define the identity of MPMV as an oncornavirus.
Roles of the Gut in Glucose Homeostasis
Authors: Jens Juul Holst, Fiona Gribble, Michael Horowitz, Chris K. Rayner
Journal: Diabetes Care (2016)

The gastrointestinal tract plays a major role in the regulation of postprandial glucose profiles. Gastric emptying is a highly regulated process, which normally ensures a limited and fairly constant delivery of nutrients and glucose to the proximal gut. The subsequent digestion and absorption of nutrients are associated with the release of a set of hormones that feeds back to regulate subsequent gastric emptying and regulates the release of insulin, resulting in downregulation of hepatic glucose production and deposition of glucose in insulin-sensitive tissues. These remarkable mechanisms normally keep postprandial glucose excursions low, regardless of the load of glucose ingested. When the regulation of emptying is perturbed (e.g., pyloroplasty, gastric sleeve or gastric bypass operation), postprandial glycemia may reach high levels, sometimes followed by profound hypoglycemia. This article discusses the underlying mechanisms.
Hypocalcemia induced by bisphophonates in cancer patients with vitamin D deficiency
Authors: C. F. Yazbeck, A. M. Gonzalez-Angulo, S. A. Shaw, S. G. Waguespack, R. Vassilopoulou-Sellin, N. L. Busaidy
Journal: Journal of Clinical Oncology (2007)

19644 Background: The use of bisphosphonates for treatment of hypercalcemia, bone pain and reduction of skeletal morbidity in metastatic breast cancer is increasing. Moreover, vitamin D deficiency is commonly associated with cancer. Hypocalcemia has been reported following IV bisphosphonate use. Methods: We present the clinical and lab findings in 6 cases of bisphosphonate-induced hypocalcemia, caused by unmasked vitamin D deficiency. Results: Our 1st patient was diagnosed with breast cancer and developed metastases 6yrs later. She was given Zolendronic acid 4 mg IV with a baseline calcium level (Ca) of 9.7 mg/dl, normal albumin, and elevated alkaline phosphatase. 3 days later, she developed symptomatic severe hypocalcemia with tetany: Ca dropped to 6.1 mg/dl with recovery. After her 2 nd dose of Zolendronic acid, Ca dropped again to 6 mg/dl with normal albumin, intact parathyroid hormone (PTH) of 637 pg/ml (range 10–65) and 25-hydroxy vitamin D levels (25-OHD) of 4 ng/ml (range 20–100). Our 2nd patient presented with metastatic breast cancer and was treated with Zolendronic acid for hypercalcemia with a baseline Ca of 13 mg/dl, PTH-related protein of 2.8 pmol/l (range &lt;1.8) and PTH of 7 pg/ml. She then developed hypocalcemia with corrected Ca of 7.7 mg/dl and 25-OHD of 13 ng/ml. Our 3rd patient with breast cancer was also treated with Zolendronic acid for bone metastases and hypercalcemia. She then presented with symptomatic hypocalcemia: ionized Ca level of 1.09 mmol/l (range 1.13–1.32), PTH of 211 pg/ml and 25-OHD of 13 ng/ml. Our other 3 cases had similar presentations to the above and will be discussed in detail. All 6 cases were treated with ergocalciferol and long-term oral calcium and vitamin D therapy. All of our cases presented with symptomatic hypocalcemia with vitamin D levels less than 30ng/mL. Conclusions: Since bisphosphonate use is increasing in cancer patients and vitamin D deficiency is not an uncommon finding in this population, consideration should be given to routine checking of 25-OHD levels before initiating treatment with bisphosphonates and supplementing with calcium and vitamin D when necessary (&lt;30ng/mL). This could potentially prevent further morbidity. Further prospective studies would be needed for early replacement with vitamin D and calcium in those with vitamin D deficiency. No significant financial relationships to disclose.
Abstract A58: Bispecific anti-CD3-folate for the treatment of ovarian cancer.
Authors: Jinming Xia, Kristine deDios, Evelyn Rodrigo, Robin Humphreys, Alan Wahl, Marco Gymnopoulos
Journal: Clinical Cancer Research (2016)

Abstract Folic acid receptor 1 (FOLR1, FRα) is highly expressed in 80% of ovarian tumors and has a low nanomolar affinity for folic acid. Although ovarian tumors are intrinsically immunogenic, immune reactions to them are inhibited by a suppressive environment. We are developing a bispecific anti-CD3-folate to redirect T cells to engage with and kill tumor cells. Folic acid was site-specifically conjugated to a FAb fragment of an anti-CD3 antibody through an engineered linkable non-natural amino acid. Anti-CD3-folate bispecific FAb is able to engage T cells and exert cytotoxicity in a variety of tumor cell lines including ovarian; OV-90, OVCAR3, and breast cancer; SKOV-3. Cytotoxicity assays generated EC50 in the femtomolar range. This cytotoxicity could be modulated by varying folic acid concentrations in the assay medium. T-cell activation was confirmed by appearance of activation markers on the cell surface and secretion of pro-inflammatory cytokines after treatment of tumor cells in combination with human PBMC's. T cell activation and subsequent cytokine release is dependent on simultaneous binding of tumor and T cell to anti-CD3-Folate. In a xenograft mouse model of ovarian cancer, anti-CD3-folate significantly inhibited tumor growth, and increased life span (ILS)of 30% and 50% for SKOV-3 and OV-90, respectively when compared to control treated animals. These data suggest that anti-CD3-folate bispecifc FAb- mediated T cell engagement could be a powerful tool for immune-ablation of ovarian cancer. Citation Format: Jinming Xia, Kristine deDios, Evelyn Rodrigo, Robin Humphreys, Alan Wahl, Marco Gymnopoulos. Bispecific anti-CD3-folate for the treatment of ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A58.
Abstract A32: The RNA-binding protein DDX1 promotes primary microRNA maturation and inhibits ovarian tumor progression
Authors: Cecil Han, Xiongbin Lu, Xinna Zhang
Journal: Cancer Research (2016)

Abstract MicroRNAs (miRNAs) are small endogenous non-coding RNAs that regulate gene expression by repressing translation and/or promoting degradation of their target mRNAs. Aberrant dysregulation of mature miRNAs is commonly observed in many human cancers and can have a causative function in tumorigenesis. In the nucleus, primary miRNAs (pri-miRNAs) are first processed by the microprocessor containing RNaseIII enzyme Drosha and its cofactor DGCR8. Although the efficiency of Drosha-mediated process is crucial for determining miRNA abundance, the mechanisms for dynamic and specific regulation of miRNA biogenesis in the Drosha microprocessor are poorly understood. A better understanding of miRNA regulation is required to determine how aberrant miRNA activity mechanistically contributes to tumorigenesis and to predict therapeutic target miRNAs. Increasing evidence has shown that regulatory RNA-binding proteins may confer the specificity on the core components (Drosha and DGCR8) in the Microprocessor for recruiting and processing premature pri-miRNAs. Here, we identified a RNA-binding protein, DEAD-box RNA helicase 1 (DDX1) as a key regulatory component in the Drosha complex, which promotes the processing of a subset of miRNAs including miR-200 family (miR-200a, -200b, -200c, -141, -429). A suppressive role of miR-200s in cancer metastasis has been well known in several cancer types such as ovarian, kidney renal and lung cancer. Inhibiting DDX1 promotes tumor burden in the previous syngeneic ovarian mouse models. Consistent with, low level of DDX1 is associated with poor clinical outcome in patients with serous ovarian cancer and kidney renal clear cell carcinoma. Interestingly, DDX1-dependent miR-200a and miR-200b were also induced after DNA damage and this induction is facilitated by the ATM-mediated phosphorylation of DDX1. These findings suggest that DDX1 may be a key modulator in miRNA maturation in response to cellular signaling pathway and that alteration of level/function of DDX1 may play an important role in tumor progression through dysregulated microRNA pathway. Citation Format: Cecil Han, Xiongbin Lu, Xinna Zhang. The RNA-binding protein DDX1 promotes primary microRNA maturation and inhibits ovarian tumor progression. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr A32.
Neuroleptic-induced supersensitivity psychosis: clinical and pharmacologic characteristics
Authors: G Chouinard, B D Jones
Journal: American Journal of Psychiatry (1980)

Tardive dyskinesia is thought to result from neostriatal dopaminergic receptor supersensitivity induced by chronic treatment with neuroleptics. The authors suggest that dopaminergic supersensitivity also occurs in the mesolimbic region after chronic neuroleptic exposure, resulting in the development of a supersensitivity psychosis. Neuroleptic-induced supersensitivity psychosis is illustrated by data from 10 patients that demonstrate the syndrome's clinical and pharmacologic characteristics. An implication of neuroleptic-induced mesolimbic supersensitivity is that the tenaency toward psychotic relapse in such patients is determined by more than just the normal course of the illness.
Results Of a Randomized, Double-Blind, Placebo-Controlled Phase III Study (JAKARTA) Of The JAK2-Selective Inhibitor Fedratinib (SAR302503) In Patients With Myelofibrosis (MF)
Authors: Animesh Pardanani, Claire N Harrison, Jorge E. Cortes, Francisco Cervantes, Ruben A. Mesa, Donald Milligan, Tamás Masszi, Elena Mishchenko, Eric Jourdan, Alessandro M. Vannucchi, Mark Drummond, Mindaugas Jurgutis, Kazimierz Kuliczkowski, Emanuil Gheorghita, Francesco Passamonti, Frank Neumann, Guozhi Gao, Ayalew Tefferi
Journal: Blood (2013)
Suppressor cell function in solid tumor cancer patients.
Authors: J Von Roenn, J E Harris, D P Braun
Journal: Journal of Clinical Oncology (1987)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1987.5.1.150 Journal of Clinical Oncology - published online before print September 22, 2016 PMID: 2949064 Suppressor cell function in solid tumor cancer patients. J Von RoennxJ Von RoennSearch for articles by this author , J E HarrisxJ E HarrisSearch for articles by this author , D P BraunxD P BraunSearch for articles by this author https://doi.org/10.1200/JCO.1987.5.1.150 First Page PDF © 1987 by American Society of Clinical Oncology
Abstract PR08: Macrophage-mediated trogocytosis leads to death of antibody-opsonized tumor cells
Authors: Ramraj Velmurugan, Dilip K. Challa, Sripad Ram, Raimund J. Ober, E. Sally Ward
Journal: Cancer Research (2016)

Abstract The interplay between innate immune cells and antibodies to control cancerous growth is of central importance for mediating direct anti-tumor effects and the induction of long-lived anti-tumor immunity. Phagocytosis of antibody-opsonized cells by macrophages through Fcgamma receptor interactions is well characterized and leads to cell death through target cell engulfment into phagosomes. By contrast, the contribution of the related process called trogocytosis, involving the ingestion of limited amounts of the target cell by phagocytic cells, to cell attrition is less certain. In the current study we have developed a high throughput, quantitative assay to distinguish whole cell phagocytosis (WCP) and trogocytosis for different macrophage:breast cancer cell combinations. These analyses, combined with long term microscopic imaging, demonstrate that trogocytosis leads to target cell death. The implementation of multifocal plane microscopy to investigate trogocytic events at high spatiotemporal resolution reveals that these processes involve tubular extensions of opsonized tumor cells that are subsequently pinched off by the recipient macrophage. Of relevance to the design of second generation antibodies with improved efficacy, antibody engineering to enhance Fcgamma receptor interactions results in increased trogocytic activity. Collectively, these studies have significance to the rapidly expanding use of antibodies to treat cancer. Citation Format: Ramraj Velmurugan, Dilip K. Challa, Sripad Ram, Raimund J. Ober, E. Sally Ward. Macrophage-mediated trogocytosis leads to death of antibody-opsonized tumor cells. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr PR08.
Abstract IA26: Selective activation of gene expression by targeting long noncoding RNA
Authors: Jim Barsoum
Journal: Cancer Research (2016)

Abstract Long noncoding RNA (lncRNA) can regulate transcription by recruiting epigenetic regulatory complexes to target genes. Polycomb repressive complex 2 (PRC2), an epigenetic transcriptional repressor, is recruited to its target genes via lncRNA. PRC2 represses transcription through the action of the histone methyltransferase EZH2, which methylates histone H3 at lysine 27 (applying the H3K27me3 repressive mark). Using RIP-Seq, we identified the genome-wide pool of RNA sequences that interact with PRC2. We design short single-strand oligonucleotides that hybridize to an individual lncRNA, and sterically block its binding to PRC2, without degrading the lncRNA. These oligonucleotides selectively block PRC2 binding to a specific lncRNA, thereby de-repressing the expression of an associated target mRNA, resulting in increased amounts of the therapeutic protein. This approach was used to increase SMN2 transcription as a potential treatment for Spinal Muscular Atrophy (SMA). Oligonucleotides that target an antisense lncRNA selectively increase SMN2 mRNA and protein levels in SMA patient cells in vitro and in a mouse SMA model that carries the human SMN2 locus. Data support a mechanism of action whereby the oligonucleotides block recruitment of PRC2 to SMN2 chromatin, decrease the H3K27me3 repressive chromatin mark, increase the presence of activating chromatin marks and increase RNA polymerase II association along the SMN2 gene. This therapeutic approach potentially can be used to elevate the expression of many genes whose gene products are limiting in various human diseases. Citation Format: Jim Barsoum. Selective activation of gene expression by targeting long noncoding RNA. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr IA26.