tbuckley/cabot-search huggingface dataset:
ABCG2 AND MDR PROMOTE BRAINSTEM GLIOMAGENESIS AND LIMIT THE EFFICACY OF DASATINIB IN A DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) MOUSE MODEL
Authors: O. J. Becher, R. Mittapali, A. H. Chung, D. Crabtree, W. Elmquist
Journal: Neuro-Oncology (2014)

BACKGROUND: DIPG is an incurable tumor that arises in the brainstem of children. Our laboratory generates murine DIPGs by expressing PDGF-B and deleting p53 in nestin progenitors of the neonatal brainstem using the RCAS/tv-a system. Dasatinib, an inhibitor of PDGFR-A and SRC activation, has been evaluated in clinical trials for children with DIPG but with disappointing results. As dasatinib is a substrate of the ABC transporters ABCG2 and MDR, we hypothesized that ABCG2 and MDR may limit the efficacy of dasatinib in DIPG. METHODS: We generated murine DIPGs driven by PDGF-B and p53 loss in ABC WT (ABCG2+/+; MDRa+/+; MDRb+/+) and ABC KO (ABCG2-/-; MDRa-/-; MDRb-/-) mice. Next, we investigated whether dasatinib is efficacious in ABC KO and ABC WT DIPG-bearing mice. We treated ABC WT DIPG-bearing mice with dasatinib alone, elacridar (a dual ABCG2/MDR inhibitor) alone, and dasatinib in combination with elacridar. We also measured dasatinib levels in the tumor and plasma of all of the different tumor cohorts. Lastly, we evaluated the blood-brain-barrier (BBB) of our DIPG mouse model with Dextran Texas Red. RESULTS: Surprisingly, we observed a significant difference in tumor latency between untreated ABC KO and untreated ABC WT mice in this PDGF-B; p53 deficient DIPG model. Median survival of DIPG-bearing ABC KO was longer than DIPG-bearing ABC WT: 43 days vs. 34 days respectively (p = 0.02). We observed that dasatinib almost doubled the survival of DIPG-bearing mice in the ABC KO model: 44 days vs. 80 days (p = 0.0004). Dasatinib modestly prolonged survival in ABC WT mice: 33 days vs. 42 days (p < 0.0001). Co-treatment with elacridar significantly increased the efficacy of dasatinib in the ABC WT model 42 days vs. 59 days (p < 0.0001). However, elacridar alone did not significantly prolong survival in the ABC WT mice 33 days vs. 34 days (p = 0.38). Pharmacokinetic analysis demonstrated that genetic ablation of the ABC transporters or inhibition of ABC transporters with elacridar significantly increased dasatinib delivery into normal brain but not into tumor. Dextran Texas Red studies demonstrated a disrupted BBB in DIPG models independent of ABC transporters. CONCLUSIONS: 1. ABC transporters promote brainstem gliomagenesis 2. ABC transporters regulate dasatinib delivery into normal brain but not into the tumor as BBB is disrupted in our DIPG mouse model 3. ABC transporter activity limits the efficacy of dasatinib in vivo. Our results suggest that ABCG2 and MDR inhibitors may have a therapeutic role in the treatment of DIPG. SECONDARY CATEGORY: Preclinical Experimental Therapeutics.
Abstract 4755: Importance of an induction dose to the immunogenicity of cancer vaccines: A reverse translational study
Authors: David A. Berd, Donald Braun, Margalit B. Mokyr
Journal: Cancer Research (2010)

Abstract We have described a human cancer vaccine consisting of autologous, irradiated melanoma cells modified with the hapten, dinitrophenyl (DNP), and mixed with BCG. Because of its immunopotentiating effect, low dose cyclophosphamide (CY) was administered 3 days before the first of a series of vaccine injections. The vaccine induced T cell immunity to both haptenized and unmodified autologous melanoma cells; clinical effectiveness was suggested by tumor regression in some stage IV patients and an unexpectedly high proportion of 5-year survivors in stage IIIB and IIIC patients. A serendipitous finding from these studies was the critical importance of what we came to call an “induction dose” of vaccine - a single injection of irradiated, autologous melanoma cells without BCG 5-7 days prior to CY. Patients who received a properly timed induction dose had more intense T cell responses (positive DTH to unmodified melanoma cells 73% vs. 20%, p&amp;lt;.01) and were more likely to survive 5 years (51% vs. 33%, p=.007) than those who did not. To support this finding in a controlled experimental system, we developed a mouse model using the mammary carcinoma, 410.4. After injection of 410.4 cells into the mammary fat pads, primary tumors developed and were excised. Then we assessed the anti-metastatic activity of low dose CY followed by a DNP-modified vaccine prepared and administered in a manner comparable to the human melanoma vaccine. The published study showed that this regimen significantly prolonged tumor-free survival in the mice while CY followed by a control vaccine (irradiated, non-haptenized cells) did not. To mimic the induction dose used in the clinical trial, a cohort of mice was injected with irradiated, DNP-modified tumor cells without BCG 3-7 days prior to CY. The relapse-free survival (RFS) of mice receiving the induction dose (N=41) was significantly longer (p &amp;lt; .01) than that of mice receiving DNP-vaccine without the induction dose (N=27) (e.g., RFS day 37: CY+irradiated vaccine=30.8%, CY+irradiated-haptenized vaccine=40.7%, CY+induction dose+ irradiated-haptenized vaccine=53.7%). In this reverse translational model, the murine experiments corroborated a serendipitous clinical observation. Taken together our results suggest a new strategy for increasing the effectiveness of cancer vaccines. 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 4755.
Efficacy and Safety of Recombinant Human Activated Protein C for Severe Sepsis
Authors: Gordon R. Bernard, Jean-Louis Vincent, Pierre-Francois Laterre, Steven P. LaRosa, Jean-Francois Dhainaut, Angel Lopez-Rodriguez, Jay S. Steingrub, Gary E. Garber, Jeffrey D. Helterbrand, E. Wesley Ely, Charles J. Fisher
Journal: New England Journal of Medicine (2001)

Drotrecogin alfa (activated), or recombinant human activated protein C, has antithrombotic, antiinflammatory, and profibrinolytic properties. In a previous study, drotrecogin alfa activated produced dose-dependent reductions in the levels of markers of coagulation and inflammation in patients with severe sepsis. In this phase 3 trial, we assessed whether treatment with drotrecogin alfa activated reduced the rate of death from any cause among patients with severe sepsis.
PD-017 A multicenter phase I/II study of TAS-102 with bevacizumab for metastatic colorectal cancer refractory to standard therapies (C-TASK FORCE)
Authors: T. Nishina, Y. Kuboki, E. Shinozaki, K. Yamazaki, T. Kajiwara, K. Shitara, T. Matsumoto, T. Tsushima, W. Okamoto, N. Mochizuki, S. Nomura, A. Sato, A. Ohtsu, T. Yoshino
Journal: Annals of Oncology (2015)
Follow-up after colonic polypectomy in 2014: is there a French paradox?
Authors: Denis Heresbach, Patrice Pienkowski
Journal: Endoscopy (2014)

We have read the Guideline on post-polypectomy colonoscopy surveillance recently published by the European Society of Gastrointestinal Endoscopy (ESGE) [1]. A corresponding French guideline was published in November 2013 [2]. The working group, convened by the Haute Autorité de Santé (HAS), included representatives from the Société Française d’Endoscopie Digestive (SFED), the Fédération des Spécialistes des Maladies de l’Appareil Digestif (FSMAD), and the Conseil National Professionnel d’Hépato Gastro Entérologie (CNP-HGE), and the summarized findings are available online [2].
Uterine Visualization with Tc-99m Human Polyclonal Immunoglobulin G Scintigraphy To Detect Molar Pregnancy
Authors: Angelica Arka, Katerina Stipsanelli, Vasilis Papantoniou, Anastasia Leondi, Georgia Sampaliotou, Cherry Zerva, Sakellaris Karpathios
Journal: Clinical Nuclear Medicine (2002)

ARKA, ANGELICA M.D.*; STIPSANELLI, KATERINA M.D.*; PAPANTONIOU, VASILIS M.D.*; LEONDI, ANASTASIA M.D.*; SAMPALIOTOU, GEORGIA M.D.†; ZERVA, CHERRY M.D.*; KARPATHIOS, SAKELLARIS M.D.† Author Information
P13.17 * STEREOTACTIC RADIOSURGERY WITH GAMMA KNIFE FOR NEUROFIBROMATOSIS 2-ASSOCIATED VESTIBULAR SCHWANNOMAS
Authors: A. L. Presti, P. De Andres, M. E. Kusak, J. M. De Campos, N. Martinez, R. Martinez
Journal: Neuro-Oncology (2014)

BACKGROUND: It is though that Stereotactic Radiosurgery (SRS) is less effective in achieving local tumor control in Neurofibromatosis 2 (NF2)-related vestibular schwannomas (VSs) compared with sporadic tumors. There is scarce literature on optimal dosing, clinical outcomes and eventual increased risk for malignant transformation among these patients. It is also possible that radiation induced tumors, in patients bearing an abnormality in a tumor suppressor gene, are misinterpreted as part of the natural history of NF2, where new tumors are expected to develop. OBJECTIVE: To evaluate the results of Gamma Knife (GK) Radiosurgery in the management of NF2-related VSs versus the sporadic VSs group treated at the same Center. METHOD: A prospectively maintained clinical database including all patients who underwent SRS for VSs was reviewed, and all subjects fulfilling the Manchester diagnostic criteria for NF2 were identified. Between 1994 and 2012, 35 patients with NF2 underwent SRS for 55 presumed VSs at our institution. The mean age at time of treatment was 30.8 years and the mean follow-up period was 4.3 years (1-14.75 years). The median margin dose used was 12 Gy and a total of 62 treatments were performed. Outcome measures, including imaging progression, hearing preservation, trigeminal and facial nerve function, were analyzed. RESULTS: Regarding tumor control 53.4% remained unchanged in size, 22.4% were smaller and 22.4% showed progression requiring further microsurgical resection or SRS. Hearing worsening occurred in 37% of tumors; 2 patients developed facial neuropathy, one of them bilateral and the other transient; trigeminal neuropathy occurred in 4 patients, one of them with previous mild impairment. No cases of malignant transformation were reported. Compared to the sporadic VSs group, NF2 patients showed lower local tumor control and higher incidence of facial and trigeminal neuropathy. CONCLUSION: NF2-related VSs treated with GK show worse clinical and imaging outcomes compared to the sporadic tumors. Although results do not seem to be as good as for patients with sporadic unilateral tumors, GK radiosurgery, using conventional doses, seems to offer acceptable local tumor control rates (75.8%), indicating that radiosurgery could be considered for primary tumor management in selected patients. In order to confirm if radiation therapy is a predisposing factor for the development of new tumors in these patients, a larger multicenter study needs to be designed.
FREE T4 (FT4) ESTIMATION IN PATIENTS WITH NONTHYROIDAL ILLNESSES.
Authors: L. R. Witherspoon, S. E. Shuler, J. Gonzales, S. Gilbert, F. Husserl
Journal: Clinical Nuclear Medicine (1983)

Witherspoon, L. R.; Shuler, S. E.; Gonzales, J.; Gilbert, S.; Husserl, F. Author Information
Pitfalls in the Measurement of Bone Mineral Density by the Dual-Energy X-Ray Absorptiometric Method
Authors: F. SUNA KIRAÇ, DO&GbreveANGÜN YÜKSEL, OLGA TAŞKAYA YAYLALI
Journal: Clinical Nuclear Medicine (2001)

SUNA KIRAÇ, F. M.D.; YÜKSEL, DO&GbreveANGÜN M.D.; TAŞKAYA YAYLALI, OLGA M.D. Author Information
Replacement Therapy for Inherited Enzyme Deficiency — Macrophage-Targeted Glucocerebrosidase for Gaucher's Disease
Authors: Norman W. Barton, Roscoe O. Brady, James M. Dambrosia, Adrian M. Di Bisceglie, Samuel H. Doppelt, Suvimol C. Hill, Henry J. Mankin, Gary J. Murray, Robert I. Parker, Charles E. Argoff, Raji P. Grewal, Kian-Ti Yu
Journal: New England Journal of Medicine (1991)

Gaucher's disease, the most prevalent of the sphingolipid storage disorders, is caused by a deficiency of the enzyme glucocerebrosidase (glucosylceramidase). Enzyme replacement was proposed as a therapeutic strategy for this disorder in 1966. To assess the clinical effectiveness of this approach, we infused macrophage-targeted human placental glucocerebrosidase (60 IU per kilogram of body weight every 2 weeks for 9 to 12 months) into 12 patients with type 1 Gaucher's disease who had intact spleens. The frequency of infusions was increased to once a week in two patients (children) during part of the trial because they had clinically aggressive disease.
Abstract LB-258: Developing therapeutic siRNA against HER2 in breast cancer cells
Authors: Zhi Hu, Shenda Gu, Juha Rantala, Worapol Ngamcherdtrakul, Wassana Yantasee, Joe W. Gray
Journal: Cancer Research (2012)

Abstract Over-expression of oncogene HER2 was found in 20-30% primary breast cancers which involved in tumor initiation and progression. Breast cancer patients with high levels of HER2 (HER2 positive) showed poor clinical outcome. Increasing evidence indicated that the majority of patients with HER2 positive did not respond well to anti-HER2 drugs Trastuzumab (Herceptin) and Lapatinib. Even those who showed initial response ultimately became resistant to the treatment. The molecular mechanism of resistance includes the mutation of HER2 gene and the blocking of antigen of HER2 protein. The discovery of small interfering RNA (siRNA) raises the possibility of exploring new approach for cancer treatment. The siRNA against HER2 (siHER2) can reduce HER2 protein level by degrading mRNA expression. In our study, seventy-six siRNA sequences targeting the coding region of human HER2 gene were designed and synthesized. We quantified the RNA levels of HER2 and cell viability after HER2+ breast cancer cells (BT474, SkBr3 HCC1954) were transfected with siHER2 and scramble control siRNAs. Ten siRNA sequences were selected with greater than 50% knockdown efficiency and 40% inhibition of cell viability. We also measured the dose of 50% inhibition of cell growth (GI50) of top 5 siHER2 sequences in 20 HER2+ cell lines. The GI50 data showed that most of cell lines which were resistant to Trastuzumab were still sensitive to siHER2 treatment. Therefore, our data indicated that the siRNA against HER2 can potentially be used to overcome resistance of HER2 drugs, making it an alternative cancer therapeutic for HER2 positive patients. Currently, in vivo delivery of optimized siHER2 using nanoparticle is under evaluation. 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 LB-258. doi:1538-7445.AM2012-LB-258
Hyponatremia and Renal Wasting of Sodium in Patients with Malfunction of the Central Nervous System
Authors: Martin Goldberg, Joseph S. Handler
Journal: New England Journal of Medicine (1960)

SEVERAL reports of patients with Central-nervous-system disorders, hyponatremia and an abnormally high urinary excretion of sodium have appeared in the literature.1 2 3 4 In some the defect in electrolyte physiology was attributed to faulty renal tubular reabsorption of sodium. More recently, Schwartz et al.,5 , 6 Epstein and Levitin,7 Carter, Rector and Seldin,8 McCrory and Macaulay9 and Fourman and Leeson10 have presented cases of hyponatremia that were apparently related to a sustained and inappropriate secretion of antidiuretic hormone.In the past two years we have observed 4 patients with manifestations of deranged function of the central nervous system in whom hyponatremia appeared to be . . .
Clinical and Phonocardiographic Observations on the Flint Murmur
Authors: J. H. Currens, W. B. Thompson, M. B. Rappaport, H. B. Sprague
Journal: New England Journal of Medicine (1953)

IT is an established clinical observation that certain patients with aortic regurgitation have an apical presystolic murmur without mitral stenosis demonstrable at autopsy. This phenomenon was originally described ninety years ago by the American physican, Austin Flint,1 who made his first observations in New Orleans. From the original report in 1862 it is difficult to determine whether Flint was describing a murmur in mid-diastole or in presystole. This was due to the terminology used in his time for describing cardiac murmurs. However, there is little doubt from a later report (1886)2 that he was describing a murmur in presystole. This . . .
Abstract 3483: Modeling circulating tumor cells in the peripheral blood and CSF of breast cancer patients.
Authors: Joshua E. Allen, Akshal S. Patel, David T. Dicker, Jonas M. Sheehan, Michael Glantz, Wafik S. El-Deiry
Journal: Cancer Research (2013)

Abstract The enumeration of circulating tumor cells (CTCs) using the CellSearch system (Veridex LLC) is a valuable prognostic clinical tool in several epithelial malignancies. Surveillance methods for metastatic disease involving the central nervous system (CNS) lack adequate sensitivity, specificity, and reproducibility in the clinic. We previously reported a method to enumerate CTCs in the cerebrospinal fluid (CSF) of breast cancer patients with metastases involving the CNS. The enumeration of CTCs in CSF by this method is highly sensitive, accurate, reproducible, and correlates with disease burden by several measures. Here, we concomitantly monitor CTCs in the peripheral blood and CSF of five patients with neoplastic meningitis receiving intrathecal (IT) chemotherapy. In each patient, CTC counts have been more sensitive than conventional cytology, and have predicted the course of symptoms and overall survival more precisely than conventional cytology. We observed a striking inverse relationship between CTC counts in the peripheral blood and CSF. This observation generated the hypothesis that CTCs migrate from the blood to the CSF and the converse as sanctuary sites during compartmentalized therapy to result in systemic disease recurrence. To test this hypothesis we created mouse models of these clinical phenomena including injection of triple-negative breast cancer into the peripheral blood or intracranially. Injection of luciferase-infected MDA-MB-231 or MDA-MB-468 human triple-negative breast cancer cells into the brain of athymic nude mice resulted in primary tumors at the site of injection. The MDA-MB-231, unlike the MDA-MB-468, generated detectable tumor cell dissemination into the CSF of inoculated mice that correlated with a significantly declined survival. CSF collected from the cisterna magna of inoculated mice corroborated these observations. Current studies are examining the impact of compartmentalized therapy on the migration of these tumor cells as well as profiling unique genetic drivers of the subset of tumors cells that disseminate into the CSF. The intercompartmental cycling of tumor cells may represent an important mechanism for disease persistence and recurrence, and suggests that concurrent systemic and CNS-directed therapy may be warranted. Citation Format: Joshua E. Allen, Akshal S. Patel, David T. Dicker, Jonas M. Sheehan, Michael Glantz, Wafik S. El-Deiry. Modeling circulating tumor cells in the peripheral blood and CSF of breast cancer patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3483. doi:10.1158/1538-7445.AM2013-3483
A8.2 An unconventional anti-inflammatory role for TNF recpetor (TNFR)1 in tregs: TNFR1 and 2 differetnialy modulate FOXP3+ TREG function
Authors: Marilena Patsalidou, Amy Anderson, Anja Krippner-Heidenreich
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background and Objectives</h3> Regulatory T cells (Tregs) can protect against rheumatoid arthritis (RA), but their function is compromised in RA. Anti-TNF therapy restores Treg function. However, despite its clinical significance, TNF responses in Tregs are incompletely understood. TNF exists in two forms, the soluble (sTNF) and membrane-bound (mTNF) form, which differentially activate two distinct TNF receptors (TNFR). Notably, only mTNF, but not sTNF, efficiently activates TNFR2 (CD120b), whereas TNFR1 (CD120a) is activated equally well by both TNF forms. Activation of TNFR1 and TNFR2 often result in opposing TNF responses, including pro-and anti-inflammatory actions. The potential importance of TNFR1 in the regulation of natural regulatory T cells (nTreg) is widely underscored by the apparent lack of TNFR1 expression and the high level expression of TNFR2 on these cells. However, since even very low TNFR1 levels are sufficient for profound TNF-mediated cell responses, previous negative results to detect TNFR1 do not rule out a significant role of TNFR1 in the TNF-mediated modulation of nTreg functions. This study sought to assess the expression, function and crosstalk of TNFR1 and TNFR2 in modulating nTreg function. <h3>Material and Methods</h3> nTreg (CD4<sup>+</sup>CD25<sup>++</sup>FoxP3<sup>+</sup> cells) were isolated from healthy donors and expanded for 2-3 weeks <i>in vitro</i>. TNFR function was assessed by stimulating nTregs or monocyte-depleted PBMCs with unique TNF variants selectively stimulating TNFR1, TNFR2 or both receptors. nTreg phenotype was analysed using flow cytometry and cytokine production of the expanded Tregs was determined by ELISA. The modulation of nTreg function was assessed in T cell proliferation suppression assays. <h3>Results</h3> nTregs express TNFR1 comparable to effector T cells (CD4<sup>+</sup>CD25<sup>-</sup>FoxP3<sup>-</sup> cells) at low but significant levels, whereas the cell surface expression of TNFR2 is higher on nTregs. Similar TNFR expression levels were observed for freshly isolated nTregs and expanded Tregs. Furthermore, using TNFR-selective ligands, we have demonstrated signalling competence for both TNFR1 and TNFR2 on expanded nTregs. Surprisingly, our data indicate that TNFR1-mediated signalling enhances the suppressive activity of nTregs in proliferation suppression assays, whereas TNFR2-signalling does not affect nTreg function<i> in vitro.</i> <h3>Conclusion</h3> Our data indicate that TNFR1 and TNFR2 differentially control nTreg function and challenge the current model of TNF-mediated modulation of Tregs. A more detailed understanding of TNF-mediated modulation of Treg function will facilitate the development of new strategies to improve anti-TNF therapies.