tbuckley/cabot-search huggingface dataset:
Abstract P4-07-06: Imipramine Blue - A safe and potent therapeutic regimen that suppresses breast cancer growth and progression by targeting DNA damage surveillance pathway
Authors: S Rajamanickam, P Subbarayalu, S Timilsina, A Gorthi, MT Drake, Y Chen, R Vadlamudi, AJR Bishop, JL Arbiser, MK Rao
Journal: Cancer Research (2016)

Abstract Despite improvement in overall survival of breast cancer patients, many women don't survive this disease. Moreover, the quality of life for patients who do survive is often substantially reduced due to the toxicity associated with the chemotherapy. Here, we report that imipramine blue (IB), a novel analogue of anti-depressant imipramine that we recently synthesized, may serve as a safe and potent therapeutic agent for treating breast cancers. We show that IB reduced cell growth, migration and invasion of breast cancer cells. Systemic delivery of IB using nanoparticle-based drug delivery approach suppressed breast cancer growth and metastasis without inducing any toxicity in pre-clinical orthotropic mouse models. Notably, using ex-vivo model of tumor explants from breast cancer patients, we demonstrated that IB inhibited breast cancer growth without affecting normal mammary epithelial cell proliferation. Furthermore, IB improved the sensitivity of breast cancer cells to chemotherapy drugs paclitaxel and doxorubicin. Our results revealed that IB mediated its anti-tumor effect by targeting genes involved in cell cycle progression, microtubule dynamics and DNA damage surveillance pathway including Forkhead Box M1 (FOXM1), stathmin1, S-phase kinase-associated protein 2 (Skp2) and XRCC3, which we show to be highly expressed in breast cancer patients. Importantly, we demonstrated that IB inhibited breast cancer cell's ability to repair DNA strand breaks by impairing homologous recombination events. These findings highlight the potential of IB to be used as a potent therapeutic regimen for treating breast cancer patients. Since IB-1 is derived from a FDA approved drug it has potential to be rapidly translated to the clinic. Citation Format: Rajamanickam S, Subbarayalu P, Timilsina S, Gorthi A, Drake MT, Chen Y, Vadlamudi R, Bishop AJR, Arbiser JL, Rao MK. Imipramine Blue - A safe and potent therapeutic regimen that suppresses breast cancer growth and progression by targeting DNA damage surveillance pathway. [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 P4-07-06.
Abstract A45: GAS5-encoded intronic snoRNAs produce specific sdRNAs overexpressed in aggressive prostate cancer
Authors: Elena S. Martens-Uzunova, Anton Kalsbeek, Youri Hoogstrate, Adam Baker, Soren Jensby Nielsen, Tapio Visakorpi, Chris Bangma, Guido Jenster
Journal: Cancer Research (2016)

Abstract Small non-coding RNAs, such as miRNAs, are implicated in carcinogenesis. To investigate changes in the entire small RNA transcriptome in prostate cancer (PCa) we analyzed 11 clinical sample pools representing different stages of PCa by deep sequencing. We found that most C/D-box small nucleolar RNAs (snoRNAs) are specifically processed to smaller snoRNA-derived RNAs (sdRNAs) highly expressed in PCa. In particular, SNORD78 produces sdRNAs strongly up-regulated in PCa. Together with 9 other snoRNAs, SNORD78 is encoded in the introns of the Growth Arrest Specific 5 gene (GAS5). Examination of SNORD78 and the positioned in a neighboring intron SNORD44 showed that both snoRNAs produce predominantly one sdRNA fragment each, specifically originating from the 3'-arm (SNORD78) or the 5'-arm (SNORD44) of the precursor sequence. Inspection of the secondary structures of SNORD44 and SNORD78 revealed that they have a degenerated C'/D' box and can fold in a tight hairpin similarly to miRNAs. In contrast, SNORD74 and SNORD81 that also encoded in introns of GAS5, contain canonical C'/D' boxes and each produce three equally expressed sdRNAs. Quantitative real time PCR analysis in an independent patient cohort of 106 fresh-frozen clinical samples confirmed the significant up-regulation of all four snoRNAs and their derivative sdRNAs in PCa samples compared to normal tissue. Interestingly, the increased expression of snoRNAs and sdRNAs was not associated with elevated levels of GAS5 transcript. Based on these results, we conclude that (i) separate regulatory mechanisms control the posttranscriptional processing of the spliced GAS5 transcript and the encoded in its introns snoRNAs; (ii) SNORD44, SNORD78, SNORD74 and SNORD81 function as precursors of different sdRNAs; (iii) SNORD44, SNORD78, SNORD74 and SNORD81 and their derivative sdRNAs are significantly up-regulated in PCa and carry biomarker potential for this disease. Citation Format: Elena S. Martens-Uzunova, Anton Kalsbeek, Youri Hoogstrate, Adam Baker, Soren Jensby Nielsen, Tapio Visakorpi, Chris Bangma, Guido Jenster. GAS5-encoded intronic snoRNAs produce specific sdRNAs overexpressed in aggressive prostate cancer. [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 A45.
Co-localization of C-reactive protein and complement in human hearts during acute myocardial infarction
Authors: W.K. Lagrand, H.W.M. Niessen, G.J. Wolbink, L.H. Jaspars, C.A. Visser, F.W.A. Verheugt, C.J.L.M. Meijer, C.E. Hack
Journal: Journal of the American College of Cardiology (1997)
Anesthesiology
Authors: Richard A. Wiklund, Stanley H. Rosenbaum
Journal: New England Journal of Medicine (1997)

A century and a half after the first administration of ether, at the Massachusetts General Hospital in Boston, and almost 30 years since the last review of anesthesiology in the Journal, it is fitting to consider recent advances in the field.1 In the late 1960s, the National Institutes of Health decided to support training in clinical anesthesiology.2 Since that time, anesthesia-related deaths have decreased dramatically. In this review, we discuss the preparation of patients for surgery, recent developments in anesthetic agents and techniques, multimodal pain management, and postoperative complications related to anesthesia.Preoperative Assessment and PreparationApproximately 28 million patients . . .
Pancreatic cancer stem cells in patient pancreatic xenografts are sensitive to drozitumab, an agonistic antibody against DR5
Authors: Jason W.-L. Eng, Thomas A. Mace, Rohit Sharma, Danielle Y. F. Twum, Peng Peng, John F. Gibbs, Rosemarie Pitoniak, Chelsey B. Reed, Scott I. Abrams, Elizabeth A. Repasky, Bonnie L. Hylander
Journal: Journal for ImmunoTherapy of Cancer (2016)

Therapeutic resistance and tumor recurrence are two major hurdles in the treatment of pancreatic ductal adenocarcinoma. Recent findings suggest that both of these attributes are associated with a small subset of pancreatic tumor initiating cancer stem cells (CSCs). Here, we demonstrate that drozitumab, a human agonistic monoclonal antibody which binds the death receptor DR5, selectively eliminates CSCs, resulting in tumor growth inhibition and even regression of pancreatic tumors.To examine the efficacy of drozitumab against pancreatic CSCs, we treated patient-derived pancreatic tumor xenografts (PDX) in immunocompromised SCID mice and evaluated tumor control. To assess apoptosis following drozitumab treatment, we identified the CSCs as CD24+, CD44+, and EpCAM+ by FACS analysis, and measured in vivo and in vitro levels of cleaved caspase-3. Lastly, in vitro evaluation of DR5 re-expression was performed using isolated patient pancreatic cancer xenograft cells along with the cell line, Panc-1. After treatment with drozitumab, the remaining DR5- cells were assessed by FACS analysis for DR5 expression at the cell surface at 8, 24 and 48 h post-treatment. All in vivo growth data was analyzed by 2-way Anova, incidence data was analyzed using Mantel-Cox, and in vitro studies statistics were performed with a t-test.We find that while 75-100 % of CSCs express DR5, only 25 % of bulk tumor cells express the death receptors at any one time. Consequently, drozitumab treatment of SCID mice bearing PDX kills higher percentages of CSCs than bulk tumor cells. Additionally, SCID mice implanted with isolated CSCs and then immediately treated with drozitumab fail to ever develop tumors. In vitro studies demonstrate that while drozitumab treatment reduces the DR5+ cell population, the remaining tumor cells begin to express DR5, suggesting a mechanism by which continuous administration of drozitumab can ultimately result in tumor regression despite the initially low percentage of DR5+ cells.Overall, our work reveals that treatment of pancreatic tumors with the drozitumab can lead to long-term tumor control by targeting both bulk cells and CSCs.
Modulation of respiration by tissue oxygen: A study in the mutant mouse with presbyterian hemoglobinopathy
Authors: Mieczyslaw Pokorski, Masahiko Izumizaki
Journal: European Respiratory Journal (2013)

Modulation of respiratory responses by tissue oxygen, as opposed to arterial blood gas content, has not yet been convincingly documented. In the present study we used genetically engineered Presbyterian mice that carry a low affinity variant of Hb (Hb-Presb), which is characterized by a rightward shift in the oxygen dissociation curve and innately increased tissue oxygenation. The study seeks to determine the influence of tissue oxygenation on ventilation by comparing the chemosensory responses in the Hb-Presb and wild-type mice. The animals were anesthetized with urethane and spontaneously breathing. Ventilation and its responses to changes in inspired oxygen, from hyperoxia to hypoxia, and to hyperoxic hypercapnia were measured breath by breath in a whole body plethysmograph before and after carotid body denervation. We found that all the chemosensory responses were significantly downregulated in Hb-Presb. Furthermore, Hb-Presb mice with intact carotid body innervation were more vulnerable to hypoxia, showing a more intense hypoxic ventilatory falloff than the wild type mice. Bilateral carotid body denervation in Hb-Presb mice, performed in normoxia, invariably led to respiratory arrest. The study brought out an interaction between the HB-oxygen dissociation curve and respiration. We conclude that there is a metabolic component of respiratory regulation, linked to tissue oxygenation. The hypoxic vulnerability of respiration and its reliance on carotid body input in Hb-Presb might be of importance in human cases of this hemoglobinopathy.
A Preliminary Report of Electron Microscopic and Bioassay Studies on the Rous Sarcoma I Virus
Authors: Françoise Haguenau, A. J. Dalton, J. B. Moloney
Journal: JNCI Journal of the National Cancer Institute (1958)

A Preliminary Report of Electron Microscopic and Bioassay Studies on the Rous Sarcoma I Virus Get access Françoise Haguenau, Françoise Haguenau Institut de Recherches sur le Cancer, Villejuif, France, and National Cancer Institute,5Bethesda, Maryland Search for other works by this author on: Oxford Academic PubMed Google Scholar A. J. Dalton, A. J. Dalton Institut de Recherches sur le Cancer, Villejuif, France, and National Cancer Institute,5Bethesda, Maryland Search for other works by this author on: Oxford Academic PubMed Google Scholar J. B. Moloney J. B. Moloney Institut de Recherches sur le Cancer, Villejuif, France, and National Cancer Institute,5Bethesda, Maryland Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 20, Issue 3, March 1958, Pages 633–649, https://doi.org/10.1093/jnci/20.3.633 Published: 01 March 1958 Article history Received: 26 November 1957 Published: 01 March 1958
Comparison of the immunogenicity of Montanide ISA 51 adjuvant and cytokine-matured dendritic cells in a randomized controlled clinical trial of melanoma vaccines
Authors: D. W. O'Neill, S. Adams, J. D. Goldberg, J. B. Escalon, L. M. Rolnitzky, C. M. Cruz, A. Angiulli, L. Old, A. C. Pavlick, N. Bhardwaj
Journal: Journal of Clinical Oncology (2009)

3002 Background: Dendritic cell (DC) vaccines have been widely used in clinical trials to treat cancer. However, no study has compared the immunogenicity of the most commonly used DC type (cytokine-matured, monocyte-derived DCs) to more traditional vaccine adjuvants. We performed a randomized controlled trial comparing the immunogenicity of cytokine-matured DCs loaded with 6 HLA-A2-restricted peptide antigens and a foreign protein, KLH, to a vaccine containing the same antigens emulsified in the mineral oil adjuvant Montanide ISA 51 VG. Methods: 51 HLA-A2+ patients with resected stage IIb-IIIc melanoma were randomized to receive DCs (25 patients) or Montanide (26 patients). DCs were differentiated from autologous blood monocytes with IL-4 and GM-CSF, then matured with IL- 1β, IL-6, TNFα and PGE2. 18 million DCs were given i.d. every 4 weeks x 4, and immune responses analyzed (MHC multimers, T cell proliferation, cytokine secretion, antibodies). A 3-fold increase over baseline was considered a response. Results: Both vaccines were well tolerated. Immunogenicity was significantly greater with Montanide, as demonstrated by response rates to Flu, Melan-A and NY-ESO-1 peptides by IFNγ ELISPOT. Similar results were obtained by MHC multimer staining, with higher response rates seen using pre-sensitized assays. T cell proliferation to KLH was seen in both arms (90% DC, 100% Montanide), but the magnitude of response was significantly higher for Montanide (36-fold vs. 14-fold increase over baseline, p=0.002, Wilcoxon). KLH-specific CD4+ T cells that produced IFNγ, TNFα and IL-2 were seen only with Montanide, and all Montanide patients, but only 5% of DC patients, developed antibodies to KLH (p&lt;0.001, Fisher's). Conclusions: A water-in-oil vaccine adjuvant, Montanide ISA 51, was significantly more immunogenic than DCs. Future studies of new DC vaccines should compare DCs to standard adjuvants to determine if their added difficulty and expense are truly warranted. [Table: see text] [Table: see text]
The Interplay between Heart and Muscle Disease
Authors: Elizabeth Mcnally
Journal: Circulation (2011)

One of the leading causes of congestive heart failure is cardiomyopathy, a disorder with a high heritable component. Dilated cardiomyopathy and hypertrophic cardiomyopathy are clinically distinct, but many of the same genetic defects can be associated with both forms of cardiomyopathy. Within these major forms of cardiomyopathy, it is not possible on clinical grounds to make a genetic diagnosis, yet genetic information helps predict outcome, particularly for complications such as conduction system disease, noncompaction, right ventricular involvement and extra-cardiac manifestations. Progressive skeletal muscle weakness can accompany cardiomyopathy, as it often does in the muscular dystrophies. A common mutation in the gene encoding γ-sarcoglycan, a dystrophin associated protein, leads to a range of cardiomyopathy and muscle weakness. The variable phenotype in patients with this same Sgcg null mutation suggests the presence of genetic modifiers. Using the Sgcg mouse model of muscular dystrophy and cardiomyopathy, we interbred mice with mild and severe disease and then undertook a genomewide mapping strategy to search for modifier genes. We identified Ltbp4 as a major modifier of muscle disease. Ltbp4 encodes the latent TGFβ binding protein 4, a component of the extracellular matrix in both heart and muscle that sequesters and holds TGFβ inactive. TGFβ signaling has now emerged as a major mediator of not only fibrosis but also the stability of the sarcolemma. We also uncovered unique genetic modifiers of cardiac and diaphragm muscle fibrosis. These genetic interactions reveal the complexity of single gene disorders and highlight the value of studying a genetically well-defined cohort.
A pilot study of assertive community treatment for patients with chronic psychotic disorders
Authors: A B Santos, G D Hawkins, B Julius, P A Deci, T H Hiers, B J Burns
Journal: American Journal of Psychiatry (1993)

This study measured hospital utilization and residential status of 51 patients with chronic psychoses before and after a 1-year program of assertive community treatment. Time hospitalized was reduced by 94%, and 82% of the patients previously living in hospitals or group homes attained independent living status, suggesting that this form of clinical management may reduce institutional care and costs to mental health care systems.
Abstract IA17: Deciphering cancer genome evolution in heterogenous tumors
Authors: Nicholas McGranahan
Journal: Cancer Research (2016)

Abstract Cancer drug resistance is almost inevitable in the majority of patients with advanced metastatic tumors. Intratumor heterogeneity, facilitating rapid tumor evolution, is one of the main causes of tumor adaptation and resistance to cancer therapies. In this talk I will explore how cancer genome sequencing data can shed light on diversity within tumors and the processes shaping cancer genome evolution over space and time. Harnessing both extensive multi-region and single-sequencing data we have investigated intra-tumor heterogeneity across 10 major cancer types, focusing on non-small cell lung cancer, clear cell renal cell carcinoma, and esophageal adenocarcinoma. I will discuss our findings shedding light on the extent to which mutations in known driver genes, and “actionable mutations,” linked to targeted therapies, are clonal or subclonal. Tumor phylogenies and whether patterns of tumor evolution can be deciphered in these cancer types will also be explored. Temporal dissection of mutational signatures across cancer types will be used to reveal the dynamics of mutational processes during tumor evolution. I will explore how APOBEC mediated-mutagenesis can be linked to branched tumor evolution, and the acquisition of subclonal driver events across cancer types. Finally, the challenges and clinical implications of intratumor heterogeneity will be discussed. Citation Format: Nicholas McGranahan. Deciphering cancer genome evolution in heterogenous tumors. [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 IA17.
A first-in-human phase I trial of PBI-05204 (oleandrin), an inhibitor of Akt, FGF-2, NF-Kb, and p70S6K in advanced solid tumor patients
Authors: S. Bidyasar, R. Kurzrock, G. S. Falchook, A. Naing, J. J. Wheler, J. Durand, P. Yang, M. J. Johansen, R. A. Newman, R. Khan, D. Hong
Journal: Journal of Clinical Oncology (2009)

3537 Background: PBI-05204 contains oleandrin, a cardiac glycoside, which inhibits the α-3 subunit Na-K ATPase pump. Over-expression of the α-3 subunit in malignant cells correlates with the tumor proliferation. Oleandrin inhibits FGF- 2 export and activation of NF-Kβ and inhibits phosphorylation of Akt. PBI-05204 also inhibits p70S6K, decreasing mTOR activity. In this ongoing study of PBI-05204, we sought to determine the DLTs, MTD and recommended phase II dose in advanced solid tumors patients (pts) and to characterize its’ pharmacokinetics (PK) and pharmacodynamics (PD). Methods: This was a standard 3+3 phase I design. PBI-05240 was given orally for 21 days of 28 days. Dose was increased by 100% if no related grade 2 adverse event (AE) was observed and increased by 50% if a grade 2 AE occurred. If no other grade 2 AE were observed then subsequent dose escalation was resumed at 100%. In order to determine drug-mediated changes in pAkt, p70S6K, and S6 (mTOR effectors) expression as a surrogate marker of target effect, peripheral blood mononuclear cells (PBMCs) were obtained in addition to PKs. Results: To date 15 pts have received PBI-05204 at 5 dose levels (0.6 mg to 10.2 mg/day), 2 pts are currently active at dose level 5. No DLT has been observed thus far. 10 out of 15 pts (67%) experienced only grade 1 AEs, most common: fatigue and constipation (20%). No significant cardiac toxicities have been observed, only first degree AV block and grade 2 PVC's. Of the 15 evaluable pts, 3 had stable disease for &gt; 4 months, with bladder, colorectal, and fallopian tube cancer pts having an 11, 16, and 10% reduction by RECIST respectively. PKs initially show dose-dependent peak plasma oleandrin concentrations are reached at 2–4 hr following administration with &gt; 50% cleared in 6 hrs. Western blots of PBMCs showed PBI-05204 markedly reduced phosphorylation of Akt, p70S6K, and S6 in a time dependent manner in 4 pts (1 at dose level 2, and 3 and 2 at dose level 5). Reduction of these effectors was observed concomitantly with relatively higher levels of Na, K-ATPase α-3 subunit expression. Conclusions: PBI-05204 is tolerated up to 10.2/mg/day with very little AE's or cardiotoxicity. Initial response evaluation shows activity in diverse tumors with PD analysis suggesting target effect. [Table: see text]
Predicting improvement in diffuse scleroderma: lessons learnt
Authors: Janet E Pope
Journal: Annals of the Rheumatic Diseases (2016)

Dobrota et al 1 have analysed the EUSTAR (EULAR Scleroderma Trials and Research) systemic sclerosis (SSc, scleroderma) database using a subset of diffuse cutaneous SSc (dcSSc) to determine predictors of skin improvement over 1 year in randomised trials.The idea is to enrol more informative patients in a randomised controlled trial (RCT), as incident dcSSc is rare.However, you could want patients who progress/worsen (if not on effective treatment) or those who regress/improve more when on treatment, or some of each subgroup in the sample studied.More than 900 patients were included in the EUSTAR early dcSSc study, 1 and like a Bell curve, with a smaller tail, a quarter improved, two-thirds had no change and one-tenth worsened.In order to have a sample size that is enriched for patients who may improve with effective treatment compared with a control, or conversely may worsen without effective treatment, then more informative patients are included and the study size can be smaller.They found that by varying the baseline modified Rodnan skin score (mRSS), the proportion of those who regressed went from 13% to 19% if the mRSS was <18 to 25, respectively.Therefore, the range of mRSS from 18 to 25 was most likely to enrich for those who would progress over an observation period.This can simply be that patients in mid-range skin scores in early dcSSc do not have as much of a floor or ceiling effect; that is, very low scores may worsen but are unlikely to improve and very high mRSS scores are unlikely to progress as they already have a high amount of skin involvement (ceiling).Conversely, they observed that 44% improved if the mRSS was more than 25.The mean mRSS was 16 at baseline in the EUSTAR analysis, 1 so not all patients would be eligible for a trial.Using data from the Canadian Scleroderma Research Group (CSRG), Choy et al 2 found the baseline mRSS for patients with dcSSc initiating immune suppressive treatment was 21.This is aligned with the data from EUSTAR.