tbuckley/cabot-search huggingface dataset:
The dipeptidyl peptidase inhibitor linagliptin and the angiotensin II receptor blocker telmisartan show renal benefit by different pathways in rats with 5/6 nephrectomy
Authors: Oleg Tsuprykov, Ryotaro Ando, Christoph Reichetzeder, Karoline von Websky, Viktoriia Antonenko, Yuliya Sharkovska, Lyubov Chaykovska, Jan Rahnenführer, Ahmed A. Hasan, Harald Tammen, Markus Alter, Thomas Klein, Seiji Ueda, Sho-ichi Yamagishi, Seiya Okuda, Berthold Hocher
Journal: Kidney International (2016)

Dipeptidyl peptidase (DPP)-4 inhibitors delay chronic kidney disease (CKD) progression in experimental diabetic nephropathy in a glucose-independent manner. Here we compared the effects of the DPP-4 inhibitor linagliptin versus telmisartan in preventing CKD progression in non-diabetic rats with 5/6 nephrectomy. Animals were allocated to 1 of 4 groups: sham operated plus placebo; 5/6 nephrectomy plus placebo; 5/6 nephrectomy plus linagliptin; and 5/6 nephrectomy plus telmisartan. Interstitial fibrosis was significantly decreased by 48% with linagliptin but a non-significant 24% with telmisartan versus placebo. The urine albumin-to-creatinine ratio was significantly decreased by 66% with linagliptin and 92% with telmisartan versus placebo. Blood pressure was significantly lowered by telmisartan, but it was not affected by linagliptin. As shown by mass spectrometry, the number of altered peptide signals for linagliptin in plasma was 552 and 320 in the kidney. For telmisartan, there were 108 peptide changes in plasma and 363 in the kidney versus placebo. Linagliptin up-regulated peptides derived from collagen type I, apolipoprotein C1, and heterogeneous nuclear ribonucleoproteins A2/B1, a potential downstream target of atrial natriuretic peptide, whereas telmisartan up-regulated angiotensin II. A second study was conducted to confirm these findings in 5/6 nephrectomy wild-type and genetically deficient DPP-4 rats treated with linagliptin or placebo. Linagliptin therapy in wild-type rats was as effective as DPP-4 genetic deficiency in terms of albuminuria reduction. Thus, linagliptin showed comparable efficacy to telmisartan in preventing CKD progression in non-diabetic rats with 5/6 nephrectomy. However, the underlying pathways seem to be different.
Multiple Autotransplantation of Rat Mammary Tumors Induced by 7,12-Dimethylbenz[ a ]anthracene: Brief Communication 2
Authors: Chung Lee, Ann Shih, Ryoichi Oyasu
Journal: JNCI Journal of the National Cancer Institute (1978)

Mammary tumors induced in outbred Sprague-Dawley rats by 7,12-dimethylbenz[a]anthracene were excised, cut into 1- to 2-mm3 pieces, and then autotransplanted sc along the mammary line at six sites. Following an average period of 20–30 days, these autografts grew to approximately 2 em in diameter in 32 of 48 rats (67%). Autografts in the other 33% of the rats remained dormant. Mammary tumors transplanted into allogeneic hosts failed to grow. Tumors derived from autotransplantation were indistinguishable from their primary tumors with respect to their histologic features, the nature of hormone dependency, the content of estrogen receptors, and their ability to incorporate [3H]leucine. Furthermore, autotransplanted tumors derived from a single primary tumor varied little with regard to the preceding parameters; thus they provided an opportunity for serial sampling of individual tumors for repeated morphologic and biochemical evaluations.
Results of ARIEL2: A Phase 2 trial to prospectively identify ovarian cancer patients likely to respond to rucaparib using tumor genetic analysis.
Authors: Iain A. McNeish, Amit M. Oza, Robert L. Coleman, Clare L. Scott, Gottfried E. Konecny, Anna Tinker, David M. O'Malley, James Brenton, Rebecca Sophie Kristeleit, Katherine Bell-McGuinn, Ana Oaknin, Alexandra Leary, Kevin Lin, Mitch Raponi, Heidi Giordano, Sandra Goble, Lindsey Rolfe, Roman Yelensky, Andrew R. Allen, Elizabeth M. Swisher
Journal: Journal of Clinical Oncology (2015)

5508 Background: At least 50% of high-grade serous ovarian cancers (OC) may have homologous recombination deficiency (HRD). Germline BRCA1 and BRCA2 mutations (gBRCAmut) account for ~1/3. Identification of BRCAwt HRD tumors likely to respond to a PARP inhibitor remains challenging. ARIEL2 prospectively tested a novel next generation sequencing-based HRD assay and algorithm to predict rucaparib sensitivity by assessing tumor BRCA status and genome-wide loss of heterozygosity (LOH). Methods: ARIEL2 enrolled pts with platinum-sensitive, recurrent, high-grade serous or endometrioid OC. The primary objective was to evaluate clinical activity of 600 mg BID rucaparib in 3 pre-defined HRD subgroups: tumor BRCAmut, BRCAwt/LOHhigh and BRCAwt/LOHlow. Known gBRCAmut pt enrollment was limited. Tumor HRD status was assessed in pre-treatment biopsies and archival tumor. Response was assessed by RECIST and GCIG CA-125 criteria. Results: In 206 treated pts: median age=64 [range 31-86]; 64% ECOG=0; 96% high-grade serous; 46% with ≥2 prior regimens. Treatment-related AEs in ≥15% of pts were GI symptoms (nausea, dysgeusia, ↓ appetite, vomiting, constipation, diarrhea), fatigue, ↓ Hgb, and transient ALT/AST elevations with no other evidence of liver dysfunction. Efficacy data for 135 pts indicate RECIST + CA125 ORRs of 69%, 39%, and 11% in BRCAmut, BRCAwt/LOHhigh, and BRCAwt/LOHlow pts, respectively (Table 1, p<0.0001, Cochran-Armitage trend test). Responses occurred in both gBRCAmut (14/19, 74%) and somatic BRCAmut (10/16, 63%) tumors. Only 15/161 (9%) BRCAwt tumors had a loss-of-function mutation or homozygous deletion in a HR gene; 4/15 (27%) alterations were in RAD51C. All 4 tumors were LOHhighand responded to rucaparib, suggesting a potential HRD mechanism. Importantly, matched archival and screening tumor analysis revealed an increase in genomic LOH over time in a subset of tumors. Conclusions: ARIEL2 data indicate a tumor HRD assay and algorithm combining BRCA analysis and genomic LOH identifies OC pts likely to respond to rucaparib. Clinical trial information: NCT01891344.Response by HRD status. HRD Subgroup # of Pts RECIST, % RECIST & CA-125, % BRCAmut 35 66 69 BRCAwt/LOHhigh 56 32 39 BRCAwt/LOHlow 44 11 11
The 2016 revision of the World Health Organization classification of lymphoid neoplasms
Authors: Steven H. Swerdlow, Elias Campo, Stefano A. Pileri, Nancy Lee Harris, Harald Stein, Reiner Siebert, Ranjana Advani, Michele Ghielmini, Gilles A. Salles, Andrew D. Zelenetz, Elaine S. Jaffe
Journal: Blood (2016)
Abstract 5510: Tamoxifen induces estrogen receptor-independent bioenergetic stress: A synthetic lethality approach to target tumor metabolism
Authors: Natalie A. Daurio, Stephen Tuttle, Constantinos Koumenis
Journal: Cancer Research (2015)

Abstract Tamoxifen, a selective estrogen receptor modulator (SERM) is clinically used for adjuvant treatment of estrogen receptor (ER) positive breast cancer. Recent data from our lab has shown that tamoxifen inhibits oxygen consumption at high, yet clinically relevant, doses. We hypothesize that this occurs through a non-ER dependent, direct effect on the mitochondria, and causes metabolic and signaling changes that can be exploited for therapeutic benefit. ER+, MCF7 breast cancer cells have a higher basal respiratory rate and lower glycolytic rate than ER, MDA231, cells. However, tamoxifen inhibited oxygen consumption to a similar degree in both cell lines Pharmacological inhibition of ERα expression or CRISPR-Cas9 mediated knock out of the ERα did not affect the ability of tamoxifen to decrease oxygen consumption. In response to tamoxifen inhibition of oxygen consumption, tumor cells increased dependence on glycolysis. Glucose deprivation or treatment with glycolytic inhibitors, 2-deoxy glucose (2DG) or 3-bromo-pyruvate significantly sensitized breast cancer cells to tamoxifen treatment. Tamoxifen combined with glucose deprivation or treatment with 2-DG led to robust activation of the AMPK signaling pathway. Knockout of AMPKα1 in breast cancer cells ameliorated cytotoxicity. Based on these data we’ve also demonstrated clinical usefulness of tamoxifen in a non-breast cancer model. BRAF inhibitor resistant melanoma exhibits a higher rate of oxidative phosphorylation over to the BRAF inhibitor sensitive melanoma cells. Tamoxifen-induced inhibition of oxygen consumption increased cytotoxicity in the OxPhos-addicted, BRAF inhibitor-resistant, population compared to the BRAF inhibitor sensitive cells. Our results indicate a new and unanticipated mechanism of action for tamoxifen in ER+ and ER-breast cancers. Moreover, since this effect is not ER dependent, tamoxifen may have clinical use in a wider spectrum of cancers especially when combined with inhibitors of glycolysis. Citation Format: Natalie A. Daurio, Stephen Tuttle, Constantinos Koumenis. Tamoxifen induces estrogen receptor-independent bioenergetic stress: A synthetic lethality approach to target tumor metabolism. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5510. doi:10.1158/1538-7445.AM2015-5510
<italic>Brief Communication:</italic> Loss of Marrow Allograft Resistance in Mice With Transplanted Methylcholanthrene-Induced Sarcomas<xref ref-type="fn" rid="fn2">2</xref>
Authors: V Kumar, M Bennett
Journal: JNCI Journal of the National Cancer Institute (1975)

To determine if the effector cells responsible for allogeneic marrow stem cell rejections were suppressed in mice with tumors, C57BL/6 (B6) mice were inoculated with 3-methylcholanthrene (MCA)-induced sarcoma cells. When the tumor reached 2.0--2.5 cm in diameter, these mice and control B6 and (BALB/c times A)F1 (CAF1) uninoculated animals were irradiated and given BALB/c marrow cells in the first of a two-step "stem cell rescue" experiment. Four days later, spleen cells of the primary hosts were reinoculated into irradiated CAF1 secondary hosts compatible with BALB/c marrow cells and immunized against B6 antigens. Splenic uptake (percent) of 125I-5-iodo-2'-deoxyuridine 5 days after spleen cell regrafting was used as a measure of cell proliferation and reflected growth of the stem cells in the primary hosts. BALB/c stem cells grew as well in B6 mice with tumors as in CAF1 primary hosts but were rejected by B6 controls. Seeding efficiency of BALB/c stem cells 6 hours after infusion of marrow cells and growth of syngeneic B6 stem cells were enhanced twofold in spleens of tumor-bearing B6 mice. To exclude the possibility that enhanced seeding resulted in greater survival of allogeneic stem cells, more DBA/2 marrow cells were infused into control B6 primary hosts than into tumor-bearing B6 and control DBA/2 mice. Control B6 mice resisted growth of even 7.5 times 10(6) DBA/2 marrow cells, whereas B6 tumor bearers allowed growth of 2.5 times 10(6) cells. No "suppressor cells" capable of inhibiting marrow cell allograft reactions were detected in spleens of tumor-bearing mice. Thus transplanted syngeneic MCA-induced sarcomas abrogated the ability of mice to reject allogeneic marrow stem cells.
PTU-246 Augmentation of a sphincter repair
Authors: NN Alam, SK Narang, IR Daniels, NJ Smart
Journal: Gut (2015)

<h3>Introduction</h3> Faecal incontinence (FI) affects between 1–10% of adults in varying degrees. Current epidemiological studies have shown that up to 1% of adults have regular episodes of faecal incontinence that adversely impacts their quality of life. A variety of synthetic and biological agents have been used for both overlapping sphincter repair (OSR) and as an anal bulking agent. The aim of this review is to provide an overview of the use of biological materials in the augmentation of the sphincter repair. <h3>Method</h3> A systematic search of PubMed was conducted using the search terms ‘anal bulking agents’, ‘anal sphincter repair’ or ‘overlapping sphincter repair’. Studies that utilised biological material for either sphincter repair or as a bulking agent were included. Overall, 5 studies were indentified for analysis after inclusion and exclusion criteria were applied. <h3>Results</h3> There were 3 studies with 127 patients of which 122 underwent anal bulking with a biological agent. 105 patients received a cross-linked porcine dermal collagen in the form of PermacolTM and a further 17 received Glutaraldehyde cross-linked (GAX) collagen, a highly purified bovine dermal collagen. Anorectal physiology was carried out in 27 patients and demonstrated deterioration in maximum resting pressure, and no significant change in maximum squeeze increment. Quality of life scores such as St Mark’s incontinence score, SF-36 and the Cleveland Clinic Florida Incontinence Score (CCFIS) demonstrated an improvement in scores at 6 weeks and 6 months, but this had deteriorated at 12 month follow up. There were no complications reported. 10 patients received a cross-linked porcine dermal collagen (PermacolTM) for OSR and 13 patients received porcine intestinal submucosa (Surgisis©) to carry out an anal encirclement procedure. Improvements in Faecal Incontinence Severity Index (FISI), CCFIS and two subscales of Faecal Incontinence Quality of Life (FIQL) (coping/behaviour and embarrassment) were observed in the group of patients undergoing OSR. Furthermore, the FISI, Wexner score and all components of FIQL score (lifestyle, coping/behaviour, depression and embarrassment) showed an improvement following anal encirclement using biological material. Incontinence episodes decreased to an average of one per week from 8 to 10 preoperatively and no complications were reported. <h3>Conclusion</h3> Sphincter augmentation with biological material has demonstrated significantimprovement in continence and quality of life scores in the short term compared to traditional repair. Long-term studies are necessary to determine if this effect is sustained. <h3>Disclosure of interest</h3> None Declared.
An analysis of cancer-specific Twitter conversations among physicians in 2013.
Authors: Brian Bowers Reid, Kayla Nicole Rodriguez, Michael A. Thompson, Greg Dean Matthews
Journal: Journal of Clinical Oncology (2014)

e17644 Background: While the widespread and growing consumer use of social media in the context of health care has been well-documented, less attention has been paid to physician use of social tools. Existing analyses of physician conversations on Twitter, in particular, have looked at datasets that were limited in duration or scope. We wished to extend analysis from the Social Oncology Project (2012 data, www.wcgworld.com/mdigitallife) Methods: Using a proprietary database of physicians on Twitter that matches individual Twitter accounts with National Provider Identifier (NPI) and associated information (MDigitalLife, W2O Group), we examined all tweets from 12,355 validated U.S. physicians during the calendar year 2013 for overall mentions of cancer-related keywords as well as keywords related to the five most common cancer causes of death (lung, colon, breast, pancreas, prostate) and the five cancers with the highest incidence rates (prostate, breast, lung, colon, melanoma). Results: The database yielded 82,383 cancer-related tweets from 4,155 different U.S. physicians. Volume of cancer-related tweets grew approximately 20% over the course of 2013, with greater volume seen in May and June, around the American Society for Clinical Oncology (ASCO) 2013 Annual Meeting (#ASCO13), and around October, Breast Cancer Awareness Month. Tweets about breast cancer represented more than 26% of all cancer-related tweets, followed by prostate cancer (10%) and lung cancer (8%). Medical oncologists accounted for 23% of all tweets, followed by surgeons (13%), internists (8%) and family medicine practitioners (6%). Conclusions: Twitter conversations around cancer by physicians are increasing over time. In aggregate, specific events, including medical conferences and awareness months, tend to drive increases in conversation volume on cancer-related topics among physicians. The data showed clear disparities in the cancer types most likely to be discussed by physicians on Twitter; future research should focus on effort to understand the impact of demographics and disease burden on online conversation.
A Phase 2 Study of Paclitaxel and Ifosfamide Plus Either Cisplatin or Carboplatin for Patients with Metastatic Non-Transitional Cell Carcinoma of the Bladder and the Urinary Tract
Authors: P. Giannatempo, D. Magazzù, D. Raggi, E. Farè, M. Marongiu, E. Coradeschi, N. Nicolai, L. Piva, M. Catanzaro, D. Biasoni, T. Torelli, M. Maffezzini, S. Stagni, P. Valagussa, R. Salvioni, A. Necchi
Journal: Annals of Oncology (2014)
Pharmacokinetics/pharmacodynamics (PKPD) of blinatumomab in patients with relapsed/refractory B-precursor acute lymphoblastic leukemia (r/r ALL).
Authors: Min Zhu, Andrea Kratzer, Jessica Johnson, Chris Holland, Christian Brandl, Indrajeet Singh, Andreas Wolf, Sameer Doshi
Journal: Journal of Clinical Oncology (2015)

2561 Background: Blinatumomab is a CD19-directed bispecific T-cell engager antibody construct indicated for treatment of Ph-negative r/r ALL. We evaluated blinatumomab PK/PD and explored their associations with efficacy/safety in 189 r/r ALL patients in a phase 2 study (Topp et al. Lancet Oncol 2015;16:57). Methods: Blinatumomab was given by continuous IV infusion (4 wk on/2 wk off) for ≤ 5 cycles (Cycle 1: 9 µg/d days 1–7; then 28 µg/d; thereafter: 28 µg/d). Association between exposure and measures of efficacy (complete response [CR]/CR with partial hematologic recovery [CRh] within the first 2 cycles) and safety (cytokine release syndrome [CRS]; neurologic events [NE]) was evaluated by logistic regression. Impact of covariates on exposure-response was assessed in multivariate analyses. Results: Blinatumomab PK was linear; mean (SD) serum steady state concentration (Css) at 28 µg/d was 621 (502) pg/mL in Cycle 1. IL-6, IL-10 and IFNγ were transiently elevated in > 50% of pts on days 1–2 of Cycle 1, much less in later cycles; interpatient variability was high. In Cycle 1, mean peripheral B cells fell from 4660 to ≤ 10 cells/µL. Responders had lower percentages of CD19+ B cells and bone marrow (BM) blasts and higher percentages of CD3+ T cells and granulocytes at screening than nonresponders (P< .001); absolute counts were not associated with response. In multivariate analyses, higher Css (OR, 1.90 [95% CI, 1.12–3.21]; P= .017), higher peak IL-10 levels (1.59 [1.13–2.22]; P= .007) and lower percentage of BM blasts at screening (0.78 [0.69–0.89]; P< .001) were associated with CR/CRh. No association between Css and time to CR/CRh was found after adjusting for percentage of blasts and B/T cell ratio. Higher platelet counts (0.996 [95% CI, 0.992–1.0]; P= .03), CD19+ B cell counts at screening (0.90 [0.84–0.97]; P= .004) and Css (1.40 [1.01–1.94]; P= .046) were associated with time to NE. Cytokine peaks were not associated with NE or CRS. Css was not associated with CRS. Conclusions: We found empirical associations of blinatumomab PK, PD and disease-related prognostic factors with CR/CRh and NE. Confounding factors and confirmation of the associations deserve further evaluation. Clinical trial information: NCT01466179.
Allogeneic Peripheral Blood Stem Cell Transplantation Using Reduced-Intensity Conditioning Regimen with Fludarabine and Busulfan from HLA-Matched Related Donor for Elderly Adult T-Cell Leukemia/Lymphoma: Results of Multicenter Phase II Study (ATL-NST-3)
Authors: Ryuji Tanosaki, Ilseung Choi, Mototsugu Shimokawa, Atae Utsunomiya, Masahito Tokunaga, Nobuaki Nakano, Takahiro Fukuda, Hirohisa Nakamae, Shigeki Takemoto, Shigeru Kusumoto, Takeaki Tomoyose, Eisaburo Sueoka, Motoaki Shiratsuchi, Youko Suehiro, Takeharu Yamanaka, Jun Okamura, Naokuni Uike
Journal: Blood (2014)
A blood RNA signature for tuberculosis disease risk: a prospective cohort study
Authors: Daniel E Zak, Adam Penn-Nicholson, Thomas J Scriba, Ethan Thompson, Sara Suliman, Lynn M Amon, Hassan Mahomed, Mzwandile Erasmus, Wendy Whatney, Gregory D Hussey, Deborah Abrahams, Fazlin Kafaar, Tony Hawkridge, Suzanne Verver, E Jane Hughes, Martin Ota, Jayne Sutherland, Rawleigh Howe, Hazel M Dockrell, W Henry Boom, Bonnie Thiel, Tom H M Ottenhoff, Harriet Mayanja-Kizza, Amelia C Crampin, Katrina Downing, Mark Hatherill, Joe Valvo, Smitha Shankar, Shreemanta K Parida, Stefan H E Kaufmann, Gerhard Walzl, Alan Aderem, Willem A Hanekom
Journal: The Lancet (2016)
Junior doctors welcome strike suspension
Authors: Abi Rimmer
Journal: BMJ (2016)

Junior doctors have welcomed the BMA’s decision to suspend their industrial action on Tuesday 26 January.

The association announced on Tuesday 19 January that it had suspended the action, so as to continue talks with the government on the new contract for junior doctors, facilitated by Acas (the Advisory, Conciliation and Arbitration Service).1

Rhiannon Harries, president of the Association of Surgeons in Training, said that the move was a positive step. “Ultimately all junior doctors do not want to unnecessarily inconvenience patients, but we simply cannot allow a contract that is unsafe for patients, doctors, or the NHS,” she said. …
Abstract 18096: Trehalose, a Natural Dissacharide, Reduces Cardiac Remodeling After Myocardial Infarction Through Autophagy Activation
Authors: Sebastiano Sciarretta, Peiyong Zhai, Massimo Volpe, Junichi Sadoshima
Journal: Circulation (2012)

Trehalose is a disaccharide synthesized by lower organisms. Trehalose has a high water retention capability in cells, thereby protecting intracellular organelles from disruption by the hydration/de...
Polyamine Antagonist Therapies Inhibit Neuroblastoma Initiation and Progression
Authors: Nicholas F. Evageliou, Michelle Haber, Annette Vu, Theodore W. Laetsch, Jayne Murray, Laura D. Gamble, Ngan Ching Cheng, Kangning Liu, Megan Reese, Kelly A. Corrigan, David S. Ziegler, Hannah Webber, Candice S. Hayes, Bruce Pawel, Glenn M. Marshall, Huaqing Zhao, Susan K. Gilmour, Murray D. Norris, Michael D. Hogarty
Journal: Clinical Cancer Research (2016)

Deregulated MYC drives oncogenesis in many tissues yet direct pharmacologic inhibition has proven difficult. MYC coordinately regulates polyamine homeostasis as these essential cations support MYC functions, and drugs that antagonize polyamine sufficiency have synthetic-lethal interactions with MYC Neuroblastoma is a lethal tumor in which the MYC homologue MYCN, and ODC1, the rate-limiting enzyme in polyamine synthesis, are frequently deregulated so we tested optimized polyamine depletion regimens for activity against neuroblastoma.We used complementary transgenic and xenograft-bearing neuroblastoma models to assess polyamine antagonists. We investigated difluoromethylornithine (DFMO; an inhibitor of Odc, the rate-limiting enzyme in polyamine synthesis), SAM486 (an inhibitor of Amd1, the second rate-limiting enzyme), and celecoxib (an inducer of Sat1 and polyamine catabolism) in both the preemptive setting and in the treatment of established tumors. In vitro assays were performed to identify mechanisms of activity.An optimized polyamine antagonist regimen using DFMO and SAM486 to inhibit both rate-limiting enzymes in polyamine synthesis potently blocked neuroblastoma initiation in transgenic mice, underscoring the requirement for polyamines in MYC-driven oncogenesis. Furthermore, the combination of DFMO with celecoxib was found to be highly active, alone, and combined with numerous chemotherapy regimens, in regressing established tumors in both models, including tumors harboring highest risk genetic lesions such as MYCN amplification, ALK mutation, and TP53 mutation with multidrug resistance.Given the broad preclinical activity demonstrated by polyamine antagonist regimens across diverse in vivo models, clinical investigation of such approaches in neuroblastoma and potentially other MYC-driven tumors is warranted. Clin Cancer Res; 22(17); 4391-404. ©2016 AACR.