tbuckley/cabot-search huggingface dataset:
An Analysis of Dose-Response for Animals Treated with Aminopterin and Citrovorum Factor&lt;xref ref-type="fn" rid="fn1"&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/xref&gt;
Authors: Abraham Goldin, Nathan Mantel, John M. Venditti, Samuel W. Greenhouse
Journal: JNCI Journal of the National Cancer Institute (1953)

An Analysis of Dose-Response for Animals Treated with Aminopterin and Citrovorum Factor Get access Abraham Goldin, Abraham Goldin Search for other works by this author on: Oxford Academic PubMed Google Scholar Nathan Mantel, Nathan Mantel Search for other works by this author on: Oxford Academic PubMed Google Scholar John M. Venditti, John M. Venditti Search for other works by this author on: Oxford Academic PubMed Google Scholar Samuel W. Greenhouse Samuel W. Greenhouse Clinical Research Unit, National Camer Institute, U. S. Public Health Service Hospital, Baltimore, and the Biometrics Section of the National Cancer Institute4, Bethesda, Md. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 13, Issue 6, June 1953, Pages 1463–1471, https://doi.org/10.1093/jnci/13.6.1463 Published: 01 June 1953 Article history Received: 30 July 1952 Published: 01 June 1953
Association between Zika virus and microcephaly in French Polynesia, 2013–15: a retrospective study
Authors: Simon Cauchemez, Marianne Besnard, Priscillia Bompard, Timothée Dub, Prisca Guillemette-Artur, Dominique Eyrolle-Guignot, Henrik Salje, Maria D Van Kerkhove, Véronique Abadie, Catherine Garel, Arnaud Fontanet, Henri-Pierre Mallet
Journal: The Lancet (2016)
EML4-ALK Fusion Detected by RT-PCR Confers Similar Response to Crizotinib as Detected by FISH in Patients with Advanced Non-Small-Cell Lung Cancer
Authors: Yan Wang, Jun Zhang, Guanghui Gao, Xuefei Li, Chao Zhao, Yayi He, Chunxia Su, Shijia Zhang, Xiaoxia Chen, Jie Zhang, Wei Li, Bing Li, Jing Zhao, Likun Hou, Chunyan Wu, Shengxiang Ren, Caicun Zhou, Jun Zhang
Journal: Journal of Thoracic Oncology (2015)
Neddylation Inhibition Activates the Extrinsic Apoptosis Pathway through ATF4–CHOP–DR5 Axis in Human Esophageal Cancer Cells
Authors: Ping Chen, Tao Hu, Yupei Liang, Pei Li, Xiaoyu Chen, Jingyang Zhang, Yangcheng Ma, Qianyun Hao, Jinwu Wang, Ping Zhang, Yanmei Zhang, Hu Zhao, Shengli Yang, Jinha Yu, Lak Shin Jeong, Hui Qi, Meng Yang, Robert M. Hoffman, Ziming Dong, Lijun Jia
Journal: Clinical Cancer Research (2016)

Abstract Purpose: Targeting the protein neddylation pathway has become an attractive anticancer strategy; however, the role of death receptor–mediated extrinsic apoptosis during treatment remained to be determined. Experimental Design: The activation of extrinsic apoptosis and its role in MLN4924 treatment of human esophageal squamous cell carcinoma (ESCC) were evaluated both in vitro and in vivo. The expression of the components of extrinsic apoptotic pathway was determined by immunoblotting analysis and downregulated by siRNA silencing for mechanistic studies. Results: Pharmaceutical or genetic inactivation of neddylation pathway induced death receptor 5 (DR5)–mediated apoptosis and led to the suppression of ESCC in murine models. Mechanistically, neddylation inhibition stabilized activating transcription factor 4 (ATF4), a Cullin-Ring E3 ubiquitin ligases (CRL) substrate. Transcription factor CHOP was subsequently transactivated by ATF4 and further induced the expression of DR5 to activate caspase-8 and induce extrinsic apoptosis. Moreover, the entire neddylation pathway was hyperactivated in ESCC and was negatively associated with patient overall survival. Conclusions: Our findings highlight a critical role of ATF4–CHOP–DR5 axis-mediated extrinsic apoptosis in neddylation-targeted cancer therapy and support the clinical investigation of neddylation inhibitors (e.g., MLN4924) for the treatment of ESCC, a currently treatment-resistant disease with neddylation hyperactivation. Clin Cancer Res; 22(16); 4145–57. ©2016 AACR.
Do post-approval phase III trials for accelerated approved cancer drugs violate equipoise?
Authors: A. J. Lurie, B. Djulbegovic, J. R. Nebeker, C. Angelotta, L. I. Gordon, D. W. Raisch, P. R. Yarnold, K. R. Carson, J. M. McKoy, C. L. Bennett
Journal: Journal of Clinical Oncology (2006)

6026 Background: Since 1992, the Food and Drug Administration (FDA) has allowed accelerated approval of novel cancer drugs based on improvements in surrogate outcomes, provided that subsequent phase III trials, in compliance with subpart H, show evidence of clinical benefits. However, drugs that receive accelerated approval must already show promise, making it difficult to recruit for randomized studies in which patients might get other drugs which are likely to be inferior. We evaluated whether drugs granted accelerated approval were just as likely to be superior as inferior to standard therapy during phase III clinical trials, a necessary condition known as equipoise, which is used as the ethical basis for recruitment. Methods: Descriptions of marketing approval decisions and subpart H commitments for all drugs that received accelerated approval for oncology indications between 1992 and 2005 were obtained from the FDA website, transcripts of the Oncologic Drug Advisory Committee of the FDA, and PubMed searches. Results: Accelerated approval has been granted for 25 drugs and 29 indications. These approvals have been based on phase II clinical trials (23 indications) or phase III trials (6 indications). 14 approvals were for novel cancer therapeutic drugs. Post-approval phase III clinical trials, outlined in subpart H commitments, have been reported for 9 indications associated with common cancers of the colon, lung, or breast, and 1 indication associated with multiple myeloma, a less common cancer, for which 9 studies identified improved clinical outcomes with the accelerated approved drug. Of 15 drugs that received accelerated approval prior to 2003 for cancers that affect small numbers of patients, 13 are years behind planned recruitment milestones for post-approval phase III trials. Conclusion: While the equipoise theory would predict that 50% of the completed phase III trials would support the novel therapy, empirical data have identified that 90% of the studies required by subpart H commitments support the novel therapy. Therefore, it is likely to hinder recruitment to ongoing phase III trials evaluating other accelerated approved cancer drugs. No significant financial relationships to disclose.
The Combination Of Hypomethylating Agents and Histone Deacetylase Inhibitors(HDACi) Are Synergistically Cytotoxic and Reverse The Malignant Phenotype In Preclinical Models Of T-Cell Lymphoma
Authors: Owen A. O'Connor, Enrica Marchi, Kelly Zullo, Luigi Scotto, Jennifer E. Amengual, Fabio Fuligni, Pier Luigi Zinzani, Stefano A. Pileri, Pier Paolo Piccaluga
Journal: Blood (2013)
Doctors on demand
Authors: Navjoyt Ladher
Journal: BMJ (2016)

Oliver Cromwell reportedly suffered from renal stones, which feature on our cover this week. According to his doctor, as recorded in The Death of Oliver Cromwell , his preferred coping mechanism was “to swill down several sorts of liquor, and then stir his body by some violent motion . . . that by such agitation he might disburden his bladder.” Medical management has come on a lot since then, as Monica Morgan and Margaret Pearle describe in their State of the Art clinical review (doi:10.1136/bmj.i52).

A modern day Cromwell would …
Effect of pan-histone deacetylase inhibitor panobinostat (LBH589) on CXCR4 levels and signaling and on anti-leukemia activity in combination with CXCR4 antagonists
Authors: A. P. Jillella, A. Mandawat, W. Fiskus, R. Rao, Z. Wang, Y. Wang, P. Atadja, N. Fujii, S. Peiper, K. N. Bhalla
Journal: Journal of Clinical Oncology (2008)

14541 Background: Bone marrow stroma-derived factor-1 (SDF-1, CXCL12) binds and activates the chemokine receptor CXCR4, which regulates the trafficking and mobilization of normal and leukemic hematopoietic cells. CXCR4 signaling thorough AKT and c-Raf also promotes survival and decreases sensitivity of AML cells to anti-leukemia agents. Both CXCL12 and CXCR4 are overexpressed and confer poor prognosis in AML. Treatment with the CXCR4 antagonist AMD3100 sensitizes AML cells to anti-leukemia drugs. We determined the effect of panobinostat (P) and/or FC-131 (a new generation CXCR4 inverse agonist) on CXCR4 expression and signaling in cultured and primary AML cells. Methods: Following treatment of human AML OCI-AML3, HL-60, and Jurkat cells, as well as primary AML cells with P (10 to 50 nM) and/or FC-131 (10 nM) with our without 10 nM of CXCL12, cell surface expression of CXCR4 and apoptosis (Annexin V/PI staining) were determined by flow cytometry. Intracellular protein levels of CXCR4, p-AKT, p-ERK1/2, heat shock protein (hsp) 70 and hsp90 were determined by immunoblot (IB) analyses. Binding of CXCR4 to hsp90 and hsp70, as well as CXCR4 acetylation, were determined by immunoprecipitation (IP)/IB analyses. Results: Treatment with P depleted the intracellular and surface expression of CXCR4 in the presence or absence of CXCL12. P induced acetylation of hsp90 and decreased its binding to CXCR4. P also induced acetylation and increased membrane binding of CXCR4 to hsp70. P promoted degradation of CXCR4 by the proteasome. Treatment with P alone also decreased p-AKT and p-ERK1/2. Co- treatment with P markedly attenuated the phosphorylation (p) of AKT and ERK1/2 induced by CXCL12, casuing apoptosis of up to 50% of cultured and primary AML cells. Co-treatment with P and FC-131 caused greater depletion of CXCR4, p-AKT and p-ERK1/2 levels, and synergistically induced apoptosis of the cultured AML cells (combination indices of < 1.0, utilizing isobologram analysis). Conclusions: CXCR4 is chaperoned by hsp90, and treatment with P depletes CXCR4 levels and signaling in AML cells. The novel combination of FC-131 and P is synergistically active and its in vivo ant-AML efficacy is currently under evaluation. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis Institute for Biomedical Research Inc. Novartis Institute for Biomedical Research Inc. Merck & Co., Novartis, Novartis Institute for Biomedical Research Inc.
Abstract 11108: Improved Long-term Survival With Multiple Arterial Grafting Compared With Percutaneous Coronary Intervention or Conventional Coronary Artery Bypass Grafting: Analysis of 12,615 Patients With Stable Multivessel Disease
Authors: Chaim Locker, Hartzell V Schaff, Richard C Daly, Robert L Frye, Malcolm R Bell, Joseph A Dearani, Zhuo Li, Ryan J Lennon, Lyle D Joyce, Kevin L Greason, John M Stulak, Alberto Pochettino, Amir Lerman
Journal: Circulation (2013)

Background: Coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) are frequently used for revascularization of multivessel coronary artery disease (MVCAD), but limited...
Tumor‐derived exosomes elicit tumor suppression in murine hepatocellular carcinoma models and humans in vitro
Authors: Quan Rao, Bingfeng Zuo, Zhen Lu, Xianjun Gao, Abin You, Chenxuan Wu, Zhi Du, HaiFang Yin
Journal: Hepatology (2016)

Hepatocellular carcinoma (HCC) remains a global challenge due to high morbidity and mortality rates and poor response to treatment. Immunotherapy, based on introduction of dendritic cells (DCs) activated by tumor cell lysates as antigens ex vivo , shows limited response rates in HCC patients. Here, we demonstrate that tumor cell–derived exosomes (TEXs), displaying an array of HCC antigens, can elicit a stronger immune response than cell lysates in vitro and in vivo . Significant tumor growth inhibition was achieved in ectopic and orthotopic HCC mice treated with TEX‐pulsed DCs. Importantly, the tumor immune microenvironment was significantly improved in orthotopic HCC mice treated by TEX‐pulsed DCs, demonstrated by increased numbers of T lymphocytes, elevated levels of interferon‐γ, and decreased levels of interleukin‐10 and tumor growth factor‐β in tumor sites. As expected, T cells played an essential role in the TEX‐pulsed DC‐mediated immune response. Notably, exosomes from HCC cells not only promoted HCC‐specific cytolysis but also provided cross‐protective effects against pancreatic cancer cells. Moreover, HCC‐specific cytolysis, elicited by DCs pulsed with human HepG2 cell–derived exosomes, was observed across different human HCC cells irrespective of human leukocyte antigen types. Conclusion : HCC TEXs can potently carry HCC antigens, trigger a strong DC‐mediated immune response, and improve the HCC tumor microenvironment. (H epatology 2016;64:456‐472)
Unplugging JAK/STAT in Chronic Myelomonocytic Leukemia
Authors: Eric Solary
Journal: Clinical Cancer Research (2016)

The proliferative component of chronic myelomonocytic leukemia, related to an increased sensitivity of myeloid progenitors to granulocyte macrophage-colony stimulating factor, suggests dedicated therapeutic approaches. In this issue, ruxolitinib, a JAK1 and -2 inhibitory drug, is shown to induce objective responses in chronic myelomonocytic leukemia patients. Clin Cancer Res; 22(15); 3707-9. ©2016 AACRSee related article by Padron et al., p. 3746.
OC-044 Antisecretory effects of<i>Lactobacillus rhamnosus</i>-conditioned medium prompts the notion of lactobacilli species as probiotics of the upper gastrointestinal tract
Authors: I T Padol, R H Hunt
Journal: Gut (2010)

<h3>Introduction</h3> The <i>Lactobacillus</i> genus has evolved over thousands of years together with humans through its<i>9</i> natural role in milk and dairy products. However, recent attention of the gastro-intestinal (GI) probiotic effect has concentrated on intestinal function rather than on gastric function. The antibacterial properties of Lactobacilli in controlling gastric colonisation by Helicobacter pylori are well recognised1 but little is known about the effects of these acidophilic bacteria on gastric physiology. Recent evidence that <i>Lactobacillus</i> species have been found in the stomachs of animals and humans suggests that they may also modulate acid secretion. <h3>Methods</h3> <i>Lactobacillus rhamnosus</i> (LRH) was chosen because its probiotic properties are well documented, it has been isolated from healthy human gastrointestinal mucosa and its genome was completely sequenced recently.2 LRH was grown in liquid medium for 48 h and conditioned medium (CM) was obtained by centrifugation and micro filtration. The effect of LRH CM was studied using a mouse gastric gland preparation with <sup>14</sup>C-aminopirine accumulation as the indirect method for measurement of acid secretion. Culture medium alone was used as control. <h3>Results</h3> LRH CM inhibited 0.1 M histamine stimulated acid secretion by 100% at dilution of 1/40 while the control medium showed only marginal non-significant effect at this dilution (n=4). The IC<sub>50</sub> (50% of acid inhibition) was ∼1/120 dilution and at this concentration LRH CM did not cause a shift in the histamine dose response curves indicating that histamine H<sub>2</sub>-receptor antagonism is not involved although the efficacy of the response was inhibited by 47.7% (n=5). Furthermore, LRH CM inhibited 0.01 M carbachol and 1.0 M cAMP stimulated acid secretion by 100% and 95%, respectively (n=5), the latter also being suggestive of a post receptor effect. This raises the possibility that bioactive bacterial products secreted into the culture medium act directly on the proton pump or other aspects of parietal cell physiology/metabolism. <h3>Conclusion</h3> This is the first report showing that <i>Lactobacillus</i> or its products exert a gastric antisecretory effect. This prompts the notion that colonisation of the gastric mucosa by these acidophilic bacteria or ingestion of their products may modulate acid secretion with the possibility of a beneficial impact on acid related diseases. Future <i>in vivo</i> and clinical studies on the role of <i>Lactobacillus sp</i> on gastric physiology are needed to explore the potential role of these probiotics in the stomach.
Adjuvant therapy (AT) with raltitrexed (RAL) in colorectal cancer (CRC) patients (pts) intolerant of 5-fluorouracil (5FU)
Authors: K. S. Wilson, J. B. Barnett, S. Gill, K. E. Khoo, C. A. Fitzgerald
Journal: Journal of Clinical Oncology (2006)

3571 Background: Severe 5FU toxicity in AT of CRC may require discontinuation or change of therapy. RAL, a TS inhibitor, has different toxicity but similar efficacy in metastatic CRC. Excess mortality from RAL in the PETACC trial has limited its role in CRC AT. RAL AT (3 mg/m 2 IV q3w) was offered at BCCA to pts with demonstrated intolerance to bolus (Mayo) 5FU. We sought to explore retrospectively the safety &amp; efficacy of RAL AT in these pts. Methods: A search of BCCA Pharmacy &amp; Clinical Records from Oct. 1999 to June 2004 identified CRC pts who received 5FU AT and RAL AT. Data was collected on pt and disease characteristics, therapy &amp; follow-up (FU) status. Kaplan-Meier survival proportions were compared with historical experience. Results: Of 1,456 CRC pts who received 5FU AT, 44 pts (3%) received RAL following 5FU intolerance (42 pts GI/hem toxicity, 2 pts due to angina). Median age was 62.3 y (range 39.8 - 83.2); 31 female; 31 colon primary. Stage III: 39 pts (88.6%); N2: 14 (31.8%). Median # 5FU cycles given prior to RAL was 2 (1 - 4). 21 pts (48%) had only 1 cycle of 5FU before RAL. Grade ≥3 toxicities from 5FU occurred in 39 pts; 17 pts were hospitalised for 2 - 29d (median 8). Twelve of 44 pts also received RT. Median # RAL cycles: 5 (1–8); 77% received &gt;3 cycles; 84% completed all planned RAL. Gr 1, 2, 3 RAL toxicity rates: 55%, 27%, 7% respectively. 1 pt was hospitalised (4 days, FN); no deaths. Median FU of living pts is 4.2 yr (range 1.4 - 6.5). Median survival for all pts is not yet reached. 3 Year Relapse free (RFS) and Overall Survival (OS) proportions were 72% (95% CI 58.5% - 85.5%) and 83.2% (95% CI 71.8% - 94.6%) resp. Stage III 3 Year RFS was 70.8% (95% CI 56.1% - 85.5%) and 3 Year OS was 83.6% (95% CI 71.4% - 95.8%). For N1 &amp; N2 pts, 3 Year RFS was 83.8% (95% CI 69.3% - 98.3%) and 49% (95% CI 22.3% - 75.7%), and OS 91.4% (95% CI 80% - 100%) &amp; 70.7% (95% CI 46.4% - 95%) resp. Conclusions: Severe 5FU intolerance was seen in 3% of pts. RAL AT can be given safely if further 5FU is contraindicated. Outcomes appear similar to historical experience with 5FU AT. [Table: see text] No significant financial relationships to disclose.
A hundred years of service.
Journal: BMJ (1978)

The Printing Industries Federation of South Africa (PIFSA), which represents a R45-billion industry with more than 45 000 employees through six regional chambers, celebrates its centenary year in 2011. However, the history of printing in South Africa dates back to 1784 when the first printer, Johann Christiaan Ritter, first arrived in the Cape, bringing a small press with him. The Cape Governing Council recognised his work by authorising the purchase and establishment of an official printing office with Ritter as superintendent. Before the equipment even arrived, the Dutch East India Company went bankrupt.
Classic Architecture with Multicentricity and Local Recurrence, and Absence of TERT Promoter Mutations are Correlates of BRAF V600E Harboring Pediatric Papillary Thyroid Carcinomas
Authors: Semen Onder, Sule Ozturk Sari, Gulcin Yegen, Ismail Cem Sormaz, Ismail Yilmaz, Sukran Poyrazoglu, Yasemin Sanlı, Yasemin Giles Senyurek, Yersu Kapran, Ozgur Mete
Journal: Endocrine Pathology (2016)
Abstract 14628: Acute Kidney Injury in Pediatric Acute Heart Failure
Authors: Shivanand S Medar, Daphne T Hsu, Jacqueline Lamour, Scott I Aydin
Journal: Circulation (2013)

Objective: Acute kidney injury (AKI) in adult patients with acute heart failure (AHF) is associated with increased morbidity and mortality. There is limited literature in the population of pediatri...
A phase II trial of interferon-alpha and celecoxib in metastatic renal carcinoma: clinical and anti-angiogenic effects
Authors: B. Rini, V. Weinberg, B. Cadman, A. Elchinoff, N. Yu, R. Bok, E. Small
Journal: Journal of Clinical Oncology (2004)

4604 Background: Interferon-alpha (IFNA) is a standard initial therapy in renal cell carcinoma (RCC) with anti-tumor effects via immunologic and anti-angiogenic mechanisms. Cyclooxygenase-2 (COX-2) is an enzyme involved in the formation of prostaglandin E2 and may play a major role in development of cancer through numerous mechanisms, including neovascularization. COX-2 is expressed in the majority of RCC tumors and correlates with stage, grade and microvessel density. Based on potential additive or synergistic anti-antiangiogenic effects, IFNA and celecoxib, an oral COX-2 inhibitor, were tested in metastatic RCC patients. Methods: Patients with untreated, metastatic RCC received IFNA 3 MU s.c. daily and celecoxib 400 mg p.o. BID continuously until disease progression or unacceptable toxicity. Plasma for bFGF and VEGF levels was collected at baseline, end of cycles 1, 2, and every other cycle until off-study. Parffin-embedded RCC tumor samples were stained for COX-2 expression. A 50% increase in the median time to disease progression (TTP) versus historical controls was sought as the primary endpoint. Results: Twenty patients have been treated to date. Two partial responses (10%) have been observed. The median TTP is 3.4 months (range 1.2–9.3+ months). There was no increase in observed toxicities over what was expected from IFNA alone. Dose reduction for toxicity was required to 2 MU QD (6 pts.) and to 1 MU QD (2 pts.). Median TTP was longer for pts. who had a treatment-induced decline in bFGF levels compared with patients with no decline in bFGF levels (5.6 vs. 3.9 months). The mean % change at cycle 2 versus baseline for bFGF was inversely correlated with TTP (r = -0.5, p = .05). Conclusions: Combination therapy of low dose, daily IFNA and celecoxib is safe and feasible in metastatic RCC. The final clinical efficacy of this combination is not yet determined. Change in bFGF levels at cycle 2 versus baseline may predict clinical outcome. Staining of archived RCC tumor samples is ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Research funding provided by NCCN through a grant from Pharmacia (now Pfizer)