tbuckley/cabot-search huggingface dataset:
CpG oligodeoxynucleotide (ODN) is a potent enhancer of fractionated radiotherapy
Authors: K. A. Mason, R. Neal, N. R. Hunter, H. Ariga, A. M. Krieg, J. K. Whisnant, L. Milas
Journal: Journal of Clinical Oncology (2004)

3113 Background: CpG(ODNs) are synthetic DNA sequences containing unmethylated cytosine-guanine motifs having potent immunomodulatory and antitumor effects. Based on known CpG(ODN) mechanisms and previously demonstrated in vivo radiopotentiation by bacterial immunotherapeutic agents, we tested CpG-1826 for its ability to enhance tumor response to fractionated radiotherapy. Methods: C3Hf mice bearing an immunogenic sarcoma (FSa) received single or fractionated irradiation to the tumor with or without CpG(ODN). An ODN with no CpG motif was used as an inactive control. CpG(ODN) was given sc peritumorally 3 x 100 μg per mouse at: 6mm diameter, 8mm diameter when tumors were irradiated, and 7 days later. Tumor growth delay (TGD) and tumor cure were treatment endpoints. A single radiation dose of 20 Gy or 20 Gy in 2 Gy-fractions were used. Fractionated irradiation (10 doses in 5 days) was given twice daily (6–7 h apart). Results:CpG (ODN) strongly enhanced the effect of single and fractionated radiation by factors of 2.49 and 6.91, respectively. Importantly, neither CpG (ODN) nor radiation alone produced tumor cure whereas combined treatment cured 60% for single dose and 44% for fractionated treatment. Based on these promising results we initiated full radiation dose response studies (1–9 Gy) to more accurately quantify the TCD50 (dose required to cure 50% of the tumors) in combination with CpG (ODN). Conclusions: CpG (ODN) strongly enhanced radioresponse measured by TGD and tumor cure. Therefore, CpG (ODN) may have strong potential to improve efficacy of clinical radiotherapy. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Coley Pharmaceutical Group Coley Pharmaceutical Group Coley Pharmaceutical Group Coley Pharmaceutical Group Coley Pharmaceutical Group
Safety, Pharmacokinetics (Pk) and Efficacy of Cyclin-Dependent Kinase (Cdk) 4 and 6 Inhibitor, Palbociclib (Pd-0332991): Results from a Phase 1 Study in Japanese Patients (Pts)
Authors: H. Mukai, T. Yoshino, S. Osera, M. Sasaki, C. Shimizu, K. Yonemori, M. Koudaira, Y. Tanabe, N. Matsuda, N. Mizutani, Y. Mori, S. Hashigaki, T. Nagasawa, Y. Umeyama, S. Randolph, K. Tamura
Journal: Annals of Oncology (2014)
Phase II trial of Gliadel plus O<sup>6</sup>-benzylguanine (O<sup>6</sup>-BG) for patients with recurrent glioblastoma multiforme
Authors: J. A. Quinn, J. J. Vredenburgh, J. N. Rich, D. A. Reardon, A. Desjardins, S. Gururangan, A. H. Friedman, K. Lavin, S. Sathornsumetee, S. Threatt, H. S. Friedman
Journal: Journal of Clinical Oncology (2006)

1568 Background. The major mechanism of resistance to alkylnitrosourea therapy involves the DNA repair protein O 6 -alkylguanine-DNA alkyltransferase (AGT) which removes chloroethylation or methylation damage from the O 6 -position of guanine. O 6 -BG is an AGT substrate that inhibits AGT by suicide inactivation. A previous phase III randomized, placebo-controlled trial has shown that Gliadel wafer significantly prolongs 6-month survival (55.5% for Gliadel vs. 35.6% for placebo) and median survival (28 weeks for Gliadel vs. 20 weeks for placebo) in patients with recurrent glioblastoma multiforme (GBM) (Brem et al 1995). Despite the success of Gliadel in prolonging survival we may be able to improve on this success by depleting AGT. Methods. Thus, we have designed a phase 2 trial where we define the activity and the toxicity of Gliadel in combination with a 5-day infusion of O 6 -BG in patients with recurrent GBM. In a prior study the O 6 -BG dose found to be effective in depleting tumor AGT activity at 48 hours was an IV bolus of 120 mg/m 2 over 1 hour followed by a continuous infusion of 30 mg/m 2 /d for 48 hours. In order to guarantee depletion of tumor AGT activity for at least 5 days after Gliadel placement, this O 6 -BG bolus was repeated on days 3 and 5 while continuing the infusion. Results. To date, 24 patients have been enrolled out of a planned accrual of 50 patients. Seventeen of these patients received prior nitrosourea therapy. The 6-month survival is 68% and the median survival is 36 weeks. The adverse events include the following: 2 episodes of CSF leak (8%), 4 episodes of wound infection at craniotomy site (16%), 5 episodes of grade ≥ 3 seizures (21%) and 3 episodes of hyponatremia (12%). These adverse events were similar in frequency to those seen in patients receiving Gliadel in prior placebo-controlled Gliadel trials. Conclusions. Thus far, this data demonstrates an increase in the efficacy of Gliadel when combined with O 6 -BG. Twenty-six additional patients will be enrolled for a total accrual of 50 patients. [Table: see text]
Distinct Biological and Transcriptional Features Of FLT3-ITD Variants In Vitro and In Vivo
Authors: Patricia Arreba-Tutusaus, Lars Bullinger, Anja Polanetzki, Tina M Schnoeder, Raghavan V. Thangapandi, Konstanze Döhner, Thomas Fischer, Florian H Heidel
Journal: Blood (2013)
TCT-645 Poorer Left Ventricular Global Longitudinal Strain and Less Tricuspid Regurgitation Predicts Improvement in Left Ventricular Function Following Transcatheter Aortic Valve Replacement
Authors: Juyong B. Kim, Daniel Brenner, Yukari Kobayashi, Ryan O'Malley, Yuhei Kobayashi, Catherine Dao, Thu Vu, Alan Yeung, D. Craig Miller, Michael Fischbein, Joseph C. Wu, Francois Haddad, William F. Fearon
Journal: Journal of the American College of Cardiology (2015)
Routine Amoxicillin for Uncomplicated Severe Acute Malnutrition in Children
Authors: Sheila Isanaka, Céline Langendorf, Fatou Berthé, Smaila Gnegne, Nan Li, Nassirou Ousmane, Souley Harouna, Hamidine Hassane, Myrto Schaefer, Eric Adehossi, Rebecca F. Grais
Journal: New England Journal of Medicine (2016)

High-quality evidence supporting a community-based treatment protocol for children with severe acute malnutrition, including routine antibiotic use at admission to a nutritional treatment program, remains limited. In view of the costs and consequences of emerging resistance associated with routine antibiotic use, more evidence is required to support this practice.In a double-blind, placebo-controlled trial in Niger, we randomly assigned children who were 6 to 59 months of age and had uncomplicated severe acute malnutrition to receive amoxicillin or placebo for 7 days. The primary outcome was nutritional recovery at or before week 8.A total of 2412 children underwent randomization, and 2399 children were included in the analysis. Nutritional recovery occurred in 65.9% of children in the amoxicillin group (790 of 1199) and in 62.7% of children in the placebo group (752 of 1200). There was no significant difference in the likelihood of nutritional recovery (risk ratio for amoxicillin vs. placebo, 1.05; 95% confidence interval [CI], 0.99 to 1.12; P=0.10). In secondary analyses, amoxicillin decreased the risk of transfer to inpatient care by 14% (26.4% in the amoxicillin group vs. 30.7% in the placebo group; risk ratio, 0.86; 95% CI, 0.76 to 0.98; P=0.02).We found no benefit of routine antibiotic use with respect to nutritional recovery from uncomplicated severe acute malnutrition in Niger. In regions with adequate infrastructure for surveillance and management of complications, health care facilities could consider eliminating the routine use of antibiotics in protocols for the treatment of uncomplicated severe acute malnutrition. (Funded by Médecins sans Frontières Operational Center Paris; ClinicalTrials.gov number, NCT01613547.).
Multiplicity of Cell Response to the BAI strain A (Myeloblastosis) Avian Tumor Virus. VI. Ultrastructural Aspects of Adenosinetriphosphatase Activity of Nephroblastoma Cells and Virus&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: Guy de Thé, Hideo Ishiguro, Ursula Heine, Dorothy Beard, J. W. Beard
Journal: JNCI Journal of the National Cancer Institute (1963)

Renal tumors with characteristics of nephroblastomas were induced in the chicken by inoculation of the BAI strain A avian tumor virus. Ultracy to chemical studies were made to determine the presence or absence of adenosinetriphosphatase in epithelial, sarcomatous, and chondromatous cellular components of the tumor, and of the enzyme associated with virus elaborated by the respective cells. Evidence of adenosinetriphosphatase was observed only at the brush border of cells corresponding to analogous elements of the proximal convoluted tubules of the normal nephron and at the membrane of cells resembling those of the distal convoluted tubule of the normal nephron. Virus budded from the membranes of the latter cells reacted positively for adenosinetriphosphatase. There was no reaction by virus associated with cells showing no enzyme at the cytoplasmic membrane. Virus in pellets sedimented from the blood plasma of chickens with myeloblastosis and treated with the same procedures gave a pronounced adenosinetriphosphatase reaction. The findings indicated that adenosinetriphospha tase in the virus in the nephroblastoma depended directly on incorporation of the enzyme into the particle as it budded from the membrane. The significance of the findings is discussed in relation to the influence of the respective host cells on the nature of the agent derived from them.
A phase II prospective study of gemcitabine and platin-based combination as first-line chemotherapy for metastatic Bellini duct carcinoma patients. Results of GETUG study
Authors: S. Culine, S. Oudard, B. Duclos, E. Banu, F. Priou, F. Rousseau, D. Langlois, A. Banu, F. Rolland
Journal: Journal of Clinical Oncology (2005)

4543 Background: Immunotherapy is rarely effective in patients (pts) with Bellini duct carcinoma (BDC), a rare (< 1% off all renal cancers) and aggressive variant of kidney cancer. Gemcitabine (GEM) and platinum salt combination was considered as a potential regimen (Oudard, J Urol. 2003). Methods: We conducted a prospective, multicenter, phase II study to assess the efficacy and safety of GEM-platinum association in metastatic BDC pts. Central pathology review was performed. Treatment consisted of GEM (1250 mg/m2, day 1, 8) and platinum salt (cisplatin 70 mg/m2 or carboplatine AUC 5, day 1, for pts with mild or moderate renal insufficiency), q3w. Overall response rate (WHO criteria) was the primary end point. Additionally, progression-free survival (PFS) and overall survival (OS) was evaluated. Kaplan-Meier and Cox hazard regression methods were used to estimate survival data (PFS, OS) and the relationship with baseline variables. Toxicity was evaluated according CTC-NCI version 2 criteria. Results: Between October 2001 and August 2004, 20 pts were treated in six French centers. Pts characteristics: median age was 62 years [18–73], M/F: 8/12, ECOG performance status (PS) 0/1/2: 5/12/3. Sites of metastases included: lung (65%), bone (20%), lymph nodes (45%), liver (30%) and others (20%), with 80% of pts having > 2 metastatic sites. Four pts (20%) with renal insufficiency at inclusion were treated with carboplatine and other two pts were switched to the same platinum salt for renal toxicity. Pts distribution according to response was: 5 (25%) PR, 8 (40%) SD, 4 (20%) PD and 3 (15%) not yet evaluable. The PFS and OS were 7.9 months (95% CI, 1.8–14 months) and 9.5 months (95% CI, 2.7–16.3 months), respectively. PFS and OS percentages at 1-year were 33% and 48%, respectively. No relationship was demonstrated between survival data and age, PS, sex or baseline hemoglobin. Toxicity was predominantly hematologic, with two severe neutropenia and trombocytopenia. Two mild renal toxicity were registered. Conclusions: This is the first prospective study showing that combination of gemcitabine and platinum salt is an active regimen for pts with metastatic BDC. No significant financial relationships to disclose.
Routine tests during follow-up of patients after primary treatment for operable breast cancer
Authors: D. Crivellari, K.N. Price, M. Hagen, A. Goldhirsch, R.D. Gelber, M. Castiglione, A.S. Coates, C.-M Rudenstam, J. Collins, J. Lindtner, H. Córtes-Funes, A. Gudgeon, E. Simoncini, M. Byrne, H.G. Schniirch, M. Fey, M.H.N. Tattersall, J.F. Forbes, F. Cavalli, R. Reed, H.-J Senn
Journal: Annals of Oncology (1995)
Efficacy and safety of use of somatostatin (SS) analogues in metastatic neuroendocrine tumours
Authors: T. A. Rodrigues, A. Quintela, L. Costa
Journal: Journal of Clinical Oncology (2008)

15641 Background: Malignant neuroendocrine gastroenteropancreatic tumours (GEP) showed a 5-year survival rate of 20%. It has been described that in about 50% of the patients with metastatic or locally advanced NETs, SS analogues therapy result in disease stabilization. The risk of developing gallstones in patients undergoing SS analogs approaches 50%, nevertheless only <1% of patients require cholecystectomy. We analysed caracteristics, clinical outcome and toxicity, of patients with progressive metastatic NET undergoing SS analogues therapy. Methods: Twenty six evaluable patients, not previously treated, identified between 2004 and 2007, classified as metastatic NETs, were given long-acting SS analogues (octreotide 30 mg: n=27; lanreotide gel: n=2 every 28 days) until evidence of disease progression. Mean age: 69 (51–94), 14 men, 8 NET were identified has hormone producing tumours. The primary tumour was determined in 19 patients: 8-pancreatic, 2-gastric, 1-bronchial and 8-midgut. As concerns to sites of metastases: 17 patients had liver metastases only, 2-lung, 2-liver and lymph node, 1-liver and bone; 1- mesentery, 1-mediastinum, and 1-liver, mesentery and mediastinum. Octreoscan was positive in 17 patients. The treatment activity was evaluated by objective response with CT scans according RECIST criteria. Safety and tolerability were also assessed. Results: The mean time on SS analogues therapy was 19 months (2–61). Three partial objective tumour responses were obtained (5, 12 and 36 month duration); disease stabilization over 3 months (3–61 months) was achieved in 16 patients (64%); progressive disease was observed in 6 patients (one patient died 5 months after diagnosis). Among the patients that achieved partial response all had ki67 index<10%. In all functioning tumours symptomatic and biochemical response was observed. In respect to toxicity, 12% (n=3) of patients had gallbladder stones development, one with cholecystitis. All patients were in SS analogues therapy for > 3 months (6, 59, 61 months respectively). Conclusions: Long-acting SS analogues were seen to be effective in controlling the disease and were well tolerated. The main adverse event was gallblader stones development, that seems to be related with duration of SS analogues therapy. No significant financial relationships to disclose.
Acute serum amyloid A is an endogenous TLR2 ligand that mediates inflammatory and angiogenic mechanisms
Authors: Mary Connolly, Peter R Rooney, Trudy McGarry, Ashwini X Maratha, Jennifer McCormick, Sinead M Miggin, Douglas J Veale, Ursula Fearon
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Introduction</h3> Acute-phase serum amyloid A (A-SAA) has cytokine-like properties and is expressed at sites of inflammation. We examined whether A-SAA-induced pro-inflammatory mechanisms are mediated through Toll-like receptor 2 (TLR2) in rheumatoid arthritis (RA). <h3>Methods</h3> The effect of A-SAA on human embryonic kidney (HEK), TLR2 or TLR4 cells was quantified by nuclear factor (NF)-κB luciferase reporter assays. A-SAA-induced RASFC and dHMVEC function were performed in the presence of a specific neutralising anti-TLR2 mAb (OPN301) (1 μg/mL) and matched IgG isotype control Ab (1 μg/mL). Cell surface expression of intracellular adhesion molecule (ICAM)-1, chemokine expression, cell migration, invasion and angiogenesis were assessed by flow cytometry, ELISA, Matrigel invasion chambers and tube formation assays. MyD88 expression was assessed by real-time PCR and western blot. <h3>Results</h3> A-SAA induced TLR2 activation through induction of NF-κB (p&lt;0.05), but failed to induce NF-κB in HEK-TLR4 cells, confirming specificity for TLR2. A-SAA-induced proliferation, invasion and migration were significantly inhibited in the presence of anti-TLR2 (all p&lt;0.05), with no significant effect observed for tumour necrosis factor-α-induced events. Additionally, A-SAA-induced ICAM-1, interleukin-8, monocyte chemoattractant protein-1, RANTES and GRO-α expression were significantly reduced in the presence of anti-TLR2 (all p&lt;0.05), as was A-SAA induced angiogenesis (p&lt;0.05). Finally, A-SAA induced MyD88 signalling in RASFC and dHMVEC (p&lt;0.05). <h3>Conclusions</h3> A-SAA is an endogenous ligand for TLR2, inducing pro-inflammatory effects in RA. Blocking the A-SAA/TLR2 interaction may be a potential therapeutic intervention in RA.
Sex differences in pulmonary hypertension: are we cleaning up the mess?
Authors: Tim Lahm
Journal: European Respiratory Journal (2016)

When I was looking for a research project to pursue as a fellow in 2006, I became interested in sex differences in pulmonary arterial hypertension (PAH). When I proposed the idea of pursuing this topic further to a well-regarded expert in the field, his sobering answer was "That area is a mess"; and what a mess it was! We knew at that time that oestrogens exert protective effects in acute and chronic hypoxia-induced pulmonary hypertension (PH) [1–3], as well as in monocrotaline-induced PH (MCT–PH) [4]. However, we also knew that women are more prone to PAH [5], a finding at odds with the data derived from animal studies. Soon after that, we learned that women, despite being more prone to PAH development, exhibit better survival and better right ventricular function than their male counterparts [6, 7]. The superior survival in female patients ultimately was linked at least in part to improved right ventricular function [8, 9]. Epidemiological studies in healthy subjects implicated oestrogens and dehydroepiandrosterone as mediators of superior right ventricular function, whereas testosterone was associated with higher right ventricular mass, higher volumes and lower right ventricular ejection fraction (RVEF) [10]. Genomic and non-genomic factors determine disparate right ventricular and pulmonary vascular effects of sex steroids http://ow.ly/WdBNQ
Low-dose deoxycoformycin in lymphoid malignancy.
Authors: M R Grever, J M Leiby, E H Kraut, H E Wilson, J A Neidhart, R L Wall, S P Balcerzak
Journal: Journal of Clinical Oncology (1985)

Deoxycoformycin (dCF), a potent inhibitor of adenosine deaminase (ADA), was explored for its antineoplastic potential in 28 patients with advanced lymphoid malignancy. Both normal and malignant B lymphocytes have low levels of ADA activity, and low doses of dCF profoundly inhibit this enzyme in the peripheral blood of patients with chronic lymphocytic leukemia (CLL). The low doses of dCF administered in this trial (4 mg/m2) were not associated with prohibitive toxicity. Five of 28 patients had an objective response. Four additional patients had clinical improvement. No significant difference in the pretreatment ADA activity existed between responding patients and treatment failures. The demonstration of responses to dCF following failure on standard alkylating agents suggests that dCF may not be cross-resistant with current agents used to treat CLL. Additional studies should be pursued using low-dose dCF in patients with advanced malignancy.
Bromodomain mimics reduce oxidative stress-induced inflammation in human epithelial cells
Authors: Younis Khan, Paul Kirkham, Ian Adcock
Journal: European Respiratory Journal (2013)

Background:  Chronic obstructive pulmonary disease (COPD) is caused by prolonged cigarette smoke exposure and is associated with increased inflammation and oxidative stress under the control of histone acetylation. The recent development of bromodomain inhibitors which prevent the effects of histone acetylation may interfere with inflammatory gene expression.   Method:  Human epithelial (BEAS-2B) cells were stimulated with IL-1β (1ng/ml) in the presence or absence of H 2 O 2  (100µM) and the effect of pre-treatment with bromodomain inhibitors (JQ-1 and PFI-1) was investigated. Pro-inflammatory mediators (CXCL8 and IL-6) were measured by ELISA and transcripts by RT-PCR. H3 and H4 acetylation and recruitment of p65 and Brd4 to native promoters was investigated using chromatin immunoprecipitation (ChIP). The impact of Brd2 and Brd4 siRNA knockdown on inflammatory mediators was also investigated.   Result:  H 2 O 2  enhanced IL1β-induced IL-6 and CXCL8 expression in BEAS-2B cells whereas H 2 O 2  alone did not have any affect. H3 was acetylated at  IL-6  and  IL-8  promoters and this was associated with recruitment of both p65 and Brd4 proteins. The inactive Brd4 mimic (-)-JQ1 had no effect on IL-6 or CXCL8 expression whereas the active enantiomer (+)-JQ1 and PFI-1 reduced IL-6 and CXCL8 expression significantly. Brd4, but not Brd2, knockdown markedly reduced IL-6 and CXCL8 release. JQ-1 also inhibited p65 and Brd4 recruitment to the  IL-6  and  IL-8  promoters.   Conclusion:  The oxidative stress (H 2 O 2 ) enhanced IL1β-induced IL-6 and CXCL8 expression was significantly reduced by JQ-1 and PFI-1. Brd4 plays an important role in the induction of inflammation and provides a potential anti-inflammatory therapeutic target.
Black box warning on lenalidomide-associated venous thromboembolism (VTE) in off-label setting: A preemptive and unusual safety initiative
Authors: C. Angelotta, A. J. Lurie, P. R. Yarnold, S. Singhal, J. Mehta, E. A. Lyons, C. L. Bennett
Journal: Journal of Clinical Oncology (2006)

6074 Background: Half of cancer therapies are used off-label, but regulations prohibit package inserts from describing toxicities that occur only in these settings. In 2003, RADAR reported VTE rates of 20% to 62% when thalidomide, approved for leprosy treatment, was used off-label (with dexamethasone) for multiple myeloma. In 2005, the Connecticut attorney general requested that a black box warn of high rates of VTE when thalidomide is used off-label. Subsequently, the thalidomide analogue, lenalidomide, received FDA approval as a myelodysplasia therapy. In phase II/III trials, multiple myeloma response rates were 60% to 92% with lenalidomide/dex therapy. Methods: Published literature, abstracts, and package inserts were reviewed for VTE rates in lenalidomide-treated multiple myeloma. Results: VTE rates were 8.5% to 75% in multiple myeloma treated with lenalidomide and dex or erythropoietin; rates were &lt;3.4% when aspirin prophylaxis was added. The FDA approved package insert for lenalidomide preemptively includes a black box warning describing high VTE rates with off-label use of lenalidomide and advises physicians that VTE prophylaxis should be considered, although the effectiveness of various prophylaxis regimens is unknown. Conclusions: Six months after the attorney general requested that a black box warning describe high VTE rates with off-label use of thalidomide, the manufacturer preemptively included an analogous black box warning in the package insert for the thalidomide analogue, lenalidomide, but did not include similar warnings for this toxicity in the package insert for thalidomide. The FDA should require that package inserts describe severe toxicities that commonly occur with off-label use of cancer therapies. This is especially important for severe class-related toxicities such as lenalidomide- and thalidomide- associated VTE. [Table: see text] No significant financial relationships to disclose.