tbuckley/cabot-search huggingface dataset:
Phase II, 3-arm study of CCI-779 in combination with letrozole in postmenopausal women with locally advanced or metastatic breast cancer: preliminary results
Authors: J. Baselga, P. Fumoleau, M. Gil, R. Colomer, H. Roche, H. Cortes-Funes, H. Burstein, P. Kaufman, S. Kong, L. Moore
Journal: Journal of Clinical Oncology (2004)

544 Background: CCI-779, a novel mTOR kinase inhibitor, is well tolerated and has shown antitumor activity in heavily pretreated patients (pts) with metastatic breast cancer (MBC). The combination of CCI-779 (CCI) and antiestrogens has an additive effect in preclinical models of breast cancer. Thus, the objective of this clinical trial is to evaluate preliminary activity of CCI in combination with letrozole. Methods: Randomization is in a 1:1:1 ratio (∼30 evaluable pts/arm), letrozole alone: letrozole with CCI daily (CCI daily arm): letrozole with CCI daily for 5 days every 2 weeks (CCI intermittent arm). All pts receive 2.5 mg letrozole daily. Results: Fifty-five pts have been enrolled. Initially, 6 pts were enrolled on each of the high-dose (HD) schedules, 25 mg CCI daily and 75 mg CCI intermittent; 3 pts in each arm had toxicity that resulted in dose delay/reduction or discontinuation. Thus, the protocol was amended and doses were reduced to low-dose (LD) schedules, 10 mg CCI daily and 30 mg CCI intermittent. As of 01 Dec 2003, 12 and 23 pts were enrolled on the HD and LD schedules, respectively. The median age was 60 yrs (range, 42–81). Safety data are available for 12 pts treated with the HD schedules (25 mg, 6 pts; 75 mg, 6 pts), 11 pts treated with the LD schedules (10 mg, 4 pts; 30 mg, 7 pts), and 12 pts treated with letrozole alone. The most frequently occurring grade 3–4 CCI-related toxicity was stomatitis for the HD schedules (2/6 pts, 2/6 pts) and diarrhea for the LD schedules (0 pts, 1/7 pts). No grade 3–4 toxicities were reported for pts treated with letrozole alone. Of 55 pts, 7 have been on study for 40+ wks. Preliminary tumor responses (RECIST) are available for 19 evaluable pts. CCI pts (n=13) had 1 complete response (HD schedule), 3 partial responses (HD schedules), 9 stable disease (6 pts on HD schedules, 3 on LD schedules; SD ≥ 24 wks for 4 pts on HD schedules). Letrozole-alone pts (n=6) had 2 PR and 4 SD (SD ≥ 24 wks for 1 pt). Conclusions: The combination of letrozole with 10 mg CCI daily or 30 mg CCI intermittent showed favorable results for tolerability. Accrual is continuing. A phase 3 study will be performed to confirm efficacy. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Wyeth Research Wyeth Pharmaceuticals Wyeth Pharmaceuticals Wyeth
A novel role of endothelium in activation of latent pro-membrane type 1 MMP and pro-MMP-2 in rat aorta
Authors: Sören Otto, Andreas Deussen, Birgit Zatschler, Bianca Müller, Anja Neisser, Kathrin Barth, Henning Morawietz, Irakli Kopaliani
Journal: Cardiovascular Research (2015)

Aortic stiffness is an independent risk factor for progression of cardiovascular diseases. Degradation of elastic fibres in aorta due to angiotensin II (ANGII)-stimulated overactivation of latent membrane type 1 matrix metalloproteinase (MT1MMP) and matrix metalloproteinase-2 (MMP2) is regarded to represent an important cause of aortic stiffness. Therefore, clarification of the causal mechanisms triggering the overactivation of these MMPs is of utmost importance. This study addresses the endothelium as a novel key activator of latent pro-MT1MMP and pro-MMP2 in rat aorta. Using a co-culture model of rat aortic endothelial cells (ECs) and smooth muscle cells (SMCs), we found that ANGII stimulation resulted in activation of latent pro-MT1MMP and pro-MMP2 in SMCs exclusively when co-cultured with ECs (assessed with western blot and gelatin zymography, respectively). EC-specific AT1 receptor stimulation triggered endothelin-1 release and paracrine action on SMCs. Endothelin-1 increased expression and activity of pro-protein convertase furin in SMCs via endothelin receptor type A (assessed with qPCR and furin activity assay, respectively). Consequently, furin acted in two ways. First, it increased the activation of latent pro-MT1MMP and, second, it activated pro-αvβ3 integrin. Both pathways led to overactivation of latent pro-MMP2. In vitro findings in the co-culture model were fully consistent with the ex vivo findings obtained in isolated rat aorta. We propose that the endothelium under ANGII stimulation acts as a novel and key activator of latent pro-MT1MMP and pro-MMP2 in SMCs of rat aorta. Therefore, endothelium may critically contribute to pathophysiology of aortic stiffness.
Inhibition of ALK mutated neuroblastomas by the selective inhibitor PF-02341066
Authors: A. C. Wood, M. Laudenslager, E. A. Haglund, E. F. Attiyeh, B. Pawel, J. Courtright, J. Plegaria, J. G. Christensen, J. M. Maris, Y. P. Mosse
Journal: Journal of Clinical Oncology (2009)

10008b Background: Mutations in the ALK oncogene are the major cause of hereditary neuroblastoma (NB), and may offer a tractable therapeutic target. Methods: We resequenced the ALK tyrosine kinase domain in 496 primary NBs. We integrated data from 76 primary tumors analyzed using Illumina HumanHap550 SNP and Human-6 mRNA expression arrays. We stained a tissue microarray (TMA) of 134 NBs with anti-ALK and anti-pALK antibodies. We evaluated the in vitro and in vivo activity of PF-02341066, a small molecule inhibitor of ALK. Computational chemistry was used to homology map ALK interaction with PF-02341066. Results: Mutations were discovered in 38/496 NBs (8%), across the spectrum of phenotypes. R1275Q substitutions were most common (45%), followed by F1174L (15%). Evaluation of matched constitutional DNAs demonstrated 10% carried occult germline mutations. Integration of primary tumor microarrays from 76 samples showed that ALK mRNA expression was highly correlated with ALK DNA copy number (p=0.0005). ALK protein was nearly universally expressed (129/134; 93%), and there was evidence for ALK activation in 15% of tumors (pALK moderate or strong staining in 20/134), suggesting an additional and alternative pathway to ALK activation. A panel of 18 NB cell lines showed differential in vitro sensitivity to PF-2341066 dependent on ALK mutation and copy number status. A wild type (WT) amplified line and 2 lines harboring R1275Q mutations were sensitive (IC50 145 - 301 nM). Lines harboring F1174L mutations were more resistant (IC50 &gt;950nM) as were lines with no ALK aberrations. Inhibition of proliferation was associated with abolishing phosphorylation of ALK, STAT3 and AKT. PF-02341066 caused complete regression of R1275Q xenografts, but caused only minimal growth delay in F1174L and WT xenografts. Based on homology mapping to a crystal structure of PF-02341066 bound to c-Met, the F1174L mutation is predicted to destabilize the specific conformation of the kinase activation loop required for binding PF-02341066. Conclusions: ALK pathway activation occurs in at least 15% of human neuroblastomas. PF-02341066 is a potent inhibitor of the most common ALK mutation, but there is a structural basis for resistance to F1174L mutations. Co-crystallization studies are ongoing and a phase 1 study is planned. No significant financial relationships to disclose.
Multinational outbreak of Salmonella Enteritidis infection during an international youth ice hockey competition in Riga, Latvia, preliminary report, March and April 2015
Authors: A K Pesola, T Pärn, S Huusko, J Perevoščikovs, J Ollgren, S Salmenlinna, T Lienemann, C Gossner, N Danielsson, R Rimhanen-Finne
Journal: Eurosurveillance (2015)

A multinational outbreak of salmonellosis linked to the Riga Cup 2015 junior ice-hockey competition was detected by the Finnish health authorities in mid-April and immediately notified at the European Union level. This prompted an international outbreak investigation supported by the European Centre for Disease Prevention and Control. As of 8 May 2015, seven countries have reported 214 confirmed and suspected cases, among which 122 from Finland. The search for the source of the outbreak is ongoing.
The Role of Neoadjuvant Trials in Drug Development for Solid Tumors
Authors: Samuel A. Funt, Paul B. Chapman
Journal: Clinical Cancer Research (2016)

The relatively low success rate of phase II oncology trials in predicting success of novel drugs in phase III trials and in gaining regulatory approval may be due to reliance on the endpoint of response rate defined by the RECIST. The neoadjuvant treatment paradigm allows the antitumor activity of a novel therapy to be determined on a pathologic basis at the time of surgery instead of by RECIST, which was not developed to guide clinical decision making or correlate with long-term outcomes. Indeed, the FDA endorsed pathologic complete response (pCR) as a surrogate for overall survival (OS) in early-stage breast cancer and granted accelerated approval to pertuzumab based on this endpoint. We propose that pCR is a biologically rational method of determining treatment effect that may be more likely to predict OS. We discuss some advantages of the neoadjuvant trial design, review the use of neoadjuvant therapy as standards of care, and consider the neoadjuvant platform as a method for drug development. Clin Cancer Res; 22(10); 2323-8. ©2016 AACR.
Totally implantable system for peritoneal access.
Authors: C E Pfeifle, S B Howell, M Markman, W E Lucas
Journal: Journal of Clinical Oncology (1984)

A totally implantable system for providing access to the peritoneal cavity was evaluated. Fifty-six Port-A-Cath (Pharmacia Nu Tech, Piscataway, NJ) peritoneal access systems were implanted in 54 cancer patients receiving intraperitoneal chemotherapy. The catheters are accessed by transcutaneous placement of a Huber point needle through a silicone septum at the top of the portal. A total of 32 patient years of experience are reported. The Port-A-Caths have been in place for a median of 22 weeks (range, one to 85). A total of 401 entries have been made for paracentesis, chemotherapy administration, antibiotic administration, peritoneal lavage for cytology, and catheter flushing. There have been six episodes of peritonitis (five Staphylococcus epidermidis, one S aureus) in three patients. There have been no mechanical failures of the Port-A-Caths. Loss of bidirectional flow through the catheter due to fibrin deposition about the catheter has been the major cause of catheter failure. Patient acceptance of the Port-A-Cath has been excellent.
Cancer of the Integumentary Tissues in Uganda Africans: The Basis for Prevention&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: J. N. P. Davies, M.D., R. Tank, M.D., R. Meyer, M.D., P. Thurston, M.D.
Journal: JNCI Journal of the National Cancer Institute (1968)

Superficial cancers in the Uganda African occur in certain localizations which differ greatly from those in the European. Most squamous carcinomas in the Uganda African develop from antecedent lesions which can be identified, such as tropical phagedenic ulceration, burns, scars, sinuses, and fistulae. There are reasons for suspecting that sunlight is a major factor in producing squamous cancers of the cranial region, including the common conjunctival cancers. Melanomas are similarly virtually confined to restricted areas of the superficial tissues, and they may be induced by local heat. There is every indication that the overwhelming majority of integumentary tissue cancers of Uganda are preventable by measures which for the most part would be acceptable to the population.
Evolution of the 28S ribosomal RNA gene in anurans: regions of variability and their phylogenetic implications.
Authors: D M Hillis, S K Davis
Journal: Molecular Biology and Evolution (1987)

Fifteen restriction sites were mapped to the 28S ribosomal RNA gene of individuals representing 54 species of frogs, two species of salamanders, a caecilian, and a lungfish. Eight of these sites were present in all species examined, and two were found in all but one species. Alignment of these conserved restriction sites revealed, among anuran 28S rRNA genes, five regions of major length variation that correspond to four of 12 previously identified divergent domains of this gene. One of the divergent domains (DD8) consists of two regions of length variation separated by a short segment that is conserved at least throughout tetrapods. Most of the insertions, deletions, and restriction-site variations identified in the 28S gene will require sequence-level analysis for a detailed reconstruction of their history. However, an insertion in DD9 that is coextensive with frogs in the suborder Neobatrachia, a BstEII site that is limited to representatives of two leptodactylid subfamilies, and a deletion in DD10 that is found only in three ranoid genera are probably synapomorphies.
Severe Congenital Neutropenia Patients With Point Mutations in the Granulocyte Colony-Stimulating Factor (G-CSF ) Receptor mRNA Express a Normal G-CSF Receptor Protein
Authors: Brigitte Kasper, Andreas Herbst, Christina Pilz, Manuela Germeshausen, Nicola Tidow, Martin R. Hadam, Karl Welte
Journal: Blood (1997)
Immunoglobulin Bound In Vivo to Fc Receptor-Positive Cells in Human Central Nervous System Tumors&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: Wood, Gary W., Morantz, Robert A., Tilzer, Seth A., Gollahon, Katherine A.
Journal: JNCI Journal of the National Cancer Institute (1980)

Fifteen human central nervous system tumors of various histopathologic types were assessed qualitatively and quantitatively by indirect immunofluorescence for the presence of in vivo bound IgG, IgA, and IgM. The tumors were selected to reflect varying degrees of infiltration with Fc receptor-positive macrophages. The major purpose of the study was to determine the relative contribution of immunoglobulin (Ig) bound to tumor cells as compared to Ig bound to the Fc receptor-positive host macrophages. Of the 15 tumors, 1 tumor contained no detectable IgG, IgA, or IgM, 2 tumors contained only IgG and IgA bound in a smooth, homogeneous pattern to the surface of tumor cells, and 8 contained only IgG, IgA, and IgM attached to Fc receptor-positive cells. Four tumors contained significant numbers of tumor cells with cytoplasmic Ig, and two of those tumors also were infiltrated with Fc receptor-positive cells with membrane-associated Ig. Ig was removed from Fc receptor-positive cells but not from tumor cells by prolonged washing of sections of tumor at 37 degrees C, which suggested that Ig was associated with Fc receptors. That possibility was strengthened by the observation that the IgG subclass distribution of the Fc receptor-associated Ig was predominantly IgG1 and IgG3, whereas no predominant subclass existed for IgG bound to tumor cells. Furthermore, the Fc receptor-associated Ig appeared to be in the form of antigen-antibody complexes because it had a granular quality and because IgA and sometimes even IgM were involved in the Fc receptor-bound complexes.
γ-Interferon Production in Peripheral Blood Mononuclear Cells and Tumor Infiltrating Lymphocytes From Kaposi's Sarcoma Patients: Correlation With the Presence of Human Herpesvirus-8 in Peripheral Blood Mononuclear Cells and Lesional Macrophages
Authors: Maria Caterina Sirianni, Laura Vincenzi, Valeria Fiorelli, Simone Topino, Enrico Scala, Stefania Uccini, Antonio Angeloni, Alberto Faggioni, Decio Cerimele, Francesca Cottoni, Fernando Aiuti, Barbara Ensoli
Journal: Blood (1998)
Statins for Prevention of Cardiovascular Events in a Low-Risk Population With Low Ankle Brachial Index
Authors: Rafel Ramos, Maria García-Gil, Marc Comas-Cufí, Miquel Quesada, Jaume Marrugat, Roberto Elosua, Joan Sala, María Grau, Ruth Martí, Anna Ponjoan, Lia Alves-Cabratosa, Jordi Blanch, Bonaventura Bolíbar
Journal: Journal of the American College of Cardiology (2016)

Evidence is lacking about the effectiveness of risk reduction interventions in patients with asymptomatic peripheral arterial disease. This study aimed to assess whether statin therapy was associated with a reduction in major adverse cardiovascular events (MACE) and mortality in this population. Data were obtained from 2006 through 2013 from the Catalan primary care system's clinical records database (SIDIAP). Patients age 35 to 85 years with an ankle-brachial index ≤0.95 and without clinically recognized cardiovascular disease (CVD) were included. Participants were categorized as statins nonusers or new-users (first prescription or represcribed after at least 6 months) and matched 1:1 by inclusion date and propensity score for statin treatment. Conditional Cox proportional hazards modeling was used to compare the groups for the incidence of MACE (myocardial infarction, cardiac revascularization, and ischemic stroke) and all-cause mortality. The matched-pair cohort included 5,480 patients (mean age 67 years; 44% women) treated/nontreated with statins. The 10-year coronary heart disease risk was low (median: 6.9%). Median follow-up was 3.6 years. Incidence of MACE was 19.7 and 24.7 events per 1,000 person-years in statin new-users and nonusers, respectively. Total mortality rates also differed: 24.8 versus 30.3 per 1,000 person-years, respectively. Hazards ratios were 0.80 for MACE and 0.81 for overall mortality. The 1-year number needed to treat was 200 for MACE and 239 for all-cause mortality. Statin therapy was associated with a reduction in MACE and all-cause mortality among participants without clinical CVD but with asymptomatic peripheral arterial disease, regardless of its low CVD risk. The absolute reduction was comparable to that achieved in secondary prevention.
Abstract P014: Impact of Antihypertensive Class on Central Systolic Blood Pressure and Augmentation Index: A Meta-Analysis
Authors: Tracey J McGaughey, Emily A Fletcher, Sachin A Shah
Journal: Circulation (2015)

Introduction: New evidence suggests central systolic blood pressure (cSBP) is a superior predictor of adverse cardiovascular outcomes as compared to peripheral systolic blood pressure (pSBP). Additionally, augmentation index (AI) provides a surrogate assessment of vascular stiffness. We performed a meta-analysis to assess the impact of antihypertensive drug classes on cSBP and AI. METHODS: Search terms related to blood pressure and AI were used to identify relevant articles in PubMed, Cochrane Library and CINAHL limited to randomized trials in humans and publications in English. Appropriate data on cSBP, pSBP and AI were extracted along with other study characteristics. Weighted mean differences (WMD) between the pSBP and cSBP with 95% confidence intervals (CI) were calculated using the DerSimonian-Laird random-effects methodology. For AI, the WMD from baseline was determined. Further, the data was sorted by antihypertensive class (angiotensin converting enzyme inhibitors (ACE-Is), angiotensin II receptor blockers (ARBs), beta-blockers (BBs), calcium channel blockers (CCBs) and diuretics) to determine their impact on cSBP and AI. Subgroup analyses were performed to assess robustness of results by limiting to the fixed-effects model, a primary diagnosis of hypertension, and excluding studies with JADAD scores &lt; 3. Publication bias was assessed using the Egger’s statistic and visual inspection of funnel plots. Statistical heterogeneity was assessed using the I2 statistic. RESULTS: Fifty-one and 58 studies incorporating 4381 and 3716 unique subjects were included for cSBP and AI respectively. Overall, antihypertensives reduced pSBP more than cSBP (2.52mmHg, 95%CI 1.35 to 3.69; I2 =21.9%). ACE-Is, ARBs, CCBs and diuretics reduced cSBP and pSBP in a similar manner (-2.40mmHg, 95%CI -4.89 to 0.08; 1.12mmHg, 95%CI -2.25 to 4.49; 1.01mmHg, 95%CI -2.17 to 4.19; 0.65mmHg, 95%CI -2.47 to 3.77 respectively). BBs posed a significantly greater reduction in pSBP as compared to cSBP (5.19mmHg, 95%CI 3.21 to 7.18). The change in AI from baseline was (-3.09, 95%CI -3.90 to -2.28; I2 =84.5%). A significant reduction in AI was seen with ACE-Is, ARBs, CCB and diuretics (-5.61, 95%CI -6.95 to -4.27; -5.28, 95%CI -8.61 to -1.95; -5.36, 95%CI -6.95 to -3.77; -3.24, 95%CI -5.45 to -1.03 respectively). BBs reduced AI non-significantly (-0.32, 95% CI -1.48 to 0.84). While the Egger’s statistic showed a lack of publication bias (p&gt;0.125), it cannot be ruled out based on visual inspection of funnel plots. CONCLUSIONS: BBs are not as beneficial in reducing cSBP as opposed to ACE-Is, ARBs, CCBs and diuretics. In contrast, ACE-Is, ARBs, CCBs and diuretics significantly reduce AI, which is not evident with BB therapy. The views expressed in this material are those of the author(s), and do not reflect the official policy or position of the U.S. Government, the Department of Defense, or the Department of the Air Force.
Comparison of intratumoral loading of Flt3L/TK-recruited dendritic cells and systemic vaccination with tumor-lysate loaded dendritic cells in the stringent syngeneic CNS1 rat glioma model: Effect of temozolomide on anti-glioma immunity.
Authors: P. R. Lowenstein, Y. Mineharu, G. King, M. Candolfi, W. Xiong, H. Assi, K. Yagiz, K. Kroeger, S. Bannykh, M. Castro
Journal: Journal of Clinical Oncology (2010)

2093 Background: Conditional-cytotoxic/immuno-stimulatory therapy using adenoviruses expressing HSV1-thymidine kinase (Ad-TK) and fms-like tyrosine kinase 3 ligand (Ad-Flt3L) achieves long term survival, and immunological memory to tumor rechallenge, in > 70% of rats bearing large (> 35 mm3) intracranial syngeneic gliomas (GBM) at the time of treatment. Gene therapy induced glioma cell death induces the release of tumor antigens and HMGB1, an endogenous Toll receptor 2 agonist that is indispensable to activate DCs. We compared the efficacy of gene therapy with DC vaccination strategies. Methods: Rat bone marrow cells were cultured with recombinant human hFlt3L and hIL-6 to expand DCs. Apoptosis was induced in CNS-1 cells, and such lysates were used to load DCs, which were injected subcutaneously with CpG2006. Rats were vaccinated either before or after glioma implantation, each receiving a total of three subcutaneous DC injections. Results: DC vaccination using Flt3L-generated DCs loaded with Ad- TK/GCV treated CNS-1 lysate given prior to tumor implantation inhibited tumor growth in all animals; given 4 days after tumor implantation, it protected ∼50% of animals, and given 9 days after tumor implantation it protected 20%. Gene therapy administered 9 days after tumor implantation achieved ∼80% of long term survivors; given 4 days after tumor implantation, gene therapy achieves 100% survival. Temozolomide did not inhibit gene therapy's efficacy. Conclusions: We conclude that gene therapy was more effective in treating large established gliomas compared to DC vaccination, suggesting that combinations of gene therapy and DC-vaccination could further enhance the treatment of human tumors. No significant financial relationships to disclose.
Junior doctors to be balloted on industrial action
Authors: Tom Moberly
Journal: BMJ (2015)

Junior doctors across England will be balloted over potential industrial action in response to plans to impose a new contract on junior doctors from August 2016.

At its meeting on 26 September, the BMA’s UK Junior Doctors Committee voted not to re-enter contract negotiations and to ballot members. The BMA will release further detail about the ballot and the proposed industrial action in the coming weeks.

In a statement the BMA said that the decision was made “after it became clear that junior doctors would not be able to …