tbuckley/cabot-search huggingface dataset:
Allergen presensitization drives an eosinophil-dependent arrest in lung-specific helminth development
Authors: Pedro H. Gazzinelli-Guimaraes, Rafael de Queiroz Prado, Alessandra Ricciardi, Sandra Bonne-Année, Joshua Sciurba, Erik P. Karmele, Ricardo T. Fujiwara, Thomas B. Nutman
Journal: Journal of Clinical Investigation (2019)

This study investigates the relationship between helminth infection and allergic sensitization by assessing the influence of preexisting allergy on the outcome of helminth infections, rather than the more traditional approach in which the helminth infection precedes the onset of allergy. Here we used a murine model of house dust mite-induced (HDM-induced) allergic inflammation followed by Ascaris infection to demonstrate that allergic sensitization drives an eosinophil-rich pulmonary type 2 immune response (Th2 cells, M2 macrophages, type 2 innate lymphoid cells, IL-33, IL-4, IL-13, and mucus) that directly hinders larval development and reduces markedly the parasite burden in the lungs. This effect is dependent on the presence of eosinophils, as eosinophil-deficient mice were unable to limit parasite development or numbers. In vivo administration of neutralizing antibodies against CD4 prior to HDM sensitization significantly reduced eosinophils in the lungs, resulting in the reversal of the HDM-induced Ascaris larval killing. Our data suggest that HDM allergic sensitization drives a response that mimics a primary Ascaris infection, such that CD4+ Th2-mediated eosinophil-dependent helminth larval killing in the lung tissue occurs. This study provides insight into the mechanisms underlying tissue-specific responses that drive a protective response against the early stages of the helminths prior to their establishing long-lasting infections in the host.
Association between treatment duration and mortality or relapse in adult patients with Staphylococcus aureus bacteraemia: a retrospective cohort study
Authors: M. Abbas, A. Rossel, M.E.A. de Kraker, E. von Dach, C. Marti, S. Emonet, S. Harbarth, L. Kaiser, I. Uçkay
Journal: Clinical Microbiology and Infection (2019)
Efficacy and safety of gemcitabine in combination with TH-302 compared with gemcitabine in combination with placebo in previously untreated patients with metastatic or locally advanced unresectable pancreatic adenocarcinoma: The MAESTRO trial.
Authors: Eric Van Cutsem, Robert J. Fram, Michael Schlichting, David P. Ryan
Journal: Journal of Clinical Oncology (2013)

TPS4148 Background: Tumors often consist of highly hypoxic subregions that are resistant to chemotherapy and radiotherapy. The investigational hypoxia-targeted drug TH-302 is reduced at its nitroimidazole group, and under hypoxic conditions releases the DNA alkylator bromo-isophosphoramide mustard (Br-IPM). A randomized Phase IIb trial of TH-302 in pts with metastatic or locally advanced unresectable pancreatic adenocarcinoma (PDAC) confirmed a significant PFS improvement (p=0.008) in pts treated with TH-302 at 340 mg/m 2 + gemcitabine compared with gemcitabine alone (Borad et al, ESMO 2012). Skin and mucosal toxicities, mainly Grade 1/2, and myelosuppression (thrombocytopenia, neutropenia and anemia) were the most common AEs related to TH-302 and did not lead to increases in treatment discontinuation. Grade 3/4 myelosuppression was more frequent in the TH-302 + gemcitabine arm. AEs leading to treatment discontinuation as well as non-hematological serious AEs were balanced across arms. Methods: This is a Phase III, randomized, double-blind, placebo-controlled trial (NCT01746979) of gemcitabine + TH-302 compared with gemcitabine + placebo in pts with locally advanced unresectable or metastatic PDAC. The study is designed to detect a 25% risk reduction of death with 90% power and two-sided alpha of 5%. A total of 660 pts are planned to be randomized 1:1. Key eligibility criteria include histologically or cytologically confirmed disease, no prior chemotherapy or systemic therapy (except as specified in the protocol), ECOG performance status 0 – 1, and bilirubin ≤ 1.5x upper limit of normal. Randomized pts receive TH-302 + gemcitabine or gemcitabine + placebo in 4-week cycles until progressive disease, intolerable toxicity, or pt withdrawal. The primary objective is to evaluate OS. Secondary objectives include PFS, objective response, and disease control; safety and tolerability; pt-reported QoL and pain; CA 19-9 levels and PK of TH-302; exploratory pharmacogenomic markers and potential predictive biomarkers. Enrollment to the study is ongoing. Clinical trial information: NCT01746979.
Geographic and network analysis of oncology trials: Portfolio assessment of ClinicalTrials.gov.
Authors: Steven Kunyuan Cheng, Bradford Richard Hirsch, Robert M Califf, Asba Tasneem, Kevin A. Schulman, Amy Pickar Abernethy, David M. Dilts
Journal: Journal of Clinical Oncology (2012)

6047 Background: Increasing complexity and specificity of cancer trials (CT) necessitates collaboration across the CT network to optimize research efforts. The relationship among CT sites and networks provide unique insights into improving coordination and accrual. Methods: 5971 interventional CTs registered between 2007 and 2010 were aggregated by trial and location. CTs in the Aggregate Analysis dataset from ClinicalTrials.gov (AACT) were identified using MeSH terms. The distribution of mid-phase (MP)(phase I/II,II) and late-phase (LP)(PII/III,PIII) CTs for the ten most represented cancer types by number of sites was assessed using network graph theory and geographic analysis comparing distribution of trials across metropolitan statistical areas. Results: 66,566 CT sites were identified across the sample, 59.6% were in the United States (MP: 50.2%; LP: 42.9%). Geographical availability of CTs and local cancer incidence rates were highly correlated (0.797, p≤ 0.001) but varied depending upon disease type. Network density (the degree of dyadic interconnections between sites studying similar cancer types) showed overall that MP trials were less dense with sparser interconnections among sites than LP trials. Network density of LP trials was higher for cancer types that had poorer correlation between geographic distribution of incidence and enrolling sites (-0.777, p=0.008). MP trials did not show a similar trend. Conclusions: The relationship between the distribution of CT and site location can be envisaged through geographic and network analysis of CT registry data. LP high-density networks should strive to diversify trial locations to better meet regional incidence rates. [Table: see text]
Response by Fan et al to Letter Regarding Article, “Dectin-1 Contributes to Myocardial Ischemia/Reperfusion Injury by Regulating Macrophage Polarization and Neutrophil Infiltration”
Authors: Qin Fan, Ruiyan Zhang, Xiaoxiang Yan
Journal: Circulation (2019)

we believe that studying the role of Dectin-1 in heart rhythm or cardiac conduction is important and potentially interesting, this is beyond the scope of the current study. 4We will explore its specific functions in future studies.However, Dectin-1 was found to be dispensable for the development of atherosclerosis in one study, 5 suggesting that Dectin-1 may mediate cardiac ischemia/reperfusion injury, in particular.In summary, we completely agree that understanding the specific function of macrophage subsets during cardiac injury, and the steady state, as well, will provide novel insights into our understanding of this pathophysiological process and our search for potential therapeutic strategies.
Gefitinib in combination with paclitaxel (P) and carboplatin (C) as second-line therapy for ovarian, tubal or peritoneal adenocarcinoma: Final results of a phase II study
Authors: P. Pautier, F. Joly, P. Kerbrat, P. Bougnoux, P. Fumoleau, T. Petit, O. Rixe, F. Ringeisen, C. Lhommé
Journal: Journal of Clinical Oncology (2007)

5566 Background: High EGFR expression occurs in 35–70% of primary ovarian tumors and is often associated with poor prognosis. This Phase II, open-label, non-comparative multicenter study investigated the efficacy and tolerability of gefitinib (Iressa) in combination with paclitaxel (P) and carboplatin (C) for second-line treatment of patients (pts) with ovarian, tubal or peritoneal adenocarcinoma. Methods: Women (&gt;18 years) with platinum-resistant/refractory (relapsed &lt;6 months after first-line platinum-based and P chemotherapy), or platinum-sensitive (relapsed &gt;6 months) disease were enrolled. Pts received gefitinib (500 mg/day), P (175 mg/m 2 ) and C (AUC 5) every 3 weeks for 6–8 cycles, after which pts could continue to receive gefitinib. The primary endpoint was objective response rate (ORR) assessed using RECIST or Rustin criteria. Results: Sixty-eight pts (26 resistant/refractory and 42 sensitive) were enrolled (median age [range]: 57 [34–72] years; ECOG performance status 0/1/2: 41/26/1). ORR and disease control rates were 19.2% and 69.2%, respectively, for resistant/refractory; and 61.9% and 81.0%, respectively, for sensitive pts (see table ). Grade 3/4 toxicities (in =10% pts) were neutropenia (59%), diarrhea (25%), leukopenia (22%), anemia (13%), and acne (13%). Two myelodysplastic syndromes (MDS) and one acute biphenotypic leukemia were observed during treatment. Another pt developed MDS 34 months after study treatment discontinuation. Conclusions: Gefitinib (Iressa) in combination with P and C has promising activity as second-line treatment for ovarian, tubal or peritoneal adenocarcinoma and is generally well tolerated. The hemopathies are under further investigation. [Table: see text] No significant financial relationships to disclose.
Comparison of Residual Neoplastic Plasma Cell Number Using Multicolor Flow Cytometry and Various Stages of International Myeloma Working Group-Defined Responses in Patients with Multiple Myeloma
Authors: Kentaro Narita, Hiroyuki Takamatsu, Hiroki Kobayashi, Yoshiaki Abe, Masami Takeuchi, Kosei Matsue
Journal: Blood (2017)
Ponatinib and Bosutinib Discontinuation in Chronic Myeloid Leukemia (CML): Single Center Experience
Authors: Mansour Alfayez, Hagop M. Kantarjian, Tapan M. Kadia, Guillermo Garcia-Manero, Farhad Ravandi, Gautam Borthakur, Courtney D. DiNardo, Mary B. Rios, Elias J. Jabbour, Jorge E. Cortes
Journal: Blood (2018)
Improving Global Cardiovascular Health
Authors: Sidney C. Smith
Journal: JAMA Cardiology (2019)

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Value of Ki-67 in prediction of response to neoadjuvant chemotherapy in breast cancer.
Authors: Kwanil Kim, Kyunghee Lee, Heungkyu Park
Journal: Journal of Clinical Oncology (2013)

e12025 Background: The expression of the human Ki-67 protein has been described as being associated with cellular proliferative activity. The objective of this study is to assess the potential value of Ki-67 for the prediction of therapeutic response after neoadjuvant chemotherapy in breast cancer. Methods: Sixty-eight patients who underwent anthracyclin based neoadjuvant chemotherapy between 2007 and 2012 were included for this study. The chemotherapy response was evaluated by comparing the pre- and post-neoadjuvant chemotherapy tumor size on radiologic imaging study with the tumor size at pathologic specimens according to RECIST (response evaluation criteria in solid tumors) version 1.1. We analyzed immunohistochemical(ER, PR, HER2, Ki-67, p53) profiles from both pre-neoadjuvant core biopsy and postoperative specimens to find their correlations with chemotherapy response. Results: Ten patients(14.7%) achieved pathologic complete response(pCR), 38 patients(55.9%) had pathologic partial response(pPR) and 20 patients(29.4%) had pathologic stable disease(pSD). The mean Ki-67 value of tumors with pCR was 61.0%, the Ki-67 value of tumors with pPR was 35.9%, and the Ki-67 value of tumors with pSD was 21.0%(p = 0.013). The analysis of Ki-67 values of the patients also showed that 25% of Ki-67 level is a reasonable cut-off value for defining higher Ki-67 level. In subgroup analysis, the higher Ki-67 level was significant factor of the response to neoadjuvant chemotherapy, especially in ER negative patients(p = 0.009) and HER2 negative patients(p = 0.009). In addition, the analaysis of response group showed that ER negative(p = 0.027), HER2 positive(p = 0.048), and higher Ki-67 level(p = 0.002) were predictive indicators of complete response. Conclusions: The higher Ki-67 level of breast cancer tissue may effectively indicate the higher response rate to chemotherapy and also the higher complete response rate. The results of our study suggest that the Ki-67 value before neoadjuvant chemotherapy is a predictive factor for the response to neoadjuvant chemotherapy. Moreover, the Ki-67 is a predictive factor of the pathologic complete response especially in patients with ER negative or HER2 positive.
Lack of p21/Waf-1 expression and lymphocyte infiltration in primary ovarian cancer correlate with the somatic HLA-A2 expression
Authors: E. Andersson, L. Villabona, L. Kanter, Z. Gamzatova, R. Kiessling, T. Dalianis, K. Bergfeldt, G. V. Masucci
Journal: Journal of Clinical Oncology (2007)

21059 Background: HLA-A2 allele is highly prevalent in Scandinavia and decreases with latitude in Europe. Similarly, ovarian cancer mortality decreases with latitude in European countries. We have previously shown that HLA-A2 is associated to a severe prognosis in serous adenocarcinoma of the ovary in stage III-IV. Others have shown that lack of p21/Waf-1 and lymphocyte infiltration in this tumour is correlated to poorer prognosis as well. Here we analyse a possible linkage between these variables. Methods: Thirty eight Swedish women with epithelial ovarian cancer were analyzed for the HLA-A genotype locus by PCR/sequence-specific oligonucleotide hybridization procedure (PCR/SSOP). Tissue slides from paraffin embedded tumour material were stained with haematoxylin and antibodies anti-p21 and -p53. Results: Twenty two patients were HLA-A2 positive. Fourteen of them (37%) lacked lymphocyte infiltration wich differed significantly from HLA-A2 negative patients (n=4, 11 %) (p=0.002). All of the HLA-A2 positive patients, with serous adenocarcinoma that showed absence of tumour lymphocyte infiltration, did not express p21/waf-1 (n=7 18 %). No cases in the HLA-A2 negative group with the same parameters were identified (p=0.009). Conclusions: These observations identify a high risk group of patients by linking together the somatic expression of HLA-A2 to the lack of lymphocyte infiltration and absence of p21/Waf-1 expression at the tumour level as prognostic negative factors. The information might have a relevant impact on the patient management.. In order to obtain a stronger power the analysis will be extended to a larger group of patients. No significant financial relationships to disclose.
Sensitivity of malignant mesothelioma lacking Merlin to the FAK inhibitor VS-6063: Evaluation of merlin/NF2 status in clinical samples.
Authors: Jonathan A. Pachter, Irina M Shapiro, David T. Weaver, Christian M. Vidal, Jennifer E. Ring, Mitchell Keegan, Qunli Xu, Craig Menges, Joseph R. Testa, Daniel Paterson
Journal: Journal of Clinical Oncology (2013)

e18541 Background: Malignant pleural mesothelioma (MPM) is an aggressive tumor in the pleural lining of the lung often resulting from prior exposure to asbestos. MPM patients are usually diagnosed at an advanced stage of disease and the prognosis is poor. Median survival after diagnosis is 9 to 12 months and standard-of-care agents such as cisplatin and pemetrexed have only a modest impact on median survival time for MPM patients. New therapeutic modalities are urgently needed to improve the prognosis of MPM patients. 40-50% of MPM patients exhibit homozygous disruption of the NF2 tumor suppressor gene by mutation and/or deletion resulting in lack of expression of functional merlin protein. Methods: Proliferation of drug-treated mesothelioma cell lines in 3-dimensional (3D) Matrigel culture was assessed by MTS, and MPM xenograft growth was measured in vehicle- vs. FAK inhibitor-treated SCID mice. Since absence of merlin expression can theoretically result from several mechanisms including NF2 mutation and chromosome 22 abnormalities, we assessed NF2 gene deletion by FISH and merlin protein levels by IHC in the same human mesothelioma tumor samples. Results: Among a panel of mesothelioma cell lines in 3D culture, MPM lines lacking expression of merlin protein were found to be especially sensitive to the selective FAK inhibitor VS-6063. In contrast, MPM cell lines with wildtype merlin were less sensitive with EC50 values greater than 1 μM. Accordingly, oral dosing with a FAK inhibitor induced significant tumor growth inhibition in a merlin-negative mesothelioma model in mice. To enable the planned stratification of MPM patients by merlin status, an immunohistochemistry (IHC) assay has been optimized to quantify merlin protein levels. A merlin IHC H-score below the defined cutoff was associated with loss of at least one copy of chromosome 22, indicating that chromosomal deletion is an important mechanism of merlin loss in mesothelioma patients. Conclusions: These data support the clinical development of VS-6063 for treatment of malignant pleural mesothelioma patients stratified by merlin/NF2 status. A potentially pivotal mesothelioma trial is set to initiate in 2013.
Differential expression of EGFR, HER2, P16, and high-risk (hr) HPV status in oropharyngeal (Or) and oral cavity (OC) squamous cell carcinoma (SCC).
Authors: Anne Sudaka, Esma Saada, Romain Natale, Gilles Poissonnet, Karen Benezery, Alexandre Bozec, Christophe Hebert, Olivier Dassonville, Frederic Peyrade
Journal: Journal of Clinical Oncology (2012)

5521 Background: We aimed to better characterize the expression of epidermal growth factor receptors family in Or and OC SCC and correlate it to hr HPV status and anatomoclinical features. Methods: In formalin fixed paraffin embedded tumor tissues, chromogenic in situ hybridization (CISH) was performed to detect hr HPV and immunohistochemistry to evaluate EGFR (positive score: 4 to 6), HER2 (0=negative, 1=positive) and P16 (positive score:≥70% labeled cells) expression. Baseline data were collected and analyze will be used. Results: Among 128 pts, 69 were tobacco users and 58 male. Median age at diagnosis was 61 y [23-95]. EGFR, Her2, P16 expression and hrHPV positivity were seen in 84 (65%), 12 (9%), 47 (37%) and 47 (37%) respectively. P16 signal was linked with absence of tobacco (31% vs. 72%, Pearson chi 2 test: p&lt;10 -3 ), absence of alcohol (48% vs. 83%, p&lt;10 -3 ), Or site (53% vs. 76%, p=0.005), T1 (34% vs. 19%, p=0.06), N0 (52% vs. 23%, p=0.003), absence of nodal capsular rupture (85% vs. 68%, p=0.02), WHO grade 3 (37% vs. 68%, p=0.001), hr HPV detection (17% vs. 70%, p&lt;10 -3 ). Multivariate analysis confirmed the link between P16 expression and hr HPV CISH positivity (OR=0.05, CI 95% [0.01-0.21], p&lt;10 -3 ) , absence of tobacco (OR=9.2, CI 95% [2.1-40.7], p=0.03) and N0 (OR=0.2, CI 95% [0.04- 0.75], p=0.02). EGFR signal was linked with tobacco (31% vs 78%,p=10 -3 ), alcohol (57% vs 81%, p=0.02), OC localization (77% vs 58%, p=0.03), well differentiated SCC (73% WHO grade 1-2 vs 56% grade 3, p=0.04), absence of hr HPV detection (74% vs 52%, p=0.01) and absence of P16 labeling (78% vs 44%, p&lt;10 -3 ). Multivariate analysis confirmed the link between EGFR positivity and tobacco (OR=0.32, CI 95% [0.1-0.9], p=0.03), alcohol (OR=9.5, CI 95% [1.2- 72.8], p=0.03) and OC localization (OR=0.3, CI 95% [0.1-1], p=0.05). HER2 signal was linked with alcohol (5% vs 18%, p=0.04), history of tobacco associated neoplasia (10% vs 0%, p=0.02), Or site (14% vs 2%, p=0.03) and who grade 3 (5% vs 14%, p=0.06). Her2 labeling was not associated with tobacco, sex, hr HPV detection, P16 positivity or EGFR one. Conclusions: Hr HPV associated SCC have a low expression of EGFR and are not associated with HER2 labeling.
The Thymidine Dideoxynucleoside Analogue, Alovudine, Inhibits the Mitochondrial DNA Polyermase, POLG, Impairs Oxidative Phosphorylation and Promotes Monocytic Differentiation in AML
Authors: Dana Yehudai-Ofir, Sanduni U. Liyanage, Rose Hurren, Marcela Gronda, Danny V. Jeyaraju, Xiaoming Wang, Thirushi Siriwardena, Yulia Jitkova, Aaron D. Schimmer, Biljana Rizoska, Paul Targett-Adams, Mark Albertella
Journal: Blood (2017)