tbuckley/cabot-search huggingface dataset:
Alteration of calponin h1 expression in blood vessels of human malignant tumors
Authors: Yoko Yanagisawa, Michiko Takeoka, Takashi Ehara, Emi Ota, Shun’ichiro Taniguchi
Journal: Cancer Research (2006)

2799   Calponin h1 is an actin-binding protein, largely expressed in smooth muscle cells that regulates and stabilizes the actin filament system. Previously we reported that calponin h1-deficient (CN-/-) mice exhibited morphological fragility of the tissues, including the uterus and blood vessels. In particular, we frequently observed bleeding into the surrounding tissue from blood vessels of the ocular fundus in CN-/- mice. Recent data it was demonstrated that weak expression of calponin h1 in blood vessels within human malignant melanoma, hepatocellular carcinoma (HCC) and renal cell carcinoma. In HCC, calponin h1 expression level correlated with the disease prognosis. Though it is supposed that calponin h1 may become a useful marker for prediction of tumor metastasis or patients prognosis, there is not enough evidence about other cancers. Here we examined alteration of calponin h1 expression in blood vessels in human colon cancer and lung cancer. Forty-two cases of colon cancer were selected. Tissues from colectomy specimens were stained with monoclonal antibodies to ∈±smooth muscle actin, calponin h1 and CD34. In thirty-three cases, calponin h1 expression in blood vessels nearby/in tumor tissues was weaker than vessels distant from tumor tissues. In nine cases, calponin h1 expression between blood vessels nearby/in tumor tissues and the surrounding normal tissues was almost the same. In addition, eight of nine cases were in relatively early stages such as Dukes A, B. As for primary lung cancer, we examined twenty cases. We observed that expression of calponin h1 in blood vessels within cancer tissues in fourteen cases was weaker than normal lung tissues. Seven cases exhibited weak expression of calponin h1 even in the blood vessels of normal tissues close to cancer tissues. In particular of adenocarcinoma, it is note worthy that there was a correlation between the calponin h1 expression and the tumor differentiation. These results indicated that smooth muscle cells and/or pericytes in cancer tissues are immature, seemingly resulting in the fragility of the blood vessels advantage to cancer metastasis. We believe that not only enhanced angiogenesis in cancer tissue but also the immaturity of the blood vessels are important to understand mechanism of cancer metastasis.
Should reversibility be assessed in all asthmatic children with normal spirometry?
Authors: Edouard Dufetelle, Plamen Bokov, Christophe Delclaux, Nicole Beydon
Journal: European Respiratory Journal (2018)

Spirometry is usually normal at baseline in asthmatic children referred for pulmonary function tests (PFTs) [1]; however, a positive response to bronchodilator can be evidenced in these children [2, 3]. The detection of a significant bronchodilator response (BDR) is not meaningless as it confirms asthma and independently predicts subsequent level of forced expiratory volume in 1 s (FEV1) [4], response to inhaled corticosteroids [5] or correlates to increased exhaled NO [6]. In asthmatic children with normal baseline spirometry, a significant reversibility is detected in only 4.9% of cases <http://ow.ly/RrBK30k9WIs>
“Three-in-one” Nanohybrids as Synergistic Nanoquenchers to Enhance No-Wash Fluorescence Biosensors for Ratiometric Detection of Cancer Biomarkers
Authors: Xiaolin Huang, Zhimei He, Dan Guo, Yijing Liu, Jibin Song, Bryant C. Yung, Lisen Lin, Guocan Yu, Jun-Jie Zhu, Yonghua Xiong, Xiaoyuan Chen
Journal: Theranostics (2018)

Purpose: Early diagnosis of cancer enables extended survival and reduced symptoms. To this end, a "three-in-one" nanohybrid of MOF@AuNP@GO is designed as synergistic nanoquencher to develop a novel fluorescence biosensor for rapid and sensitive detection of cancer-related biomarkers. Methods: The ssDNA absorption affinities and fluorescence quenching abilities of the MOF@AuNP@GO were evaluated using FAM-labeled single-stranded DNA (ssDNA). Then, two specific dye-labeled ssDNA and aptamer probes were designed for the recognition of p53 gene and prostate specific antigen (PSA), respectively. Fluorescence spectra were recorded and ratiometric signal processing was performed. Results: The designed nanohybrids exhibit enhanced ssDNA binding affinities and fluorescence quenching abilities, which significantly decrease the background signal and increase the signal-to-noise (S/N) ratio, thus lowering the detection limit (LOD). Accordingly, with ratiometric measurement, this developed nanosensor can sensitively measure p53 gene and PSA with LODs of 0.005 nM and 0.01 ng mL-1, respectively. Besides, this method also displays excellent performances with respect to universality, multiplexed detection, specificity, and practicality in human serum. Conclusion: The designed MOF@AuNP@GO-based fluorescence biosensor can serve as a promising platform for washing-free, rapid and sensitive measurement of cancer biomarkers, making this method well-suited for point-of-care (POC) diagnosis.
Immunotherapy of Primary Brain Tumors: Facts and Hopes
Authors: Robin A. Buerki, Zinal S. Chheda, Hideho Okada
Journal: Clinical Cancer Research (2018)

The field of cancer immunotherapy has made exciting progress for some cancer types in recent years. However, recent failures of late-phase clinical trials evaluating checkpoint blockade in patients with glioblastoma (GBM) represent continued challenges for brain cancer immunotherapy. This is likely due to multiple factors including but not limited to marked genetic and antigenic heterogeneity, relatively low mutational loads, and paucity of GBM-infiltrating T cells. We review recent and ongoing studies targeting the checkpoint molecules as monotherapy or in combination with other modalities, and discuss the mechanisms underlying the unresponsiveness of GBM to single-modality immunotherapy approaches. We also discuss other novel immunotherapy approaches that may promote T-cell responses and overcome the "cold tumor" status of GBM, including oncolytic viruses and adoptive T-cell therapy. Clin Cancer Res; 24(21); 5198-205. ©2018 AACR.
Ado-trastuzumab emtansine (T-DM1) induced pulmonary toxicity: A retrospective analysis of a single institution experience.
Authors: Heidi Egloff, Kelley M. Kidwell, Anne F. Schott
Journal: Journal of Clinical Oncology (2018)

e13004 Background: T-DM1 is an antibody drug conjugate with proven efficacy in metastatic breast cancer for progressive disease refractory to trastuzumab. FDA prescribing information cites a pneumonitis incidence of 0.8% (7/884 cases) based on clinical trial experience. We sought to identify the incidence of this toxicity at our institution. Furthermore, we attempted to identify potential risk factors for drug induced pneumonitis and examine the clinical course leading to resolution of pulmonary symptoms. Methods: We performed a retrospective analysis of EMR data inclusive of all women and men, age 18 and older, treated with T-DM1 at out institution from 1/1/2013-11/1/2017 for breast cancer. Records were reviewed for clinical symptoms and or radiographic evidence concerning for pneumonitis. We identified variables of interest with regard to potential risk factors for toxicity. Results: Upon review, 50 patients were included, 6 (12%) of whom had radiographic and/or clinical symptoms concerning for T-DM1 induced pneumonitis. Grade 3 pneumonitis was observed in 3/6 patients. All 6 patients had metastatic or unresectable breast cancer. Out of the 6 patients, 5 (83%) had suspected pulmonary metastases, 1 (17%) had a history of underlying lung disease, and 5 (83%) had a history of prior taxane therapy. Pulmonary metastases (p=0.38), median number of treatment cycles (p=0.29), prior taxane (p=1), underlying lung disease (p=1), and hormone receptor positivity (p=0.66) did not meet statistical significance for an association with pneumonitis. Time (days) on T-DM1 did not predict for pneumonitis (p=0.32). Steroids were given in 4/6 of the cases, with a time to complete resolution of 29.6 days (range 3-81 days). Conclusions: Pneumonitis is a recognized toxicity of T-DM1. While our sample size is small, the number of events was higher than described in the literature, which may be an artifact of referral bias. Future studies with a larger sample population may detect potential risk factors for toxicity. Reassuringly, patients who received steroids with cessation of T-DM1 achieved improvement of pneumonitis and resolution of symptoms.
Assesment of cardiac effects of ado-trastuzumab emtansine through strain rate imaging in metastatic breast cancer.
Authors: Vasiliki Michalaki, George Koutroulis, Ioannis Kontis, George Frangulidis, Nikolaos Dafnios, Eleni Karvouni, Christos Papadimitriou
Journal: Journal of Clinical Oncology (2018)

e13007 Background: Human epidermal growth factor receptor- (HER2-) targeted therapy with the he antibody-drug conjugate Ado-trastuzumab emtansine (T-DM1) has revolutionized the management of HER2-positive metastatic breast cancer (MBC). Although well-tolerated , cardiotoxicity has been documented. Sequential left ventricular (LV) ejection fraction (EF) assessment has been mandated to detect myocardial dysfunction. Changes in cardiac function induced by this therapy, however, are difficult to quantitate by conventional echocacardiography. Tissue Doppler myocardial imaging (TDI) derived wall motion velocity, and strain rate (SR) have been shown to sensitively quantify abnormalities in cardiac function. The aim of this study was to determine if sensitive indices of LV dysfunction, would be useful for addressing the early detection of cardiotoxic side effects of TDM1. Methods: Patients (N = 36 median age 56.8 years) with HER2-positive MBC who had received prior therapy with a taxane plus trastuzumab, received T-DM1 at 3.6 mg/kg once every 3 weeks until disease progression. Conventional and TDI echocardiography were obtained at baseline and every 4 cycles of treatment. Segmental peak systolic longitudinal and radial velocity, SR and strain, were measured. Results: at baseline, median LV-EF was > 55 %. Median T-DM1 treatment duration was 7.0 months (range, 3-31 months; median follow-up, 12 months), with 22.5% of patients having received more than 18 cycles. There was no overall change in LV dimensions, EF and peak systolic velocity. In contrast, a significant reduction in longitudinal and radial SR and strain was found after 9 cycles (longitudinal strain -11.2% +/- 1.8% vs baseline 23 +/- 4.8%, P = .001; radial strain 28.1% +/- 6,2% vs baseline 48.3% +/- 9.5%, P < .001). Changes in radial strain appeared earlier and were more pronounced than longitudinal strain. Conclusions: In this study we confirm the clinical use of TDI parameters for early detection of TDM1 mediated cardiac dysfunction. TDI detected subtle changes of LV function after 9 cycles of therapy, earlier than conventional measures in women undergoing treatment with anti-HER2 therapy.
The Association of <i>FCGR2A</i> and <i>FCGR3A</i> polymorphisms with outcomes in cetuximab treated metastatic colorectal cancer patients: CCTG and AGITG CO.20 trial analysis.
Authors: Daniel Shepshelovich, Amanda Rose Townsend, Osvaldo Espin-Garcia, Lidija Latifovic, Christopher J. O'Callaghan, Derek J. Jonker, Dongsheng Tu, Eric Chen, Eric Morgen, Timothy Jay Price, Jeremy David Shapiro, Lillian L. Siu, Kouros Owzar, Mark J. Ratain, Michiaki Kubo, Alexander Dobrovic, Wei Xu, Taisei Mushiroda, Geoffrey Liu
Journal: Journal of Clinical Oncology (2018)

633 Background: We previously reported that the Fc-gamma receptor (FCGR) germline polymorphism in the FCGR2A gene (rs1801274; His (H) to Arg (R) substitution) but not FCGR3A (rs396991; Phe (F) to Val (V)) was associated with cetuximab benefit on overall survival (OS) in metastatic colorectal cancer patients (CCTG CO.17 trial). We performed a validation of these results in CO.20, a randomized trial of cetuximab+placebo vs. cetuximab+brivanib for metastatic, chemotherapy refractory, wild type K-RAS colorectal cancer. Methods: After genotyping DNA extracted from whole blood, the polymorphism relationships with OS and progression-free survival (PFS) were assessed using log-rank tests and hazard ratios (HR) from Cox proportional hazard models, adjusting for known prognostic factors. Results: Of 592/725 (82%) K-RAS wild type patients with available DNA and genotyping, those carrying the higher affinity FCGR2A H/H genotype (N = 165; 28%) had improved OS (HR 0.53; 95%CI:0.41-0.68) and PFS (HR 0.65; 95%CI:0.51-0.83) compared to those carrying the lower affinity R/R genotype (N = 128; 22%), corresponding to median absolute benefits of 3.7 (OS) and 3.3 months (PFS). The H/R genotype (N = 299; 50%) had intermediate outcomes. No significant associations were found between FCGR3A genotype and OS or PFS. No interaction between FCGR polymorphisms and treatment arm was observed. Patients carrying the double wild type combination of FCGR2A H/H and FCGR3A F/F genotypes (N = 45; 7.6%) had significantly better outcomes than other patients, particularly those carrying the rare (N = 11; 2%) R/R+ V/V genotype combination, corresponding to median absolute benefits of 12.5 (OS; HR 0.33 95%CI:0.16-0.68) and 4.5 (PFS; HR 0.45 95%CI:0.22-0.92) months. There were no significant associations between FCGR polymorphisms and either any grade of 3/4 toxicity or skin rash. Conclusions: In KRAS-wild type, cetuximab-treated patients, FCGR2A polymorphism was independently replicated to be associated with clinical outcome without affecting toxicity profiles. Additionally, in this large dataset, FCGR3A appears to modulate the relationship between FCGR2A polymorphism and outcome.
The Tumor Suppressor CIC Directly Regulates MAPK Pathway Genes via Histone Deacetylation
Authors: Simon Weissmann, Paul A. Cloos, Simone Sidoli, Ole N. Jensen, Steven Pollard, Kristian Helin
Journal: Cancer Research (2018)

Abstract Oligodendrogliomas are brain tumors accounting for approximately 10% of all central nervous system cancers. CIC is a transcription factor that is mutated in most patients with oligodendrogliomas; these mutations are believed to be a key oncogenic event in such cancers. Analysis of the Drosophila melanogaster ortholog of CIC, Capicua, indicates that CIC loss phenocopies activation of the EGFR/RAS/MAPK pathway, and studies in mammalian cells have demonstrated a role for CIC in repressing the transcription of the PEA3 subfamily of ETS transcription factors. Here, we address the mechanism by which CIC represses transcription and assess the functional consequences of CIC inactivation. Genome-wide binding patterns of CIC in several cell types revealed that CIC target genes were enriched for MAPK effector genes involved in cell-cycle regulation and proliferation. CIC binding to target genes was abolished by high MAPK activity, which led to their transcriptional activation. CIC interacted with the SIN3 deacetylation complex and, based on our results, we suggest that CIC functions as a transcriptional repressor through the recruitment of histone deacetylases. Independent single amino acid substitutions found in oligodendrogliomas prevented CIC from binding its target genes. Taken together, our results show that CIC is a transcriptional repressor of genes regulated by MAPK signaling, and that ablation of CIC function leads to increased histone acetylation levels and transcription at these genes, ultimately fueling mitogen-independent tumor growth. Significance: Inactivation of CIC inhibits its direct repression of MAPK pathway genes, leading to their increased expression and mitogen-independent growth. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/15/4114/F1.large.jpg. Cancer Res; 78(15); 4114–25. ©2018 AACR.
Abstract 20427: A Higher Levels Of Pcsk9 is Associated With Coronary Spotty Calcification in Patients With Acute Coronary Syndromes
Authors: Mami Watanabe, Fumiyuki Hayashi, Masahide Tokue, Raisuke Iijima, Hidehiko Hara, Masao Moroi, Masato Nakamura
Journal: Circulation (2016)

Background: Proprotein convertase subtilisin kexin type 9 (PCSK9) is recognized as a key target in the treatment of hypercholesterolemia, but its clinical utility in the management of acute coronar...
Analgesic Use and Ovarian Cancer Risk: An Analysis in the Ovarian Cancer Cohort Consortium
Authors: Britton Trabert, Elizabeth M Poole, Emily White, Kala Visvanathan, Hans-Olov Adami, Garnet L Anderson, Theodore M Brasky, Louise A Brinton, Renee T Fortner, Mia Gaudet, Patricia Hartge, Judith Hoffman-Bolton, Michael Jones, James V Lacey, Susanna C Larsson, Gerardo G Mackenzie, Leo J Schouten, Dale P Sandler, Katie O’Brien, Alpa V Patel, Ulrike Peters, Anna Prizment, Kim Robien, V Wendy Setiawan, Anthony Swerdlow, Piet A van den Brandt, Elisabete Weiderpass, Lynne R Wilkens, Alicja Wolk, Nicolas Wentzensen, Shelley S Tworoger
Journal: JNCI Journal of the National Cancer Institute (2018)

Aspirin use is associated with reduced risk of several cancers. A pooled analysis of 12 case-control studies showed a 10% decrease in ovarian cancer risk with regular aspirin use, which was stronger for daily and low-dose users. To prospectively investigate associations of analgesic use with ovarian cancer, we analyzed data from 13 studies in the Ovarian Cancer Cohort Consortium (OC3).The current study included 758 829 women who at study enrollment self-reported analgesic use, among whom 3514 developed ovarian cancer. Using Cox regression, we assessed associations between frequent medication use and risk of ovarian cancer. Dose and duration were also evaluated. All statistical tests were two-sided.Women who used aspirin almost daily (≥6 days/wk) vs infrequent/nonuse experienced a 10% reduction in ovarian cancer risk (rate ratio [RR] = 0.90, 95% confidence interval [CI] = 0.82 to 1.00, P = .05). Frequent use (≥4 days/wk) of aspirin (RR = 0.95, 95% CI = 0.88 to 1.03), nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs; RR = 1.00, 95% CI = 0.90 to 1.11), or acetaminophen (RR = 1.05, 95% CI = 0.88 to 1.24) was not associated with risk. Daily acetaminophen use (RR = 1.28, 95% CI = 1.00 to 1.65, P = .05) was associated with elevated ovarian cancer risk. Risk estimates for frequent, long-term (10+ years) use of aspirin (RR = 1.15, 95% CI = 0.98 to 1.34) or nonaspirin NSAIDs (RR = 1.19, 95% CI = 0.84 to 1.68) were modestly elevated, although not statistically significantly so.This large, prospective analysis suggests that women who use aspirin daily have a slightly lower risk of developing ovarian cancer (∼10% lower than infrequent/nonuse)-similar to the risk reduction observed in case-control analyses. The observed potential elevated risks for 10+ years of frequent aspirin and NSAID use require further study but could be due to confounding by medical indications for use or variation in drug dosing.
Potential adjustment methodology for missing data and reporting delay in the HIV Surveillance System, European Union/European Economic Area, 2015
Authors: Magdalena Rosinska, Nikos Pantazis, Janusz Janiec, Anastasia Pharris, Andrew J Amato-Gauci, Chantal Quinten, ECDC HIV
Journal: Eurosurveillance (2018)

Accurate case-based surveillance data remain the key data source for estimating HIV burden and monitoring prevention efforts in Europe. We carried out a literature review and exploratory analysis of surveillance data regarding two crucial issues affecting European surveillance for HIV: missing data and reporting delay. Initial screening showed substantial variability of these data issues, both in time and across countries. In terms of missing data, the CD4 + cell count is the most problematic variable because of the high proportion of missing values. In 20 of 31 countries of the European Union/European Economic Area (EU/EEA), CD4 + counts are systematically missing for all or some years. One of the key challenges related to reporting delays is that countries undertake specific one-off actions in effort to capture previously unreported cases, and that these cases are subsequently reported with excessive delays. Slightly different underlying assumptions and effectively different models may be required for individual countries to adjust for missing data and reporting delays. However, using a similar methodology is recommended to foster harmonisation and to improve the accuracy and usability of HIV surveillance data at national and EU/EEA levels.
Continuous metronomic temozolamide with propranolol and etodolac in recurrent globlastoma: A pilot study.
Authors: Gouri Shankar Bhattacharyya, Anantbhushan Ranade, Hemant Malhotra, Kanaka Govind Babu, Tanweer Shahid, Purvish M. Parikh, Newell F. Bascomb, Amitabha Shankar Chanda
Journal: Journal of Clinical Oncology (2014)

e13005 Background: Glioblastoma is a extremely difficult disease to treat and recurrences are extremely high. Salvage treatment is of limited value. This remains an unmet need in oncology. Methods: Since 2003 to 2012, 32 patients of recurrent glioblastoma, post radiotherapy (concomitant with Temozolamide, followed by adjuvant Temozolamide) were taken. 32 patients were above the age of 65years and of the 32 in 9 patients it was partially resected. Patients were randomized to 2 groups, Arm A - with metronomic therapy with temozolamide and Arm B - of metronomic temozolamide combined with propranolol (eccentric dosing) and etodolac, (VT-122). Propranolol was titrated to maintain heart rate around 80 per minute. The primary end point was progression free survival at 6 months. Patients were assessed by MRI using Mac Donalds criteria. DWI criteria for vascularization was used. Results: The median time to progression was 5.2 months in Arm A and in Arm B it was 8.8 months. 6 months survival was 40% and 63% respectively in Arm A & B. 1 year survival was 12% in Arm A and 22% in Arm B. 1 patient in Arm A had neutropenia, and lymphopenia. In Arm B, 1 patient had lymphopenia. Conclusions: Metronomic temozolamide is an effective therapy and addition of VT-122 (Propranolol and Etodolac) improves the results in terms of time to progression free survival as well as over all survival without any relevant toxicity.
Correction to: Latanoprostene Bunod Ophthalmic Solution 0.024%: A Review in Open-Angle Glaucoma and Ocular Hypertension
Authors: Sheridan M. Hoy
Journal: Drugs (2018)

The article Latanoprostene Bunod Ophthalmic Solution 0.024%: A Review in Open-Angle Glaucoma and Ocular Hypertension, written by Sheridan Hoy, was originally published Online First without open access