tbuckley/cabot-search huggingface dataset:
Real-world experience of exemestane-everolimus (EXE-EVE) in elderly patients with hormone-receptor positive (HR+) metastatic breast cancer (MBC).
Authors: Stefania Redana, Elisavet Papadimitraki, David Odhiambo Okonji, Komel Khabra, Eirini Thanopoulou, Jaseela Chiramel, Panagiotis Papanastasopoulos, Andrew M. Wardley, Martin S. Hogg, Sacha Jon Howell, Giorgia Zucchini, Laura M. Kenny, Alistair E. Ring, Stephen R. D. Johnston
Journal: Journal of Clinical Oncology (2016)

576 Background: EXE-EVE significantly improved progression free survival (PFS) in patients (pts) with HR+ MBC progressing on a nonsteroidal aromatase inhibitor regardless of age, at the expenses of acceptable toxicities. The majority of elderly MBC pts have HR+ disease and EXE-EVE is a valuable treatment option. Toxicities are likely to be more frequent in non-trial populations, and tolerability in elderly pts is of particular interest. Methods: We retrospectively analysed efficacy and safety of EXE-EVE in 63 elderly ( ≥ 70 years of age) MBC pts treated at 5 UK Institutions between May 2012 and April 2015. Efficacy end points: PFS, response rate (complete CR + partial response PR), clinical benefit rate (CBR = CR + PR + stabilization ≥ 24 weeks), overall survival (OS). Safety end points: dose reductions and interruptions, toxicities. Results: Median age is 74 (range 70-85) years. 24% of pts had ECOG PS 2; 21% had bone only disease. 21% of pts received EXE-EVE as 1st line treatment for MBC, 40% as 3rd line or beyond and 21% had received prior chemotherapy for MBC. At a median follow-up of 11 months (range 1-33), median PFS and OS were 8.3 months (range 5.5-11.1) and 19.6 months (range 13.4-21.1), respectively. RR was 9.5% (95% CI: 4.2-20.0), CBR was 63.5% (95% CI: 50.0-74.6). Median exposure to EXE-EVE was 13.6 weeks (range 0.6-81.4+). Toxicities lead to dose reductions in 27% of pts and interruptions in 51% of pts. 92% of pts discontinued treatment, the main reasons being disease progression (52%) and toxicities (40%). Most frequent any grade toxicities were: stomatitis (59%, 13% grade 3), fatigue (48%), rash (24%) and non infectious pneumonitis (22%, 5% grade 3). No grade 4 toxicities occurred. Conclusions: About 23% of pts in BOLERO-2 were ≥ 70 years. Compared to an exploratory analysis of these pts, our off-study pts were more heavily pre-treated, had worse ECOG PS, and reported higher rate of any grade toxicities. However, we report similar PFS and higher CBR despite shorter exposure to treatment. Our study confirms that EXE-EVE is a valuable treatment option for elderly MBC pts in the real world, nevertheless monitoring toxicities and early dose modifications remain crucial.
Erratum to “Human liver regeneration in advanced cirrhosis is organized by the portal tree” [J Hepatol 66 (2017) 778–786]
Authors: Katalin Dezső, András Rókusz, Edina Bugyik, Armanda Szücs, András Szuák, Bence Dorogi, Mátyás Kiss, Ágnes Nemeskéri, Péter Nagy, Sándor Paku
Journal: Journal of Hepatology (2017)
Decrease of Aggregation By Platelet Impedance Aggregometry ( MULTIPLATE ) in Patients Treated with Dabigatran
Authors: Valentin Cabañas, Juan Jose Cerezo-Manchado, Faustino Garcia-Candel, Eduardo Salido, Raul Lopez-Perez, Ana Garcia-Hernandez, Merecedes Berenguer, Francesca Labbadia, Miguel Blanquer Blanquer, Jose Maria Moraleda
Journal: Blood (2016)
Association of body mass index (BMI) and stage in patients with non-small cell lung cancer harboring <i>KRAS</i> mutations.
Authors: Ananta Bhatt, Catherine Mueller, Jiang Gui, Konstantin H. Dragnev, Laura J. Tafe
Journal: Journal of Clinical Oncology (2017)

e13071 Background: Body mass index (BMI) is inversely associated with lung cancer risk, particularly in former or current smokers. KRAS mutant non-small cell lung cancer (NSCLC) has been shown to be highly associated with smoking status. Therefore, we sought to investigate the association of BMI and stage in a cohort of patients with KRAS mutant NSCLC. Methods: Patients with KRAS mutant lung cancer who underwent tumor genotyping using next generation sequencing testing were identified. BMI( kg/m 2 ) was categorized as: Underweight ( &lt; 18.5), normal weight (18.5 – 24.9), overweight (25-29.9) and obese (≥30). Chi-square and t-tests were performed to test association between stage (I vs. II+) and BMI (4 categories), and stage and BMI as a continuous variable, respectively. Results: From 5/2013 to 9/2016, 201 patients with KRAS mutant NSLC were identified. Of these, 178 (88.6%) were current or former/ever smokers (SM) and 23 (11.4%) were never smokers (NS). In the SM group, 114 were female and 64 male with a median age at diagnosis of 66.5 years (range 45-93). In the NS group, 15 were female and 8 male with a median age at diagnosis of 71.5 years (range 51-92) (age for NS vs. SM p = 0.0439). Fifty-two (25.9%) patients presented with stage I disease, 149 (74.1%) presented with advanced (stage II-IV) disease. There was no significance in the BMI at diagnosis of SM vs. NS or by sex. There was a difference (p = 0.0430) in the BMI between patients with stage I disease (mean 28.6) and patients with stage II or greater disease (mean 26.6). This was also seen in SM with stage I vs. II+ disease (p = 0.0417); however, this was no longer significant in SM when broken out by sex or in NS alone. Conclusions: We identified a significant difference in BMI in patients with KRAS mutant NSCLC with stage I vs. advance stage disease, with a higher BMI associated with early stage disease at diagnosis. The lower BMI in patients with more advanced stage may be a confounding variable explained by comorbidities, and the lung cancer itself. It is unlikely that treatment effects were a factor as the KRAS testing was done prior to initiating therapy. Further studies looking at BMI and survival analysis in patients with mutant KRAS NSCLC are warranted.
Striking Clinical, Molecular and Immunological Outcomes in Non-Human Primate Hematopoietic Stem Cell Transplantation Using a Novel OX40L Blockade Agent, KY1005, Combined with Rapamycin
Authors: Victor Tkachev, Scott N. Furlan, Ben Watkins, Betty Zheng, Daniel Hunt, Angela Panoskaltsis-Mortari, Kayla Betz, Melanie Brown, Katie Zeleski, Alison Yu, Bruce R. Blazar, Duncan Casson, Ian Kirby, Phil Bland-Ward, Leslie Kean
Journal: Blood (2016)
Therapeutic antibody targeting of Notch3 signaling prevents mural cell loss in CADASIL
Authors: Arturo I. Machuca-Parra, Alexander A. Bigger-Allen, Angie V. Sanchez, Anissa Boutabla, Jonathan Cardona-Vélez, Dhanesh Amarnani, Magali Saint-Geniez, Christian W. Siebel, Leo A. Kim, Patricia A. D’Amore, Joseph F. Arboleda-Velasquez
Journal: The Journal of Experimental Medicine (2017)

Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a neurological syndrome characterized by small vessel disease (SVD), stroke, and vascular cognitive impairment and dementia caused by mutations in NOTCH3 No therapies are available for this condition. Loss of mural cells, which encompass pericytes and vascular smooth muscle cells, is a hallmark of CADASIL and other SVDs, including diabetic retinopathy, resulting in vascular instability. Here, we showed that Notch3 signaling is both necessary and sufficient to support mural cell coverage in arteries using genetic rescue in Notch3 knockout mice. Furthermore, we show that systemic administration of an agonist Notch3 antibody prevents mural cell loss and modifies plasma proteins associated with Notch3 activity, including endostatin/collagen 18α1 and Notch3 extracellular domain in mice with the C455R mutation, a CADASIL variant associated with Notch3 loss of function. These findings open opportunities for the treatment of CADASIL and other SVDs by modulating Notch3 signaling.
Diagnosis of asthma in symptomatic children based on measures of lung function: an analysis of data from a population-based birth cohort study
Authors: Clare Murray, Philip Foden, Lesley Lowe, Hannah Durrington, Adnan Custovic, Angela Simpson
Journal: The Lancet Child & Adolescent Health (2017)

Concerns have been expressed about asthma overdiagnosis. The UK National Institute of Health and Care Excellence (NICE) proposed a new diagnostic algorithm applying four lung function measures sequentially (ratio of forced expiratory volume in 1 s [FEV
Lymphatic Endothelial Cells Control Initiation of Lymph Node Organogenesis
Authors: Lucas Onder, Urs Mörbe, Natalia Pikor, Mario Novkovic, Hung-Wei Cheng, Thomas Hehlgans, Klaus Pfeffer, Burkhard Becher, Ari Waisman, Thomas Rülicke, Jennifer Gommerman, Christopher G. Mueller, Shinichiro Sawa, Elke Scandella, Burkhard Ludewig
Journal: Immunity (2017)
Abstract P306: Maintenance of Intracellular Zinc Homeostasis Contributes to the Mechanism by Which Postconditioning Protects the Heart from Ischemia/Reperfusion Injury
Authors: Zhelong Xu, Seok Jai Kim, Juan Zhou, Jin Huh, Rachel McIntosh, David Zvara
Journal: Circulation Research (2011)

Myocardial ischemia/reperfusion causes zinc depletion and supplementation of zinc can attenuate ischemia/reperfusion injury. The purpose of this study was to determine the role of the intracellular homeostasis in the cardioprotective mechanism of ischemic postconditioning. Isolated rat hearts were subjected to 30 min regional ischemia followed by 2 h of reperfusion. Postconditioning was elicited by six cycles of 10 second reperfusion and 10 seconds ischemia. Zinc concentration was measured with inductively coupled plasma optical spectroscopy (ICPOES). Upon reperfusion cytosolic zinc levels were dramatically decreased but this was prevented by postconditioning, indicating that postconditioning can prevent reperfusion-induced zinc loss. Moreover, postconditioning could also attenuate mitochondrial zinc loss upon reperfusion. In agreement with these observations, the anti-infarct effect of postconditioning was reversed by the zinc chelator N,N,N’,N’-tetrakis-(2-pyridylmethyl) ethylenediamine (TPEN), and exogenous zinc given at reperfusion mimicked the effect of postconditioning by reducing infarct size, suggesting that intracellular zinc account for the cardioprotective effect of postconditioning. Finally, postconditioning enhanced phosphorylation of Akt, ERK, and GSK-3β upon reperfusion, and these effects of postconditioning were inhibited by TPEN, indicating that zinc may mediate the cardioprotective effect of postconditioning by activating the RISK pathway. In conclusion, these data suggest that postconditioning may protect the heart by maintaining intracellular zinc homeostasis and activation of the RISK pathway may account for zinc-mediated cardioprotection of postconditioning.
Role of the Polycomb Methyltransferase Ezh1 in Myelodysplastic Syndrome Induced By Ezh2 Insufficiency
Authors: Kazumasa Aoyama, Makiko Mochizuki-Kashio, Motohiko Oshima, Shuhei Koide, Yaeko Nakajima-Takagi, Mitsutaka Maeda, Goro Sashida, Atsushi Iwama
Journal: Blood (2016)
Identification of genes with clonal mutations for the tumorigenesis of breast cancer subtypes.
Authors: Yee Him Cheung, Jie Wu, Nevenka Dimitrova
Journal: Journal of Clinical Oncology (2017)

e13006 Background: Current analyses on somatic mutations mainly involve counting samples as either carriers or non-carriers. Such a binary approach misses to take into account the fraction of tumor cells that carry a mutation, which is a significant measure of the influence of a mutation on the overall phenotype, such as gene expressions, subtype and pathway activity. Methods: In this study, we re-analyzed the 72,084 non-synonymous somatic mutation in 16,164 genes of 817 TCGA breast cancer samples (HER2+: 65, Luminal A: 415, Luminal B: 176, Basal: 136 and Normal-like: 25) using variant allele frequency (VAF) adjusted by sample purity derived from multiple methods. We obtained a gene-based VAF by choosing the maximum VAF among all mutations found in each gene for each sample. For each breast cancer subtype, we filtered for top 100 genes with highest number of mutation carriers and then ranked them by decreasing average VAF across all samples. We assume genes with higher average VAF are more likely to harbor clonal mutations in early tumor progression. We further evaluated the Pearson correlation between VAF of genes having at least ten mutation carriers and the expression levels of ESR1, PGR and ERBB2 in Luminal A subtype. Results: The top two genes with highest VAF for each of the four subtypes are as follows: (a) HER2+: ERBB2 (VAF = 0.39 ± 0.21, n = 4), KAT6A (0.31 ± 0.09, 4), (b) Luminal A: CTCF (0.41 ± 0.19, 13), MAP2K4 (0.37 ± 0.14, 24), (c) Luminal B: MAP2K4 (0.46 ± 0.11, 5), TP53 (0.46 ± 0.17, 64), and (d) Basal: SCN10A (0.46 ± 0.29, 5), MYH9 (0.43 ± 0.16, 5). The strongest correlations for Luminal A are: (i) SPEN (corr. = 0.85, n= 14), KMT2C (0.73, 24) and DMD (0.73, 11) with ESR1, (ii) DMD (0.69, 11) and NBL1 (0.67, 10) with PGR, and (iii) TBX3 (-0.51, 12) and MUC12 (0.47, 14) with ERBB2. Conclusions: While carrier count is effective for identifying genes prone to mutations, average VAF opens another perspective for uncovering genes that tend to harbor clonal mutations. Our work shows the potential of VAF analysis for identifying driver genes, understanding tumor progression and evaluating the impact of a mutation on a patient. As future work, we may improve the VAF estimates by adjusting for copy number variations and weight each variant by pathogenicity.
Phase 1 clinical trial of carboxyamidotriazole orotate (CTO) in combination with lomustine (CCNU) for adult patients with recurrent malignant glioma (MG).
Authors: Henry S. Friedman, Katherine B. Peters, Gordana Vlahovic, Dina Randazzo, Susan Boulton, Sarah Woodring, Eric S Lipp, James Emmett Herndon, Patrick Healy, Elizabeth Miller, Rashida A. Karmali, Annick Desjardins
Journal: Journal of Clinical Oncology (2015)

e13004 Background: CTO is an oral inhibitor of non-voltage-dependent calcium signaling, which modulates several pathways (EGFR, MEK, RAS, HDAC, HSP90, WNT/B-catenin, Akt, ERK, VEGF, Bcr-Abl). We postulated that bevacizumab-naïve recurrent WHO grade III or IV MG patients (pts) may benefit from the combination of CTO with CCNU. We are reporting on phase 1 of the study. Methods: Study objectives were to assess the maximum tolerated dose (MTD), dose limiting toxicity (DLT) and activity of CTO when combined with CCNU among pts with recurrent WHO grade III or IV MG. CTO dose escalation has followed a classical 3+3 design at a dose ranging from 225-642mg/m2/day. CCNU was administered at 110 mg/m2 orally every six weeks on dose levels 1 and 2, and afterward was reduced to 82.5 mg/m2 every six weeks (dose level 2b and following levels). Pharmacokinetic sampling is performed during cycle 1 at each dose level. MRI of the brain is evaluated at baseline and every 6 weeks using RANO criteria. Results: To date, 9 pts have been enrolled on study, 4 WHO grade III MG and 5 WHO grade IV MG. Median age at enrollment is 50 (25-66) years in three females and six males. Three pts each were treated at dose levels 1 (225mg/m2/day) and 2 (293 mg/m2/day) of CTO in combination with CCNU 110 mg/m2. Due to significant hematologic toxicity of the combination, CCNU was dose-reduced to 82.5 mg/m2 starting with dose level 2b. Grade 3 or higher study-related adverse events on dose levels 1 and 2 included: lymphopenia (grade 3, n = 3), neutropenia (grade 3, n = 2), and thrombocytopenia (grade 3, n = 2, grade 4, n = 1). Grade 3 or higher study-related adverse events on dose level 2b included: lymphopenia (grade 3, n = 1) and diverticulitis (grade 3, n = 1). One DLT each was observed on dose levels 2 and 2B, grade 4 thrombocytopenia and grade 3 diverticulitis, respectively. No grade 5 study-related adverse events were observed. Conclusions: Additional patients are being enrolled on CTO at a dose of 293mg/m2/day given in combination with CCNU at 82.5mg/m2 orally and further dose escalation is anticipated to determine the Phase II dose. Clinical trial information: NCT01989052.
Sequential chemotherapy of hepatic arterial infusion of FOLFOX and FOLFIRI with intravenous bevacizumab in unresectable liver metastases from colorectal cancer after systemic chemotherapy failure.
Authors: Osamu Itano, Satoshi Itano, Hiroaki Nagamatsu, Hiromitsu Jinno, Yuko Kitagawa
Journal: Journal of Clinical Oncology (2012)

e14080 Background: At present, systemic chemotherapy is the only established treatment in patients with unresectable colorectal liver metastases (CRLM). The regimen combining irinotecan or oxaliplatin to 5-FU/LV is recommended as a first and second line treatment. However, after failure of oxaliplatin- or irinotecan-based combination chemotherapy, there is no effective regimenremained. This pilot clinical trial explored the feasibility, safety, and efficacy of sequential chemotherapy of hepatic arterial infusion of FOLFOX and FOLFIRI with Intravenous Bevacizumab in unresectable CRLM after systemic chemotherapy failure. Methods: Patients with unresectable CRLM and history of systemic chemotherapy failure were treated with HAI oxaliplatin (35 mg/m 2 2 hours: HAI-FOLFOX) or irinotecan (50 mg/m 2 2 hours: HAI-FOLFIRI) followed by 5FU (1500mg 46hours) combined with intravenous Bevacizumab (200mg 90min) and LV (200mg 2hours) every 2 weeks until disease progression. Basically, HAI-FOLFOX was applied first, and after disease progression or limiting toxicity, HAI-FOLFIRI followed when the patient was still able to receive treatment. Results: Fourteen consecutive patients (median age 65 years; mean therapeutic term of prior systemic chemotherapy regimens,533 ± 266 days) were included, of whom 11 (79%) had previously received oxaliplatin (n =5), irinotecan (n = 2), or both (n = 4). Patients received a median of 13 cycles of HAI-FOLFOX (range 4–32) and among those, 7 patients sequentially received a median of 22 cycles of HAI-FOLFIRI (range 2–42). There was no technical nonfeasibility to discontinue treatment. The regimen was generally well tolerated; the most common side effects were grade 1 fatigue, anorexia, and/or hypertension. The complete and partial response rate totaled 71.4% in this sequential therapy. Median survival time was 20.1 months. Conclusions: A sequential chemotherapy of hepatic arterial infusion of FOLFOX and FOLFIRI with intravenous bevacizumab is feasible, safe, and shows promising activity in unresectable CRLM after systemic chemotherapy failure.
Advances in the causes and management of community acquired pneumonia in adults
Authors: Richard G Wunderink, Grant Waterer
Journal: BMJ (2017)

Community acquired pneumonia remains a common cause of morbidity and mortality. Usually, the causal organism is not identified and treatment remains empiric. Recent computed tomography and magnetic resonance imaging studies have challenged the accuracy of the clinical diagnosis of pneumonia, and epidemiologic studies are changing our perspective of what causes community acquired pneumonia, especially the role of viral pathogens and the frequent finding of multiple pathogens. The past decade has seen increasing overuse of empiric coverage of meticillin resistant <i>Staphylococcus aureus</i> and antibiotic resistant Gram negative pathogens owing to inappropriate application of guidelines for healthcare associated pneumonia. Optimal treatment remains a matter for debate, especially in very sick patients, including the role of combination antibiotic therapy and corticosteroids. Pneumonia care bundles are being defined to improve outcomes. Increased recognition of both acute and long term cardiac complications is shifting our concept of pneumonia from an acute lung disease to a multisystem problem with adverse chronic health consequences.
Targeting Activated Platelets: A Unique and Potentially Universal Approach for Cancer Imaging
Authors: May Lin Yap, James D McFadyen, Xiaowei Wang, Nicholas A Zia, Jan David Hohmann, Melanie Ziegler, Yu Yao, Alan Pham, Matthew Harris, Paul S Donnelly, P Mark Hogarth, Geoffrey A Pietersz, Bock Lim, Karlheinz Peter
Journal: Theranostics (2017)

RationaleThe early detection of primary tumours and metastatic disease is vital for successful therapy and is contingent upon highly specific molecular markers and sensitive, non-invasive imaging techniques.We hypothesized that the accumulation of activated platelets within tumours is a general phenomenon and thus represents a novel means for the molecular imaging of cancer.Here we investigate a unique single chain antibody (scFv), which specifically targets activated platelets, as a novel biotechnological tool for molecular imaging of cancer.Methods The scFvGPIIb/IIIa, which binds specifically to the activated form of the platelet integrin receptor GPIIb/IIIa present on activated platelets, was conjugated to either Cy7, 64 Cu or ultrasound-enhancing microbubbles.Using the Cy7 labelled scFvGPIIb/IIIa, fluorescence imaging was performed in mice bearing four different human tumour xenograft models; SKBr3, MDA-MB-231, Ramos and HT-1080 cells.Molecular imaging via PET and ultrasound was performed using the scFvGPIIb/IIIa-64 Cu and scFvGPIIb/IIIa-microbubbles, respectively, to further confirm specific targeting of scFvGPIIb/IIIa to activated platelets in the tumour stroma.Results Using scFvGPIIb/IIIa we successfully showed specific targeting of activated platelets within the microenvironment of human tumour xenografts models via three different molecular imaging modalities.The presence of platelets within the tumour microenvironment, and as such their relevance as a molecular target epitope in cancer was further confirmed via immunofluorescence of human tumour sections of various cancer types, thus validating the translational importance of our novel approach to human disease. ConclusionOur study provides proof of concept for imaging and localization of tumours by molecular targeting activated platelets.We illustrate the utility of a unique scFv as a versatile biotechnological tool which can be conjugated to various contrast agents for molecular imaging of cancer using three different imaging modalities.These findings warrant further development of this activated platelet specific scFvGPIIb/IIIa, potentially as a universal marker for cancer diagnosis and ultimately for drug delivery in an innovative theranostic approach.
Pathological correlations between traumatic brain injury and chronic neurodegenerative diseases
Authors: Marcela Cruz-Haces, Jonathan Tang, Glen Acosta, Joseph Fernandez, Riyi Shi
Journal: Translational Neurodegeneration (2017)

Traumatic brain injury is among the most common causes of death and disability in youth and young adults. In addition to the acute risk of morbidity with moderate to severe injuries, traumatic brain injury is associated with a number of chronic neurological and neuropsychiatric sequelae including neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. However, despite the high incidence of traumatic brain injuries and the established clinical correlation with neurodegeneration, the causative factors linking these processes have not yet been fully elucidated. Apart from removal from activity, few, if any prophylactic treatments against post-traumatic brain injury neurodegeneration exist. Therefore, it is imperative to understand the pathophysiological mechanisms of traumatic brain injury and neurodegeneration in order to identify potential factors that initiate neurodegenerative processes. Oxidative stress, neuroinflammation, and glutamatergic excitotoxicity have previously been implicated in both secondary brain injury and neurodegeneration. In particular, reactive oxygen species appear to be key in mediating molecular insult in neuroinflammation and excitotoxicity. As such, it is likely that post injury oxidative stress is a key mechanism which links traumatic brain injury to increased risk of neurodegeneration. Consequently, reactive oxygen species and their subsequent byproducts may serve as novel fluid markers for identification and monitoring of cellular damage. Furthermore, these reactive species may further serve as a suitable therapeutic target to reduce the risk of post-injury neurodegeneration and provide long term quality of life improvements for those suffering from traumatic brain injury.