tbuckley/cabot-search huggingface dataset:
Abstract 261: Robust Cardioprotection Afforded by a Previously Unrecognized Link between the Unfolded Protein Response and the Hexosamine Biosynthetic Pathway
Authors: Zhao V Wang, Yingfeng Deng, Ningguo Gao, Zully Pedrozo, Dan Li, Cyndo Morales, Alfredo Criollo, Xiang Luo, Wei Tan, Nan Jiang, Mark Lehrman, Beverly Rothermel, Ann-Hwee Lee, Sergio Lavandero, Pradeep Mammen, Anwarul Ferdous, Thomas Gillette, Philipp Scherer, Joseph Hill
Journal: Circulation Research (2014)

Background: The hexosamine biosynthetic pathway (HBP) generates UDP-GlcNAc (uridine diphosphate N-acetylglucosamine) for glycan synthesis and O-linked GlcNAc (O-GlcNAc) protein modifications. Despite the established role of the HBP in glucose metabolism and multiple diseases, regulation of the HBP remains largely undefined. Methods &amp; Results: Here, we show that spliced Xbp1 (Xbp1s), the most conserved signal transducer of the unfolded protein response (UPR), is a direct transcriptional activator of the HBP. We demonstrate that the UPR triggers activation of the HBP by means of Xbp1s-dependent transcription of genes coding for key, rate-limiting enzymes. We establish that this previously unrecognized UPR-HBP axis is triggered in a variety of stress conditions known to promote O-GlcNAc modification. We go on to demonstrate that Xbp1s, acutely stimulated by ischemia/reperfusion (I/R) in heart, confers robust cardioprotection against I/R injury. We also show that HBP induction is required for this cardioprotective response. Mechanistically, HBP may mediate the adaptive branch of the UPR by activating autophagy and ER-associated degradation. Conclusion: These studies reveal that Xbp1s couples the UPR to the HBP, promoting robust cardioprotection during I/R.
"Interferon- release assays for the diagnosis of latent Mycobacterium tuberculosis infection: a systematic review and meta-analysis." R. Diel, D. Goletti, G. Ferrara, G. Bothamley, D. Cirillo, B. Kampmann, C. Lange, M. Losi, R. Markova, G.B. Migliori, A. Nienhaus, M. Ruhwald, D. Wagner, J.P. Zellweger, E. Huitric, A. Sandgren and D. Manissero. Eur Respir J 2011; 37: 88-99.
Authors: C Hewson, J Haas, N Bartlett, S Message, V Laza-Stanca, T Kebadze, G Caramori, J Zhu, M Edbrooke, L Stanciu, O Kon, A Papi, P Jeffery, M Edwards
Journal: European Respiratory Journal (2012)
Maternal phthalate exposure promotes allergic airway inflammation over 2 generations through epigenetic modifications
Authors: Susanne Jahreis, Saskia Trump, Mario Bauer, Tobias Bauer, Loreen Thürmann, Ralph Feltens, Qi Wang, Lei Gu, Konrad Grützmann, Stefan Röder, Marco Averbeck, Dieter Weichenhan, Christoph Plass, Ulrich Sack, Michael Borte, Virginie Dubourg, Gerrit Schüürmann, Jan C. Simon, Martin von Bergen, Jörg Hackermüller, Roland Eils, Irina Lehmann, Tobias Polte
Journal: Journal of Allergy and Clinical Immunology (2017)

Prenatal and early postnatal exposures to environmental factors are considered responsible for the increasing prevalence of allergic diseases. Although there is some evidence for allergy-promoting effects in children because of exposure to plasticizers, such as phthalates, findings of previous studies are inconsistent and lack mechanistic information.We investigated the effect of maternal phthalate exposure on asthma development in subsequent generations and their underlying mechanisms, including epigenetic alterations.Phthalate metabolites were measured within the prospective mother-child cohort Lifestyle and Environmental Factors and Their Influence on Newborns Allergy Risk (LINA) and correlated with asthma development in the children. A murine transgenerational asthma model was used to identify involved pathways.In LINA maternal urinary concentrations of mono-n-butyl phthalate, a metabolite of butyl benzyl phthalate (BBP), were associated with an increased asthma risk in the children. Using a murine transgenerational asthma model, we demonstrate a direct effect of BBP on asthma severity in the offspring with a persistently increased airway inflammation up to the F2 generation. This disease-promoting effect was mediated by BBP-induced global DNA hypermethylation in CD4+ T cells of the offspring because treatment with a DNA-demethylating agent alleviated exacerbation of allergic airway inflammation. Thirteen transcriptionally downregulated genes linked to promoter or enhancer hypermethylation were identified. Among these, the GATA-3 repressor zinc finger protein 1 (Zfpm1) emerged as a potential mediator of the enhanced susceptibility for TH2-driven allergic asthma.These data provide strong evidence that maternal BBP exposure increases the risk for allergic airway inflammation in the offspring by modulating the expression of genes involved in TH2 differentiation through epigenetic alterations.
Interventions to Teach Inhaler Techniques, Risk Stratification of Asthma Exacerbations with Sputum Eosinophils, and High-Dose Infusion of Magnesium Sulfate for Severe Asthma
Authors: Sebastián Rodríguez-Llamazares, Joel Arroyo-Hernández, Heber Rodríguez-Bautista, Luis Torre-Bouscoulet
Journal: American Journal of Respiratory and Critical Care Medicine (2017)
Erratum: CMC-544 (inotuzumab ozogamicin), an anti-CD22 immuno-conjugate of calicheamicin, alters the levels of target molecules of malignant B-cells
Authors: A Takeshita, N Yamakage, K Shinjo, T Ono, I Hirano, S Nakamura, K Shigeno, T Tobita, M Maekawa, H Kiyoi, T Naoe, K Ohnishi, Y Sugimoto, R Ohno
Journal: Leukemia (2009)
HER2-Overexpressing Breast Cancers Amplify FGFR Signaling upon Acquisition of Resistance to Dual Therapeutic Blockade of HER2
Authors: Ariella B. Hanker, Joan T. Garrett, Mónica Valeria Estrada, Preston D. Moore, Paula González Ericsson, James P. Koch, Emma Langley, Sharat Singh, Phillip S. Kim, Garrett M. Frampton, Eric Sanford, Philip Owens, Jennifer Becker, M. Reid Groseclose, Stephen Castellino, Heikki Joensuu, Jens Huober, Jan C. Brase, Samira Majjaj, Sylvain Brohée, David Venet, David Brown, José Baselga, Martine Piccart, Christos Sotiriou, Carlos L. Arteaga
Journal: Clinical Cancer Research (2017)

Dual blockade of HER2 with trastuzumab and lapatinib or pertuzumab has been shown to be superior to single-agent trastuzumab. However, a significant fraction of HER2-overexpressing (HER2
Genetic polymorphisms of CES2 and their functional consequences
Authors: A. Jenabian, N. Goasgen, J. P. Flinois, S. Gad, P. Beaune, P. Laurent-Puig
Journal: Journal of Clinical Oncology (2004)

2065 Background: The carboxylesterase 2 (CES2) is a key enzyme for irinotecan bioactivation. The aims of this work were i) to search for genetic polymorphisms in promoter, coding sequence and intron-exon junctions of CES2, ii) to characterize the reported SNPs in data bases and iii) to study the functional consequences of these polymorphisms. Methods: First we analysed the coding and the promoter region of CES2 by direct sequencing in a set of 60 human liver DNA. Second, the CES2 activity was measured in the cytosols and in the microsomes of the same set of human liver by spectrophotometry with the 4-Methylumbelliferyl acetate which is a human CES2 specific substrate. CES2 RNA expression was also quantified by real time PCR from RNA extracted from a subset of 31 human livers. Results: No SNP was found in the coding sequence and in intron-exon boundaries of the CES2 gene. However, 5 SNPs were identified in non coding regions: -1050 C>T, -1035 G>A, -363 C>G, 7555 G>A, 8772 A>G (allelic frequencies were respectively 2.5%, 4.2%, 10%, 11%, 3.3%). All of these SNPs were in linkage disequilibrium. The overall CES2 activity was on average 7 fold more important in cytosols than in microsomes. The range of CES2 activity in cytosols was 1 to 8.3 fold. Although a significant association was found between the −363 C/G genotype and the 7555 G/A genotype and a low level of CES2 RNA expression, no significant difference in CES2 activity was observed among the different genotypes. Conclusions: The level of CES2 activity appears to be variable between individuals but this variability is not explained by genetic polymorphisms. The study of irinotecan metabolism should continue by using a polygenic pharmacogenetic approach of other implicated enzymes. No significant financial relationships to disclose.
A toddler with a cough and wheeze refractory to treatment
Authors: Shivanthan Shanthikumar, Tommy Lwin, Chung W Chow, Joe Crameri, Jo Harrison
Journal: Thorax (2017)

A 20-month-old girl weighing 12 kg presented with 2 weeks of worsening dry cough and wheeze. Aside from respiratory symptoms she was otherwise well, without fever or weight loss. There was no history of foreign body inhalation or choking. She had no significant personal or family medical history, and her immunisations were up to date. Prior to admission she had been treated for 1 week for a community-acquired pneumonia with oral amoxicillin and roxithromycin, as well as for a first presentation asthma exacerbation with oral prednisolone (2 mg/kg) and inhaled salbutamol, three hourly. Despite these interventions no clinical improvement had been noted. On examination, her respiratory rate and oxygen saturations were normal. She had mild respiratory distress, a loud biphasic wheeze and a prolonged expiratory phase. A chest X-ray (CXR) demonstrated hyperinflation of the right lung (figure 1A). Given the suspicion of a foreign body obstructing a right-sided airway, a rigid bronchoscopy was performed which showed an isolated submucosal lesion in the right main bronchus causing airway narrowing (figure 1B). To further characterise the lesion, a CT of the chest was performed, which demonstrated a subcarinal mass (figure 1C), causing significant extrinsic compression of the distal right main bronchus and bronchus intermedius. There was no intraluminal perforation of the mass.



Figure 1 
(A) Chest X-ray at presentation showing hyperinflation of right lung. (B) Image from rigid bronchoscopy showing occlusion of right main bronchus by submucosal lesion. (C) Initial CT scan showing subcarinal mass compressing the right main bronchus. (D) Lymph node biopsy demonstrating necrosis with nuclear debris surrounded by a thin layer of caseation and epithelioid cells with occasional Langhans giant cells. (E) Repeat CT scan showing reduction in size of mass with ongoing right main bronchus compression.



The most likely differential diagnoses for a subcarinal mass in this patient include a neoplastic …
A new concept of continuous gemcitabine infusion: Fixed-dose-rate gemcitabine plus Platinum in metastatic transitional cancer –preliminary results of a phase I study
Authors: C. M. Lippert, T. Meisel, E. Becht, G. Staehler
Journal: Journal of Clinical Oncology (2004)

4641 Background: The intracellular accumulation rate of Gemcitabine (G) is saturated at a serum concentration of G of 15–20 micromol/l. A continuous infusion of 10 mg/m2/min achieves this level (26,5 +/- 9 micromol/l). Therefore we conducted a phase I study, where the standard infusion (30 min) in a 3-week schedule was replaced by the fixed-dose-rate infusion of 10mg/m2/min. Method: A phase I study was designed in cooperation with the GU-group of the german cancer society, which has two arms starting in each with G 800mg/m2/80min stepping up to 1600mg/m2/160min (d1+8) combined with Cisplatin (70mg/m2) or Carboplatin (AUC5) on day 2 dependent on renal function. A cohort of 3 patients /level was planned. Primary objectives are MTD and efficacy. DLT observed in the first cycle were defined. Between January 2002 and Sept 2003 we recruited 19 Patients with advanced or metastatic urothelium cancer. Measurable lesion, no prior chemo or radiation therapy were the most important inclusion criteria. Results: Of the 19 patients 9 started initially with G+Cis and 10 with G+Carbo. Due to decreased renal function we had to change from Cis- to Carbo after 3 cycles (800 level) in two patients with solitary kidney. Both completed 6 cycles. Mean number of cycles 4.4 (range 1–6). 6 Patients (46%) completed protocol with 6 cycles. Two DLT occurred: one grade 4 thrombopenia at the 800 level in the Carbo arm, so that 3 more patients have to be recruited; the other DLT was neutropenic fever plus grade 4 thrombopenia leading to a stop of the 1200 level in the cisplatin arm. 11 patients are evaluable for response: 2 CR, 3 PR,2 SD, 4 PD; resulting in an OR of 45%. Conclusion: The described 3-week schedule with the Fixed-Dose-Rate Gemcitabine of 10mg/m2/min is feasible. Toxicities are more frequent than in the standard infusion of 1200mg/m2/30min. Therefore the MTD for G (Cis-arm) is 1000mg/m2/100min. The recruitment for G (Carbo-arm) is ongoing but a reduced level of 800mg/m2/80min is the expected MTD due to more hematotoxicities of Carboplatin compared to Cisplatin. A randomized phase II will be planned if overall response is about 50%. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly Germany
A score based in toll-like receptors expression to predict prognostic in molecular subtypes of breast cancer treated with neoadjuvant chemotherapy (NAC).
Authors: Joseph A. Pinto, Claudio J. Flores, Priscila I. Valdiviezo, Rodolfo Velazco, MIguel Garay, Juan F. Suazo, Alfredo Aguilar, Henry Gomez, Carlos S. Vallejos
Journal: Journal of Clinical Oncology (2013)

e22165 Background: To evaluate toll-like receptors (TLRs1-9) and IRAK 1,3 and 4 expression in a breast cancer patients dataset that were treated with NAC as prognostic factors in terms of recurrence-free survival (RFS). Methods: Weretrieved normalized gene expression data from a public database (GEO: GSE25066) that includes 253 samples of breast cancer patients treated with NAC (antracyclines/taxanes) profiled with the U133A microarray. The median of RFS was 3.2 years (52 relapses observed). Distribution of molecular subtypes was: Luminal A (31.2%), Luminal B (17.4%), HER2 (7.1%), Basal (36.4%) and Normal (7.9%). We build a ratio of target gene/reference gen (ATCB) with to obtain replicable cut-points in other datasets. Levels of Gene expression were divided in three cut-points (Q1, Q2, and Q3). A cox-model was used to select gene expression cut-points with significant effects in the RFS. Results: According to molecular subtypes, there were significant differences in expression of TLR5 (higher in basal and Luminal A), TLR6 and IRAK1 (higher in basal and HER2). There were not differences of expression according to the pathologic response. The multivariate analysis shown that genes associated with the RFS were: TLR5 (HR=2.1 for the lower quartile), TLR6 (HR=2.4 for upper Q2), IRAK1 (HR=2.0 for upper quartile) and IRAK 3 (HR=2.2 for upper Q2). A TLR-Score was constructed (1 point added for each unfavorable gene-group). Cases were grouped in two categories (score 0-1 as good prognostic and score ≥ 2 as poor prognostic). There were and overall significant differences in both score-groups (poor prognostic: HR=4.9). In Basal and luminal B tumors there were significant differences (logrank test: P&lt;0.001 and P=0.014, respectively), in HER2 tumors there were differences although not significant (P=0.143). There were not differences in Luminal A tumors. Conclusions: These data support the exploration of a TLR expression-based score to predict for RFS in breast cancer treated with NAC.
Randomized, adaptive, phase II selection trial of four chemotherapy regimens in androgen independent prostate cancer (AIPC)
Authors: R. E. Millikan, P. Thall, L. Pagliaro, D. Williams, M. Brown, C. Logothetis
Journal: Journal of Clinical Oncology (2004)

4561 Background: Several chemotherapy regimens provide palliative benefit in AIPC. With the goal of efficiently selecting promising regimens for more advanced trials, we applied a novel trial design (Thall, Stat Med 19:1011, 2000) in order to analyse first- and second-line activity of 4 regimens in common use at our institution. Methods: Patients (pts) were initially randomized equally among 4 regimens: ketoconazole/doxorubicin alternating with vinblastine/estramustine (KA/VE), cyclophosphamide/vincristine/dexamethasone (CVD), paclitaxel/estramustine/etoposide (TEE) or paclitaxel/estramustine/carboplatin (TEC). After the first course, treatment was assigned adaptively, based on response as determined after each 8-week course. Criteria for continuing with a regimen at 8 weeks were: improving symptoms and PSA decline of at least 40% from baseline. Criteria for “overall success” after 16 weeks (i.e. 2 courses) were: no cancer-related symptoms, decrease of soft-tissue or visceral disease by 50%, and PSA decline of at least 80% from baseline. Pts not meeting these thresholds of success were randomized to receive a second regimen (from the remaining 3). Results: 150 pts participated from 12/1998 to 1/2003. Median follow-up for survival is 30 mo, and 95 pts (63%) have died. For all pts, the Kaplan-Meier estimates of survival at 12, 24 and 36 months were 80%, 45% and 25%. Overall success by initial treatment assignment was: TEC, 14/38; KA/VE, 6/36; TEE 9/39; CVD, 4/37. Overall success by means of second-line therapy was: TEC, 3/19; KA/VE, 5/9; TEE, 0/15; CVD, 2/16. Median survial of 44 pts (29%) with PSA response was 36 mo vs. 19 mo (p < .0001) for the 106 pts not responding. Conclusions: These results confirm response and survival previously reported for these regimens. In addition, they strongly support more advanced trials of TEC, which emerges as a deliverable regimen with clinically relevant activity, both first- and second-line. Finally, the prognostic importance of PSA response (defined as 80% reduction maintained for at least 8 weeks) was strikingly confirmed, and is an informative surrogate for clinical investigation. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abbott Laboratories; Novartis
A decade of oncology drug development: FDA-approved drug trends between 2005 and 2015.
Authors: Akwasi Asabere, Alex Bastian
Journal: Journal of Clinical Oncology (2015)

e17788 Background: The FDA has been working to get efficacious and safe drugs quickly out to patients who would benefit from them, creating different categories to speed up the review process. In oncology, where the need may be urgent, this has resulted in a substantial increase in the number of oncology approvals over the last decade. Here, we analyze marketed oncology drugs to take note of progress, and gaps, from the last decade of FDA approvals Methods: FDA drug approvals (N = 268) from 2005 to 2015 were obtained from the FDA website, from which non-oncology, pediatric, indication extensions and palliative drugs were excluded. For the remaining oncology drugs (n = 58) information about each drug, including: indication setting, target patient population, presence of a genetic biomarker, tumor type, route of administration and line-of-therapy was obtained from the FDA package insert. An analysis was conducted across all these variables to identify trends and gaps Results: The number of approved drugs doubled from 19 in the first half of decade to 39 in the 2ndhalf. More solid tumor drugs were approved in the latter half of the decade (9 vs 26) while blood tumors have stayed the same (10 vs 13). The number of biomarker-linked approvals tripled in the second half of the decade (4 vs 15) with most approvals in solid tumor drugs. The rate of monotherapy drug approvals doubled in the second half of the decade (15 vs 31) while combination drug approvals have remained consistent. No changes have been noted in the rate of approval for drugs by route of administration, line of therapy, or other features studied in this analysis Conclusions: The number of oncology drug approvals has expanded greatly over the past decade, especially for solid tumors. The approval of monotherapy and biomarker-linked drugs in cancer increased two- and three-fold in the last decade, raising optimism that novel therapies may be shifting the approach towards treating oncologic malignancies
Outpatient hematologist and oncologist perceptions of inpatient continuity visits at an urban academic medical center.
Authors: Christopher Chen, Sara DeGregorio, Margaret Soriano, Inga Tolin Lennes, Ryan Thompson, Timothy Ferris
Journal: Journal of Clinical Oncology (2017)

99 Background: In 2012, in an effort to improve continuity between inpatient and outpatient care, Massachusetts General Hospital (MGH) began sending automated email notifications to outpatient physicians when patients with whom they have an established relationship are admitted to MGH. Physicians are allowed to bill internally for a “continuity visit” if they visit their patient during an inpatient stay. We sought to study MGH hematologist and oncologist perceptions of care continuity and the efficacy of this continuity visit program. Methods: In the summer of 2015, all MGH hematology and oncology attending physicians, regardless of whether they had previously billed for a continuity visit, were provided a small financial incentive to participate in an online survey. Ninety-one of 116 physicians responded to the survey (78%). Results: Of the respondents, 74% had previously billed for a continuity visit, although others may have performed continuity visits without formally billing for them. Ninety-six percent of respondents felt that continuity visits are either highly useful or moderately useful to their patients, namely because patients view continuity visits as an expression of interest in their well-being (90%) and/or as a welcome surprise (58%). Ninety-one percent of respondents felt that continuity visits are highly or moderately useful to the inpatient team, because they are able to informally share clinical insights that improve clinical care (71%) and/or answer questions or confirm the inpatient attending’s plan of care (79%). Furthermore, 72% of respondents felt that continuity visits improve their longitudinal relationship with their patients. Lastly, 84% of respondents expressed high or moderate satisfaction with making continuity visits. Conclusions: MGH hematologists and oncologists reported that visiting their hospitalized patients is useful to inpatient care teams and their patients. A small incentive payment may encourage such continuity visits. The next step is to evaluate whether continuity visits make a difference in clinical outcomes, such as patient experience, readmissions, and inpatient length-of-stay.
Mutant Huntingtin Disrupts the Nuclear Pore Complex
Authors: Jonathan C. Grima, J. Gavin Daigle, Nicolas Arbez, Kathleen C. Cunningham, Ke Zhang, Joseph Ochaba, Charlene Geater, Eva Morozko, Jennifer Stocksdale, Jenna C. Glatzer, Jacqueline T. Pham, Ishrat Ahmed, Qi Peng, Harsh Wadhwa, Olga Pletnikova, Juan C. Troncoso, Wenzhen Duan, Solomon H. Snyder, Laura P.W. Ranum, Leslie M. Thompson, Thomas E. Lloyd, Christopher A. Ross, Jeffrey D. Rothstein
Journal: Neuron (2017)