tbuckley/cabot-search huggingface dataset:
The impact of read length on quantification of differentially expressed genes and splice junction detection
Authors: Sagar Chhangawala, Gabe Rudy, Christopher E. Mason, Jeffrey A. Rosenfeld
Journal: Genome biology (2015)

Abstract Background The initial next-generation sequencing technologies produced reads of 25 or 36 bp, and only from a single-end of the library sequence. Currently, it is possible to reliably produce 300 bp paired-end sequences for RNA expression analysis. While read lengths have consistently increased, people have assumed that longer reads are more informative and that paired-end reads produce better results than single-end reads. We used paired-end 101 bp reads and trimmed them to simulate different read lengths, and also separated the pairs to produce single-end reads. For each read length and paired status, we evaluated differential expression levels between two standard samples and compared the results to those obtained by qPCR. Results We found that, with the exception of 25 bp reads, there is little difference for the detection of differential expression regardless of the read length. Once single-end reads are at a length of 50 bp, the results do not change substantially for any level up to, and including, 100 bp paired-end. However, splice junction detection significantly improves as the read length increases with 100 bp paired-end showing the best performance. We performed the same analysis on two ENCODE samples and found consistent results confirming that our conclusions have broad application. Conclusions A researcher could save substantial resources by using 50 bp single-end reads for differential expression analysis instead of using longer reads. However, splicing detection is unquestionably improved by paired-end and longer reads. Therefore, an appropriate read length should be used based on the final goal of the study.
Secreted frizzled-related protein 1 (Sfrp1) as key mediator of growth-factor induced invasion
Authors: Bettina Oehrle, Gerald Burgstaller, Martin Irmler, Stefan Dehmel, Ashley Cornett, Tiffany Hwang, Johannes Beckers, Susanne Krauss-Etschmann, Eric S. White, Silke Meiners, Oliver Eickelberg
Journal: European Respiratory Journal (2014)

Introduction/Aims

Targeting an invading fibroblast phenotype may pose a therapeutic approach for neoplastic and non-neoplastic lung diseases. We uncovered the transcriptional profile of this phenotype and identified Secreted frizzled-related protein 1 (Sfrp1), a modulator of Wnt-signaling, as novel functional target.

Methods/Results

With a collagen-based 3D invasion assay, invading and non-invading MLg 2908 (MLg) or primary human lung fibroblasts (phF) were separated after 72 or 96h of invasion and RNA of both fractions was applied to whole transcriptome analysis.

Within the profile of invading fibroblasts, Sfrp1 was the only Sfrp-isoform found to be substantially expressed and regulated. Further, the pro-fibrotic and -invasive cytokines TGFβ1 (5 ng/ml) and EGF (50 ng/ml) significantly down-regulated Sfrp1. Upstream regulator analysis (Ingenuity) identified FGF2 as putative inducer of fibroblast invasion (activation z-score 3.3) and FGF2 (10 ng/ml) significantly lowered Sfrp1 expression with a concomitant increase in invasion. Notably, Sfrp1 protein levels were found to be reduced in phF derived from lungs of ILD patients compared to lung transplant donors. Sfrp1 protein expression negatively correlated with the invading capacity of EGF-stimulated phF and staining revealed a mutual exclusion of Sfrp1 with αSMA+ phF. Consequently, specific inhibition of Sfrp1 by a diphenylsulfone-sulfonamide compound for 48h significantly augmented invasion (10.8±3.2% - 16±3.5%).

Conclusion

We postulate that reduced Sfrp1 levels pose an essential feature in the molecular signature of invading lung fibroblasts. Thus, Sfrp1 may serve as novel therapeutic target for neoplastic and non-neoplastic lung diseases.
Physicochemical properties of mucus gel in CF and healthy controls assessed by Raman spectroscopy and force-distance atomic force microscopy
Authors: Andrey Malkovskiy, Jacquelyn Zirbes, Jayakumar Rajadas, Carlos Milla
Journal: European Respiratory Journal (2013)

Current models of the basic defect in CF propose a dehydration of mucosal surfaces affecting the properties of secretions. Most studies of CF secretions have utilized sputum, which is a mix of mucus and other components. We attempted to define the properties of secreted CF mucus by studying Sub-mandibular salivary gland secretions, which have similar mucin composition to bronchial glands. Saliva was collected in 2 CF patients (DF508 homozygotes) and 4 healthy controls (HC). Mucus gel was separated by centrifugation and its properties analyzed by Raman spectroscopy and force-distance atomic force microscopy (AFM) elasticity measurements. All experiments were conducted blinded to the sample identity. Raman spectra of CF mucus showed a sharp distinct peak at 2080 cm-1, which was absent in HC. No particular signatures were found in the 400-800 cm-1 region, where disulfide bonds occur. By AFM, when small clusters of the mucus gel were probed the CF specimens exhibited higher stiffness than the HC samples. We are conducting further experiments with sharper cantilevers in order to determine if larger differences in stiffness can be detected. In addition, AFM imaging of highly-dilute mucus revealed that HC samples separated in small clusters and separate chains, in contrast to CF samples where no separate chains were observed. In conclusion, significant abnormalities in the measurable properties of gland secreted mucus from CF patients have been detected. Current work is directed at fully characterizing the peak detected by Raman spectroscopy. The Raman signature of CF mucus can be potentially used as a biomarker of the basic defect of this disease.
<i>CCR</i> 20th Anniversary Commentary: Gene-Expression Signature in Breast Cancer—Where Did It Start and Where Are We Now?
Authors: Isabelle Gingras, Christine Desmedt, Michail Ignatiadis, Christos Sotiriou
Journal: Clinical Cancer Research (2015)

Desmedt and colleagues published two articles, one in the June 1, 2007 issue, and the other in the August 15, 2008, issue of Clinical Cancer Research, that showed gene-expression signatures to be proliferation driven and time dependent, with their prognostic power decreasing with increasing follow-up years. Moreover, the articles showed that immune response is a crucial determinant of prognosis in the HER2-positive and estrogen receptor-negative/HER2-negative subtypes, providing a rationale to further explore the role of the antitumor immune response in these breast cancer subtypes.
Quantitative Studies of Antigen Expression in Cultured Murine Lymphoma Cells. I. CellSurface Antigens in “Asynchronous” Cultures2
Authors: Matko Cikes, George Klein
Journal: JNCI Journal of the National Cancer Institute (1972)

Journal Article Quantitative Studies of Antigen Expression in Cultured Murine Lymphoma Cells. I. CellSurface Antigens in “Asynchronous” Cultures Get access Matko Cikes, Matko Cikes Search for other works by this author on: Oxford Academic PubMed Google Scholar George Klein George Klein Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 49, Issue 6, December 1972, Pages 1599–1606, https://doi.org/10.1093/jnci/49.6.1599 Published: 01 December 1972 Article history Received: 12 May 1972 Accepted: 08 August 1972 Published: 01 December 1972
Relationship between exposure to pazopanib (P) and efficacy in patients (pts) with advanced renal cell carcinoma (mRCC).
Authors: B. Suttle, H. A. Ball, M. Molimard, D. Rajagopalan, R. S. Swann, R. G. Amado, L. Pandite
Journal: Journal of Clinical Oncology (2010)

3048 Background: Pazopanib (Votrient), an oral angiogenesis inhibitor targeting VEGFR, PDGFR, and c Kit, was approved recently by the US FDA for the treatment of pts with mRCC. The recommended dose of P 800mg once daily p.o. was selected based on biological and clinical effects observed in a phase (Ph) I study (Hurwitz, Clin Cancer Res 15,2009:4220). In this analysis we investigated the relationships between plasma P concentrations at week (wk) 4 and wk12 and efficacy endpoints in pts with mRCC. Methods: Pts with mRCC were treated with 800 mg P once daily in a Ph II trial (Hutson, J Clin Onc 27,2009:1). P trough concentrations (Cmin) were collected. The relationship between PFS and wk4 and wk12 Cmin was evaluated using Cox regression analysis. Next, deciles of wk4 Cmin were used as thresholds: the PFS of pts above each threshold was compared to the remaining pts using a log-rank test. Response rates (Rr= CR+PR) and tumor shrinkage (max. decrease from baseline in sum of the longest diameters) in pts whose Cmin values were above and below each threshold were also compared with Fisher exact and t-test tests, respectively. Results: Out of 225 pts, PK data were available for 205 pts at 4 wks and 185 at 12 wks. PFS was significantly correlated with wk12 plasma P log-transformed Cmin (p=0.00028) with a trend at wk4 (p=0.11). The wk4 Cmin threshold of 20.6μ g/mL (30th percentile) yielded the most significant separation of the Kaplan-Meier PFS curves. Median PFS in pts with Cmin above 20.6μ g/mL (n=143) was 49.4 wks vs. 20.3 wks for those with Cmin below (n=62, p=.0041). Pts with wk4 Cmin >20.6mg/mL compared to pts with Cmin ≤20.6mg/mL had a significantly better RR (64/143 vs. 11/62 or 45% vs.18%, p= 1.7e-5), and greater mean percent tumor shrinkage (37.8 vs. 8.8, p=2.1e-10). Conclusions: Exploratory analyses of data from a Ph II study indicate that P Cmin >20.6mg/mL at wk4 is associated with improved efficacy (PFS, RR, tumor shrinkage). The high proportion of pts with Cmin >20.6 mg/mL supports a starting dose of 800 mg P once daily. Further explorations in clinical trials are necessary to assess strategies to optimize systemic exposure to P in those patients who may not have derived clinical benefit and have a Cmin ≤20.6mg/mL Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline
Hippocampal circuit dysfunction in the Tc1 mouse model of Down syndrome
Authors: J Witton, R Padmashri, L E Zinyuk, V I Popov, I Kraev, S J Line, T P Jensen, A Tedoldi, D M Cummings, V L J Tybulewicz, E M C Fisher, D M Bannerman, A D Randall, J T Brown, F A Edwards, D A Rusakov, M G Stewart, M W Jones
Journal: Nature Neuroscience (2015)
Intracellular Components of Neoplastic and Normal Alveolar Cells From Mouse Lungs: Quantitative Ultrastructural Comparison&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: Robert E. Brooks, Bessie Adkison
Journal: JNCI Journal of the National Cancer Institute (1971)

A quantitative subcellular comparison was made of alveolar tumor cells of the mouse lung and normal alveolar cells of the same type. For this comparison, lung tumors induced in utero were harvested from a single litter of 8 strain A/He mice. For quantitation, thin sections of tumor cells and type B alveolar cells were sampled by electron microscopy. The resultant electron micrographs were measured by a square-grid overlay. Cellular elements beneath each grid corner were identified and counted. In the cytoplasm, mitochondria, cytosomes, granular endoplasmic reticulum, Golgi apparatus, multivesicular bodies, “sequestrcflen figures,” microvilli, and ground cytoplasm were counted. In the nucleus, heterochromatin, euchromatin, and nucleoli were enumerated. Approximately 3,200 2,800 µ2 of tumor cells and 2,800 µ2 of type B alveolar cells were evaluated. Type B alveolar cells showed a nucleus/cytoplasm mean ratio of 0.356 and tumor cells a mean ratio of 0.590. Significant differences were Found in all nuclear categories but only in three cytoplasmic groups. Mitochondria and function-related cytosomes occupied a greater proportion of type-B cell cytoplasm, but granular endoplasmic reticulum comprised a greater proportion of tumor cell cytoplasm. Euchromatin and nucleoli composed a greater part of tumor cell nucleoplasm. The euchromatin/heterochromatin mean ratio was 1.95 for type B cells and 3.20 for tumor cells.
Intensive weekly chemotherapy for good-prognosis patients with small-cell lung cancer.
Authors: D W Miles, H M Earl, R L Souhami, P G Harper, R Rudd, C M Ash, L James, C W Trask, J S Tobias, S G Spiro
Journal: Journal of Clinical Oncology (1991)

A weekly, intensive chemotherapy regimen has been used to treat 70 patients with small-cell lung cancer (SCLC). Forty-five patients had limited disease (LD) and 25 extensive disease (ED) with good prognostic features. The regimen consisted of cisplatin 50 mg/m2 intravenously (IV) day 1 and etoposide 75 mg/m2 IV days 1 and 2, alternating weekly with ifosfamide 2 g/m2 IV day 8 and doxorubicin 25 mg/m2 IV day 8, for a total of 12 weeks. Dose modifications were made according to defined hematologic criteria. Responding patients with limited disease subsequently received mediastinal radiotherapy. Overall response to chemotherapy was 91% with a complete response (CR) rate of 50%. Forty-five patients with limited disease (LD) achieved an overall response rate of 91% with a CR rate of 51%, and 25 patients with extensive disease (ED) achieved an overall response rate of 92% with a CR rate of 48%. Median survival for the whole group was 54 weeks (LD, 58 weeks; ED, 42 weeks). Hematologic toxicity was predictable, without the wide fluctuations in WBC count seen in conventional 3-weekly regimens. In all, one quarter of treatment courses were delayed, most frequently because of leukopenia. Dose reductions were required in 63% of cases. The average delivered dose intensity was calculated and shown to be 73% of projected. Nonhematologic toxicity was mild with nausea and vomiting being the most common. This weekly schedule of chemotherapy has proved to be active and well tolerated and is currently being compared with conventional 3-weekly chemotherapy in a randomized study.
Is spirometry less accurate than chest computed tomography in primary ciliary dyskinesia with pulmonary deterioration
Authors: Marco Maglione, Andrew Bush, Silvia Montella, Carmine Mollica, Angelo Manna, Antonietta Esposito, Virginia Mirra, Francesca Santamaria
Journal: European Respiratory Journal (2011)

Background:  Aggressive treatment of primary ciliary dyskinesia (PCD) often stabilizes spirometry over time. We hypothesized that spirometry may overestimate the degree of stability.   Methods:  Twenty PCD patients (median age, 11.6 yrs; range, 6.5-27.5 yrs) underwent spirometry and HRCT at median 2.3 yrs interval. The first evaluation was made in stable state and the second because of deterioration unresponsive to standard therapy. CT scans were scored blind by two experienced raters.   Results:  At the second evaluation, spirometry did not change while CT scores significantly worsened ( p   Age was significantly related to CT total score (r=0.5;  p =0.02). At both evaluations CT total score was related with FEV 1  Z score (r= –0.5;  p =0.015 and r= –0.7;  p = 0.001, respectively) and FVC Z score (r= –0.6;  p = 0.006 and r= -0.7;  p =0.001, respectively). No relationship was found between the change in CT scores and the change in spirometry.   Conclusions:  In PCD patients with pulmonary deterioration, spirometry may fail to detect worsening CT findings. Structural changes may progress with stable spirometry, calling into question the usefulness of serial spirometries to monitor PCD lung disease.
Adjuvant Fluorouracil, Leucovorin, and Oxaliplatin in Stage II to III Colon Cancer: Updated 10-Year Survival and Outcomes According to <i>BRAF</i> Mutation and Mismatch Repair Status of the MOSAIC Study
Authors: Thierry André, Armand de Gramont, Dewi Vernerey, Benoist Chibaudel, Franck Bonnetain, Annemilaï Tijeras-Raballand, Aurelie Scriva, Tamas Hickish, Josep Tabernero, Jean Luc Van Laethem, Maria Banzi, Eduard Maartense, Einat Shmueli, Goran U. Carlsson, Werner Scheithauer, Demetris Papamichael, Marcus Möehler, Stefania Landolfi, Pieter Demetter, Soudhir Colote, Christophe Tournigand, Christophe Louvet, Alex Duval, Jean-François Fléjou, Aimery de Gramont
Journal: Journal of Clinical Oncology (2015)

Purpose The MOSAIC (Multicenter International Study of Oxaliplatin/Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer) study has demonstrated 3-year disease-free survival (DFS) and 6-year overall survival (OS) benefit of adjuvant oxaliplatin in stage II to III resected colon cancer. This update presents 10-year OS and OS and DFS by mismatch repair (MMR) status and BRAF mutation. Methods Survival actualization after 10-year follow-up was performed in 2,246 patients with resected stage II to III colon cancer. We assessed MMR status and BRAF mutation in 1,008 formalin-fixed paraffin-embedded specimens. Results After a median follow-up of 9.5 years, 10-year OS rates in the bolus/infusional fluorouracil plus leucovorin (LV5FU2) and LV5FU2 plus oxaliplatin (FOLFOX4) arms were 67.1% versus 71.7% (hazard ratio [HR], 0.85; P = .043) in the whole population, 79.5% versus 78.4% for stage II (HR, 1.00; P = .980), and 59.0% versus 67.1% for stage III (HR, 0.80; P = .016) disease. Ninety-five patients (9.4%) had MMR-deficient (dMMR) tumors, and 94 (10.4%) had BRAF mutation. BRAF mutation was not prognostic for OS (P = .965), but dMMR was an independent prognostic factor (HR, 2.02; 95% CI, 1.15 to 3.55; P = .014). HRs for DFS and OS benefit in the FOLFOX4 arm were 0.48 (95% CI, 0.20 to 1.12) and 0.41 (95% CI, 0.16 to 1.07), respectively, in patients with stage II to III dMMR and 0.50 (95% CI, 0.25 to 1.00) and 0.66 (95% CI, 0.31 to 1.42), respectively, in those with BRAF mutation. Conclusion The OS benefit of oxaliplatin-based adjuvant chemotherapy, increasing over time and with the disease severity, was confirmed at 10 years in patients with stage II to III colon cancer. These updated results support the use of FOLFOX in patients with stage III disease, including those with dMMR or BRAF mutation.
Immunoproteasome Assembly: Cooperative Incorporation of Interferon γ (IFN-γ)–inducible Subunits
Authors: Thomas A. Griffin, Dipankar Nandi, Miguel Cruz, Hans Jörg Fehling, Luc Van Kaer, John J. Monaco, Robert A. Colbert
Journal: The Journal of Experimental Medicine (1998)

LMP2, LMP7, and MECL are interferon γ–inducible catalytic subunits of vertebrate 20S proteasomes, which can replace constitutive catalytic subunits (delta, X, and Z, respectively) during proteasome biogenesis. We demonstrate that MECL requires LMP2 for efficient incorporation into preproteasomes, and preproteasomes containing LMP2 and MECL require LMP7 for efficient maturation. The latter effect depends on the presequence of LMP7, but not on LMP7 catalytic activity. This cooperative mechanism favors the assembly of homogeneous “immunoproteasomes” containing all three inducible subunits, suggesting that these subunits act in concert to enhance proteasomal generation of major histocompatibility complex class I–binding peptides.
Prognostic Impact of Her2, Egfr, and C-Met Status on Overall Survival of Advanced Gastric Cancer Patients Treated with Standard Chemotherapy Without Trastuzumab in a First-Line Treatment: a Japanese Multicenter Collaborative Retrospective Study
Authors: E. Shinozaki, N. Fuse, Y. Kuboki, T. Kuwata, T. Nishina, S. Kadowaki, N. Machida, S. Yuki, A. Ooki, S. Kajiura, T. Kimura, T. Yamanaka, T. Sasaki, K. Shitara, A. Nagatsuma, T. Yoshino, A. Ochiai, A. Ohtsu
Journal: Annals of Oncology (2014)
Reinjury of Arterial Lesions Induces Intimal Smooth Muscle Cell Replication That Is Not Controlled by Fibroblast Growth Factor 2
Authors: Hiroyuki Koyama, Michael A. Reidy
Journal: Circulation Research (1997)

In this study we have examined the response of rat carotid arteries with intimal lesions to an angioplasty injury. Rat carotid arteries were subjected to injury with a 2F Fogarty catheter (first injury), and 28 days later the same arteries were subjected to reinjury with a 1.5-mm-diameter coronary dilation catheter (second injury) or a sham operation. After the second injury, the injured arterial surfaces were covered by a platelet monolayer, with occasional small thrombi. The size of the intimal area was significantly increased 28 days after the second injury, although the luminal area was not changed at this time. Intimal and medial cell replication, measured by 5-bromo-2 prime-deoxyuridine labeling, was significantly increased at 2 days after the second injury but was markedly reduced by 7 days. Addition of fibroblast growth factor-2 (FGF2, 60 micro g IV) did not increase smooth muscle cell (SMC) replication in arteries subjected to the second injury, and replication was not inhibited with an antibody against FGF2 (120 mg IV). Both these reagents, however, did significantly affect SMC replication in normal carotid arteries subjected to Fogarty catheter injury. In a similar manner, heparin (888 UPS units/kg body wt IV) did not inhibit cell replication after second injury, although it did suppress SMC replication after a single injury. One conclusion is that rat intimal cells in vivo are different from medial SMCs and that other, as-yet-unknown, factors are important for their proliferation.
Lung Development and Regeneration: Lung Biology in Health and Disease, Vol. 190.
Authors: R. Loddenkemper
Journal: European Respiratory Journal (2005)

Lung Development and Regeneration: Lung Biology in Health and Disease, Vol. 190.     Edited by D.J. Massaro, G. DeCarlo Massaro and P. Chambon     Published by Marcel Dekker, New York, 2004.     Pages: 593. ISBN: 0-8247-5439-5

Although its title is not fully indicative in this respect, this book focuses on two chronic diseases with disordered lung alveolar structure; chronic obstructive pulmonary disease/emphysema (COPD), which results from structure destruction, and bronchopulmonary dysplasia (BPD) of the premature neonate, which results from impaired structure development. The objective of this book is to present supportive experimental and technological means aimed at achieving remediation of both diseases. The rationale for bringing together various aspects of these …
Oxidative stress, inflammation and endothelial function in patients with combined flow of chronic obstructive pulmonary disease and arterial hypertension
Authors: Vitalii Kryvenko
Journal: European Respiratory Journal (2012)

Objective: to study oxidative stress, inflammation and endothelial function in patients with combined flow of chronic obstructive pulmonary disease (COPD) and arterial hypertension (AH).  Design and methods: 106 patients with COPD and combined flow of COPD and AH were examined. The first group was formed by patients with combined flow of COPD and AH (n=61), the second by patients with COPD (n=45). All patients underwent clinical examination, measurement of C-reactive protein (CRP), ultrasound estimation of endothelium-independent vasodilation (EINVD). As oxidative and nitrosative stress markers – the levels of spontaneous and iron induced aldehydephenylhydrazone9s (SAPH and ISAPH) and carboxyphenylhydrazone9s (SCPH and ICPH) were measured.  Results: Patients with COPD and AH had higher levels of CRP (7,1 mg/l; CI 95% 5,21 -9,22) while comparing with COPD group - CRP (5,1 mg/l; CI 95% 2,79-7,56; p=0,03). The patients with combined flow had impaired EINVD (7,5%; CI 95% 4,19-10,99) than COPD only (15,7%; CI 95% 11,79-19,63; p