tbuckley/cabot-search huggingface dataset:
Plant Proteins are Smaller Because They are Encoded by Fewer Exons than Animal Proteins
Authors: Obed Ramírez-Sánchez, Paulino Pérez-Rodríguez, Luis Delaye, Axel Tiessen
Journal: Genomics Proteomics & Bioinformatics (2016)

Abstract Protein size is an important biochemical feature since longer proteins can harbor more domains and therefore can display more biological functionalities than shorter proteins. We found remarkable differences in protein length, exon structure, and domain count among different phylogenetic lineages. While eukaryotic proteins have an average size of 472 amino acid residues (aa), average protein sizes in plant genomes are smaller than those of animals and fungi. Proteins unique to plants are ∼81 aa shorter than plant proteins conserved among other eukaryotic lineages. The smaller average size of plant proteins could neither be explained by endosymbiosis nor subcellular compartmentation nor exon size, but rather due to exon number. Metazoan proteins are encoded on average by ∼10 exons of small size [∼176 nucleotides (nt)]. Streptophyta have on average only ∼5.7 exons of medium size (∼230 nt). Multicellular species code for large proteins by increasing the exon number, while most unicellular organisms employ rather larger exons (&amp;gt;400 nt). Among subcellular compartments, membrane proteins are the largest (∼520 aa), whereas the smallest proteins correspond to the gene ontology group of ribosome (∼240 aa). Plant genes are encoded by half the number of exons and also contain fewer domains than animal proteins on average. Interestingly, endosymbiotic proteins that migrated to the plant nucleus became larger than their cyanobacterial orthologs. We thus conclude that plants have proteins larger than bacteria but smaller than animals or fungi. Compared to the average of eukaryotic species, plants have ∼34% more but ∼20% smaller proteins. This suggests that photosynthetic organisms are unique and deserve therefore special attention with regard to the evolutionary forces acting on their genomes and proteomes.
Supportive care for hand-foot syndrome and stomatitis in relapsed ovarian cancer patients receiving pegylated liposomal doxorubicin.
Authors: M. Shimada, S. Sato, T. Otsuki, T. Takano, N. Yaegashi, H. Fujiwara, M. Suzuki, S. Nagao, K. Fujiwara, Y. Yokoyama, H. Mizunuma, S. Kumagai, T. Sugiyama, H. Kurachi, K. Takizawa, M. Hiura, H. Yoshikawa, K. Takehara, K. Ochiai, J. Kigawa
Journal: Journal of Clinical Oncology (2011)

e19722 Background: Hand-foot syndrome (HFS) and stomatitis, which are the most common adverse events associated with pegylated liposomal doxorubicin (PLD), decrease quality of life (QOL) and induce treatment delay and dose reduction. We conducted this prospective study to establish more effective, safe, and well-tolerated PLD chemotherapy. Methods: Eighty-seven patients with relapsed ovarian cancer (53 platinum-resistant and 34 platinum-sensitive) were enrolled. All patients received PLD alone at dose of 50mg/m2. The supportive care for HFS was defined as follows: patients’ education, local cooling on hand and foot, pyridoxine for grade 1 HFS, and oral dexamethasone for grade 2 HFS, and those for stomatitis was defined as follows: patients’ education, azulene sodium sulfate mouthwashes, and xylocaine added mouthwashes for grade 1 stomatitis. The result of previous phase II trial for PLD in Japan was used as historical control. Results: The incidence of HFS, particularly more than grade 2, was significantly lower than that of phase II trial (Table). Stomatitis was similarly observed in this study compared with phase II trial. Grade 3 and 4 hematological toxicity did not significantly differ from that for phase II study. No grade 4 non-hematological toxicity was observed in this study. The overall response rate was 16.3%, and the disease control rate including stable disease was 71.0%. Conclusions: The supportive care for HFS defined in this study may be useful preventive strategy for patients receiving PLD chemotherapy. However, new prevention strategy for stomatitis should be necessary. The incidence of HFS and stomatitis. Grade 1 Grade 2 Grade 3 Total HFS Current study 30 (34.5%) 19 (21.8%)* 6 (6.7%)* 55 (63.2%)** Phase II 20 (27.0%) 26 (35.1%) 12 (16.2%) 58 (78.4%) Stomatitis Current study 27 (31.0%) 28 (32.2%) 8 (9.2%) 63 (72.4%) Phase II 29 (39.2%) 22 (29.7%) 6 (8.1%) 57 (77.0%) * p=0.0034; ** p=0.0361
Preclinical development of small-molecule CRM1 inhibitors as novel therapy for the treatment of colorectal cancer (CRC).
Authors: S. Shacham, M. Kauffman, V. Sandanayaka, G. Draetta, S. Shechter, J. Williams, R. Nir
Journal: Journal of Clinical Oncology (2011)

430 Background: CRM1 (XPO1) is a key nuclear export protein which controls the location of multiple tumor suppressor (TSP) and growth regulatory (GRP) proteins including p53, PI3K/AKT, Wnt/ß-catenin and NF-kB. Forced nuclear expression of TSP and GRP by CRM1 inhibition can lead to apoptosis in cancer cells while sparing normal cells. Methods: Novel small-moleculeCRM1 inhibitors were synthesized and nuclear distribution studies were performed in cells transfected with HIV-rev GFP proteins. Cell proliferation studies were performed in 16 CRC cell lines: LS-123, SW-626, Colo-201, Colo-205, Colo-320DM, Colo-320HSR, Lovo, DLD-1, HCT-15, WiDi, LS-174T, LS-180, SW-620, C2BBe1, HCT-8, HCT-116, and in human peripheral leukocytes (PBMC). Cellular distribution and apoptosis assays were performed on HCT-116. Antitumor activity is assessed in human HCT-116 xenografts in scid-mice. Results: The lead CRM1 inhibitor, KPT-0127, blocks CRM1 mediated nuclear export of HIV-Rev-GFP, FOXO, and p53 with an IC50 of ∼300 nM. KPT-0127 is cytotoxic to various CRC cell lines with EC50s of 0.07-1.1 μM; in 9 CRC lines EC50s were &lt; 0.3 mM. In contrast, normal cell lines and PBMCs had EC50 &gt; 5-20 μM. In HCT- 116 cells, KPT-0127 induces cell cycle arrest at both G1/S and G2/M checkpoints and dose dependently increases nuclear p53, followed by an increase in caspase 3. KTP-0127 10μM shows no significant effect on 37 proteins including several cysteine proteases. In mice, KPT-0127 given by SC injection of 30-100 mg/kg leads to serum levels exceeding the effective CRM1 inhibitory concentration for at least 4 hours and is well tolerated. KPT-0127 given SC to mice bearing HCT-116 colon xenografts results in dose-dependent antitumor activity. Conclusions: The novel small- molecule CRM1 inhibitor KTP-0127 kills CRC lines with multiple TSP, GRP, and oncogenic abnormalities, including p53 mutations/deletions and PTEN deficiency/AKT activation, while sparing normal cells. This likely reflects the ability of CRM1 inhibition to affect multiple critical and non-redundant regulatory pathways. These results support the development of CRM1 inhibitors for the treatment of CRC. IND-enabling CMC and toxicology work are in preparation. [Table: see text]
Surgery for Patients With Rectal Cancer—Time to Listen to the Patients and Recognize Reality
Authors: John R. T. Monson, Reza Arsalanizadeh
Journal: JAMA Oncology (2016)

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319. Rationally Designed AAV Inverted Terminal Repeats Enhance Gene Targeting
Authors: Matthew Hirsch, Jerry Wu
Journal: Molecular Therapy (2016)

Basic and clinical applications of mammalian genetic engineering rely on selective pressure and/or, ironically, DNA damage at or near the modification site to obtain relevant efficiencies. In regards to the later situation, continuously evolving endonuclease technologies remain focused on the generation of a site-specific DNA double strand break to stimulate homology directed repair (HDR). The stimulation of HDR is thus dictated by the ability of the endonuclease platform to specifically recognize its cognate site, with safety concerns dictated by its promiscuity influenced by its persistence. To eliminate the serious safety concerns associated with designer endonucleases while maintaining efficient HDR, it was hypothesized that rational modification of a viral DNA repair substrate would enhance gene editing without the requirement for induced chromosomal damage. Specifically, modifications of the adeno-associated virus (AAV) inverted terminal repeat sequence (ITR), in a viral vector context, were evaluated for stimulation of HDR in human cells. The results demonstrate an approximate 30-fold enhancement of AAV gene targeting using a particular rationally designed ITR sequence. Characterization of this event suggests that differences in the inherent ITR-initiated transcriptional activity and altered interactions with host DNA repair proteins contribute to the enhancement in HDR. The collective results demonstrate for the first time that alterations in the ITR sequence can enhance AAV gene targeting. Importantly, the refinement of such vectors may offer a safer alternative to site-specific endonuclease technologies as on- and off-target DNA cleavage concerns are eliminated.
A pragmatic review of palliative chemotherapy regimens in locally advanced or metastatic pancreatic cancer: Efficacy and experience in a single institution.
Authors: G. De Velasco, C. Gomez-Martin, I. Ghanem, E. Garralda, B. Homet, S. Hoyos, H. Cortes-Funes
Journal: Journal of Clinical Oncology (2011)

e19639 Background: Palliative chemotherapy (CT) is the mainstay in the management of advanced pancreatic adenocarcinoma (PaC). To assess the efficacy of different gemcitabine regimens in the day to day clinical practice, we conducted this retrospective cohort study from a single institution. Methods: From Jan 2005 to Dec 2009, 97 patients underwent palliative CT for locally advanced or metastatic PaC in our institution. In this study we assess the efficacy of different gemcitabine-based chemotherapies, quantifying the visits to the clinic during first line treatment as a surrogate marker of quality of life. Prognostic factors for survival were analyzed by the Cox proportional hazard model. Results: Of the 97 patients treated there were 44 (51%) males and 43 (49%) females. Age at diagnosis ranged from 38 to 85 years (mean=63, 8). Sixty five (69%) had PS 0-1, 26 (28%) PS 2, and 1 patient was treated being PS 3. Forty-five pts (46%) had locally advanced disease and 51 (53%) had metastates at diagnosis. Thirty-eight (39%) received gemcitabine monotherapy (GM) as first line treatment and 57 (58%) received gemcitabine in combinations (GC's) with erlotinib, oxaliplatin, or bevacizumab as first line treatment. Twenty-three patients (24%) received a second line treatment. Median clinic visits was 15 (one day for every 16 alive) during first-line therapy. Median progression free survival (PFS) for the 97 pts was 7.6 months with a one year survival rate of 27%. The median overall survival (OS) was 8.3 months for all patients. The median PFS was 9.3 for GC and 5.7 for GM (p=0.08) with no difference in number of hospital visits. Cox hazard model analyses revealed no thromboembolic events (p=0.01), visits number (p<0.001) and previous surgery (p=0.01) as prognostic factors. In our series there was no impact on survival according to locally advanced or metastatic PanC (p=0.25), presence of liver metastases (p=0.2), need of prosthetic devices (p=0.12), bilirubin (p=0.7) or CA19.9 levels at diagnosis (p=0.07). Conclusions: In our study GC improved PFS compared to GM and it remained the same low frequency of visits. Gem (G) G/erlotinib (E) G/BVZ/E G/oxaliplatin G/others 38 14 17 15 10 39% 14% 17% 15% 10%
355. Minicircles Show Improved Hepatic Expression of Their Transgene from a Natural Endogenous Promoter and Are Lost Upon Partial Hepatectomy Due to the Episomal Nature of the Vector
Authors: Hiu-Man Viecelli, Andrea Schlegel, Tanja Scherer, Gabirella Allegri, Martin Schleef, Cary O Harding, Johannes Häberle, Beat Thöny
Journal: Molecular Therapy (2016)

We have previously showed the successful treatment of phenylketonuria (PKU) in the PKU mouse model (C57Bl/6-Pahenu2) by using non-viral naked DNA minicircle (MC) vectors, which are devoid of any viral or bacterial sequences, upon liver-directed phenylalanine hydroxylase (Pah) gene transfer via hydrodynamic vein injection (Viecelli et al., Hepatology 2014). Here we improved the efficacy of transgene expression and investigated the fate of MC vectors in mouse liver. We found that the therapeutic doses of MCs could be significantly lowered by using a codon-optimized murine Pah cDNA in combination with a truncated 5'-intron. Moreover, when using the natural or endogenous 3.6 kb murine Pah-promoter to drive the Pah transgene, vector doses could again be lowered compared to two other "minimal" liver-specific promoters, a synthetic hybrid enhancer/promoter (P3) or the classical CBA (modified cytomegalovirus enhancer/chicken β-actin) promoter. Following 70% partial hepatectomy, MC-vector-treated PKU mice showed normal liver regeneration and blood L-Phe concentration increased to pretreatment levels, indicating that treated PKU mice had lost therapeutic MC vectors during liver regeneration. These results corroborate previous observations that MC-DNA do not integrate - or only at a very low frequency that cannot be detected by our assays - and thus express their transgene as episomal vectors. In conclusion, MC-vectors which do not have a defined size-limitation, offer a favorable safety profile due to their non-integrating behavior in combination with a (large) natural or endogenous promoter, and at the same time have the potential for long-term gene-therapy of liver defects.
Bone Marrow Stromal Cells Reverse Proapoptotic Effects of JAK2 Inhibitor Atiprimod in Cells Carrying the JAK2V617F mutation
Authors: Taghi Manshouri, Zeev Estrov, Jan Burger, Ana Livun, Ying Zhang, Shuhuang Ma, Amos Gaikwad, David Harris, Hagop M Kantarjian, Srdan Verstovsek
Journal: Blood (2008)
Notch 4 Plymorphism Associated with Risk of Aplastic Anemia.
Authors: Hee Nam Kim, Jeong-Hwa Choi, Ju-Hyun Yun, Yeo-Kyeoung Kim, Il-Kwon Lee, Deok-Hwan Yang, Myung-Geun Shin, Hoon Kook, Tai Ju Hwang, Moo-Rim Park, Deog-Yeon Jo, Jong Ho Won, HyeoungJoon Kim
Journal: Blood (2006)
Abstract 1863: Using a cell based model system to characterize CYP17A1 genetic variants
Authors: Cameron P. Capper, Jiayan Liu, Lauren McIntosh, José M. Larios, Michael D. Johnson, Paul F. Hollenberg, Richard J. Auchus, James M. Rae
Journal: Cancer Research (2015)

Abstract Androgen and estrogen steroid hormones are potent growth stimuli for both prostate and breast cancer. Cytochrome P450 17A1 (CYP17A1), a P450 monooxygenase, is required for the synthesis of these hormones and is the target of abiraterone, a drug approved for the treatment of castration-resistant prostate cancer. CYP17A1 catalyzes the 17α hydroxylation of the C21 steroids pregnenolone and progesterone and has a lyase activity that cleaves the C17-20 bond to produce the sex steroid precursors, dehydroepiandrosterone (DHEA) and androstenedione. We identified twelve nonsynonymous single nucleotide polymorphisms (SNPs) in CYP17A1 and hypothesized that the resultant amino acid changes might alter hydroxylase and lyase activity and thereby impact steroid hormone synthesis. This hypothesis was examined by transiently transfecting HEK293T cells, with either wild-type or polymorphic CYP17A1 constructs. Cells were treated for 3 hours with tritiated ([3H]) progesterone and the production of hydroxylated (OH) metabolites analyzed by HPLC. In cells transfected with wild-type CYP17A1, 8.11% and 55.5% of the [3H]-progesterone was recovered as 16-OH progesterone, and 17-OH progesterone, respectively. Using the ratio of 17-OH progesterone to 16-OH progesterone as a quantitative measure of CYP17A1 enzyme activity, wild-type CYP17A1 yields a ratio of 6.9+/- 0.05. In contrast, the SNP (rs200063521) which causes an aspartic acid to histidine amino acid change at residue 216, results in a 2.2 fold decrease in 16OH-progesterone synthesis compared to wild-type suggesting altered hydroxylase function. CYP17A1 protein expression, as determined by western blot analysis, suggests that a glycine to arginine conversion at residue 162 (rs141821705) results in decreased protein levels. Studies to further characterize the CYP17A1 variants are underway. This work could lead to a better understanding of the role of CYP17A1 SNPs in cancer progression and response to CYP17A1 targeted therapies. Citation Format: Cameron P. Capper, Jiayan Liu, Lauren McIntosh, José M. Larios, Michael D. Johnson, Paul F. Hollenberg, Richard J. Auchus, James M. Rae. Using a cell based model system to characterize CYP17A1 genetic variants. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1863. doi:10.1158/1538-7445.AM2015-1863
Association between levels of hormones implied in steroid biosynthesis pathway and activity of abiraterone acetate (AA) in patients (pts) with metastatic castration- resistant prostate cancer (mCRPC): an exploratory analysis
Authors: M. Tucci, V. Bertaglia, F. Vignani, C. Buttigliero, A. Berruti, G.V. Scagliotti, M. Di Maio
Journal: Annals of Oncology (2015)
Abstract 4580A: Metabolic activation of 3-nitrobenzanthrone by human aldo-keto reductases (AKR1C1-AKR1C4)
Authors: Jessica R. Murray, Meng Huang, Tianzhu Zang, Volker M. Arlt, Heinz H. Schmeiser, Trevor M. Penning
Journal: Cancer Research (2015)

Abstract In 2012, the International Agency for Research on Cancer (IARC) classified diesel exhaust as a Group 1 carcinogen due to sufficient evidence that exposure is associated with increased risk for lung cancer in humans. However, only a subset of individuals exposed to diesel exhaust develops cancer, indicating the need to identify the genes involved in metabolic activation of these compounds and their genetic variants. Nitro-polycyclic aromatic hydrocarbons (NO2-PAH) are a major component of diesel exhaust and require metabolic activation to exert their carcinogenic activity. A representative NO2-PAH, 3-nitrobenzanthrone (3-NBA), is metabolically activated to 3-aminobenzanthrone (3-ABA) via a 6-electron nitroreduction catalyzed by NQO1 and POR. The reaction leads to the formation of 3-aminobenzanthrone (3-ABA) derived DNA adducts which promote G to T transversions. Building upon previous data that shows human aldo-keto reductase 1C3 (AKR1C3) contains nitroreductase activity towards chemotherapeutic agents (Guise, C.P., Abbattista, M.R., et al., Cancer Res, 70(4), 2010), we chose to examine the nitroreductase activity of AKR1C1-AKR1C4 towards NO2-PAH. We have demonstrated here for the first time that AKR1C enzymes catalyze the nitroreduction of 3-NBA to 3-ABA. We monitored reactions with reverse phase HPLC coupled to in-line photo-diode-array detection (PDA) and fluorescence detection (FLD) to quantify 3-NBA and 3-ABA levels. Fluorescence and UV spectroscopy were used to validate the identity of the compounds. This method was adapted for discontinuous enzymatic assays to measure steady state kinetic parameters for the nitoreductase activity of AKR1C1-AKR1C4 and NQO1. Results indicate that the NQO1 catalyzed reduction of 3-NBA has a higher specific activity, but the combined specific activities of AKR1C catalyzed reduction may play a more significant role in the overall production of 3-ABA. These results suggest that the relative expression of NQO1 and AKR1C enzymes will determine their respective contribution to 3-NBA reduction, especially since all the aforementioned enzymes are inducible by the Nrf2-Keap1 system. This work is supported by P30E513508 and RO1 CA39504 to TMP. Citation Format: Jessica R. Murray, Meng Huang, Tianzhu Zang, Volker M. Arlt, Heinz H. Schmeiser, Trevor M. Penning. Metabolic activation of 3-nitrobenzanthrone by human aldo-keto reductases (AKR1C1-AKR1C4). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4580A. doi:10.1158/1538-7445.AM2015-4580A
Parvovirus B19 as possible triggering factor of endothelial and fibroblast alterations in systemic sclerosis
Authors: Clodoveo Ferri, Cm Magro, G Nuovo, D Giuggioli, K Zakrewska, Marco Sebastiani, Maria Teresa Mascia, A. Azzi
Journal: Annals of the Rheumatic Diseases (2004)