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1
Calvo, Olga, Nathalie Grandin, Antonio Jordán-Pla, Esperanza Miñambres, Noelia González-Polo, José E. Pérez-Ortín, and Michel Charbonneau. "The telomeric Cdc13–Stn1–Ten1 complex regulates RNA polymerase II transcription." Nucleic Acids Research 47, no. 12 (April 22, 2019): 6250–68. http://dx.doi.org/10.1093/nar/gkz279.
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Abstract Specialized telomeric proteins have an essential role in maintaining genome stability through chromosome end protection and telomere length regulation. In the yeast Saccharomyces cerevisiae, the evolutionary conserved CST complex, composed of the Cdc13, Stn1 and Ten1 proteins, largely contributes to these functions. Here, we report genetic interactions between TEN1 and several genes coding for transcription regulators. Molecular assays confirmed this novel function of Ten1 and further established that it regulates the occupancies of RNA polymerase II and the Spt5 elongation factor within transcribed genes. Since Ten1, but also Cdc13 and Stn1, were found to physically associate with Spt5, we propose that Spt5 represents the target of CST in transcription regulation. Moreover, CST physically associates with Hmo1, previously shown to mediate the architecture of S-phase transcribed genes. The fact that, genome-wide, the promoters of genes down-regulated in the ten1-31 mutant are prefentially bound by Hmo1, leads us to propose a potential role for CST in synchronizing transcription with replication fork progression following head-on collisions.
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Cho, Il-Je, Doyeon Kim, Eun-Ok Kim, Kyung-Hwan Jegal, Jae-Kwang Kim, Sang-Mi Park, Rongjie Zhao, Sung-Hwan Ki, Sang-Chan Kim, and Sae-Kwang Ku. "Cystine and Methionine Deficiency Promotes Ferroptosis by Inducing B-Cell Translocation Gene 1." Antioxidants 10, no. 10 (September 28, 2021): 1543. http://dx.doi.org/10.3390/antiox10101543.
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Ferroptosis is a type of programmed necrosis triggered by iron-dependent lipid peroxidation. We investigated the role of B-cell translocation gene 1 (BTG1) in cystine and methionine deficiency (CST/Met (−))-mediated cell death. CST/Met (−) depleted reduced and oxidized glutathione in hepatocyte-derived cells, increased prostaglandin-endoperoxide synthase 2 expression, and promoted reactive oxygen species accumulation and lipid peroxidation, as well as necrotic cell death. CST/Met (−)-mediated cell death and lipid peroxidation was specifically inhibited by pretreatment with ferroptosis inhibitors. In parallel with cell death, CST/Met (−) blocked global protein translation and increased the expression of genes associated with the integrated stress response. Moreover, CST/Met (−) significantly induced BTG1 expression. Using a BTG1 promoter-harboring reporter gene and siRNA, activating transcription factor 4 (ATF4) was identified as an essential transcription factor for CST/Met (−)-mediated BTG1 induction. Although knockout of BTG1 in human HAP1 cells did not affect the accumulation of reactive oxygen species induced by CST/Met (−), BTG1 knockout significantly decreased the induction of genes associated with the integrated stress response, and reduced lipid peroxidation and cell death in response to CST/Met (−). The results demonstrate that CST/Met (−) induces ferroptosis by activating ATF4-dependent BTG1 induction.
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Brockmann, Kathrin, Stefanie Lerche, Sarah Selina Dilger, Johannes Georg Stirnkorb, Anja Apel, Ann-Kathrin Hauser, Inga Liepelt-Scarfone, et al. "SNPs in Aβ clearance proteins." Neurology 89, no. 23 (November 8, 2017): 2335–40. http://dx.doi.org/10.1212/wnl.0000000000004705.
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Objective:To evaluate whether genetic variants in β-amyloid (Aβ) clearance proteins are associated with CSF levels of Aβ1-42 on a biological level and the onset of dementia on a clinical level in Parkinson disease (PD).Methods:We analyzed genetic variants known to be involved in Aβ clearance in a PD group comprising 456 patients, 103 of them with dementia. Single nucleotide polymorphisms in the genes APOE, cystatin C (CST), and membrane metalloendopeptidase (MME) were evaluated in relation to demographic variables, clinical phenotypes, and CSF Aβ1-42 levels using a cross-sectional approach.Results:Risk variants in the genes APOE and CST were associated with lower CSF Aβ1-42 levels. Clinically, patients with 2 risk alleles in CST tended to show a shorter interval from age at onset of PD to age at onset of dementia.Conclusions:This study suggests that genetic variants associated with Aβ clearance are involved in the pathogenesis of dementia in PD and possibly influence the onset of dementia.
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Dickinson, D. P., M. Thiesse, L. D. Dempsey, and S. J. Millar. "Genomic Cloning, Physical Mapping, and Expression of Human Type 2 Cystatin Genes." Critical Reviews in Oral Biology & Medicine 4, no. 3 (April 1993): 573–80. http://dx.doi.org/10.1177/10454411930040034401.
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Humans carry one gene encoding cystatin C and six to eight genes with homology to an S-like cystatin hybridization probe. However, the precise composition and organization of the cystatin gene family remains to be established. Further, the pattern of tissue-specific expression has not been fully defined. We have previously shown that the type 2 cystatin genes are clustered together in a ca. 270 kb region (the CST locus). To determine the structure of this region, we have sought to clone the entire CST locus. Our approach has been to isolate cosmid and lambda genomic clones carrying cystatin genes and then to use "walk" probes derived from the end regions of these clones to identify other clones, which extend them. To date, we have obtained over 320 kb of distinct sequences. Based on restriction maps, sequencing, and hybridization analyses, we have identified eight apparently nonallelic copies of cystatin genes. These include one gene for cystatin C, four closely related genes encoding S-like cystatins, and three genes encoding relatively divergent sequences. Complete assembly of these clones into an unambiguous contiguous sequence is hampered by the presence of flanking locus-specific repetitive-like sequences. RNase protection assays used to characterize the tissue-specific patterns of expression showed that cystatin C is expressed at modest, comparable levels in all tissues examined, whereas expression of the CST 1 gene, encoding cystatin SA-I, was found to be restricted to a small subset of tissues, with the highest level in the submandibular gland. The cystatin gene family, therefore, appears to have evolved by tandem gene duplication, followed by the acquisition of control elements influencing the location and level of expression. The cystatin gene family is, thus, a potentially powerful system for the future study of mechanisms of gene regulation in human salivary glands.
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Boltz, Kara A., Katherine Leehy, Xiangyu Song, Andrew D. Nelson, and Dorothy E. Shippen. "ATR cooperates with CTC1 and STN1 to maintain telomeres and genome integrity in Arabidopsis." Molecular Biology of the Cell 23, no. 8 (April 15, 2012): 1558–68. http://dx.doi.org/10.1091/mbc.e11-12-1002.
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The CTC1/STN1/TEN1 (CST) complex is an essential constituent of plant and vertebrate telomeres. Here we show that CST and ATR (ataxia telangiectasia mutated [ATM] and Rad3-related) act synergistically to maintain telomere length and genome stability in Arabidopsis. Inactivation of ATR, but not ATM, temporarily rescued severe morphological phenotypes associated with ctc1 or stn1. Unexpectedly, telomere shortening accelerated in plants lacking CST and ATR. In first-generation (G1) ctc1 atr mutants, enhanced telomere attrition was modest, but in G2 ctc1 atr, telomeres shortened precipitously, and this loss coincided with a dramatic decrease in telomerase activity in G2 atr mutants. Zeocin treatment also triggered a reduction in telomerase activity, suggesting that the prolonged absence of ATR leads to a hitherto-unrecognized DNA damage response (DDR). Finally, our data indicate that ATR modulates DDR in CST mutants by limiting chromosome fusions and transcription of DNA repair genes and also by promoting programmed cell death in stem cells. We conclude that the absence of CST in Arabidopsis triggers a multifaceted ATR-dependent response to facilitate maintenance of critically shortened telomeres and eliminate cells with severe telomere dysfunction.
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Büdel, Thomas, Esther Kuenzli, Mathieu Clément, Odette J. Bernasconi, Jan Fehr, Ali Haji Mohammed, Nadir Khatib Hassan, Jakob Zinsstag, Christoph Hatz, and Andrea Endimiani. "Polyclonal gut colonization with extended-spectrum cephalosporin- and/or colistin-resistant Enterobacteriaceae: a normal status for hotel employees on the island of Zanzibar, Tanzania." Journal of Antimicrobial Chemotherapy 74, no. 10 (July 30, 2019): 2880–90. http://dx.doi.org/10.1093/jac/dkz296.
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Abstract Objectives For low-income countries, data regarding the intestinal colonization with extended-spectrum cephalosporin-resistant (ESC-R) and colistin-resistant (CST-R) Enterobacteriaceae in the community are still scarce. Here, we investigated this phenomenon by analysing hotel employees in Zanzibar. Methods During June to July 2018, rectal swabs from 59 volunteers were screened implementing selective enrichments and agar plates. Species identification was achieved using MALDI-TOF MS. Strains were characterized using microdilution panels (MICs), microarray, PCRs for mcr-1/-8, repetitive extragenic palindromic-PCR (rep-PCR) and WGS. Results Colonization prevalence with ESC-R-, CST-R- and mcr-1-positive Enterobacteriaceae were 91.5%, 66.1% and 18.6%, respectively (average: 2.2 strains per volunteer). Overall, 55 ESC-R Escherichia coli (3 also CST-R), 33 ESC-R Klebsiella pneumoniae (1 also CST-R), 17 CST-R E. coli and 21 CST-R K. pneumoniae were collected. The following main resistance genes were found: ESC-R E. coli (blaCTX-M-15-like, 51.0%), ESC-R K. pneumoniae (blaCTX-M-9-like, 42.9%), CST-R E. coli (mcr-1, 55%) and CST-R K. pneumoniae (D150G substitution in PhoQ). ESBL-producing E. coli mainly belonged to ST361, ST636 and ST131, whereas all those that were mcr-1 positive belonged to ST46 that carried mcr-1 in a 33 kb IncX4 plasmid. ESBL-producing K. pneumoniae mainly belonged to ST17, ST1741 and ST101, whereas CST-R strains belonged to ST11. Conclusions We recorded remarkably high colonization prevalence with ESC-R and/or CST-R Enterobacteriaceae in hotel staff. Further research in the local environment, livestock and food chain is warranted to understand this phenomenon. Moreover, as Zanzibar is a frequent holiday destination, attention should be paid to the risk of international travellers becoming colonized and thereby importing life-threatening pathogens into their low-prevalence countries.
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Takahashi, Tadanobu, Kouki Murakami, Momoe Nagakura, Hideyuki Kishita, Shinya Watanabe, Koichi Honke, Kiyoshi Ogura, et al. "Sulfatide Is Required for Efficient Replication of Influenza A Virus." Journal of Virology 82, no. 12 (April 16, 2008): 5940–50. http://dx.doi.org/10.1128/jvi.02496-07.
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ABSTRACT Sulfatide is abundantly expressed in various mammalian organs, including the intestines and trachea, in which influenza A viruses (IAVs) replicate. However, the function of sulfatide in IAV infection remains unknown. Sulfatide is synthesized by two transferases, ceramide galactosyltransferase (CGT) and cerebroside sulfotransferase (CST), and is degraded by arylsulfatase A (ASA). In this study, we demonstrated that sulfatide enhanced IAV replication through efficient translocation of the newly synthesized IAV nucleoprotein (NP) from the nucleus to the cytoplasm, by using genetically produced cells in which sulfatide expression was down-regulated by RNA interference against CST mRNA or overexpression of the ASA gene and in which sulfatide expression was up-regulated by overexpression of both the CST and CGT genes. Treatment of IAV-infected cells with an antisulfatide monoclonal antibody (MAb) or an anti-hemagglutinin (HA) MAb, which blocks the binding of IAV and sulfatide, resulted in a significant reduction in IAV replication and accumulation of the viral NP in the nucleus. Furthermore, antisulfatide MAb protected mice against lethal challenge with pathogenic influenza A/WSN/33 (H1N1) virus. These results indicate that association of sulfatide with HA delivered to the cell surface induces translocation of the newly synthesized IAV ribonucleoprotein complexes from the nucleus to the cytoplasm. Our findings provide new insights into IAV replication and suggest new therapeutic strategies.
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Kimura, Takefumi, Takero Nakajima, Yuji Kamijo, Naoki Tanaka, Lixuan Wang, Atsushi Hara, Eiko Sugiyama, Eiji Tanaka, Frank J. Gonzalez, and Toshifumi Aoyama. "Hepatic Cerebroside Sulfotransferase Is Induced by PPARα Activation in Mice." PPAR Research 2012 (2012): 1–10. http://dx.doi.org/10.1155/2012/174932.
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Sulfatides are one of the major sphingoglycolipids in mammalian serum and are synthesized and secreted mainly from the liver as a component of lipoproteins. Recent studies revealed a protective role for serum sulfatides against arteriosclerosis and hypercoagulation. Although peroxisome proliferator-activated receptor (PPAR)αhas important functions in hepatic lipoprotein metabolism, its association with sulfatides has not been investigated. In this study, sulfatide levels and the expression of enzymes related to sulfatide metabolism were examined using wild-type (+/+),Ppara-heterozygous (+/−), andPpara-null (−/−) mice given a control diet or one containing 0.1% fenofibrate, a clinically used hypolipidemic drug and PPARαactivator. Fenofibrate treatment increased serum and hepatic sulfatides inPpara(+/+) and (+/−) mice through a marked induction of hepatic cerebroside sulfotransferase (CST), a key enzyme in sulfatide synthesis, in a PPARα-dependent manner. Furthermore, increases in CST mRNA levels were correlated with mRNA elevations of several known PPARαtarget genes, and such changes were not observed for other sulfatide-metabolism enzymes in the liver. These results suggest that PPARαactivation enhances hepatic sulfatide synthesis via CST induction and implicate CST as a novel PPARαtarget gene.
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Zia, Saadiya, Netasha Khan, Komal Tehreem, Nazia Rehman, Rokayya Sami, Roua S. Baty, Faris J. Tayeb, et al. "Transcriptomic Analysis of Conserved Telomere Maintenance Component 1 (CTC1) and Its Association with Leukemia." Journal of Clinical Medicine 11, no. 19 (September 29, 2022): 5780. http://dx.doi.org/10.3390/jcm11195780.
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Telomere length (TEL) regulation is important for genome stability and is governed by the coordinated role of shelterin proteins, telomerase (TERT), and CST (CTC1/OBFC1/TEN1) complex. Previous studies have shown the association of telomerase expression with the risk of acute lymphoblastic leukemia (ALL). However, no data are available for CST association with the ALL. The current pilot study was designed to evaluate the CST expression levels in ALL. In total, 350 subjects were recruited, including 250 ALL cases and 100 controls. The subjects were stratified by age and categorized into pediatrics (1–18 years) and adults (19–54 years). TEL and expression patterns of CTC1, OBFC1, and TERT genes were determined by qPCR. The univariable logistic regression analysis was performed to determine the association of gene expression with ALL, and the results were adjusted for age and sex in multivariable analyses. Pediatric and adult cases did not reflect any change in telomere lengths relative to controls. However, expression of CTC1, OBFC1, and TERT genes were induced among ALL cases. Multivariable logistic regression analyses showed association of CTC1 with ALL in pediatric [β estimate (standard error (SE)= −0.013 (0.007), p = 0.049, and adults [0.053 (0.023), p = 0.025]. The association of CTC1 remained significant when taken together with OBFC1 and TERT in a multivariable model. Furthermore, CTC1 showed significant association with B-cell ALL [−0.057(0.017), p = 0.002) and T-cell ALL [−0.050 (0.018), p = 0.008] in pediatric group while no such association was noted in adults. Together, our findings demonstrated that telomere modulating genes, particularly CTC1, are strongly associated with ALL. Therefore, CTC1 can potentially be used as a risk biomarker for the identification of ALL in both pediatrics and adults.
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Cheng, Li-Wu, Omkar Vijay Byadgi, Chin-En Tsai, Pei-Chi Wang, and Shih-Chu Chen. "Pathogenicity and Genomic Characterization of a Novel Genospecies, Bacillus shihchuchen, of the Bacillus cereus Group Isolated from Chinese Softshell Turtle (Pelodiscus sinensis)." International Journal of Molecular Sciences 24, no. 11 (June 1, 2023): 9636. http://dx.doi.org/10.3390/ijms24119636.
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The Chinese softshell turtle (CST; Pelodiscus sinensis) is a freshwater aquaculture species of substantial economic importance that is commercially farmed across Asia, particularly in Taiwan. Although diseases caused by the Bacillus cereus group (Bcg) pose a major threat to commercial CST farming systems, information regarding its pathogenicity and genome remains limited. Here, we investigated the pathogenicity of Bcg strains isolated in a previous study and performed whole-genome sequencing. Pathogenicity analysis indicated that QF108-045 isolated from CSTs caused the highest mortality rate, and whole-genome sequencing revealed that it was an independent group distinct from other known Bcg genospecies. The average nucleotide identity compared to other known Bcg genospecies was below 95%, suggesting that QF108-045 belongs to a new genospecies, which we named Bacillus shihchuchen. Furthermore, genes annotation revealed the presence of anthrax toxins, such as edema factor and protective antigen, in QF108-045. Therefore, the biovar anthracis was assigned, and the full name of QF108-045 was Bacillus shihchuchen biovar anthracis. In addition to possessing multiple drug-resistant genes, QF108-045 demonstrated resistance to various types of antibiotics, including penicillins (amoxicillin and ampicillin), cephalosporins (ceftifour, cephalexin, and cephazolin), and polypeptides, such as vancomycin.
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Hull, Dawn M., Erin Harrell, Arnoud H. M. van Vliet, Maria Correa, and Siddhartha Thakur. "Antimicrobial resistance and interspecies gene transfer in Campylobacter coli and Campylobacter jejuni isolated from food animals, poultry processing, and retail meat in North Carolina, 2018–2019." PLOS ONE 16, no. 2 (February 11, 2021): e0246571. http://dx.doi.org/10.1371/journal.pone.0246571.
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The Center for Disease Control and Prevention identifies antimicrobial resistant (AMR) Campylobacter as a serious threat to U.S. public health due to high community burden, increased transmissibility, and limited treatability. The National Antimicrobial Resistance Monitoring System (NARMS) plays an important role in surveillance of AMR bacterial pathogens in humans, food animals and retail meats. This study investigated C. coli and C. jejuni from live food animals, poultry carcasses at production, and retail meat in North Carolina between January 2018-December 2019. Whole genome sequencing and bioinformatics were used for phenotypic and genotypic characterization to compare AMR profiles, virulence factors associated with Guillain-Barré Syndrome (GBS) (neuABC and cst-II or cst-III), and phylogenic linkage between 541 Campylobacter isolates (C. coli n = 343, C. jejuni n = 198). Overall, 90.4% (489/541) Campylobacter isolates tested positive for AMR genes, while 43% (233/541) carried resistance genes for three or more antibiotic classes and were classified molecularly multidrug resistant. AMR gene frequencies were highest against tetracyclines (64.3%), beta-lactams (63.6%), aminoglycosides (38.6%), macrolides (34.8%), quinolones (24.4%), lincosamides (13.5%), and streptothricins (5%). A total of 57.6% (114/198) C. jejuni carried GBS virulence factors, while three C. coli carried the C. jejuni-like lipooligosaccharide locus, neuABC and cst-II. Further evidence of C. coli and C. jejuni interspecies genomic exchange was observed in identical multilocus sequence typing, shared sequence type (ST) 7818 clonal complex 828, and identical species-indicator genes mapA, ceuE, and hipO. There was a significant increase in novel STs from 2018 to 2019 (2 in 2018 and 21 in 2019, p<0.002), illustrating variable Campylobacter genomes within food animal production. Introgression between C. coli and C. jejuni may aid pathogen adaption, lead to higher AMR and increase Campylobacter persistence in food processing. Future studies should further characterize interspecies gene transfer and evolutionary trends in food animal production to track evolving risks to public health.
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Ignatieva, E. V., N. S. Yudin, and D. M. Larkin. "Compilation and functional classification of telomere length-associated genes in humans and other animal species." Vavilov Journal of Genetics and Breeding 27, no. 3 (June 2, 2023): 283–92. http://dx.doi.org/10.18699/vjgb-23-34.
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Telomeres are the terminal regions of chromosomes that ensure their stability while cell division. Telomere shortening initiates cellular senescence, which can lead to degeneration and atrophy of tissues, so the process is associated with a reduction in life expectancy and predisposition to a number of diseases. An accelerated rate of telomere attrition can serve as a predictor of life expectancy and health status of an individual. Telomere length is a complex phenotypic trait that is determined by many factors, including the genetic ones. Numerous studies (including genome-wide association studies, GWAS) indicate the polygenic nature of telomere length control. The objective of the present study was to characterize the genetic basis of the telomere length regulation using the GWAS data obtained during the studies of various human and other animal populations. To do so, a compilation of the genes associated with telomere length in GWAS experiments was collected, which included information on 270 human genes, as well as 23, 22, and 9 genes identified in the cattle, sparrow, and nematode, respectively. Among them were two orthologous genes encoding a shelterin protein (POT1 in humans and pot-2 in C. elegans). Functional analysis has shown that telomere length can be influenced by genetic variants in the genes encoding: (1) structural components of telomerase; (2) the protein components of telomeric regions (shelterin and CST complexes); (3) the proteins involved in telomerase biogenesis and regulating its activity; (4) the proteins that regulate the functional activity of the shelterin components; (5) the proteins involved in telomere replication and/or capping; (6) the proteins involved in the alternative telomere lengthening; (7) the proteins that respond to DNA damage and are responsible for DNA repair; (8) RNA-exosome components. The human genes identified by several research groups in populations of different ethnic origins are the genes encoding telomerase components such as TERC and TERT as well as STN1 encoding the CST complex component. Apparently, the polymorphic loci affecting the functions of these genes may be the most reliable susceptibility markers for telomere-related diseases. The systematized data about the genes and their functions can serve as a basis for the development of prognostic criteria for telomere length-associated diseases in humans. Information about the genes and processes that control telomere length can be used for marker-assisted and genomic selection in the farm animals, aimed at increasing the duration of their productive lifetime.
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Fujihara, Yoshitaka, Taichi Noda, Kiyonori Kobayashi, Asami Oji, Sumire Kobayashi, Takafumi Matsumura, Tamara Larasati, et al. "Identification of multiple male reproductive tract-specific proteins that regulate sperm migration through the oviduct in mice." Proceedings of the National Academy of Sciences 116, no. 37 (August 27, 2019): 18498–506. http://dx.doi.org/10.1073/pnas.1908736116.
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CRISPR/Cas9-mediated genome editing technology enables researchers to efficiently generate and analyze genetically modified animals. We have taken advantage of this game-changing technology to uncover essential factors for fertility. In this study, we generated knockouts (KOs) of multiple male reproductive organ-specific genes and performed phenotypic screening of these null mutant mice to attempt to identify proteins essential for male fertility. We focused on making large deletions (dels) within 2 gene clusters encoding cystatin (CST) and prostate and testis expressed (PATE) proteins and individual gene mutations in 2 other gene families encoding glycerophosphodiester phosphodiesterase domain (GDPD) containing and lymphocyte antigen 6 (Ly6)/Plaur domain (LYPD) containing proteins. These gene families were chosen because many of the genes demonstrate male reproductive tract-specific expression. AlthoughGdpd1andGdpd4mutant mice were fertile, disruptions ofCstandPategene clusters andLypd4resulted in male sterility or severe fertility defects secondary to impaired sperm migration through the oviduct. While absence of the epididymal protein families CST and PATE affect the localization of the sperm membrane protein A disintegrin and metallopeptidase domain 3 (ADAM3), the sperm acrosomal membrane protein LYPD4 regulates sperm fertilizing ability via an ADAM3-independent pathway. Thus, use of CRISPR/Cas9 technologies has allowed us to quickly rule in and rule out proteins required for male fertility and expand our list of male-specific proteins that function in sperm migration through the oviduct.
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Mortazavi, Amin, Mostafa Ghaderi-Zefrehei, Mustafa Muhaghegh Dolatabady, Mahdi Golshan, Sajad Nazari, Ayeh Sadat Sadr, Saeid Kadkhodaei, Ikhide G. Imumorin, Sunday O. Peters, and Jacqueline Smith. "An Integrated Bioinformatics Approach to Identify Network-Derived Hub Genes in Starving Zebrafish." Animals 12, no. 19 (October 10, 2022): 2724. http://dx.doi.org/10.3390/ani12192724.
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The present study was aimed at identifying causative hub genes within modules formed by co-expression and protein–protein interaction (PPI) networks, followed by Bayesian network (BN) construction in the liver transcriptome of starved zebrafish. To this end, the GSE11107 and GSE112272 datasets from the GEO databases were downloaded and meta-analyzed using the MetaDE package, an add-on R package. Differentially expressed genes (DEGs) were identified based upon expression intensity N(µ = 0.2, σ2 = 0.4). Reconstruction of BNs was performed by the bnlearn R package on genes within modules using STRINGdb and CEMiTool. ndufs5 (shared among PPI, BN and COEX), rps26, rpl10, sdhc (shared between PPI and BN), ndufa6, ndufa10, ndufb8 (shared between PPI and COEX), skp1, atp5h, ndufb10, rpl5b, zgc:193613, zgc:123327, zgc:123178, wu:fc58f10, zgc:111986, wu:fc37b12, taldo1, wu:fb62f08, zgc:64133 and acp5a (shared between COEX and BN) were identified as causative hub genes affecting gene expression in the liver of starving zebrafish. Future work will shed light on using integrative analyses of miRNA and DNA microarrays simultaneously, and performing in silico and experimental validation of these hub-causative (CST) genes affecting starvation in zebrafish.
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Boccia, A. "DG-CST (Disease Gene Conserved Sequence Tags), a database of human-mouse conserved elements associated to disease genes." Nucleic Acids Research 33, Database issue (December 17, 2004): D505—D510. http://dx.doi.org/10.1093/nar/gki011.
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Nachamkin, Irving, Jirong Liu, Ming Li, Huong Ung, Anthony P. Moran, Martina M. Prendergast, and Kazim Sheikh. "Campylobacter jejuni from Patients with Guillain-Barré Syndrome Preferentially Expresses a GD1a-Like Epitope." Infection and Immunity 70, no. 9 (September 2002): 5299–303. http://dx.doi.org/10.1128/iai.70.9.5299-5303.2002.
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ABSTRACT GM1- and GD1a-like ganglioside mimicry in Campylobacter jejuni lipooligosaccharide (LOS) is considered to be involved in the pathogenesis of Campylobacter-induced Guillain-Barré syndrome (GBS). Compared with gastroenteritis-related isolates, GBS-related C. jejuni isolates were strongly associated with the expression of GD1a-like mimicry. The presence of a few genes involved in LOS ganglioside mimicry, cst-II, cgtA, and cgtB, was also associated with GBS-related strains. GD1a-like epitope expression may be an important virulence phenotype associated with the risk of developing GBS following campylobacter infection.
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Alese, Theodora, Benjamin G. Barwick, Vikas A. Gupta, Nisha Joseph, Craig C. Hofmeister, Mala Shanmugam, Jonathan L. Kaufman, et al. "BRAF Mutations and Inflammatory Gene Expression in Myeloma Cells from Patients with Renal Dysfunction." Blood 138, Supplement 1 (November 5, 2021): 1624. http://dx.doi.org/10.1182/blood-2021-154092.
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Abstract Introduction: Multiple Myeloma (MM), the second most common blood cancer, is a clonal disease of long-lived plasma cells (PC) that is currently incurable. Symptomatic myeloma-defining events include hyper calcemia, renal dysfunction, anemia, and bone disease (CRAB criteria). Renal dysfunction is primarily due to free light chain (FLC) precipitation with uromodulin in the distal tubules resulting in light chain cast nephropathy (LCCN). Renal dysfunction may have a negative impact on patient outcomes as it can influence the ability to optimally treat patients, and in some may result in hemodialysis dependence. Therefore, understanding the factors that can contribute to renal dysfunction could allow for early intervention to prevent associated morbidity. Methods: To determine whether certain proteins or genetic mutations in MM patients are associated with renal failure, we analyzed data from the Multiple Myeloma Research Foundation's CoMMpass Study (NCT01454297, Interim Analysis 16) using creatinine levels as a surrogate for renal dysfunction (>176 μmol/L indicates renal failure). We correlated creatinine with other measures of renal dysfunction (BUN), serum protein levels (total protein, M-protein, IgG, IgA, IgM, IgL-kappa, IgL-lambda), as well as structural changes including t(11;14), t(12;14), t(14;16), t(14;20), t(6;14), t(8;14), hyperdiploidly, 1q21 gains and 17p13 loss as determined by whole genome sequencing (WGS). We used whole exosome sequencing (WES) data to assess if common mutations (KRAS, NRAS, BRAF, DIS3, FAM46C) were associated with renal dysfunction. The numbers in each comparison differed based on the availability of WGS (structural events: 621 vs. 96) or WES (SNVs: 1003 vs. 119). To study gene expression we focused on the patients with the highest and lowest creatinine levels (70/group). Since there was a sex bias in these groups we included a covariate for sex to determine gene expression changes independent of sex. Finally, we analyzed RNAseq analysis for expression of light chain variable regions to determine if there was an association of light chain usage with renal dysfunction. Results: We initially correlated BUN, serum protein levels and structural events with creatinine levels, but only found a significant correlation with BUN levels (Pearson R=0.7275, P=<0.0001, N=816). We next performed a contingency analysis comparing genetic events in patients with creatinine >176 μmol/L versus those <176 μmol/L. While there were no differences in structural events between those with normal vs. elevated creatinine, we did observe a significant increase in BRAF mutations in patients with high creatinine (Fisher's exact test, P=0.0093). We also observed a trend towards significance with KRAS mutations (Fisher's exact test P=0.0930). We examined light chain variable region usage but found no association with high creatinine levels. We expanded this analysis to all genes, and found 110 genes differentially expressed with renal dysfunction, which were enriched for genes involved in inflammatory responses (AIF1, LY96, LYVE1, MPEG1, SELL1, STAB1, TNFRSF12A) and metabolism (COX7A2, FOLR2, MT-ND1, MT-ND3). Conclusions: Our data are consistent with previous studies with respect to the lack of association of renal dysfunction with serum proteins and translocations. However, we observed interesting associations with BRAF mutations and a trend with KRAS mutations, suggesting a role in disease pathogenesis beyond driving tumorigenesis. Additionally, we detected expression changes with several genes involved in inflammatory responses. We cannot conclude if this is due to inflammation related to acute kidney disease or if the myeloma plasma cells expressing these genes are more likely to produce FLC that result in LCCN. Finally, we did not observe a variable chain usage bias, however our study is limited to expression and therefore points to the likelihood that somatic hypermutation plays an important role in whether a light chain can lead to renal disease. Taken together, these data suggest the presence of genetic and biological differences in myeloma cells associated with renal dysfunction and provide insights into identifying patients that could develop renal disease. ACKNOWLEDGEMENTS This work was supported through the STEP-UP HS program from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health, R25DK113659 Disclosures Joseph: GSK: Honoraria; BMS: Research Funding; Takeda: Research Funding; Karyopharm: Honoraria. Hofmeister: Sanofi: Other: National PI for CST; PI or co-PI IST; BMS/Celgene: Other: National PI for CST; PI or co-PI IST; Local PI of CST; Nektar Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Local PI of CST; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Local PI of CST; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: Local PI of CST; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Oncolytics: Other: National PI for CST; PI or co-PI IST; Takeda: Other: Local PI of CST; Genzyme: Membership on an entity's Board of Directors or advisory committees; Myeloma360: Membership on an entity's Board of Directors or advisory committees; Imbrium: Membership on an entity's Board of Directors or advisory committees; BioAscend: Other: CME speaker; Philips Gilmore: Other: CME speaker; Non-pharma speaker for education, research, marketing; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Other: Non-CME speaker; BlueBird Bio: Other: Non-CME speaker; Aptitude Health: Other: Non-pharma speaker for education, research, marketing; Verascity: Other: Non-pharma speaker for education, research, marketing; TRM Oncology: Other: Non-pharma speaker for education, research, marketing; DAVA Oncology: Other: Non-pharma speaker for education, research, marketing; Medscape: Other: Non-pharma speaker for education, research, marketing; Ohio State University: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: IP rights, Patents & Royalties. Kaufman: Genentech, AbbVie, Janssen: Consultancy, Research Funding; Incyte, celgene: Consultancy; Tecnofarma SAS, AbbVie: Honoraria; Amgen: Research Funding; BMS: Consultancy, Research Funding; Fortis Therapeutics: Research Funding; Heidelberg Pharma: Research Funding; Incyte, TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Novartis: Research Funding; Roche/Genetech, Tecnopharma: Consultancy, Honoraria; Sutro, Takeda: Research Funding. Lonial: AMGEN: Consultancy, Honoraria; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Merck: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding. Nooka: Takeda: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Other: Travel expenses; Amgen: Consultancy, Research Funding; Karyopharm Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy; Adaptive technologies: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy; Janssen Oncology: Consultancy, Research Funding. Boise: AstraZeneca: Consultancy, Research Funding; Abbvie: Consultancy.
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Guerry, Patricia, Cheryl P. Ewing, Thomas E. Hickey, Martina M. Prendergast, and Anthony P. Moran. "Sialylation of Lipooligosaccharide Cores Affects Immunogenicity and Serum Resistance of Campylobacter jejuni." Infection and Immunity 68, no. 12 (December 1, 2000): 6656–62. http://dx.doi.org/10.1128/iai.68.12.6656-6662.2000.
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ABSTRACT Three genes involved in biosynthesis of the lipooligosaccharide (LOS) core of Campylobacter jejuni MSC57360, the type strain of the HS:1 serotype, whose structure mimics GM2ganglioside, have been cloned and characterized. Mutation of genes encoding proteins with homology to a sialyl transferase (cstII) and a putative N-acetylmannosamine synthetase (neuC1), part of the biosynthetic pathway ofN-acetylneuraminic acid (NeuNAc), have identical phenotypes. The LOS cores of these mutants display identical changes in electrophoretic mobility, loss of reactivity with cholera toxin (CT), and enhanced immunoreactivity with a hyperimmune polyclonal antiserum generated against whole cells of C. jejuni MSC57360. Loss of sialic acid in the core of the neuC1 mutant was confirmed by fast atom bombardment mass spectrometry. Mutation of a gene encoding a putative β-1,4-N-acetylgalactosaminyltransferase (Cgt) resulted in LOS cores intermediate in electrophoretic mobility between that of wild type and the mutants lacking NeuNAc, loss of reactivity with CT, and a reduced immunoreactivity with hyperimmune antiserum. Chemical analyses confirmed the loss of N-acetylgalactosamine (GalNAc) and the presence of NeuNAc in the cgt mutant. These data suggest that the Cgt enzyme is capable of transferring GalNAc to an acceptor with or without NeuNAc and that the Cst enzyme is capable of transferring NeuNAc to an acceptor with or without GalNAc. A mutant with a nonsialylated LOS core is more sensitive to the bactericidal effects of human sera than the wild type or the mutant lacking GalNAc.
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Santoso, Adi, Endah Puji Septisetyani, Ratna Dwi Ramadani, Yana Rubiyana, Pekik Wiji Prasetyaningrum, Popi Hadi Wisnuwardhani, Arizah Kusumawati, and Neny Nuraini. "Glycoengineering of Darbepoetin-α in CHO-DG44 Cells through Overexpression of α-2,3-sialyl-transferase and CMP-sialic Acid Transporter." HAYATI Journal of Biosciences 29, no. 2 (January 18, 2022): 204–13. http://dx.doi.org/10.4308/hjb.29.2.204-213.
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Sialic acid plays a very important role in determining the circulation life span of glycoprotein in various organisms. Therefore, having a high content of sialic acid is needed by glycoprotein therapeutic agents to be able to function as desired. For example, Darbepoetin (DPO), the 5 N-linked erythropoietin showed higher bioavailability and efficacy compared to 3 N-linked erythropoietin. However, in the DPO production process, the molecular weight can vary and is highly dependent on the content of sialic acid and its production host. To improve the DPO sialic acid contents in our CHO-DG44 expressing DPO, we have engineered the cells through overexpression of α-2,3-sialyl-transferase (ST) and CMP-sialic acid transporter (CST). The DPO contained in the supernatant of the engineered cells was analyzed by Western blot and characterized by using PNGase-F or neuraminidase enzyme digestions. The results showed that, two clones, overexpressing ST or CST, were obtained. The clones showed higher molecular weight of DPO as compared to DPO expressed by the parental cells, yet retained the same protein backbone. The overexpression of these two genes does not affect cell growth. This suggests that may be these cells beneficial for therapeutic glycoproteins.
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Luo, Xuan, Zhuoxin Zu, Hasan Riaz, Xingang Dan, Xue Yu, Shuanghang Liu, Aizhen Guo, Yilin Wen, Aixin Liang, and Liguo Yang. "Evaluation of a Novel DNA Vaccine Double Encoding Somatostatin and Cortistatin for Promoting the Growth of Mice." Animals 12, no. 12 (June 8, 2022): 1490. http://dx.doi.org/10.3390/ani12121490.
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Animal growth traits are directly linked with the economics of livestock species. A somatostatin DNA vaccine has been developed to improve the growth of animals. However, the growth-promoting effect is still unsatisfying. The current study aimed to evaluate the effect of a novel eukaryotic dual expression vaccine known as pIRES-S/CST14-S/2SS, which encodes the genes obtained by fusing somatostatin (SS) and cortistatin (CST) into hepatitis B surface antigen (HBsAg). After transfection into GH3 cells with pIRES-S/CST14-S/2SS, green fluorescence signals were observed by fluorescence microscopy, suggesting the effective expression of CST and SS in GH3 cells using the IRES elements. Subsequently, both GH and PRL levels were found to be significantly lower in pIRES-S/CST14-S/2SS-treated cells as compared to the control group (p < 0.05). Furthermore, the antibody level, hormone secretion, and weight gain in the mice injected with novel recombinant plasmids were also evaluated. The anti-SS antibodies were detectable in all vaccine treated groups, resulting in significantly higher levels of GH secretion (p < 0.05). It is worth mentioning that pIRES-S/CST14-S/2SS (10 μg/100 μL) vaccinated mice exhibited a higher body weight gain in the second immunization period. This study increases the understanding of the relationship between somatostatin and cortistatin, and may help to develop an effective growth-promoting DNA vaccine in animals.
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Kazmierczak, Krystyna, Gregory Stone, and Daniel F. Sahm. "693. In Vitro Activity of Ceftazidime–Avibactam and Comparator Agents Against Enterobacteriaceae and Pseudomonas aeruginosa Collected From Patients with Bloodstream Infections as Part of the ATLAS Global Surveillance Program, 2014–2017." Open Forum Infectious Diseases 6, Supplement_2 (October 2019): S314. http://dx.doi.org/10.1093/ofid/ofz360.761.
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Abstract Background Avibactam (AVI) is a β-lactamase inhibitor with potent inhibitory activity against Class A, Class C, and some Class D serine β-lactamases. The combination of ceftazidime (CAZ) with AVI has been approved in Europe and in the United States for several indications. This study evaluated the in vitro activity of CAZ-AVI and comparators against Enterobacteriaceae (Eba) and Pseudomonas aeruginosa (Pae) isolates collected from patients with bloodstream infections as part of the ATLAS surveillance program in 2014–2017. Methods A total of 53416 Eba and 15050 Pae nonduplicate clinically significant isolates, including 5155 Eba and 845 Pae isolated from bloodstream infections, were collected by 167 hospital laboratories in 36 countries in Europe, Latin America, Asia/Pacific (excluding China), and the Middle East/Africa region. Susceptibility testing was performed by CLSI broth microdilution. CAZ-AVI was tested at a fixed concentration of 4 µg/mL AVI. Meropenem-nonsusceptible (MEM-NS) Eba and Pae isolates were screened for the presence of β-lactamase genes. Results Susceptibility data are shown in the Table. Percentages of susceptibility (% S) to the tested agents were 0.2–2.8% lower among Eba and Pae from bloodstream infections compared with isolates from combined sources in most cases. CAZ-AVI showed potent in vitro activity against all Eba bloodstream isolates and subsets of CAZ-NS and colistin-resistant (CST-R) isolates (MIC90, 0.5–2 µg/mL, 96.0–100% S). Reduced activity against MEM-NS Eba was attributable to carriage of class B metallo-β-lactamases (MBLs) because all MEM-NS MBL-negative isolates were susceptible to CAZ-AVI. CAZ-AVI also showed good in vitro activity against the majority of Pae bloodstream isolates (MIC90, 16 µg/mL, 89.5% S). Activity was reduced against CAZ-NS, MEM-NS and CST-R subsets (53.7–85.0% S), which included isolates carrying MBLs, but exceeded the activity of CAZ and MEM against these subsets by 15–65%. CST and amikacin were the only tested comparators that demonstrated comparable or greater activity against Pae bloodstream isolates. Conclusion CAZ-AVI provides a valuable therapeutic option for treating bloodstream infections caused by MBL-negative Eba and Pae isolates. Disclosures All authors: No reported disclosures.
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Iwai, Fumie, Hitomi Kaneko, Goichi Tatsumi, Tadahiko Matsumoto, Shinya Inada, Yuki Sueki, Nao Toyooka, et al. "Favorable Outcome of Reduced-Intensity Stem Cell Transplantation for Adult T-Cell Leukemia." Blood 118, no. 21 (November 18, 2011): 4480. http://dx.doi.org/10.1182/blood.v118.21.4480.4480.
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Abstract Abstract 4480 Introduction: Adult T-cell leukemia (ATL) endemic in southwestern Japan is an HTLV-I-induced mature T-cell neoplasm. It has a dismal prognosis when treated with conventional chemotherapy, mainly because ATL cells overexpress multidrug-resistance genes. Allogeneic hematopoietic stem cell transplantation (allo-SCT) has been reported to improve the prognosis. However, it is also known that allo-SCT shows high treatment-related mortality (TRM) because of disease characteristics of severely deteriorated cellular immunity. Therefore, we evaluated the outcome of reduced-intensity stem cell transplantation (RIST), compared to conventional stem cell transplantation (CST) for ATL patients (pts). Patients and methods: We retrospectively analyzed consecutive 20 pts with aggressive ATL (acute type, 16; lymphoma type, 4) who underwent allo-SCT between 2000 and 2010 in our institute. The age of pts who received RIST was significantly older than that of CST (P = <.001). The other parameters were balanced between the two groups (Table 1). All pts received induction chemotherapy with Japan Clinical Oncology Group (VCAP-AMP-VECP) regimen or biweekly CHOP prior to SCT. Nine pts received a conventional myeloablative conditioning with CY/TBI-based (n=8) or BU/CY-based (n=1) regimens and 11 pts received a reduced-intensity regimen with fludarabine(Flu)/melphalan(Mel)±TBI (Flu 25 mg/m2 on days -6 to -2 + Mel 40 mg/m2 on days -4 and -3 ± TBI 4 Gy on day -1). Graft-versus-host-disease (GVHD) prophylaxis consisted of cyclosporine plus short-term methotrexate (sMTX) for HLA-matched sibling donor recipients and tacrolimus plus sMTX for the others. Cyclosporine or tacrolimus was promptly tapered when complete chimerism was achieved. Results and discussion: The estimated 3-year overall survival (OS) and 3-year progression-free survival (PFS) rates for all pts were 59% and 55%, respectively (Fig. 1). At the median follow-up duration of 25 months (1–67), 12 pts were alive and 8 pts dead. Causes of death were disease progression (n=4) and treatment-related complications including acute GVHD and infection (n=4). The cumulative incidences of disease-associated mortality and TRM at 3 years were 21% and 20%, respectively. Importantly, after 1 year post-transplantation, the curve of PFS reached plateau phase. Therefore, allo-SCT could be a curable therapeutic option for aggressive ATL. It is notable that RIST showed excellent 3-year OS. Although not significant, 3-year OS for RIST and CST were 70% and 44% (P =.25), respectively (Fig. 2). TRM of RIST trended to be low compared with that of CST (18% vs 22%, P =.87). In addition, chronic GVHD was observed in 91% of the evaluable 11 pts (limited type, 6; extensive type, 5). It is suggested that both improvement of TRM and the induction of graft-versus-leukemia effects may contribute to the favorable outcome in RIST for ATL. Furthermore, it should be stressed that older pts who preferentially received RIST rather than CST achieved favorable survival comparable to younger pts (≥ 50 years: 58% vs < 50 years: 60%, P =.94). We would suggest that RIST should be applied to all ATL pts eligible for allo-SCT, regardless of the age. Univariate analysis for all pts revealed that only male sexuality was a significant poor prognostic factor for OS (male: 25% vs female: 82%, P =.006). Regarding disease status at SCT, CR or non-CR did not significantly affect OS (CR: 67% vs non-CR: 58%, P =.98). However, PD was an adverse impact on 3-year OS (PD: 33% vs non-PD: 64%, P =.11). It is recommended that ATL pts receive allo-SCT in early phase before the disease becomes chemo-resistant, even if they do not achieve CR. Conclusion: Allo-SCT for ATL remarkably improved the poor prognosis. Especially, RIST is a promising procedure for excellent outcome. Disclosures: No relevant conflicts of interest to declare.
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Li, Wen-Yuan, Ying Wang, Feng-Guo Zhai, Ping Sun, Yong-Xia Cheng, Ling-Xiao Deng, and Zhen-Yu Wang. "AAV-KLF7 Promotes Descending Propriospinal Neuron Axonal Plasticity after Spinal Cord Injury." Neural Plasticity 2017 (2017): 1–22. http://dx.doi.org/10.1155/2017/1621629.
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DPSN axons mediate and maintain a variety of normal spinal functions. Unsurprisingly, DPSN tracts have been shown to mediate functional recovery following SCI. KLF7 could contribute to CST axon plasticity after spinal cord injury. In the present study, we assessed whether KLF7 could effectively promote DPSN axon regeneration and synapse formation following SCI. An AAV-KLF7 construct was used to overexpress KLF7.In vitro, KLF7 and target proteins were successfully elevated and axonal outgrowth was enhanced.In vivo, young adult C57BL/6 mice received a T10 contusion followed by an AAV-KLF7 injection at the T7–9 levels above the lesion. Five weeks later, overexpression of KLF7 was expressed in DPSN. KLF7 and KLF7 target genes (NGF, TrkA, GAP43, and P0) were detectably increased in the injured spinal cord. Myelin sparring at the lesion site, DPSN axonal regeneration and synapse formation, muscle weight, motor endplate morphology, and functional parameters were all additionally improved by KLF7 treatment. Our findings suggest that KLF7 promotes DPSN axonal plasticity and the formation of synapses with motor neurons at the caudal spinal cord, leading to improved functional recovery and further supporting the potential of AAV-KLF7 as a therapeutic agent for spinal cord injury.
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Kazmierczak, Krystyna, Mark Estabrook, Gregory G. Stone, and Dan Sahm. "Activity of Ceftazidime–Avibactam Against Respiratory Isolates of Enterobacteriaceae and Pseudomonas aeruginosa Collected in Latin America as Part of the INFORM Global Surveillance Program, 2014–2016." Open Forum Infectious Diseases 4, suppl_1 (2017): S379. http://dx.doi.org/10.1093/ofid/ofx163.938.
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Abstract Background The β-lactam/non-β-lactam β-lactamase inhibitor combination ceftazidime-avibactam (CAZ-AVI) is active in vitro against isolates producing class A, C, and some class D β-lactamases, including extended-spectrum β-lactamases, stably derepressed AmpC, and serine carbapenemases. This study evaluated the in vitro activity of CAZ-AVI and comparators against respiratory isolates of Enterobacteriaceae (Eba) and Pseudomonas aeruginosa (Pae) collected in Latin America from 2014–2016 as part of the INFORM surveillance program. Methods Non-duplicate isolates from hospitalized patients with lower respiratory tract infections were collected from 24 medical centers in Argentina, Brazil, Chile, Colombia, Mexico, and Venezuela. Susceptibility (S) testing was performed by broth microdilution and interpreted using CLSI breakpoints except for CAZ-AVI (U.S. FDA) and colistin (EUCAST; Ebaonly). AVI was tested at a fixed concentration of 4 µg/mL with doubling dilutions of CAZ. Multidrug resistance (MDR) phenotype was defined as resistant by CLSI breakpoints to sentinel agents from ≥3 drug classes. Isolates were screened for β-lactamase genes by PCR and sequencing. Results CAZ-AVI showed potent in vitro activity against Eba isolates (MIC90, 0.5 µg/mL; 99.3% S) and against CAZ-non-susceptible (CAZ-NS), colistin-resistant (CST-R) and MDR subsets (>93% S). CAZ-AVI activity against meropenem-non-susceptible (MEM-NS) Eba (89.7% S) was reduced due to production of metallo-β-lactamases (MBL); MEM-NS MBL-negative isolates were 100% S. CAZ-AVI showed greater in vitro activity against Pae isolates (MIC90, 32 µg/mL; 85.4% S) than CAZ (69.2% S) or MEM (59.9% S). CAZ-AVI activity against CAZ-NS, CST-R, MEM-NS, MEM-NS MBL-negative, and MDR Paeisolates (50.4–92.6% S) also exceeded that of CAZ and MEM against these resistant subsets. Conclusion CAZ-AVI is a potential treatment option for respiratory infections in Latin America that are caused by Eba and Pae resistant to commonly used and last-in-line agents. Funding: This study was sponsored by AstraZeneca. The AstraZeneca product ceftazidime-avibactam was acquired by Pfizer in December 2016. Disclosures G. G. Stone, Pfizer: Employee, Salary AstraZeneca: Shareholder, Capital Gains
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Sommier, Isabelle. "La CGT : du service d'ordre au service d'accueil." Genèses 12, no. 1 (1993): 69–88. http://dx.doi.org/10.3406/genes.1993.1183.
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Lai, Yanzhen, Yu Wang, Yaxian Wu, Meng Wu, Shan Xing, Ying Xie, Shulin Chen, et al. "Identification and Validation of Serum CST1 as a Diagnostic Marker for Differentiating Early-Stage Non-Small Cell Lung Cancer from Pulmonary Benign Nodules." Cancer Control 29 (January 2022): 107327482211046. http://dx.doi.org/10.1177/10732748221104661.
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Background Effective means for early diagnosis are imperative to reduce death rate of non-small cell lung cancer (NSCLC) patients. We aimed to find out high-performance serologic markers to distinguish early-stage NSCLC patients from benign pulmonary nodule patients and healthy controls (HC). Cystatin-SN (CST1) is an active cysteine protease inhibitor of the CST superfamily, involving in the processes of inflammation and tumorigenesis. This is the first exploration of the diagnostic and prognostic values of serum CST1 in NSCLC. Methods We analyzed the transcriptome data from The Cancer Genome Atlas and the Gene Expression Omnibus database, screened biomarkers for NSCLC, and verified the candidate markers via the ONCOMINE database. Then, we performed ELISA, western blotting, and immunohistochemistry analysis to detect the expression levels of CST1 in NSCLC cell lines, tumor tissues, and serum samples of clinical cohorts. Results We identified 3 up-regulated secreted protein-encoding genes, validated the expression levels of CST1 in NSCLC tumor tissues and cell lines, and found that serum CST1 levels of NSCLC (4289 ± 2405 pg/mL) were significantly higher than those of PBN patients (1558 ± 441 pg/mL, P < .0001) and healthy controls (1529 ± 416 pg/mL, P < .0001). The AUC of the combination of CST1, Cytokeratin 19 fragment (Cyfra21-1), and Carcinoembryonic antigen (CEA) for distinguishing early-stage NSCLC from PBN/HC was as high as .914/0.925. Furthermore, our results suggested that the NSCLC patient with low serum CST1 level had a better survival rate. Conclusions Serum CST1 may serve as a novel diagnostic marker for differentiating early-stage NSCLC from PBN and HC, and could be used as a prognosis predictor in NSCLC patients.
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Dracheva, Tatiana, and Jin Jen. "Profiling Lung Adenocarcinoma: Insights from Genes and More Genes." Cancer Biology & Therapy 2, no. 3 (May 20, 2003): 299–300. http://dx.doi.org/10.4161/cbt.2.3.447.
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Inoue, AI, Tohru Fujiwara, Yoko Okitsu, Noriko Fukuhara, Yasushi Onishi, Kenichi Ishizawa, and Hideo Harigae. "Exploring The Mechanisms To Reveal The Contribution Of LMO2 To The Transcriptional Regulation In Human Erythroblasts." Blood 122, no. 21 (November 15, 2013): 2178. http://dx.doi.org/10.1182/blood.v122.21.2178.2178.
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Abstract Background Developmental control mechanisms often utilize multimeric complexes containing transcription factors, coregulators, and additional non-DNA binding components. LMO2 (LIM-only protein 2) is a non-DNA binding transcriptional coregulator, and is an important regulator of hematopoietic stem cell development and erythropoiesis (Warren et al. Cell. 1994). In the context of erythropoiesis, LMO2 has been demonstrated to be a part of multimetric complex, including master regulators of hematopoiesis (GATA1 and SCL/TAL1), chromatin looping factor LDB1 (referred as GATA-SCL/TAL1 complex) (Wadman et al. EMBO J. 1997). Recently, we have demonstrated that LMO2 contributes to the expression of GATA-1 target genes such as HBB and SLC4A1, through modulating the assembly of GATA-1 as well as the components of SCL/TAL1 complex at the endogeneous loci (ASH 2012). To gain new mechanistic insights, we have extended our study to reveal the contribution of LMO2 to the GATA-1 activity in human erythroblasts. Methods For LMO2, TAL1 and LDB1 knockdown, anti-LMO2, anti-TAL1, anti-LDB1 siRNA (Thermo Scientific Dharmacon) were used. Western blotting and quantitative ChIP analyses were performed using antibodies for GATA-1 (CST and abcam), LMO2, 6×His tag (abcam), TAL1 and LDB1 (Santa Cruz). Human induced pluripotent stem cell (iPS)-derived erythroid progenitor cells (HiDEP), which have a capacity to differentiate into enucleated red blood cells (Kurita et al. PLOS ONE. 2013), were included for the analysis. For the exogeneous expression of 6×His tagged wild-type GATA-1 and mutant GATA-1 in K562 cells, pBABEpuro retroviral vector and PLAT-GP packaging cell line were used (Fujiwara et al. Exp Hematol. 2013). Results We previously demonstrated that transient LMO2 knockdown in K562 cells, which did not affect the expression of GATA-1, SCL/TAL1 and LDB1, resulted in the significantly decreased chromatin occupancy of GATA-1 and the components of SCL/TAL1 complex at beta-globin locus control region (LCR) and SLC4A1 loci (ASH 2012). Based on iPS-derived erythroblasts (HiDEP), we further confirmed the significant downregulation of GATA-1-target genes (HBB, HBA and SLC4A1), and concomitant decrease in GATA-1 chromatin occupancy at the target gene loci, by siRNA-mediated LMO2 knockdown. To reveal the molecular mechanism linking LMO2 and GATA-1, we first expressed 6×His tagged wild-type GATA-1 or mutated GATA-1, including R202Q and R217D, which impaired direct binding with LMO2 (Wilkinson-White et al. PNAS. 2011), in K562 cells. Quantitative ChIP analysis anti-6×His tag antibody revealed significantly diminished occupancy of the mutated GATA-1 (R202Q and R217D) at the beta-globin LCR, HBA and SLC4A1 loci. Next, in addition to the direct interaction between GATA-1 and LMO2, we examined whether the knockdown of each individual component of the SCL/TAL1 complex, such as SCL/TAL1 and LDB1, could affect GATA-1 chromatin occupancy. The expression of GATA-1 target genes, such as HBB, HBA, and SLC4A1, were downregulated by either SCL/TAL1 or LDB1 transient knockdown, whereas the expression of GATA-1 was unaffected. Under the condition, GATA-1 chromatin occupancy was significantly reduced, suggesting that impaired assembly of the individual component of SCL/TAL1 complex may also affect GATA-1 chromatin occupancy. Conclusion LMO2 contributes to the assembly of components of the GATA-SCL/TAL1 complex at endogenous loci in erythroblasts, which may lead to dysregulation of a subset of GATA-1 target genes. Our results may lead to the identification of novel disease mechanisms involving anemia as well as leukemia. Disclosures: No relevant conflicts of interest to declare.
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Swift-Scanlan, Theresa, Russell Vang, Amanda Blackford, Mary Jo Fackler, and Saraswati Sukumar. "Methylated genes in breast cancer." Cancer Biology & Therapy 11, no. 10 (May 15, 2011): 853–65. http://dx.doi.org/10.4161/cbt.11.10.15177.
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El-Deiry, Wafik S. "Targeting and Delivering Therapeutic Genes." Cancer Biology & Therapy 1, no. 6 (November 2002): 721–22. http://dx.doi.org/10.4161/cbt.328.
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Fisel, P., E. Schaeffeler, and M. Schwab. "DNA Methylation of ADME Genes." Clinical Pharmacology & Therapeutics 99, no. 5 (February 19, 2016): 512–27. http://dx.doi.org/10.1002/cpt.343.
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Wise, Mark, Krystyna Kazmierczak, Gregory G. Stone, and Dan Sahm. "1358. In vitro Activity of Ceftazidime–Avibactam and Comparator Agents Against Pseudomonas aeruginosa Causing Intra-Abdominal, Lower Respiratory, and Urinary Tract Infections Collected in Latin America as Part of the INFORM Global Surveillance Program, 2012–2016." Open Forum Infectious Diseases 5, suppl_1 (November 2018): S416. http://dx.doi.org/10.1093/ofid/ofy210.1189.
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Abstract Background The non-β-lactam β-lactamase inhibitor avibactam (AVI) is active against class A, C, and some class D β-lactamases, in combination with ceftazidime (CAZ) has been approved by the FDA and EMA for treatment of intra-abdominal infections (IAI), lower respiratory tract infections (LRTI), and urinary tract infections (UTI). This study reports on the in vitro activity of (CAZ-AVI) and comparators vs. P. aeruginosa collected from IAIs, LRTIs, and UTIs in Latin America as part of the INFORM surveillance study from 2012 to 2016. Methods For INFORM surveillance over 2012–2016 in Latin America, 1,595 nonduplicate P. aeruginosa isolates linked to IAIs, LRTIs, and UTIs were collected from 26 clinical sites in six countries. Susceptibility testing was done using broth microdilution according to CLSI guidelines and using CLSI 2018 breakpoints. CAZ was tested with AVI at a fixed concentration of 4 mg/mL. Meropenem (MEM) nonsusceptible organisms were screened for β-lactamase genes by PCR. Results Among the full collection of P. aeruginosa, CAZ-AVI showed consistently higher % susceptibilities than all comparators except for colistin (CST) for all infection sources. The addition of AVI to CAZ resulted in an increase in susceptibility ranging from 14.2% (IAI) to 19.5% (UTI). Against the non-metallo-β-lactamase (MBL) harboring subset, CAZ-AVI showed extremely potent activity (MIC90, 8 mg/mL) for all infection sources. In this subset, the activity of CAZ-AVI approached that of colistin for IAIs (susceptibility of 93.3% vs. 96.4%, respectively). Conclusion CAZ-AVI demonstrated very good in vitro activity against P. aeruginosa isolates, especially those without MBLs. More isolates were susceptible to CAZ-AVI than to MEM for all infection types. Disclosures M. Wise, Pfizer Inc.: Consultant, Consulting fee. IHMA, Inc.: Employee, Salary. K. Kazmierczak, Pfizer Inc.: Consultant, Consulting fee. IHMA, Inc.: Employee, Salary. G. G. Stone, Pfizer Inc.: Employee, Salary. AstraZeneca: Former Employee and Shareholder, Salary. D. Sahm, Pfizer Inc.: Consultant, Consulting fee. IHMA, Inc.: Employee, Salary.
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Comeau, Christopher C., Angela H. Guo, Fang Chen, and Christopher J. Fry. "Abstract B004: Analysis of epigenetic marks and mechanisms in disease: Your guide to a successful assay." Cancer Research 82, no. 23_Supplement_2 (December 1, 2022): B004. http://dx.doi.org/10.1158/1538-7445.cancepi22-b004.
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Abstract Like the chromatin immunoprecipitation (ChIP) assay, Cleavage Under Targets & Release Using Nuclease is a powerful and versatile technique used for probing protein-DNA interactions within the natural chromatin context of the cell. The assay can be combined with downstream qPCR or NG-seq to analyze histone modifications and binding of transcription factors, DNA replication factors, or DNA repair proteins at specific target genes or across the entire genome. It provides a rapid, robust, and true low cell number assay for detection of protein-DNA interactions in the cell. Unlike the ChIP assay, it is free from formaldehyde cross-linking, chromatin fragmentation, and immunoprecipitation. Previously, we have shown that, compared to ChIP, it requires fewer starting cells (100K), has a much faster protocol (one day from cells to DNA), generates lower background signal (requires less sequencing depth), and offers spike-in control DNA for effective normalization of signal between samples and between experiments. We recently updated the CST Assay Kit for use with 5,000-20,000 cells and added protocols for fixed cells and tissue. I will discuss the basics of the assay and important factors to consider when setting up your experiment. In addition, I will provide data showing the versatility of this assay for mapping various histone modifications, transcription factor, and transcription cofactor binding across multiple sample types. Finally, I will discuss how the general protocol is optimized for greater signal to noise ratio, reduced number of starting cells, and provide an alternative digestion method to prepare the input DNA as a critical control of the experiment. Citation Format: Christopher C. Comeau, Angela H. Guo, Fang Chen, Christopher J. Fry. Analysis of epigenetic marks and mechanisms in disease: Your guide to a successful assay. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B004.
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El-Deiry, Wafik S. "Transactivation of Repair Genes by BRCA1." Cancer Biology & Therapy 1, no. 5 (September 13, 2002): 490–91. http://dx.doi.org/10.4161/cbt.1.5.162.
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Chen, Hexin, and Saraswati Sukumar. "HOX Genes — Emerging Stars in Cancer." Cancer Biology & Therapy 2, no. 5 (May 4, 2003): 524–25. http://dx.doi.org/10.4161/cbt.2.5.525.
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Prendergast, George C. "Chasing cancer: From genes to drugs." Cancer Biology & Therapy 4, no. 8 (August 2005): 901–5. http://dx.doi.org/10.4161/cbt.4.8.2154.
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Linehan, W. Marston. "Identification of the genes for kidney cancer." Cancer Biology & Therapy 5, no. 6 (June 2006): 696–99. http://dx.doi.org/10.4161/cbt.5.6.2948.
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Britto, Ramona, and Kumaravel Somasundaram. "Highly specific targeting of HPV genes using ribozymes." Cancer Biology & Therapy 3, no. 11 (November 2004): 1135–36. http://dx.doi.org/10.4161/cbt.3.11.1296.
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Noce, Toshiaki, Shino Okamoto-Ito, and Naoki Tsunekawa. "Vasa Homolog Genes in Mammalian Germ Cell Development." Cell Structure and Function 26, no. 3 (2001): 131–36. http://dx.doi.org/10.1247/csf.26.131.
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Guo, Angela H., Christopher R. Comeau, Fang Chen, and Christopher J. Fry. "Abstract 4718: Analyses of epigenetic marks and mechanisms in disease: Your guide to a successful CUT&RUN assay." Cancer Research 83, no. 7_Supplement (April 4, 2023): 4718. http://dx.doi.org/10.1158/1538-7445.am2023-4718.
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Abstract Like the chromatin immunoprecipitation (ChIP) assay, Cleavage Under Targets & Release Using Nuclease (CUT&RUN) is a powerful and versatile technique used for probing protein-DNA interactions within the natural chromatin context of the cell. The CUT&RUN assay can be combined with downstream qPCR or NG-seq to analyze histone modifications and binding of transcription factors, DNA replication factors, or DNA repair proteins at specific target genes or across the entire genome. CUT&RUN provides a rapid, robust, and true low cell number assay for detection of protein-DNA interactions in the cell. Unlike the ChIP assay, CUT&RUN is free from formaldehyde cross-linking, chromatin fragmentation, and immunoprecipitation. Previously, we have shown that, compared to ChIP, CUT&RUN requires fewer starting cells (100K), has a much faster protocol (one day from cells to DNA), generates lower background signal (requires less sequencing depth), and offers spike-in control DNA for effective normalization of signal between samples and between experiments. We recently updated the CST CUT&RUN Assay Kit for use with 5,000-20,000 cells and added protocols for fixed cells and tissue. I will discuss the basics of the CUT&RUN assay and important factors to consider when setting up your experiment. In addition, I will provide data showing the versatility of this assay for mapping various histone modifications, transcription factor, and transcription cofactor binding across multiple sample types. Finally, I will discuss how the general protocol is optimized for greater signal to noise ratio, reduced number of starting cells, and provide an alternative digestion method to prepare the input DNA as a critical control of the CUT&RUN experiment. Citation Format: Angela H. Guo, Christopher R. Comeau, Fang Chen, Christopher J. Fry. Analyses of epigenetic marks and mechanisms in disease: Your guide to a successful CUT&RUN assay. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4718.
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Li, Peng, Bo Sun, and Maozu Guo. "Identification of Novel Cancer-Related Genes with a Prognostic Role Using Gene Expression and Protein-Protein Interaction Network Data." Journal of Computing and Information Technology 27, no. 3 (May 7, 2020): 57–71. http://dx.doi.org/10.20532/cit.2019.1004856.
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Early cancer diagnosis and prognosis prediction are necessary for cancer patients. Effective identification of cancer-related genes and biomarkers and survival prediction for cancer patients would facilitate personalized treatment of cancer patients. This study aimed to investigate a method for integrating data regarding gene expression and protein-protein interaction networks to identify cancer-related prognostic genes via random walk with restart algorithm and survival analysis. Known cancer-related genes in protein-protein interaction networks were considered seed genes, and the random walk algorithm was used to identify candidate cancer-related genes. Thereafter, using the univariant Cox regression model, gene expression data were screened to identify survival-related genes. Furthermore, candidate genes and survival-related genes were screened to identify cancer-related prognostic genes. Finally, the effectiveness of the method was verified through gene function analysis and survival prediction. The results indicate that the cancer-related genes can be considered prognostic cancer biomarkers and provide a basis for cancer diagnosis.
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Høyer, Helle, Geir J. Braathen, Øyvind L. Busk, Øystein L. Holla, Marit Svendsen, Hilde T. Hilmarsen, Linda Strand, Camilla F. Skjelbred, and Michael B. Russell. "Genetic Diagnosis of Charcot-Marie-Tooth Disease in a Population by Next-Generation Sequencing." BioMed Research International 2014 (2014): 1–13. http://dx.doi.org/10.1155/2014/210401.
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Charcot-Marie-Tooth (CMT) disease is the most prevalent inherited neuropathy. Today more than 40 CMT genes have been identified. Diagnosing heterogeneous diseases by conventional Sanger sequencing is time consuming and expensive. Thus, more efficient and less costly methods are needed in clinical diagnostics. We included a population based sample of 81 CMT families. Gene mutations had previously been identified in 22 families; the remaining 59 families were analysed by next-generation sequencing. Thirty-two CMT genes and 19 genes causing other inherited neuropathies were included in a custom panel. Variants were classified into five pathogenicity classes by genotype-phenotype correlations and bioinformatics tools. Gene mutations, classified certainly or likely pathogenic, were identified in 37 (46%) of the 81 families. Point mutations in known CMT genes were identified in 21 families (26%), whereas four families (5%) had point mutations in other neuropathy genes,ARHGEF10, POLG, SETX,andSOD1. Eleven families (14%) carried thePMP22duplication and one family carried aMPZduplication (1%). Most mutations were identified not only in known CMT genes but also in other neuropathy genes, emphasising that genetic analysis should not be restricted to CMT genes only. Next-generation sequencing is a cost-effective tool in diagnosis of CMT improving diagnostic precision and time efficiency.
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Sun, Shi-Yong. "How Much Do We Know About Retinoid-Regulated Genes?" Cancer Biology & Therapy 1, no. 1 (January 2002): 28–30. http://dx.doi.org/10.4161/cbt.1.1.36.
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Ruggiero, Marco. "Static magnetic fields, blood and genes: an intriguing relationship." Cancer Biology & Therapy 7, no. 6 (June 2008): 820–21. http://dx.doi.org/10.4161/cbt.7.6.6299.
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Wartiovaara-Kautto, Ulla, Elina A. M. Hirvonen, Kaisa Kettunen, Anna Nordberg, Janna Saarela, Kimmo Porkka, Tero Kivelä, Tarja Linnankivi, and Outi Kilpivaara. "A Novel Homozygous CTC1 Germline Mutation Associated with Bone Marrow Failure." Blood 128, no. 22 (December 2, 2016): 1508. http://dx.doi.org/10.1182/blood.v128.22.1508.1508.
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Abstract Iron deficiency in young adult males is rare and necessitates prompt investigations. Here we describe a previously healthy 22-year-old male suffering from gastrointestinal bleeding leading to iron deficiency anemia and explained by a constitutional disease. His diagnosis was obtained after detecting a homozygous CTC1 mutation in his germline DNA. Conserved telomere maintenance component 1 (CTC1) is a part of the conserved telomere-associated complex (CST) participating in telomere replication. CST seems to have a role in resolving replication stress also in non-telomeric regions, but little is known about the exact mechanisms. Biallelic, typically compound heterozygous mutations in CTC1 are known to cause cerebroretinal microangiopathy with calcifications and cysts(CRMCC), which is considered as a telomere disease. It is a highly pleiotropic multi-organ disease characterized by abnormalities e.g. in the brain, retina, intestinal vasculature, as well as bone marrow failure (BMF). Some CRMCC patients have dyskeratosis congenita (DC) -like skin, nail, mucosal, and hair changes. Most patients are diagnosed in early childhood and die before teens. To date 37 patients with CRMCC and CTC1 mutations have been reported. The patient was referred to hematology due to iron deficiency anemia with coinciding thrombocytopenia. He also had a notable lymphopenia but no tendency for viral infections or other signs of immunodeficiency. Imaging revealed a patent umbilical vein, widened portal vein, and hepatosplenomegaly without parenchymal changes or lymphadenopathy. Gaucher's disease was excluded by glucocerebrosidase and genetic tests. Histology of a liver biopsy was normal. Based on these findings an idiopathic portal hypertension was diagnosed. Endoscopy revealed gastric antral vascular ectasia. The bone marrow was hypoplastic and pancytopenia persisted after supplementation with iron. He had no known family history of BMF. The patient's telomere length analyzed by a semi-quantitative PCR-test was within the normal range compared to healthy controls of the same age group. We then sequenced the patient's germline exome. Roche MedExome kit was used to target the coding regions of the genome and sequencing conducted using an Illumina HiSeq1500 sequencer. The quality of the data was assessed and the sequence data analyzed using an in-house developed analysis pipeline. The mutation analysis was targeted to genes previously reported to cause immune deficiencies, myelodysplastic syndrome and BMF. The average sequence coverage was 59x, translating into 95% of the exome being covered with a minimum of 20x. Common polymorphisms were excluded from the analysis. The patient was identified to carry a homozygous variation in CTC1 exon 12; c.1994T>G, p.V665G (rs199473676). The variant has previously been reported pathogenic, but all previously reported cases of p.V665G are compound heterozygous (in the majority of cases V665G and a frameshift mutation). The minor allele frequency for this variant in Finns is 0.0015 (10/6612 alleles) and 0.0001 (13/120608) in total (ExAC database) suggesting this mutation is a Finnish founder mutation. We validated the finding by capillary sequencing. The variant was detected heterozygous in both parents ruling out a larger deletion and verifying the mode of inheritance. A healthy sister did not carry the mutation. Identification of CTC1 p.V665G homozygosity raised a high suspicion of CRMCC and further investigations were indicated. Retinal examination as well as brain MRI/MRA revealed multiple lesions characteristic for CRMCC. This is the first report on homozygous CTC1 p.V665G and the second describing CTC1-homozygosity associated with CRMCC, strengthening the disease-causality of biallelic missense mutations in CTC1. The identification of a homozygous CTC1 p.V665G may also open new prospects for studying the effects of the mutation. Our case shows the importance and capacity of new genomic techniques in clinical management, as well: The patient's primary phenotype with iron deficiency anemia, thrombopenia and hepatosplenomegaly could have been explained by only an idiopathic portal hypertension. However, with exome sequencing we were able to reveal a more complex disease entity with major impact on patient's future care and genetic counseling, highlighting the value of germline sequencing in modern diagnostics. Disclosures No relevant conflicts of interest to declare.
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Victorian, Brande. "Genes May Predict Risk Level in Myeloma." Oncology Times 29, no. 20 (October 2007): 54. http://dx.doi.org/10.1097/01.cot.0000298607.28362.18.
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Balko, Justin M., and Ester P. Black. "Do the genes tell us the path of most resistance?" Cancer Biology & Therapy 11, no. 2 (January 15, 2011): 213–15. http://dx.doi.org/10.4161/cbt.11.2.13922.
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Singhal, Sunil, Chris G. Kyvernitis, Steven W. Johnson, Larry R. Kaiser, Michael N. Liebman, and Steven M. Albelda. "MicroArray Data Simulator For Improved Selection of Differentially Expressed Genes." Cancer Biology & Therapy 2, no. 4 (July 20, 2003): 383–91. http://dx.doi.org/10.4161/cbt.2.4.431.
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Burgar, Helen, Phillip Gould, and Peter Lund. "Homologous chaperonin genes in Rhizobium leguminosarum are not functionally equivalent." Cell Stress & Chaperones preprint, no. 2007 (2005): 1. http://dx.doi.org/10.1379/csc-227.
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Takeda, Aoi, Shigeaki Saitoh, Hiroyuki Ohkura, Kenneth E. Sawin, and Gohta Goshima. "Identification of 15 New Bypassable Essential Genes of Fission Yeast." Cell Structure and Function 44, no. 2 (2019): 113–19. http://dx.doi.org/10.1247/csf.19025.
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