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Dymova, Maya Alexandrovna, Yaroslav Alexandrovich Utkin, Maria Denisovna Dmitrieva, Elena Vladimirovna Kuligina, and Vladimir Alexandrovich Richter. "Modification of a Tumor-Targeting Bacteriophage for Potential Diagnostic Applications." Molecules 26, no. 21 (October 29, 2021): 6564. http://dx.doi.org/10.3390/molecules26216564.
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Background: Tumor-targeting bacteriophages can be used as a versatile new platform for the delivery of diagnostic imaging agents and therapeutic cargo. This became possible due to the development of viral capsid modification method. Earlier in our laboratory and using phage display technology, phages to malignant breast cancer cells MDA-MB 231 were obtained. The goal of this study was the optimization of phage modification and the assessment of the effect of the latter on the efficiency of phage particle penetration into MDA-MB 231 cells. Methods: In this work, we used several methods, such as chemical phage modification using FAM-NHS ester, spectrophotometry, phage amplification, sequencing, phage titration, flow cytometry, and confocal microscopy. Results: We performed chemical phage modification using different concentrations of FAM-NHS dye (0.5 mM, 1 mM, 2 mM, 4 mM, 8 mM). It was shown that with an increase of the modification degree, the phage titer decreases. The maximum modification coefficient of the phage envelope with the FAM–NHS dye was observed with 4 mM modifying agent and had approximately 804,2 FAM molecules per phage. Through the immunofluorescence staining and flow cytometry methods, it was shown that the modified bacteriophage retains the ability to internalize into MDA-MB-231 cells. The estimation of the number of phages that could have penetrated into one tumor cell was conducted. Conclusions: Optimizing the conditions for phage modification can be an effective strategy for producing tumor-targeting diagnostic and therapeutic agents, i.e., theranostic drugs.
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Brown, D. J., E. J. Threlfall, M. D. Hampton, and B. Rowe. "Molecular characterization of plasmids in Salmonella enteritidis phage types." Epidemiology and Infection 110, no. 2 (April 1993): 209–16. http://dx.doi.org/10.1017/s0950268800068126.
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SUMMARYPlasmids in selected type strains of 26 of the Salmonella enteritidis phage types have been characterized by restriction enzyme fingerprinting and by DNA–DNA hybridization with oligonucleotide probes for Salmonella plasmid virulence (Spv) genes. With one exception, the fingerprints of the 38 MDa plasmids studied were homogeneous but there was heterogeneity in the fingerprints of 59 MDa plasmids found in 4 of the type strains. However all 38 MDa and 59 MDa plasmids were related as was a 45 MDa plasmid identified in the type strain of phage type 19. A 3·5 kb fragment homologous to SpvC was conserved in Hind III digests of all 38 MDa and 59 MDa plasmids, and in the related 45 MDa plasmid. In contrast a 65 MDa plasmid found in the type strain of phage type 10 was not related to these three plasmid molecular weight groups and did not carry the SpvC gene.
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van Passel, Mark W. J., Arie van der Ende, and Aldert Bart. "Plasmid Diversity in Neisseriae." Infection and Immunity 74, no. 8 (August 2006): 4892–99. http://dx.doi.org/10.1128/iai.02087-05.
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ABSTRACT Horizontal gene transfer constitutes an important force in prokaryotic genome evolution, and it is well-known that plasmids are vehicles for DNA transfer. Chromosomal DNA is frequently exchanged between pathogenic and commensal neisseriae, but relatively little is known about plasmid diversity and prevalence among these nasopharyngeal inhabitants. We investigated the plasmid contents of 18 Neisseria lactamica isolates and 20 nasopharyngeal Neisseria meningitidis isolates. Of 18 N. lactamica strains, 9 harbored one or more plasmids, whereas only one N. meningitidis isolate contained a plasmid. Twelve plasmids were completely sequenced, while five plasmid sequences from the public databases were also included in the analyses. On the basis of nucleic acid sequences, mobilization, and replicase protein alignments, we distinguish six different plasmid groups (I to VI). Three plasmids from N. lactamica appeared to be highly similar on the nucleotide level to the meningococcal plasmids pJS-A (>99%) and pJS-B (>75%). The genetic organizations of two plasmids show a striking resemblance with that of the recently identified meningococcal disease-associated (MDA) phage, while four putative proteins encoded by these plasmids show 25% to 39% protein identity to those encoded by the MDA phage. The putative promoter of the gene encoding the replicase on these plasmids contains a polycytidine tract, suggesting that replication is subjected to phase variation. In conclusion, extensive plasmid diversity is encountered among commensal neisseriae. Members of three plasmid groups are found in both pathogenic and commensal neisseriae, indicating plasmid exchange between these species. Resemblance between plasmids and MDA phage may be indicative of dissemination of phage-related sequences among pathogenic and commensal neisseriae.
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Kozarsky, Phyllis E., David Rimland, Pamela M. Terry, and Kaye Wachsmuth. "Plasmid Analysis of Simultaneous Nosocomial Outbreaks of Methicillin-Resistant Staphylococcus aureus." Infection Control 7, no. 12 (December 1986): 577–81. http://dx.doi.org/10.1017/s0195941700065413.
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AbstractA large outbreak of infections caused by methicillin and aminoglycoside resistant Staphylococcus aureus provided the opportunity to evaluate mechanisms of resistance and compare the usefulness of typing systems. Between January 1979 and December 1980, 63 patients developed infections with S aureus resistant to multiple antibiotics, including methicillin and tobramycin. All isolates had an identical antibiogram and were phage type 47/54/75/77/83A. Beginning in January 1981, a superimposed outbreak caused by S aureus of the same phage type but with a resistance pattern now including gentamicin occurred. The two strains contained different aminoglycoside inactivating enzymes. The initial strain contained a single plasmid of 21.5 mDa molecular weight, whereas the subsequent strain which had acquired gentamicin resistance contained this plasmid plus a heavier one of 33 mDa. Plasmid analysis complements the analysis of antibiograms and phage types and aids in defining epidemiologic patterns of transmission.
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Pertics, Botond Zsombor, Tamás Kovács, and György Schneider. "Characterization of a Lytic Bacteriophage and Demonstration of Its Combined Lytic Effect with a K2 Depolymerase on the Hypervirulent Klebsiella pneumoniae Strain 52145." Microorganisms 11, no. 3 (March 6, 2023): 669. http://dx.doi.org/10.3390/microorganisms11030669.
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Klebsiella pneumoniae is a nosocomial pathogen. Among its virulence factors is the capsule with a prominent role in defense and biofilm formation. Bacteriophages (phages) can evoke the lysis of bacterial cells. Due to the mode of action of their polysaccharide depolymerase enzymes, phages are typically specific for one bacterial strain and its capsule type. In this study, we characterized a bacteriophage against the capsule-defective mutant of the nosocomial K. pneumoniae 52145 strain, which lacks K2 capsule. The phage showed a relatively narrow host range but evoked lysis on a few strains with capsular serotypes K33, K21, and K24. Phylogenetic analysis showed that the newly isolated Klebsiella phage 731 belongs to the Webervirus genus in the Drexlerviridae family; it has a 31.084 MDa double-stranded, linear DNA with a length of 50,306 base pairs and a G + C content of 50.9%. Out of the 79 open reading frames (ORFs), we performed the identification of orf22, coding for a trimeric tail fiber protein with putative capsule depolymerase activity, along with the mapping of other putative depolymerases of phage 731 and homologous phages. Efficacy of a previously described recombinant K2 depolymerase (B1dep) was tested by co-spotting phage 731 on K. pneumoniae strains, and it was demonstrated that the B1dep-phage 731 combination allows the lysis of the wild type 52145 strain, originally resistant to the phage 731. With phage 731, we showed that B1dep is a promising candidate for use as a possible antimicrobial agent, as it renders the virulent strain defenseless against other phages. Phage 731 alone is also important due to its efficacy on K. pneumoniae strains possessing epidemiologically important serotypes.
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Tonin, Patricia N., and Robert B. Grant. "Genetic and physical characterization of trimethoprim resistance plasmids from Shigella sonnei and Shigella flexneri." Canadian Journal of Microbiology 33, no. 10 (October 1, 1987): 905–13. http://dx.doi.org/10.1139/m87-157.
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Analysis of six Shigella flexneri and four S. sonnei isolates with trimethoprim (Tp) resistance from clinical cases in Ontario has shown that, in all isolates, the Tp resistance is mediated by gene(s) on conjugative, multiple antibiotic-resistance plasmids. The physical and genetic characterization of these plasmids revealed that there are three different Tp resistance plasmids. One group, composed of all six S. flexneri plasmids, consists of plasmids which are about 70 megadaltons (MDa) and inhibit the fertility of an Escherichia coli Hfr strain (Fi+). A representative member of this group, pPT4, demonstrates a weak incompatibility reaction with IncFI plasmid R455-2. Another group, three of the four S. sonnei plasmids, contains plasmids which are about 43 MDa, Fi−, and mediate propagation of phage PRD1. The third group, the remaining S. sonnei plasmid, is 53 MDa,fi+, mediates propagation of phages fd and MS2, and is incompatible with IncFII plasmid R100. These plasmids also have been differentiated by restriction endonuclease fragment profiles. Analysis of pPT4 has revealed that the Tp resistance of this plasmid is transposable. The transposon, Tn536, is different from previously described Tp resistance transposons; it is 16 MDa, and in addition to Tp, it encodes resistance to mercuric chloride ions, spectinomycin, streptomycin, and sulfonamides.
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Petrenko, Valery A., James W. Gillespie, Hai Xu, Tiffany O’Dell, and Laura M. De Plano. "Combinatorial Avidity Selection of Mosaic Landscape Phages Targeted at Breast Cancer Cells—An Alternative Mechanism of Directed Molecular Evolution." Viruses 11, no. 9 (August 26, 2019): 785. http://dx.doi.org/10.3390/v11090785.
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Low performance of actively targeted nanomedicines required revision of the traditional drug targeting paradigm and stimulated the development of novel phage-programmed, self-navigating drug delivery vehicles. In the proposed smart vehicles, targeting peptides, selected from phage libraries using traditional principles of affinity selection, are substituted for phage proteins discovered through combinatorial avidity selection. Here, we substantiate the potential of combinatorial avidity selection using landscape phage in the discovery of Short Linear Motifs (SLiMs) and their partner domains. We proved an algorithm for analysis of phage populations evolved through multistage screening of landscape phage libraries against the MDA-MB-231 breast cancer cell line. The suggested combinatorial avidity selection model proposes a multistage accumulation of Elementary Binding Units (EBU), or Core Motifs (CorMs), in landscape phage fusion peptides, serving as evolutionary initiators for formation of SLiMs. Combinatorial selection has the potential to harness directed molecular evolution to create novel smart materials with diverse novel, emergent properties.
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Binkin, N., G. Scuderi, F. Novaco, G. L. Giovanardi, G. Paganelli, G. Ferrari, O. Cappelli, et al. "Egg-relatedSalmonella enteritidis, Italy, 1991." Epidemiology and Infection 110, no. 2 (April 1993): 227–37. http://dx.doi.org/10.1017/s095026880006814x.
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SUMMARYIn recent years,Salmonella enteritidishas become an increasingly important public health problem in Italy. In some parts of the country, the fraction of total human salmonella isolates accounted for byS. enteritidishas risen from 3–4% in the mid-1980s to more than 30% in 1990. Between 1090 and 1991. the number of reportedS. enteritidisoutbreaks increased more than sixfold. The 33 outbreaks reported in 1991 occurred in seven contiguous regions in northern and central Italy and were clustered in time between June and October: in the majority, products containing raw or undercooked shell eggs were implicated. Five of the egg-related outbreaks that occurred within a 30 kilometre radius over a 7-week period were investigated in detail. A phage type 1 strain containing a 38·9 MDa plasmid appeared responsible for three of the outbreaks, while in the remaining two a phage type 4 strain, also with a 38·9 MDa plasmid was isolated. Efforts are being made to enhance epidemiological surveillance and laboratory evaluation, and the use of pasteurized eggs has been recommended for high-risk populations.
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Harnett, N., S. McLeod, Y. AuYong, J. Wan, S. Alexander, R. Khakhria, and C. Krishnan. "Molecular characterization of multiresistant strains ofSalmonella typhifrom South Asia isolated in Ontario, Canada." Canadian Journal of Microbiology 44, no. 4 (April 1, 1998): 356–63. http://dx.doi.org/10.1139/w98-012.
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Two hundred and fourteen isolates of Salmonella typhi submitted to our laboratory between 1992 and 1996 were tested for susceptibility to 20 antimicrobial agents. Forty-eight of the 214 isolates (22.4%), recovered from individuals who had travelled in South Asia, were multiresistant. Forty-four of the 48 isolates were resistant to ampicillin, chloramphenicol, tetracycline, streptomycin, sulfamethoxazole, trimethoprim, cotrimoxazole, ticarcillin, and piperacillin; the other four isolates were resistant to four to six agents. Forty-two of the multiresistant isolates belonged to Vi phage type E1, two isolates from the Punjab State belonged to phage type A, another from the Punjab State belonged to phage type E3, one isolate from Pakistan belonged to type M1, and one isolate from India belonged to type J1. Plasmids from 45 of 48 isolates showed a temperature-sensitive mechanism of transfer to Escherichia coli K-12 strains, characteristic of HI incompatibility group plasmids. The majority of plasmids had an estimated molecular weight of 120 MDa and encoded both citrate utilization and mercury resistance. Plasmids from three isolates had an estimated molecular weight of 112-115 MDa; one of these isolates encoded citrate utilization but not mercury resistance. Analysis of isolates by pulsed-field gel electrophoresis after digestion with XbaI and SpeI indicated that the majority of multiresistant isolates shared a common restriction profile, while four isolates had unique patterns.Key words: typing, multiresistant, Salmonella typhi.
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Stanley, J., A. P. Burnens, E. J. Threlfall, N. Chowdry, and M. Goldsworthy. "Genetic relationships among strains ofSalmonella enteritidisin a national epidemic in Switzerland." Epidemiology and Infection 108, no. 2 (April 1992): 213–20. http://dx.doi.org/10.1017/s0950268800049694.
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SUMMARYA collection ofSalmonella enteritidisstrains isolated in Switzerland (1965–90) was characterized. The phage type and plasmid profile of isolates were compared with the copy number and insertion loci of the DNA insertion element IS200. Three clonal lines ofS. enteritidiswere identified by IS200profile; the various phage types were subtypes reproducibly associated with one of these lines. All human and poultry isolates contained a 38 Mda plasmid which hybridized with a mouse virulence-associated gene probe. InS. enteritidis, the IS200profile is a race-specific molecular marker of the chromosome, and may be particularly applicable for studying the epidemiology of less common serovars.
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Al Suwayyid, Barakat A., Leah Rankine-Wilson, David J. Speers, Michael J. Wise, Geoffrey W. Coombs, and Charlene M. Kahler. "Meningococcal Disease-Associated Prophage-Like Elements Are Present in Neisseria gonorrhoeae and Some Commensal Neisseria Species." Genome Biology and Evolution 12, no. 2 (February 1, 2020): 3938–50. http://dx.doi.org/10.1093/gbe/evaa023.
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Abstract Neisseria spp. possess four genogroups of filamentous prophages, termed Nf1 to 4. A filamentous bacteriophage from the Nf1 genogroup termed meningococcal disease-associated phage (MDA φ) is associated with clonal complexes of Neisseria meningitidis that cause invasive meningococcal disease. Recently, we recovered an isolate of Neisseria gonorrhoeae (ExNg63) from a rare case of gonococcal meningitis, and found that it possessed a region with 90% similarity to Nf1 prophages, specifically, the meningococcal MDA φ. This led to the hypothesis that the Nf1 prophage may be more widely distributed amongst the genus Neisseria. An analysis of 92 reference genomes revealed the presence of intact Nf1 prophages in the commensal species, Neisseria lactamica and Neisseria cinerea in addition to the pathogen N. gonorrhoeae. In N. gonorrhoeae, Nf1 prophages had a restricted distribution but were present in all representatives of MLST ST1918. Of the 160 phage integration sites identified, only one common insertion site was found between one isolate of N. gonorrhoeae and N. meningitidis. There was an absence of any obvious conservation of the receptor for prophage entry, PilE, suggesting that the phage may have been obtained by natural transformation. An examination of the restriction modification systems and mutated mismatch repair systems with prophage presence suggested that there was no obvious preference for these hosts. A timed phylogeny inferred that N. meningitidis was the donor of the Nf1 prophages in N. lactamica and N. gonorrhoeae. Further work is required to determine whether Nf1 prophages are active and can act as accessory colonization factors in these species.
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Cremers, Geert, Lavinia Gambelli, Theo van Alen, Laura van Niftrik, and Huub J. M. Op den Camp. "Bioreactor virome metagenomics sequencing using DNA spike-ins." PeerJ 6 (February 7, 2018): e4351. http://dx.doi.org/10.7717/peerj.4351.
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With the emergence of Next Generation Sequencing, major advances were made with regard to identifying viruses in natural environments. However, bioinformatical research on viruses is still limited because of the low amounts of viral DNA that can be obtained for analysis. To overcome this limitation, DNA is often amplified with multiple displacement amplification (MDA), which may cause an unavoidable bias. Here, we describe a case study in which the virome of a bioreactor is sequenced using Ion Torrent technology. DNA-spiking of samples is compared with MDA-amplified samples. DNA for spiking was obtained by amplifying a bacterial 16S rRNA gene. After sequencing, the 16S rRNA gene reads were removed by mapping to the Silva database. Three samples were tested, a whole genome from Enterobacteria P1 Phage and two viral metagenomes from an infected bioreactor. For one sample, the new DNA-spiking protocol was compared with the MDA technique. When MDA was applied, the overall GC content of the reads showed a bias towards lower GC%, indicating a change in composition of the DNA sample. Assemblies using all available reads from both MDA and the DNA-spiked samples resulted in six viral genomes. All six genomes could be almost completely retrieved (97.9%–100%) when mapping the reads from the DNA-spiked sample to those six genomes. In contrast, 6.3%–77.7% of three viral genomes was covered by reads obtained using the MDA amplification method and only three were nearly fully covered (97.4%–100%). This case study shows that DNA-spiking could be a simple and inexpensive alternative with very low bias for sequencing of metagenomes for which low amounts of DNA are available.
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Veesler, D., S. Spinelli, J. Mahony, J. Lichiere, S. Blangy, G. Bricogne, P. Legrand, et al. "Structure of the phage TP901-1 1.8 MDa baseplate suggests an alternative host adhesion mechanism." Proceedings of the National Academy of Sciences 109, no. 23 (May 18, 2012): 8954–58. http://dx.doi.org/10.1073/pnas.1200966109.
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El Haddad, Lynn, Cynthia P. Harb, Mark Stibich, Roy F. Chemaly, and Roy F. Chemaly. "736. The Use of Bacteriophages to Inhibit Different Strains of Vancomycin-Resistant or Susceptible Enterococci." Open Forum Infectious Diseases 6, Supplement_2 (October 2019): S329—S330. http://dx.doi.org/10.1093/ofid/ofz360.804.
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Abstract Background Vancomycin-resistant Enterococci (VRE) is a well-known infectious complication among immunocompromised patients, especially hematopoietic cell transplant (HCT) recipients. VRE colonization of the gastrointestinal tract could be associated with VRE bacteremia and worse outcomes in HCT recipients. The use of systemic antibiotics to eradicate VRE colonization is highly discouraged because of the lack of efficacy, the rapid onset of antibiotic resistance, and the disruption of the normal microbiota. Bacteriophages (phages) may constitute a good alternative to antibiotics to eliminate specific pathogens without disrupting the patient’s normal microbiota. Methods Sewage samples were collected from the City of Houston for phages isolation. Samples were centrifuged, filtered and exposed to several targeted VRE host strains. After several amplification, the final filtrate was titrated and checked for the presence of VRE-specific phages. Isolated phages were observed under electron microscopy and were tested against multiple VRE strains isolated from different sources including patients’ stool samples, patients’ room environment, sewage samples, clinical isolates of daptomycin-resistant VRE strains or vancomycin-susceptible Enterococcus faecium (VSEF) and Enterococcus faecalis (VSEf) strains. Results Four VRE-specific phages were isolated from sewage samples (MDA1, MDA2, MDA3, and MDA4). All phages belong to the Caudovirales order. Phage MDA1 belongs to the Podoviridae family, phage MDA2 is a Siphoviridae, whereas MDA3 and MDA4 belong to the Myoviridae family (Figure 1A). All phages were lytic and were able to inhibit at least four VRE strains and only MDA1 had activity against VSEF and MDA4 against VSEf. The efficacy of these lytic phages complemented one another as the combination of these four phages inhibited all different VRE strains (Figure 1B). Conclusion Our results highlight the feasibility and the potential success of these phages in inhibiting VRE in vitro. These VRE-specific phage cocktails may be used in future studies to reduce VRE colonization and subsequent infections in HCT recipients. Disclosures Roy F. Chemaly, MD, MPH, FACP, FIDSA, Chimerix: Advisory Board, Research Grant; Clinigen: Advisory Board; Merck: Advisory Board, Consultant, Grant/Research Support, Research Grant, Speaker’s Bureau; Oxford immunotec: Consultant, Grant/Research Support; Shire: Research Grant, Speaker’s Bureau; Viracor: Grant/Research Support.
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Asensi, Marise Dutra, Arudy Penna Costa, Eliane Moura Falavina dos Reis, and Ernesto Hofer. "Lysotypes and plasmidial profile of Salmonella Serovar Typhimurium isolated from children with enteric processes in the cities of Rio de Janeiro, RJ, and Salvador, BA - Brazil." Revista do Instituto de Medicina Tropical de São Paulo 37, no. 4 (August 1995): 297–302. http://dx.doi.org/10.1590/s0036-46651995000400003.
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The lysotypes, plasmidial profiles, and profiles of resistance to antimicrobial agents were determined in 111 Salmonella Typhimurium strains isolated from feces and blood of children treated in Rio de Janeiro and in Salvador. Six distinct lysotypes (19, 41, 97, 105, 120 and 193) were recognized, with a predominance of lysotype 193 (59.7%) in Rio de Janeiro and of phage type 105 (38.4) in Salvador. Approximately 86.7% of the lysotype 193 strains presented multiple resistance to more than six antimicrobial agents, whereas 93% of lysotype 105 strains were fully susceptible. More than 90% of the strains presented plasmids distributed into 36 different profiles in Rio de Janeiro and into 10 profiles in Salvador. A 40 MDa plasmid was the most frequent (47%) in the strains from Rio de Janeiro, whereas a 61 MDa plasmid predominated (14.5%) in Salvador. Combined analysis of plasmid profile and classification into lysotypes (especially those belonging to types 105 and 103, proved to be more discriminatory than the other methods applied).
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Mäkelä, Anna R., Heli Matilainen, Daniel J. White, Erkki Ruoslahti, and Christian Oker-Blom. "Enhanced Baculovirus-Mediated Transduction of Human Cancer Cells by Tumor-Homing Peptides." Journal of Virology 80, no. 13 (July 1, 2006): 6603–11. http://dx.doi.org/10.1128/jvi.00528-06.
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ABSTRACT Tumor cells and vasculature offer specific targets for the selective delivery of therapeutic genes. To achieve tumor-specific gene transfer, baculovirus tropism was manipulated by viral envelope modification using baculovirus display technology. LyP-1, F3, and CGKRK tumor-homing peptides, originally identified by in vivo screening of phage display libraries, were fused to the transmembrane anchor of vesicular stomatitis virus G protein and displayed on the baculoviral surface. The fusion proteins were successfully incorporated into budded virions, which showed two- to fivefold-improved binding to human breast carcinoma (MDA-MB-435) and hepatocarcinoma (HepG2) cells. The LyP-1 peptide inhibited viral binding to MDA-MB-435 cells with a greater magnitude and specificity than the CGKRK and F3 peptides. Maximal 7- and 24-fold increases in transduction, determined by transgene expression level, were achieved for the MDA-MB-435 and HepG2 cells, respectively. The internalization of each virus was inhibited by ammonium chloride treatment, suggesting the use of a similar endocytic entry route. The LyP-1 and F3 peptides showed an apparent inhibitory effect in transduction of HepG2 cells with the corresponding display viruses. Together, these results imply that the efficiency of baculovirus-mediated gene delivery can be significantly enhanced in vitro when tumor-targeting ligands are used and therefore highlight the potential of baculovirus vectors in cancer gene therapy.
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Fernandes, Sueli A., Ângela C. R. Ghilardi, Ana T. Tavechio, Antonia M. O. Machado, and Antonio C. C. Pignatari. "Phenotypic and molecular characterization of Salmonella Enteritidis strains isolated in São Paulo, Brazil." Revista do Instituto de Medicina Tropical de São Paulo 45, no. 2 (April 2003): 59–63. http://dx.doi.org/10.1590/s0036-46652003000200001.
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In São Paulo State, Brazil, the epidemic increase in isolation of Salmonella Enteritidis has been observed since 1994. A total of 105 S. Enteritidis strains (72 from human and 33 from non-human sources) isolated during the period 1975-1995, previously characterized by phage typing, was analyzed by antimicrobial susceptibility, plasmid profile, and ribotyping. Over 70% of the strains were susceptible to all antimicrobial agents tested, however, multiple resistance to antimicrobials was observed among the studied strains, mainly those from hospitalized patients. Phage type 8 (PT-8) was predominant among the strains isolated during the period of 1975-1992, but in the following years, PT-4 was the most frequent phage type identified. Seven different plasmid profiles were detected and 96% of the isolates harbored a plasmid of approximately 36 MDa. Ribotyping discriminated fourteen ribotypes (R1 to R14) among the strains examined. By analysis of dendrogram the strains were included in three groups with similarity level of 60%. The obtained results indicate that, a single ribotype (R11), determined for PT-4 strains isolated from 1993, characterizes the epidemic clone of S. Enteritidis in our region.
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Chart, H., D. Conway, and B. Rowe. "Outer membrane characteristics of Salmonella enteritidis phage type 4 growing in chickens." Epidemiology and Infection 111, no. 3 (December 1993): 449–54. http://dx.doi.org/10.1017/s0950268800057174.
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SummaryStrains of Salmonella enteritidis belonging to phage type 4 (SE4) were grown in the peritoneal cavities of chickens, and without subculture on laboratory media examined for inducible in vivo phenotypic characteristics. These bacteria expressed three major outer membrane proteins (OMPs) of 33, 35 and 36 kilodaltons (kDa), and iron regulated OMPs of 74, 78 and 81 kDa. Bacteria growing in vivo did not express flagella, or fimbriae with a subunit molecular mass of 14 kDa (14 kDa fimbriae). Two OMPs of 55 and 23 kDa, expressed during culture in nutrient broth, were repressed during growth in chickens. Possession of a 38 MDa ‘mouse virulence’ plasmid did not influence the expression of OMPs, flagella or fimbriae. It was concluded that strains of SE4 growing in chicken tissues, use an enterobactin mediated iron uptake system to obtain ferric ions, do not express flagella or 14 kDa fimbriae and appear not to express novel OMPs involved in survival in vivo.
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Threlfall, E. J., M. D. Hampton, H. Chart, and B. Rowe. "Use of plasmid profile typing for surveillance ofSalmonella enteritidisphage type 4 from humans, poultry and eggs." Epidemiology and Infection 112, no. 1 (February 1994): 25–31. http://dx.doi.org/10.1017/s0950268800057381.
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SummaryPlasmids were found in 1022 of 1089 (94%) of drug–sensitive strains ofSalmonella enteritidisphage type 4 from humans (sporadic and outbreak cases), poultry (chickens) and eggs in England and Wales in the 5-year period 1988–92 and 25 plasmid profile patterns were identified. Strains characterized by a single plasmid of 38 MDa predominated ( = plasmid profile type SE 38), comprising over 90% of isolates from humans, 70% from poultry and 92% from eggs. Eleven profile types were identified in strains from humans, 21 in strains from poultry and 3 in strains from eggs. Eight of the 11 patterns identified in human isolates were found in strains from poultry and 2 in strains from eggs. In contrast 15 patterns seen in poultry were not found in strains from humans. Four percent of strains from humans and 13% from poultry did not carry the 38 MDa plasmid but all strains from eggs were found to carry this plasmid. The second most common profile type in strains isolated between 1981 and 1988 was not identified in strains isolated from 1988–92. It is concluded that plasmid profile typing is a useful method for rapid differentiation within phage type 4 ofS. enteritidisbut that methods which can discriminate within the predominant profile type, SE 38, are now required.
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Nisticò, Nancy, Annamaria Aloisio, Antonio Lupia, Anna Maria Zimbo, Selena Mimmi, Domenico Maisano, Rossella Russo, et al. "Development of Cyclic Peptides Targeting the Epidermal Growth Factor Receptor in Mesenchymal Triple-Negative Breast Cancer Subtype." Cells 12, no. 7 (April 3, 2023): 1078. http://dx.doi.org/10.3390/cells12071078.
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Triple-negative breast cancer (TNBC) is an aggressive malignancy characterized by the lack of expression of estrogen and progesterone receptors and amplification of human epidermal growth factor receptor 2 (HER2). Being the Epidermal Growth Factor Receptor (EGFR) highly expressed in mesenchymal TNBC and correlated with aggressive growth behavior, it represents an ideal target for anticancer drugs. Here, we have applied the phage display for selecting two highly specific peptide ligands for targeting the EGFR overexpressed in MDA-MB-231 cells, a human TNBC cell line. Molecular docking predicted the peptide-binding affinities and sites in the extracellular domain of EGFR. The binding of the FITC-conjugated peptides to human and murine TNBC cells was validated by flow cytometry. Confocal microscopy confirmed the peptide binding specificity to EGFR-positive MDA-MB-231 tumor xenograft tissues and their co-localization with the membrane EGFR. Further, the peptide stimulation did not affect the cell cycle of TNBC cells, which is of interest for their utility for tumor targeting. Our data indicate that these novel peptides are highly specific ligands for the EGFR overexpressed in TNBC cells, and thus they could be used in conjugation with nanoparticles for tumor-targeted delivery of anticancer drugs.
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Li, Dan, Hejiao English, Jessica Hong, Tianyuzhou Liang, Glenn Merlino, Chi-Ping Day, and Mitchell Ho. "Abstract 576: Shark VNAR single domain-based CAR T cells targeting PD-L1 for cancer therapy." Cancer Research 82, no. 12_Supplement (June 15, 2022): 576. http://dx.doi.org/10.1158/1538-7445.am2022-576.
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Abstract Background: Chimeric antigen receptor (CAR)-T therapy shows great potency against hematological malignancies, whereas it is difficult to transfer CAR T into solid tumors due to lack of appropriate antigenic targets and immunosuppressive tumor microenvironment. Checkpoint molecule PD-L1 is widely overexpressed on multiple tumor types, and PD-1/PD-L1 interaction is a primary mediator of immunosuppression in the TME. Here, we generated anti-PD-L1-specific shark single domain VNAR-based CAR T cell strategy and explored its anti-tumor efficacy in xenograft mouse models. Methods: We isolated anti-PD-L1 single domain antibodies from semi-synthetic shark VNAR phage display libraries. The binding of isolated VNARs was validated by ELISA, flow cytometry, and Octet. A peptide library based on human PD-L1 was synthesized to predict the epitope of select VNARs. Anti-tumor efficacy of CAR T cells was determined via cell luciferase-based cell assay as well as xenograft mouse models. Two tumor models, MDA-MB-231 (triple-negative breast cancer) and Hep3B (hepatocellular carcinoma or HCC) were used in the present study. Glypican-3 (GPC3) is a tumor-specific target in the Hep3B model. Results: We identified three anti-PD-L1 phage binders, B2, A11, and F5 from our shark phage libraries. All three binders showed cross-activity to human, mouse, and canine antigens, whereas only B2 functionally blocked the interaction of human PD-1 to PD-L1. Moreover, CAR (B2) T cells specifically lysed both MDA-MB-231 and Hep3B tumor cells by targeting constitutive and inducible expression of PD-L1. Importantly, the combination of anti-GPC3 CAR (hYP7) T cells with CAR (B2) T cells regress Hep3B tumors synergistically in mice. Conclusions: PD-L1-targeted shark VNAR single domain-based CAR T cell therapy is a novel strategy to treat breast cancer and liver cancer. This work provides a rationale for a potential use of anti-PD-L1 CAR T cells as a monotherapy or combination with a tumor-specific therapy in clinical studies for solid tumors. Citation Format: Dan Li, Hejiao English, Jessica Hong, Tianyuzhou Liang, Glenn Merlino, Chi-Ping Day, Mitchell Ho. Shark VNAR single domain-based CAR T cells targeting PD-L1 for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 576.
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Ridley, A. M., E. J. Threlfall, and B. Rowe. "Genotypic Characterization of Salmonella enteritidis Phage Types by Plasmid Analysis, Ribotyping, and Pulsed-Field Gel Electrophoresis." Journal of Clinical Microbiology 36, no. 8 (1998): 2314–21. http://dx.doi.org/10.1128/jcm.36.8.2314-2321.1998.
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Pulsed-field gel electrophoresis (PFGE) was used to resolveXbaI and SpeI macrorestriction fragments from 60 defined phage type (PT) reference strains of Salmonella enteritidis. The level of discrimination was compared to that afforded by plasmid profile analysis and ribotyping. Twenty-eight distinct XbaI pulsed-field profiles (PFPs) were observed, although a single type, PFP X1, predominated. Absence of the 57-kbspv-associated fragment was observed for three PT reference strains, and the profile was designated PFP X1A. The XbaI macrorestriction profiles of a further four PT reference strains were altered by the presence of plasmid-associated bands. Twenty-sixSpeI-generated PFPs (plus one subtype) were observed for the same strains. No SpeI fragment corresponding to the 38-MDa serovar-specific plasmid was detected. The distribution ofXbaI and SpeI profiles did not always correspond, producing a total of 32 combined PFPs for the 60 PT reference strains. This compared with a total of 18 different plasmid profiles and three PvuII ribotypes generated by the same strains. The results of this study indicate that PFGE may offer an improved level of discrimination over other genotypic typing methods for the epidemiological typing of S. enteritidis.
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Babeker, Hanan, Fabrice Njotu, Jessica Ketchmen, Florence Tikum, Alireza Doroudi, Emmanuel Nwangele, Maruti Uppalapati, and Humphrey Fonge. "Abstract 6029: 225Ac/89Zr labeled anti nectin 4 radioimmunoconjugates as theranostics against nectin 4 positive triple negative breast cancer." Cancer Research 84, no. 6_Supplement (March 22, 2024): 6029. http://dx.doi.org/10.1158/1538-7445.am2024-6029.
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Abstract Nectin4 (N4) is a biomarker that is overexpressed in ~62% of triple negative breast cancer (TNBC) and its lack of expression in normal tissues makes it an ideal target for the therapy and PET imaging of TNBC. Methods: We developed a fully human antibody against nectin 4 (anti N4) using phage display. Anti N4 was radiolabeled with 89Zr & 225Ac, respectively, for imaging & radiotherapy using TNBC xenograft & syngeneic mouse models. TNBC murine 4T1 cells were transduced with human N4 and N4 expression was confirmed by FACS. Biodistribution & PET imaging of 89Zr anti N4 radioimmunoconjugate (RIC) was studied in mice bearing N4 positive xenografts. Dosimetry of 225Ac anti N4 was studied in healthy mice & the therapeutic efficacy was evaluated for 90 days in mice bearing MDA MB 468 xenograft & transduced 4T1 syngeneic models. Mice were treated with 2 doses of 350 nCi administered at 10 days apart. Tumor growth was monitored by a digital caliper. Results: The pharmacokinetic profile of 89Zr-anti-N4 RIC showed biphasic distribution with a moderate elimination of 63 h. PET imaging & biodistribution of 89Zr anti N4 in mice bearing MDA MB 468 xenograft showed high tumor uptake of 13.2 ± 1.12 %IA/g at 120 h. 225Ac anti N4 was effectively internalized in MDA MB 468 and was cytotoxic to the cells with IC50 of 1.2 kBq/mL. Treatment with 225Ac anti N4 led to complete tumor remission in all mice bearing MDA MB 468 xenografts and 4T1 syngeneic model by day 20 and 28, respectively. Conclusions: 89Zr anti N4 was an effective PET imaging probe with specific uptake in tumor. 225Ac anti N4 was effective as a therapeutic agent resulting in complete remission of tumors in both mouse xenograft & syngeneic models. These results are promising for the development of anti-N4 RICs as theranostics for TNBC. Citation Format: Hanan Babeker, Fabrice Njotu, Jessica Ketchmen, Florence Tikum, Alireza Doroudi, Emmanuel Nwangele, Maruti Uppalapati, Humphrey Fonge. 225Ac/89Zr labeled anti nectin 4 radioimmunoconjugates as theranostics against nectin 4 positive triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6029.
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El Haddad, Lynn, Cynthia P. Harb, Mark Stibich, Roy F. Chemaly, and Roy F. Chemaly. "735. Bacteriophage Therapy Improves Survival of Galleria mellonella Larvae Injected with Vancomycin-Resistant Enterococcus faecium." Open Forum Infectious Diseases 6, Supplement_2 (October 2019): S329. http://dx.doi.org/10.1093/ofid/ofz360.803.
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Abstract Background Vancomycin-resistant Enterococcus faecium (VRE) is a major multidrug-resistant organism which may cause infection or colonization in hematopoietic cell transplant (HCT) patients. The use of VRE-specific bacteriophages (phages) may potentially help eradicate VRE colonization and subsequent infections. To test the efficacy and safety of phages against VRE in vivo, a cocktail combining four phages was used in a VRE-infected larva model. Methods The pre-screening model Greater Wax Galleria mellonella larva was used in this study. Larvae were infected with VRE by injecting a VRE strain isolated from stools of a VRE-colonized HCT patient at a concentration of 107 colony-forming units/10 μL. A single phage (MDA1) or a phage cocktail (MDA1, MDA2, MDA3, and MDA4) were also injected at a concentration of 106 colony-forming units/10 μL. Two model groups were tested; a prevention group (PG) and a treatment group (TG). For the PG, phages were administered 1 hour before bacterial injection whereas the TG were injected with phages 1 hour post bacterial injection. Control groups included larvae injected with bacteria alone, phages alone (to measure toxicity due to phage administration), sterile media (to measure any lethal effects due to physical trauma from the injection), or without any manipulation. Every group was composed of 5 larvae. The insect’s health state was observed and scored after 8 hours of incubation at 37ºC using a published health index scoring system. Results Phages improved survival of VRE-infected larvae (table). Only 32% of the VRE-infected larvae survived after 8 hours of infection whereas more than 80% survived when adding phages, whether phages were administered before or after VRE infection. The phage cocktail was shown to be more effective than the single phage MDA1 in improving survival (66% vs. 82% survival). Injecting larvae with phages alone was safe as the same survival rate was observed when compared with those injected with sterile media or those without manipulation. Conclusion The use of larva model G. mellonella allows for rapid and efficient screening of the bacterial virulence and phage efficacy and safety. Such results highlight the feasibility and the potential impact of phage therapy on VRE colonization and infections. Disclosures Roy F. Chemaly, MD, MPH, FACP, FIDSA, Chimerix: Advisory Board, Research Grant; Clinigen: Advisory Board; Merck: Advisory Board, Consultant, Grant/Research Support, Research Grant, Speaker’s Bureau; Oxford immunotec: Consultant, Grant/Research Support; Shire: Research Grant, Speaker’s Bureau; Viracor: Grant/Research Support.
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Ferrara, Fortunato, Daniela I. Staquicini, Wouter H. P. Driessen, Sara D’Angelo, Andrey S. Dobroff, Marc Barry, Lesley C. Lomo, et al. "Targeted molecular-genetic imaging and ligand-directed therapy in aggressive variant prostate cancer." Proceedings of the National Academy of Sciences 113, no. 45 (October 24, 2016): 12786–91. http://dx.doi.org/10.1073/pnas.1615400113.
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Aggressive variant prostate cancers (AVPC) are a clinically defined group of tumors of heterogeneous morphologies, characterized by poor patient survival and for which limited diagnostic and treatment options are currently available. We show that the cell surface 78-kDa glucose-regulated protein (GRP78), a receptor that binds to phage-display-selected ligands, such as the SNTRVAP motif, is a candidate target in AVPC. We report the presence and accessibility of this receptor in clinical specimens from index patients. We also demonstrate that human AVPC cells displaying GRP78 on their surface could be effectively targeted both in vitro and in vivo by SNTRVAP, which also enabled specific delivery of siRNA species to tumor xenografts in mice. Finally, we evaluated ligand-directed strategies based on SNTRVAP-displaying adeno-associated virus/phage (AAVP) particles in mice bearing MDA-PCa-118b, a patient-derived xenograft (PDX) of castration-resistant prostate cancer bone metastasis that we exploited as a model of AVPC. For theranostic (a merging of the terms therapeutic and diagnostic) studies, GRP78-targeting AAVP particles served to deliver the human Herpes simplex virus thymidine kinase type-1 (HSVtk) gene, which has a dual function as a molecular-genetic sensor/reporter and a cell suicide-inducing transgene. We observed specific and simultaneous PET imaging and treatment of tumors in this preclinical model of AVPC. Our findings demonstrate the feasibility of GPR78-targeting, ligand-directed theranostics for translational applications in AVPC.
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Reilly, Erin R., Milky K. Abajorga, Cory Kiser, Nurul Humaira Mohd Redzuan, Zein Haidar, Lily E. Adams, Randy Diaz, et al. "A Cut above the Rest: Characterization of the Assembly of a Large Viral Icosahedral Capsid." Viruses 12, no. 7 (July 5, 2020): 725. http://dx.doi.org/10.3390/v12070725.
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The head of Salmonella virus SPN3US is composed of ~50 different proteins and is unusual because within its packaged genome there is a mass (>40 MDa) of ejection or E proteins that enter the Salmonella cell. The assembly mechanisms of this complex structure are poorly understood. Previous studies showed that eight proteins in the mature SPN3US head had been cleaved by the prohead protease. In this study, we present the characterization of SPN3US prohead protease mutants using transmission electron microscopy and mass spectrometry. In the absence of the prohead protease, SPN3US head formation was severely impeded and proheads accumulated on the Salmonella inner membrane. This impediment is indicative of proteolysis being necessary for the release and subsequent DNA packaging of proheads in the wild-type phage. Proteomic analyses of gp245- proheads that the normal proteolytic processing of head proteins had not occurred. Assays of a recombinant, truncated form of the protease found it was active, leading us to hypothesize that the C-terminal propeptide has a role in targeting the protease into the prohead core. Our findings provide new evidence regarding the essential role of proteolysis for correct head assembly in this remarkable parasite.
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Evseev, Peter, Anna Lukianova, Nina Sykilinda, Anna Gorshkova, Alexander Bondar, Mikhail Shneider, Marsel Kabilov, Valentin Drucker, and Konstantin Miroshnikov. "Pseudomonas Phage MD8: Genetic Mosaicism and Challenges of Taxonomic Classification of Lambdoid Bacteriophages." International Journal of Molecular Sciences 22, no. 19 (September 26, 2021): 10350. http://dx.doi.org/10.3390/ijms221910350.
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Pseudomonas phage MD8 is a temperate phage isolated from the freshwater lake Baikal. The organisation of the MD8 genome resembles the genomes of lambdoid bacteriophages. However, MD8 gene and protein sequences have little in common with classified representatives of lambda-like phages. Analysis of phage genomes revealed a group of other Pseudomonas phages related to phage MD8 and the genomic layout of MD8-like phages indicated extensive gene exchange involving even the most conservative proteins and leading to a high degree of genomic mosaicism. Multiple horizontal transfers and mosaicism of the genome of MD8, related phages and other λ-like phages raise questions about the principles of taxonomic classification of the representatives of this voluminous phage group. Comparison and analysis of various bioinformatic approaches applied to λ-like phage genomes demonstrated different efficiency and contradictory results in the estimation of genomic similarity and relatedness. However, we were able to make suggestions for the possible origin of the MD8 genome and the basic principles for the taxonomic classification of lambdoid phages. The group comprising 26 MD8-related phages was proposed to classify as two close genera belonging to a big family of λ-like phages.
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Boerner, Julie L., Michelle L. Demory, Corinne Silva, and Sarah J. Parsons. "Phosphorylation of Y845 on the Epidermal Growth Factor Receptor Mediates Binding to the Mitochondrial Protein Cytochrome c Oxidase Subunit II." Molecular and Cellular Biology 24, no. 16 (August 15, 2004): 7059–71. http://dx.doi.org/10.1128/mcb.24.16.7059-7071.2004.
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ABSTRACT When co-overexpressed, the epidermal growth factor receptor (EGFR) and c-Src cooperate to cause synergistic increases in EGF-induced DNA synthesis, soft agar colony growth, and tumor formation in nude mice. This synergy is dependent upon c-Src-mediated phosphorylation of a unique tyrosine on the EGFR, namely, tyrosine 845 (Y845). Phenylalanine substitution of Y845 (Y845F) was found to inhibit EGF-induced DNA synthesis without affecting the catalytic activity of the receptor or its ability to phosphorylate Shc or activate mitogen-activated protein kinase. These results suggest that synergism may occur through alternate signaling pathways mediated by phosphorylated Y845 (pY845). One such pathway involves the transcription factor Stat5b. Here we describe another pathway that involves cytochrome c oxidase subunit II (CoxII). CoxII was identified as a specific binding partner of a pY845-containing peptide in a phage display screen. EGF-dependent binding of CoxII to the wild type but not to the mutant Y845F-EGFR was confirmed by coimmunoprecipitation experiments. This association also required the kinase activity of c-Src. Confocal microscopy, as well as biochemical fractionation, indicated that the EGFR translocates to the mitochondria after EGF stimulation, where it colocalizes with CoxII. Such translocation required the catalytic activity of the receptor but not phosphorylation of Y845. However, ectopic expression of the Y845F-EGFR prevented the EGF from protecting MDA-MB-231 breast cancer cells from adriamycin-induced apoptosis, whereas two mutants of Stat5b, a dominant-interfering mutant (DNstat5b) and a tyrosine mutation at 699 (Y699F-Stat5b) did not. Taken together, these data suggest that, through the ability of EGFR to translocate to the mitochondria, the binding of proteins such as CoxII to pY845 on the EGFR may positively regulate survival pathways that contribute to oncogenesis.
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Zaikin, Oleg. "Inverting Cryptographic Hash Functions via Cube-and-Conquer." Journal of Artificial Intelligence Research 81 (October 23, 2024): 359–99. http://dx.doi.org/10.1613/jair.1.15244.
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MD4 and MD5 are fundamental cryptographic hash functions proposed in the early 1990s. MD4 consists of 48 steps and produces a 128-bit hash given a message of arbitrary finite size. MD5 is a more secure 64-step extension of MD4. Both MD4 and MD5 are vulnerable to practical collision attacks, yet it is still not realistic to invert them, i.e., to find a message given a hash. In 2007, the 39-step version of MD4 was inverted by reducing to SAT and applying a CDCL solver along with the so-called Dobbertin’s constraints. As for MD5, in 2012 its 28-step version was inverted via a CDCL solver for one specified hash without adding any extra constraints. In this study, Cube-and-Conquer (a combination of CDCL and lookahead) is applied to invert step-reduced versions of MD4 and MD5. For this purpose, two algorithms are proposed. The first one generates inverse problems for MD4 by gradually modifying the Dobbertin’s constraints. The second algorithm tries the cubing phase of Cube-and-Conquer with different cutoff thresholds to find the one with the minimum runtime estimate of the conquer phase. This algorithm operates in two modes: (i) estimating the hardness of a given propositional Boolean formula; (ii) incomplete SAT solving of a given satisfiable propositional Boolean formula. While the first algorithm is focused on inverting step-reduced MD4, the second one is not area-specific and is therefore applicable to a variety of classes of hard SAT instances. In this study, 40-, 41-, 42-, and 43-step MD4 are inverted for the first time via the first algorithm and the estimating mode of the second algorithm. Also, 28-step MD5 is inverted for four hashes via the incomplete SAT solving mode of the second algorithm. For three hashes out of them, it is done for the first time.
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Zhao, Nan, Yao Ma, and Gang Liu. "Solution-phase synthesis of a muramyl dipeptide analogue MDA." Chinese Chemical Letters 22, no. 12 (December 2011): 1443–46. http://dx.doi.org/10.1016/j.cclet.2011.07.020.
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Duplessis, Martin, Céline M. Lévesque, and Sylvain Moineau. "Characterization of Streptococcus thermophilus Host Range Phage Mutants." Applied and Environmental Microbiology 72, no. 4 (April 2006): 3036–41. http://dx.doi.org/10.1128/aem.72.4.3036-3041.2006.
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ABSTRACT To investigate phage-host interactions in Streptococcus thermophilus, a phage-resistant derivative (SMQ-301R) was obtained by challenging a Tn917 library of phage-sensitive strain S. thermophilus SMQ-301 with virulent phage DT1. Mutants of phages DT1 and MD2 capable of infecting SMQ-301 and SMQ-301R were isolated at a frequency of 10−6. Four host range phage mutants were analyzed further and compared to the two wild-type phages. Altogether, three genes (orf15, orf17, and orf18) contained point mutations leading to amino acid substitutions and were responsible for the expanded host range. These three proteins were also identified in both phages by N-terminal sequencing and/or matrix-assisted laser desorption ionization-time-of-flight mass spectrometry. The results suggest that at least three phage structural proteins may be involved in phage-host interactions in S. thermophilus.
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Ajumeera, Rajanna, Ganapathi Thipparapu, Shireesha Boyapati, Bharath Singh Padya, and Vijayalaxmi Venkatesan. "Synthesis and Evaluation of Triazolyl Dihydropyrimidines as Potential Anticancer Agents." International Journal of Chemistry 10, no. 4 (November 8, 2018): 18. http://dx.doi.org/10.5539/ijc.v10n4p18.
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Novel N – triazolyl 3(a-f) and O-triazolyl (4a-f) derivatives of 4, 6-diaryl-1, 4-dihydropyrimidines were synthesized through mannich reaction. All compounds were characterized by physical and spectral data. These compounds were screened for in vitro efficiency in human breast cancer cell (MCF-7&MDA-MB-231) lines and found to have very good anti-proliferative activity. Among all compounds of 4b, 3e, 4e endowed with lesser respective IC50 values of 31.94, 55.73, 55.03 µM in MCF-7 cells and 41.50, 35.28, 32.06 µM in MDA-MB 231 cells by MTT assay. In further studies, Compounds 4b, 3e, 4e were found to arrest cell growth at S phase in MCF-7 cells. In MDA-MB 231 cells, 4b, 4e were found to arrest the cells in S phase, and compound 3e found to arrest G2/M phase when compared to the standard drug tamoxifen, arrested S phase in MCF-7 cells and G0/G1 phase in MDA-MB 231 cells.
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Ikatsu, H., T. Nakajima, N. Murayama, and T. Korenaga. "Flow-Injection Analysis for Malondialdehyde in Plasma with the Thiobarbituric Acid Reaction." Clinical Chemistry 38, no. 10 (October 1, 1992): 2061–65. http://dx.doi.org/10.1093/clinchem/38.10.2061.
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Abstract A simple, precise, and rapid method to measure plasma malondialdehyde (MDA) was developed by use of solvent extraction--flow-injection analysis. The reagent solution, containing thiobarbituric acid (TBA), 5 g/L in 100 mL/L phosphoric acid, and extraction solvent (methylisobutyl ketone, MIBK) were propelled with a double-plunger micropump at a flow rate of 0.3 mL/min, and 20 microL of sample was introduced into the reagent stream. After TBA-MDA reactant was extracted into MIBK, the organic phase was continuously separated by a successive phase-separation system equipped with two phase separators, and the absorbance of the TBA-MDA reactant was measured at 532 nm. This approach resulted in excellent sensitivity, a CV of < 1.5%, a good correlation with the conventional manual method, and a sampling frequency of 7 samples/h, suggesting that this semiautomated method is suitable for measuring plasma MDA.
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Синицын, В. В., О. Г. Рыбченко, В. Б. Ефимов, and А. А. Вирюс. "Аморфный лед средней плотности, полученный разложением водно-гелиевого геля." Физика твердого тела 65, no. 8 (2023): 1307. http://dx.doi.org/10.21883/ftt.2023.08.56147.103.
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The article presents experimental studies of structural changes that occur during heating of nanosized powders of amorphous ice obtained by decay of a water-helium gel. Thermal annealing of the obtained samples was carried out by short exposures (about 15 minutes) at different temperatures in the range of 110-230K. The behavior of the amorphous phase during annealing was analyzed within the framework of its description by a mixture of amorphous ices of low and medium density (LDA and MDA, respectively). It was found that at the such description, the virgin sample was predominantly in the MDA state, while the proportion of the LDA phase was about 7 times less (MDA/LDA ≈ 7:1). It has been established that during annealing, a multistage process of structural transformations of the initial LDA + MDA sample takes place: from initial changes in the amorphous state at 110 K through crystallization of the cubic ice phase Ic with its intensive growth at a temperature of 130 K to the transformation of cubic ice into the hexagonal phase Ih in the temperature range T =135÷230K.
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Ahmed, Shade’ A., Patricia Mendonca, Samia S. Messeha, and Karam F. A. Soliman. "Anticancer Effects of Fucoxanthin through Cell Cycle Arrest, Apoptosis Induction, and Angiogenesis Inhibition in Triple-Negative Breast Cancer Cells." Molecules 28, no. 18 (September 9, 2023): 6536. http://dx.doi.org/10.3390/molecules28186536.
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The absence of progesterone receptors, estrogen receptors, and human epidermal growth factor receptor-2 restricts the therapy choices for treating triple-negative breast cancer (TNBC). Moreover, conventional medication is not highly effective in treating TNBC, and developing effective therapeutic agents from natural bioactive compounds is a viable option. In this study, the anticancer effects of the natural compound fucoxanthin were investigated in two genetically different models of TNBC cells: MDA-MB-231 and MDA-MB-468 cells. Fucoxanthin had a significant anticancer effect in both cell lines at a concentration range of 1.56–300 µM. The compound decreased cell viability in both cell lines with higher potency in MDA-MB-468 cells. Meanwhile, proliferation assays showed similar antiproliferative effects in both cell lines after 48 h and 72 h treatment periods. Flow cytometry and Annexin V-FITC apoptosis assay revealed the ability of fucoxanthin to induce apoptosis in MDA-MB-231 only. Cell cycle arrest analysis showed that the compound also induced cell cycle arrest at the G1 phase in both cell lines, accompanied by more cell cycle arrest in MDA-MB-231 cells at S-phase and a higher cell cycle arrest in the MDA-MB-468 cells at G2-phase. Wound healing and migration assay showed that in both cell lines, fucoxanthin prevented migration, but was more effective in MDA-MB-231 cells in a shorter time. In both angiogenic cytokine array and RT-PCR studies, fucoxanthin (6.25 µM) downregulated VEGF-A and -C expression in TNF-α-stimulated (50 ng/mL) MDA-MB-231, but not in MDA-MB-468 cells on the transcription and protein levels. In conclusion, this study shows that fucoxanthin was more effective in MDA-MB-231 TNBC cells, where it can target VEGF-A and VEGF-C, inhibit cell proliferation and cell migration, and induce cell cycle arrest and apoptosis—the most crucial cellular processes involved in breast cancer development and progression.
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He, Kemeng, Yushan Sun, Zhang Qin, Yuqiang Sun, and Yuwan Gu. "The Research of Trusted Attribute Based on Model-Driven of MDA." Open Electrical & Electronic Engineering Journal 8, no. 1 (December 31, 2014): 273–77. http://dx.doi.org/10.2174/1874129001408010273.
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The research methods of trusted attribute based on model-driven for credibility problems in the development process of model-driven software proposed in the paper. An overall analysis for software requirements is carried out, considering the business specification and the need to achieve the function, testing the Integrity and accuracy of model in the PIM phase. Then, is a need to achieve the necessary component services in the concrete platform for implementing the business logic of PIM, studying the symmetry and reliability of model in the PSM phase. Finally, the use of transformation method of element mark to achieve the conversion of platform model, testing the transfer ratio of model in the phase of PIM transformed to PSM. The research of trusted attribute based on model-driven of MDA has effectively improved reliability and developing efficiency of software.
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Prestegui Martel, Berenice, Alma Delia Chávez-Blanco, Guadalupe Domínguez-Gómez, Alfonso Dueñas González, Patricia Gaona-Aguas, Raúl Flores-Mejía, Selma Alin Somilleda-Ventura, et al. "N-(2-Hydroxyphenyl)-2-Propylpentanamide (HO-AAVPA) Induces Apoptosis and Cell Cycle Arrest in Breast Cancer Cells, Decreasing GPER Expression." Molecules 29, no. 15 (July 26, 2024): 3509. http://dx.doi.org/10.3390/molecules29153509.
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In this work, we performed anti-proliferative assays for the compound N-(2-hydroxyphenyl)-2-propylpentanamide (HO-AAVPA) on breast cancer (BC) cells (MCF-7, SKBR3, and triple-negative BC (TNBC) MDA-MB-231 cells) to explore its pharmacological mechanism regarding the type of cell death associated with G protein-coupled estrogen receptor (GPER) expression. The results show that HO-AAVPA induces cell apoptosis at 5 h or 48 h in either estrogen-dependent (MCF-7) or -independent BC cells (SKBR3 and MDA-MB-231). At 5 h, the apoptosis rate for MCF-7 cells was 68.4% and that for MDA-MB-231 cells was 56.1%; at 48 h, that for SKBR3 was 61.6%, that for MCF-7 cells was 54.9%, and that for MDA-MB-231 (TNBC) was 43.1%. HO-AAVPA increased the S phase in MCF-7 cells and reduced the G2/M phase in MCF-7 and MDA-MB-231 cells. GPER expression decreased more than VPA in the presence of HO-AAVPA. In conclusion, the effects of HO-AAVPA on cell apoptosis could be modulated by epigenetic effects through a decrease in GPER expression.
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Adinew, Getinet M., Samia S. Messeha, Equar Taka, Ramesh B. Badisa, Lovely M. Antonie, and Karam F. A. Soliman. "Thymoquinone Alterations of the Apoptotic Gene Expressions and Cell Cycle Arrest in Genetically Distinct Triple-Negative Breast Cancer Cells." Nutrients 14, no. 10 (May 19, 2022): 2120. http://dx.doi.org/10.3390/nu14102120.
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Breast cancer (BC) is the most common cancer in women worldwide, and it is one of the leading causes of cancer death in women. triple-negative breast Cancer (TNBC), a subtype of BC, is typically associated with the highest pathogenic grade and incidence in premenopausal and young African American (AA) women. Chemotherapy, the most common treatment for TNBC today, can lead to acquired resistance and ineffective treatment. Therefore, novel therapeutic approaches are needed to combat medication resistance and ineffectiveness in TNBC patients. Thymoquinone (TQ) is shown to have a cytotoxic effect on human cancer cells in vitro. However, TQ’s mode of action and precise mechanism in TNBC disease in vitro have not been adequately investigated. Therefore, TQ’s effects on the genetically different MDA-MB-468 and MDA-MB-231 human breast cancer cell lines were assessed. The data obtained show that TQ displayed cytotoxic effects on MDA-MB-468 and MDA-MB-231 cells in a time- and concentration-dependent manner after 24 h, with IC50 values of 25.37 µM and 27.39 µM, respectively. Moreover, MDA-MB-231 and MDA-MB-468 cells in a scratched wound-healing assay displayed poor wound closure, inhibiting invasion and migration via cell cycle blocking after 24 h. TQ arrested the cell cycle phase in MDA-MB-231 and MDA-MB-468 cells. The three cell cycle stages in MDA-MB-468 cells were significantly affected at 15 and 20 µM for G0/G1 and S phases, as well as all TQ concentrations for G2/M phases. In MDA-MB-468 cells, there was a significant decrease in G0/G1 phases with a substantial increase in the S phase and G2/M phases. In contrast, MDA-MB-231 showed a significant effect only during the two cell cycle stages (S and G2/M), at concentrations of 15 and 20 µM for S phases and all TQ values for G2/M phases. The TQ effect on the apoptotic gene profiles indicated that TQ upregulated 15 apoptotic genes in MDA-MB-231 TNBC cells, including caspases, GADD45A, TP53, DFFA, DIABLO, BNIP3, TRAF2/3, and TNFRSF10A. In MDA-MB-468 cells, 16 apoptotic genes were upregulated, including TNFRSF10A, TNF, TNFRSF11B, FADD TNFRSF10B, CASP2, and TRAF2, all of which are important for the apoptotic pathway andsuppress the expression of one anti-apoptotic gene, BIRC5, in MDA-MB-231 cells. Compared to MDA-MB-231 cells, elevated levels of TNF and their receptor proteins may contribute to their increased sensitivity to TQ-induced apoptosis. It was concluded from this study that TQ targets the MDA-MB-231 and MDA-MB-468 cells differently. Additionally, due to the aggressive nature of TNBC and the lack of specific therapies in chemoresistant TNBC, our findings related to the identified apoptotic gene profile may point to TQ as a potential agent for TNBC therapy.
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Marcinčák, Slavomír, Jozef Sokol, Pavel Bystrický, Peter Popelka, Peter Turek, Mangesh Bhide, and Dionýz Máté. "Determination of Lipid Oxidation Level in Broiler Meat by Liquid Chromatography." Journal of AOAC INTERNATIONAL 87, no. 5 (December 1, 2004): 1148–52. http://dx.doi.org/10.1093/jaoac/87.5.1148.
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Abstract An assay was conducted for the determination of malondialdehyde (MDA) levels in broiler meat. The method involves extraction of tissues with trichloroacetic acid (TCA) and reaction of the TCA extract with 2,4-dinitrophenylhydrazine (DNPH). After separation of the MDA-DNPH complex using a solid-phase extraction C18 column, samples were eluted with 1 mL acetonitrile. Aliquots of 20 μL acetonitrile were analyzed by liquid chromatography on reversed-phase C18 column (3 μm) with UV detection. The products were eluted isocratically with the mobile phase containing acetonitrile–water–acetic acid (39 + 61 + 0.2, v/v/v). The retention time was for MDA-DNPH was 6.5 min, and the detection limit was 3.5 μg/kg. Two extraction methods (cold and hot) were also used in the study. The results showed that hot extraction increased results about 55.8% and recovery from samples spiked with 116.6 μg/kg was lower (74.6%) in comparison with cold extraction (94.7%).
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Boros, R., László Farkas, Károly Nehéz, Béla Viskolcz, and Milán Szőri. "An Ab Initio Investigation of the 4,4′-Methlylene Diphenyl Diamine (4,4′-MDA) Formation from the Reaction of Aniline with Formaldehyde." Polymers 11, no. 3 (March 1, 2019): 398. http://dx.doi.org/10.3390/polym11030398.
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The most commonly applied industrial synthesis of 4,4′-methylene diphenyl diamine (4,4′-MDA), an important polyurethane intermediate, is the reaction of aniline and formaldehyde. Molecular understanding of the 4,4′-MDA formation can provide strategy to prevent from side reactions. In this work, a molecular mechanism consisted of eight consecutive, elementary reaction steps from anilines and formaldehyde to the formation of 4,4′-MDA in acidic media is proposed using accurate G3MP2B3 composite quantum chemical method. Then G3MP2B3-SMD results in aqueous and aniline solutions were compared to the gas phase mechanism. Based on the gas phase calculations standard enthalpy of formation, entropy and heat capacity values were evaluated using G3MP2B3 results for intermediates The proposed mechanism was critically evaluated and important side reactions are considered: the competition of formation of protonated p-aminobenzylaniline (PABAH+), protonated aminal (AMH+) and o-aminobenzylaniline (OABAH+). Competing reactions of the 4,4′-MDA formation is also thermodynamically analyzed such as the formation of 2,4-MDAH+, 3,4-MDAH+. AMH+ can be formed through loose transition state, but it becomes kinetic dead-end, while formation of significant amount of 2,4-MDA is plausible through low-lying transition state. The acid strength of the key intermediates such as N-methylenebenzeneanilium, PABAH+, 4-methylidenecyclohexa-2,5-diene-1-iminium, and AMH+ was estimated by relative pKa calculation.
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Noggle, F. Taylor, Jack Deruiter, Samuel T. Coker, and Randall C. Clark. "Synthesis, Identification, and Acute Toxicity of Some 7V-AlkyI Derivatives of 3,4-Methylenedioxyamphetamine." Journal of AOAC INTERNATIONAL 70, no. 6 (November 1, 1987): 981–86. http://dx.doi.org/10.1093/jaoac/70.6.981.
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Abstract A series of iV-alkyl derivatives of 3,4-methylenedioxyamphetamine (MDA) was prepared in an effort to characterize these potential drugs of abuse. These secondary amines were synthesized via reductive amination of the corresponding ketone with alkylamines. The ultraviolet absorption spectra for these compounds produced almost equally intense absorbance at 234 and 285 nm. The compounds were separated by liquid chromatography using reverse phase (c18) procedures with a ternary mobile phase mixture. Toxicity studies showed all of the compounds to have LDM values similar to A'-methyl MDA (MDMA).
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Jen, Chia-I., and Lean-Teik Ng. "Physicochemical Properties of Different Sulfated Polysaccharide Components from Laetiporus sulphureus and Their Anti-Proliferative Effects on MDA-MB-231 Breast Cancer Cells." Journal of Fungi 10, no. 7 (June 28, 2024): 457. http://dx.doi.org/10.3390/jof10070457.
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Laetiporus sulphureus is an edible and medicinal mushroom widely used in folk medicine for treating cancer and gastric diseases. This study aimed to investigate the physicochemical properties of different sulfated polysaccharide (SPS) components (F1, F2, and F3) isolated from L. sulphureus and evaluate their activity against MDA-MB-231 breast cancer cell proliferation. Compared with F1 and F3, the results showed that F2 exhibited the most potent anti-proliferative activity on MDA-MB-231 cells, which could be attributed to the sulfate and protein contents, molecular weight, and monosaccharide composition. F2 inhibited breast cancer cell proliferation by blocking the cell cycle at the G0/G1 phase but not triggering cell apoptosis. In addition, F2 also showed selective cytotoxicity on breast cancer cells. It modulated the expression of proteins involved in G0/G1 phase progression, cell cycle checkpoints, DNA replication, and the TGFβ signaling pathway in MDA-MB-231 cells. This study demonstrated that F2, the medium-molecular-weight SPS component of L. sulphureus, possessed the most potent inhibitory effect on MDA-MB-231 cell proliferation by arresting the cell cycle at the G0/G1 phase. The main factors contributing to the differences in the potency of anti-breast cancer activity between F1, F2, and F3 could be the sulfate and protein contents, molecular weight, and monosaccharide composition of SPS.
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Merino de Paz, Nayra, Juan Carlos Quevedo-Abeledo, Fuensanta Gómez-Bernal, Antonia de Vera-González, Pedro Abreu-González, Candelaria Martín-González, Miguel Ángel González-Gay, and Iván Ferraz-Amaro. "Malondialdehyde Serum Levels in a Full Characterized Series of 430 Rheumatoid Arthritis Patients." Journal of Clinical Medicine 13, no. 3 (February 4, 2024): 901. http://dx.doi.org/10.3390/jcm13030901.
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Background. Oxidative stress has been involved in the pathogenesis of rheumatoid arthritis (RA). The serum malondialdehyde (MDA) level is a reliable biomarker of oxidative stress status. In the present work, we aimed to analyze how a comprehensive characterization of the disease characteristics in RA, including a lipid profile, insulin resistance, and subclinical atherosclerosis, relates to serum MDA levels. Methods. In a cross-sectional study that included 430 RA patients, serum MDA levels were evaluated. Multivariable analysis was performed to examine the relationship of MDA with disease activity scores and disease characteristics, including subclinical carotid atherosclerosis, a comprehensive lipid molecule profile, and indices of insulin resistance and beta cell function indices. Results. The erythrocyte sedimentation rate (ESR) showed a significant and positive relationship with MDA. However, this did not occur for other acute phase reactants such as C-reactive protein or interleukin-6. Although the DAS28-ESR score (Disease Activity Score in 28 joints) had a positive and significant association with MDA serum levels, other disease activity scores that do not use the erythrocyte sedimentation rate in their formula did not show a significant relationship with MDA. Other disease characteristics, such as disease duration and the existence of rheumatoid factor and antibodies against citrullinated protein, were not related to serum MDA levels. This also occurred for lipid profiles, insulin resistance indices, and subclinical carotid atherosclerosis, for which no associations with circulating MDA were found. Conclusions. The disease characteristics are not related to circulating MDA levels in patients with RA.
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Gichuki, Paul M., Bridget W. Kimani, Tabitha Kanyui, Collins Okoyo, Titus Watitu, Wycliff P. Omondi, and Doris W. Njomo. "Using community-based participatory approaches to improve access to mass drug administration for trachoma elimination in a pastoral conflict area of Kenya." PLOS Neglected Tropical Diseases 18, no. 11 (November 11, 2024): e0012653. http://dx.doi.org/10.1371/journal.pntd.0012653.
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In Baringo County, Kenya, trachoma remains endemic despite repeated mass drug administration (MDA) efforts, with coverage in one of the wards consistently falling short of world health organization (WHO) targets. The disease is endemic in 12 out of the 47 counties in Kenya. Baringo county is a pastoral conflict, hard to reach area where eight rounds of mass drug administration (MDA) for trachoma have been implemented. In Loyamorok ward, treatment coverage has been below 68% against the WHO recommended threshold of 80%. Community engagements that promote participatory approaches are key to MDA success. In this study, we describe community-based participatory approaches qualitatively developed and implemented during the intervention phase of a study that involved a pre-intervention, intervention and post intervention phases and aimed to address barriers of community participation and access to trachoma MDA. Interviews and focus group discussions were used to identify barriers to community participation in MDA, that included power and gender dynamics, rampant insecurity, community myths and misconceptions, migration in search of water and pastures, vastness and terrain and ineffective teams which resulted to unsupervised swallowing of drugs during MDA campaigns. Stakeholders in trachoma were identified through meetings with national, county and sub-county health management teams. The stakeholders, community members and the research team used the identified barriers to formulate MDA strategies including effective stakeholder engagement, enhanced social mobilization, community awareness creation on trachoma, effective planning and execution of MDA and implementation monitoring of the MDA campaign, all aimed at increasing MDA coverage. Overall MDA coverage in the area increased from 67.6% in 2021 to 87% in 2023 thus meeting the WHO threshold of 80%. The use of community-based, participatory approaches in the development and implementation of data driven strategies has the potential to positively influence MDA coverage for trachoma, and other neglected tropical diseases.
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Okarvi, Subhani M. "Preparation, Radiolabeling with 68Ga/177Lu and Preclinical Evaluation of Novel Angiotensin Peptide Analog: A New Class of Peptides for Breast Cancer Targeting." Pharmaceuticals 16, no. 11 (November 2, 2023): 1550. http://dx.doi.org/10.3390/ph16111550.
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Aim: Angiotensin II (AngII) is known to play a significant part in the development of breast cancer by triggering cell propagation of breast cancer, tumor angiogenesis, and regulating tumor invasion and cell migration. AngII arbitrates its action via two G-protein-coupled receptors, AngII type 1 receptor (AT1) and AngII type 2 receptor (AT2). Overexpression of the AT1 receptor in breast cancer cells seems to promote tumor growth and angiogenesis, thus targeting the AT1 receptor using AngII peptide would facilitate the detection of breast carcinoma. We developed an AngII peptide intending to assess whether the peptide of the renin–angiotensin system holds the ability to target AT1 receptor-overexpressing breast cancer in vivo. Methods: DOTA-coupled AngII peptide was synthesized by conventional solid-phase peptide synthesis according to Fmoc/HATU chemistry. 68Ga/177Lu labeled AngII peptide was evaluated for its binding with TNBC MDA-MB-231 and ER+ MCF7 cell lines. Pharmacokinetics was studied in healthy balb/c mice and in vivo tumor targeting in nude mice with MDA-MB-231 tumors xenografts. Results: DOTA-AngII peptide was labeled efficiently with 68Ga/177Lu with high labeling efficiency (≥90%). The stability of the radiopeptide in human plasma was found to be high. The AngII peptide analog showed nanomolar (<40 nM) AT1 receptor-specific binding affinity. The radioactivity internalized into MDA-MBA-231 and MCF7 cells were 14.97% and 11.75%, respectively. In vivo, biodistribution in balb/c mice exhibited efficient clearance of 68Ga/177Lu-DOTA-AngII peptide from the blood and elimination predominantly by the renal system due to its hydrophilic nature. A low amount of radioactivity was seen in the major organs including lungs, liver, stomach, spleen, and intestines (<3% ID/g) except the kidneys. A high renal-urinary excretion was observed for the radiotracer. In the TNBC MDA-MB-231 xenografts model, radiolabeled AngII peptide exhibited specific and effective AT1-based targeting in vivo. A rapid and efficient tumor targeting (2.18% ID/g at 45 min p.i.) together with fast renal excretion (~67% ID) highlights the tumor-targeting potential of the radiotracer. The AT1 receptor specificity of the radiotracer was validated by blocking assays. Furthermore, PET imaging provided sufficient visualization of MDA-MB-231 tumors in nude mice. Conclusion: Our findings suggest that 68Ga/177Lu-DOTA-AngII peptide can be useful for the theranostic application of breast carcinomas. This study suggests the potential of this innovative class of peptides for rapid and efficient targeting of tumors and warrants further evaluation.
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Baek, Bum Seo, Min Geun Kim, Jong Hyun Kim, In Young Jang, Sung Min Kim, Jeong Hwan Kim, Sang Beum Lee, Hyoung Tae Kim, and Seung-Yong Seong. "Abstract 2719: Papiliximab, a bispecific nanobody targeting CD47 and PDL1 retards tumor growth without hemolysis." Cancer Research 84, no. 6_Supplement (March 22, 2024): 2719. http://dx.doi.org/10.1158/1538-7445.am2024-2719.
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Abstract Cancer cells are known to express immune checkpoint proteins, enabling them to evade immune surveillance. In response, anti-cancer therapies targeting these proteins have been developed. While immune checkpoint inhibitors targeting PD-L1 have been clinically approved, their effectiveness as standalone therapies is limited, with only a 20% response rate. To improve responsiveness, bispecific monoclonal antibodies (MoAbs) targeting both CD47 and PD-L1 have been developed. These bispecific antibodies activate both the innate (by blocking CD47) and adaptive (by blocking PD-L1) immune systems simultaneously. However, conventional antibodies targeting CD47 have been dropped during development due to the risk of hemolysis. In this study, we developed a bispecific single-domain antibody (nanobody, Nb) that targets both CD47 and PD-L1 with a minimal hemagglutination risk. Using phage display libraries from alpacas immunized with recombinant antigens, we screened for an anti-CD47 Nb and an anti-PD-L1 Nb. The affinities (Kd) of these Nbs for their antigens were 7.0 × 10−9 and 9.7 × 10−9, respectively. To maximize affinity for both antigens, a bispecific antibody (Papiliximab) was designed to tandemly array anti-CD47 and PD-L1 Nbs with the Fc region of IgG4. Papiliximab has a lower affinity for RBC (up to 3 μM) than conventional anti-CD47 MoAbs reported earlier. Papiliximab successfully inhibited interactions between CD47/SIRP-α and PD-L1/PD-1, with IC50 values of 7.09 nM and 2.67 nM, respectively. Papiliximab induced the expression of IFN-γ by inhibiting the PD-L1/PD-1 interaction in the PBMC-based MLR (Mixed Lymphocyte reaction) assay. In addition, Papiliximab demonstrated the induction of a phagocytosis effect through CD47 blocking and its IgG4 Fc domain. Therefore, Papiliximab is a multifunctional hybrid bispecific antibody that modulates both innate and acquired immunity. Papiliximab exhibited no cross-reactivity with mouse antigens, but did with cynomolgus antigens. We tested its efficacy on the growth of human B cell lymphoma (Raji cells) and human breast cancer (MDA-MB-231 cells) in humanized NSG mice. Papiliximab was more effective in inhibiting tumor growth than mono-specific Abs and Nbs for PD-L1 or CD47, and their combination. These observations suggest that Papiliximab might be able to improve clinical remission more effectively than the combination of monotherapies without the risk of anemia associated with anti-CD47 MoAbs. We are now working to elucidate the mechanisms behind Papiliximab's superior efficacy and safety compared to the combination of monotherapies. Citation Format: Bum Seo Baek, Min Geun Kim, Jong Hyun Kim, In Young Jang, Sung Min Kim, Jeong Hwan Kim, Sang Beum Lee, Hyoung Tae Kim, Seung-Yong Seong. Papiliximab, a bispecific nanobody targeting CD47 and PDL1 retards tumor growth without hemolysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2719.
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Velmurugan, Bharath Kumar, Po-Chih Wang, and Ching-Feng Weng. "16-Hydroxycleroda-3,13-dien-15,16-olide and N-Methyl-Actinodaphine Potentiate Tamoxifen-Induced Cell Death in Breast Cancer." Molecules 23, no. 8 (August 6, 2018): 1966. http://dx.doi.org/10.3390/molecules23081966.
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In this study, we investigated whether 16-hydroxycleroda-3,13-dien-15,16-olide (HCD) and N-methyl-actinodaphine (MA) could sensitize breast cancer cells to Tamoxifen (TMX) treatment. MA or HCD alone or in combination with TMX dose-dependently inhibited MCF-7 and MDA-MB-231 cell growth, with a more potent inhibition on MDA-MB 231 cells. Furthermore, this novel combination significantly induced S and G2/M cell cycle phase in MDA-MB 231 than MCF-7 cells. Further determination of the apoptotic induction showed that MA or HCD and TMX combination inhibited MDA-MB-231 and MCF-7 cancer cells by upregulating Bax and by downregulating Bcl-2 mRNA and protein expression without altering Caspase-8 and Caspase-12 expression. These results suggest that MA or HCD pretreatment may potentiate the anti-tumor effect of tamoxifen on breast cancer.
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Gomes, Daniella A., Anna M. Joubert, and Michelle H. Visagie. "In Vitro Effects of Papaverine on Cell Proliferation, Reactive Oxygen Species, and Cell Cycle Progression in Cancer Cells." Molecules 26, no. 21 (October 22, 2021): 6388. http://dx.doi.org/10.3390/molecules26216388.
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Papaverine (PPV) is an alkaloid isolated from the Papaver somniferum. Research has shown that PPV inhibits proliferation. However, several questions remain regarding the effects of PPV in tumorigenic cells. In this study, the influence of PPV was investigated on the proliferation (spectrophotometry), morphology (light microscopy), oxidative stress (fluorescent microscopy), and cell cycle progression (flow cytometry) in MDA-MB-231, A549, and DU145 cell lines. Exposure to 150 μM PPV resulted in time- and dose-dependent antiproliferative activity with reduced cell growth to 56%, 53%, and 64% in the MDA-MB-231, A549, and DU145 cell lines, respectively. Light microscopy revealed that PPV exposure increased cellular protrusions in MDA-MB-231 and A549 cells to 34% and 23%. Hydrogen peroxide production increased to 1.04-, 1.02-, and 1.44-fold in PPV-treated MDA-MB-231, A549, and DU145 cells, respectively, compared to cells propagated in growth medium. Furthermore, exposure to PPV resulted in an increase of cells in the sub-G1 phase by 46% and endoreduplication by 10% compared to cells propagated in growth medium that presented with 2.8% cells in the sub-G1 phase and less than 1% in endoreduplication. The results of this study contribute to understanding of effects of PPV on cancer cell lines.
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Atere Adedeji, D., A. Kosamat Yekeen, O. Oluwatuyi Precious, and E. Chukwuemeka Cinderella. "Antioxidant status and acute phase reactants in pregnant women infected with Plasmodium falciparum." Rwanda Medical Journal 81, no. 1 (April 13, 2024): 15–22. http://dx.doi.org/10.4314/rmj.v81i1.2.
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INTRODUCTION: Malaria during pregnancy remains a public health issue. The most deadly plasmodium, Plasmodium falciparum, kills about 40% of the world's population, especially pregnant women and children under five. In pregnant women infected with Plasmodium falciparum, MDA, CAT, H2O2, SOD, and GPx were measured as oxidative stress markers and SAA and CRP as acute-phase proteins.
METHODS: A total of 90 subjects were recruited for this study, which was subdivided into 30 pregnant women infected with malaria (PWM), 35 pregnant women not infected with malaria (PWN), and 25 healthy women without pregnancy (WWP) who served as the control groups. 5mls of venous blood was collected and dispensed into appropriate bottles for malaria parasite assessment using a rapid diagnostic test (RDT) and MDA, CAT, H2O2, SOD, GPx, SAA, and CRP analysis using conventional laboratory techniques. Statistical analysis was done, and P values under 0.05 were significant.
RESULTS: The PWM and PWN groups had significantly higher MDA and H2O2 values, but SOD, GPx, and CAT values were significantly lower (p<0.05). When comparing CRP and SAA levels between PWM, PWN, and control groups, both groups with pregnancy had significantly greater levels (p<0.05). A negative correlation (r = -0.442, p<0.05) was found between MDA and SAA, while positive correlations were seen between CAT and CRP, and SOD and SAA in pregnant women with malaria.
CONCLUSION: This study found that malaria during pregnancy increases oxidants and decreases antioxidant enzymes, causing oxidative stress. This study showed that CRP and SAA may indicate malaria infections.
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Fauziah, Prima Nanda, Ani Melani Maskoen, Tri Yuliati, and Erlina Widiarsih. "Optimized steps in determination of malondialdehyde (MDA) standards on diagnostic of lipid peroxidation." Padjadjaran Journal of Dentistry 30, no. 2 (July 31, 2018): 136. http://dx.doi.org/10.24198/pjd.vol30no2.18329.
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Introduction: Lipid peroxidation, one of the known indices of oxidative stress, is documented in various diseases. Secondary oxidation products such as malondialdehyde (MDA) is commonly measured to observe lipid peroxidation. In this study, a spectrophotometric method was evaluated to measure thiobarbituric acid reactive substances (TBARS) with high sensitivity. This study was aimed to optimisation standard of MDA using tetraethoxypropane (TEP) 97% (FW=220.3). Methods: The method is based upon the reaction of malondialdehyde (MDA) and TBA in the glacial acetic acid medium. MDA is a known biomarker of oxidative status in a biological system. This research consists of two phases: first, making a stock of TEP, and the second phase was testing the concentration of TEP for finding the standard curve of MDA before used in diagnostic of lipid peroxidation. Results: Result showed the concentration 1,875-60 uM of TEP could form a precise standard curve. Conclusion: This concentration of TEP can be used as a reference as the standard of control in diagnostic of lipid peroxidation using TBARS method.