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The Biology And Therapeutic Application Of Mese...

Human trials for phage therapy have taken place for almost a century at several institutes in Eastern Europe, the most famous of which are the Eliava Institute of Bacteriophage and the Institute of Immunology and Experimental Therapy in Wroclaw, Poland. The Eliava Institute has extensively used phage in preclinical and clinical treatment of common bacterial pathogens such as S. aureus, E. coli, Streptococcus spp., P. aeruginosa, Proteus spp., S. dysenteriae, Salmonella spp., and Enterococcus spp.[49]. Effective applications range from surgical to gastroenterological, both therapeutic and prophylactic. In a six patient case series of antibiotic-unresponsive diabetic foot ulcers, topical application of S. aureus-specific phage was sufficient for recovery in all individuals[50]. In a 1938 clinical trial, 219 patients with bacterial dysentery (138 children and 81 adults) were treated solely with a phage cocktail consisting of a variety of phage targeting Shigella flexneri, Shigella shiga, E. coli, Proteus spp., P. aeruginosa, Salmonella typhi, Salmonella paratyphi A and B, Staphylococcus spp., Streptococcus spp. and Enterococcus spp.; cocktails were administered both orally and rectally. Within 24 h, 28% of patients with blood in their stools were relieved of this symptom, with a further 27% showing improvement within 2-3 d. Overall, 74% of the 219 patients showed improvement or were completely relieved of symptoms[51]. Additionally, during a 1974 typhoid epidemic, a cohort of 18577 children was enrolled in a prophylactic intervention trial using typhoid phages. Phage administration resulted in a 5-fold decrease in typhoid incidence compared to placebo[49]. The potential for phage therapy has yet to be fully realized since phages tend to be more effective against the target pathogen when used in combination with antibiotics[52], a treatment option that has not yet been investigated in humans.

The Biology and Therapeutic Application of Mese...

Phage lysins alone are capable of bacterial cell lysis, whereas holins are not; therefore lysins have received a lot of attention as potential antimicrobial agents. These proteins are fast acting, potent, and inactive against eukaryotic cells. Lysins have successfully saved mice from bacteremia caused by multidrug-resistant A. baumannii[65], Streptococcus pneumoniae[66], and MRSA[67], among others[63]. Combining phage lysins and antibiotics may be more effective at eliminating infections than by using antibiotics alone, as demonstrated in vitro and ex vivo in a colon model using C. difficile.[68]. Not all lysins show equal therapeutic potential, however, as demonstrated by Gilmer et al[69] who identified a uniquely potent lysin, PlySs2, which was highly effective against a range of pathogenic Streptococcus and Staphylococcus species, including MRSA, and was fully functional after 10 freeze-thaws. A single dose administered intraperitoneally to mice in a mixed S. pyogenes and MRSA bacteremia model provided a significantly higher survival rate than treatment with 3 previously characterized lysins[69]. A recent study exploring the isolation and application of phage proteins has revealed that lysins are even capable of crossing epithelial cell membranes to eliminate difficult to treat intracellular infections of S. pyogenes[70]. Phage lysins can also disrupt vegetative cells as demonstrated with the B. anthracis lysin PlyG which is capable of attacking endospores of bacillus, a distinct advantage over antibiotics[71]. Lysins can also be mass produced through common recombinant techniques. The gene for bacteriophage-derived cysteine, histidine-dependent amido hydrolase/peptidase (CHAPK) has been cloned and inserted into E. coli to be overexpressed for purification. Not only is the CHAPK lysin highly effective against MRSA, but it can disperse S. aureus biofilms[72].

Glycosylation is the most complex post-translational modification of proteins. Altered glycans on the tumor- and host-cell surface and in the tumor microenvironment have been identified to mediate critical events in cancer pathogenesis and progression. Tumor-associated glycan changes comprise increased branching of N-glycans, higher density of O-glycans, generation of truncated versions of normal counterparts, and generation of unusual forms of terminal structures arising from sialylation and fucosylation. The functional role of tumor-associated glycans (Tn, sTn, T, and sLea/x) is dependent on the interaction with lectins. Lectins are expressed on the surface of immune cells and endothelial cells or exist as extracellular matrix proteins and soluble adhesion molecules. Expression of tumor-associated glycans is involved in the dysregulation of glycogenes, which mainly comprise glycosyltransferases and glycosidases. Furthermore, genetic and epigenetic mechanisms on many glycogenes are associated with malignant transformation. With better understanding of all aspects of cancer-cell glycomics, many tumor-associated glycans have been utilized for diagnostic, prognostic, and therapeutic purposes. Glycan-based therapeutics has been applied to cancers from breast, lung, gastrointestinal system, melanomas, and lymphomas but rarely to neuroblastomas (NBs). The success of anti-disialoganglioside (GD2, a glycolipid antigen) antibodies sheds light on glycan-based therapies for NB and also suggests the possibility of protein glycosylation-based therapies for NB. This review summarizes our understanding of cancer glycobiology with a focus of how protein glycosylation and associated glycosyltransferases affect cellular behaviors and treatment outcome of various cancers, especially NB. Finally, we highlight potential applications of glycosylation in drug and cancer vaccine development for NB.

This review summarizes our understanding of cancer glycobiology and focuses on how protein glycosylation affects the cellular behavior and treatment outcomes of various cancers, especially NB. The effects exerted by glycosyltransferases, tumor cell-cell, and tumor cell-ECM interactions are also elucidated. Finally, this review discusses the advances in glycan-based therapies that have been utilized for a variety of cancers, such as glycosyltransferase inhibitors, glycomimetics, and glycan-based vaccines/immunotherapies. It is anticipated that NB-associated glycoforms regulated by genetic and epigenetic machinery will provide information with which novel therapeutic targets can be identified, and new therapies can be developed.

Outcomes for patients with CML have been greatly improved since the clinical application of Bcr-Abl1 TKIs. However, despite the high initial response rate of these inhibitors, drug resistance and adverse events are two main problems influencing the achievement of the best response and quality of life for patients. Sequential therapy with Bcr-Abl1 inhibitors leads to the continuous acquisition of novel mutations, especially compound mutants, which refers to the accumulation of more than one mutation in the same allele. Ponatinib is the latest generation of Bcr-Abl1 inhibitor, and patients treated with this drug have developed new resistance mutations, such as T315M single-point mutation and complex mutations T315I/E255V and E255V/Y253H.262,263,264 Overcoming these resistance mutations requires the development of next-generation inhibitors and combination therapy strategies. Meanwhile, it has also been reported that some mutations are sensitive to the second-generation inhibitors, such as T315A to nilotinib, E255K/V and Y253H to dasatinib and bosutinib, and patients harboring such mutations can be retreated with these drugs. The clinical use of ponatinib is associated with cardiovascular events, and concerns about arterial thrombosis may limit its treatment in some patients with T315I mutations. For these patients, omacetaxine mepesuccinate approved by the FDA in 2012 is a proper treatment option.265,266 It has shown encouraging therapeutic results in patients harboring T315I mutation and is tolerable without cardiovascular toxicity. Moreover, some patients with GIST and systemic mastocytosis can benefit from the treatment of imatinib, dasatinib, or nilotinib due to the broad-spectrum selectivity of them against c-Kit, PDGFR, or Src.267,268 Mutations of these kinases can also drive the selection of appropriate inhibitors. An in vitro study showed that imatinib-resistant mutations PDGFRα D842V and c-Kit D816V that commonly occur in GISTs and mastocytosis, respectively, could be strongly inhibited by dasatinib.269

Isoform-specific inhibitors have fewer off-target effects and side effects than pan-PI3K, pan-AKT, and dual PI3K/mTOR inhibitors. However, due to their limited therapeutic efficacy caused by compensation effects or various mutations of the PI3K/AKT/mTOR pathway, most clinical trials still tend to use pan-inhibitors. Therefore, clarifying the mutant types via molecular pathological diagnosis in advance can improve the clinical application of specific inhibitors. On the other hand, the clinical efficacy using only PI3K/AKT/mTOR inhibitors were shown to have modest effects for patients in actual treatment. More importantly, PI3K/AKT/mTOR cascade exchanges crosstalk with many other signaling pathways, such as Wnt and MAPK signaling. Hence, using such inhibitors is prone to negative feedback regulation, resulting in resistance. These problems highlight the limitations of PI3K/AKT/mTOR inhibitors as monotherapy in malignancies. Currently, efforts have focused on combination therapy, including inhibition of parallel pathways as well as targeted therapy combined with cytotoxic drugs,388 and the results of most clinical trials are promising. Moreover, treatment with PI3K pathway inhibitors could also induce adverse effects, even though isoform-specific inhibitors are no exception. For example, the PI3Kδ inhibitor idelalisib was shipped with four black-frame warnings, suggesting fatal and severe liver toxicity, diarrhea and colitis, pneumonia, and intestinal perforation.410 Other toxicities reported in clinical trials of the PI3K/AKT/mTOR inhibitors include immunosuppression, hypoglycemic, cardiac toxicity, neuropsychiatric effects, cutaneous reactions, nausea, mouth ulcers, constipation, etc. A better understanding of the mechanism of side effects caused by such drugs and their management might advance novel PI3K/AKT/mTOR inhibitors from clinical trials to the bedside, with new treatment options for patients. 041b061a72


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