Evaluation of a New 'Mix-In' Style Glycomacropeptide-Based Protein Substitute for Food and Drinks in Patients with Phenylketonuria and Tyrosinemia.

(1) Background: Poor palatability, large volume, and lack of variety of some liquid and powdered protein substitutes (PSs) for patients with phenylketonuria (PKU) and tyrosinemia (TYR) can result in poor adherence. This study aimed to evaluate a new unflavoured, powdered GMP-based PS designed to be mixed into drinks, foods, or with other PSs, in patients with PKU and TYR. (2) Methods: Paediatric and adult community-based patients were recruited from eight metabolic centres and prescribed ≥1 sachet/day (10 g protein equivalent (PE)) of the Mix-In-style PS over 28 days. Adherence, palatability, GI tolerance, and metabolic control were recorded at baseline and follow-up. Patients who completed at least 7 days of intervention were included in the final analysis. (3) Results: Eighteen patients (3-45 years, nine males) with PKU (n = 12) and TYR (n = 6) used the Mix-In-style PS for ≥7 days (mean 26.4 days (SD 4.6), range 11-28 days) alongside their previous PS, with a mean intake of 16.7 g (SD 7.7) PE/day. Adherence was 86% (SD 25), and GI tolerance was stable, with n = 14 experiencing no/no new symptoms and n = 3 showing improved symptoms compared to baseline. Overall palatability was rated satisfactory by 78% of patients, who successfully used the Mix-In-style PS in various foods and drinks, including smoothies, squash, and milk alternatives, as a top-up to meet their protein needs. There was no concern regarding safety/metabolic control during the intervention. (4) Conclusions: The 'Mix-In'-style PS was well adhered to, accepted, and tolerated. Collectively, these data show that providing a flexible, convenient, and novel format of PS can help with adherence and meet patients' protein needs.

Xenopus GLP-1-based glycopeptides as dual glucagon-like peptide 1 receptor/glucagon receptor agonists with improved in vivo stability for treating diabetes and obesity.

Peptide dual agonists toward both glucagon-like peptide 1 receptor (GLP-1R) and glucagon receptor (GCGR) are emerging as novel therapeutics for the treatment of type 2 diabetes mellitus (T2DM) patients with obesity. Our previous work identified a Xenopus GLP-1-based dual GLP-1R/GCGR agonist termed xGLP/GCG-13, which showed decent hypoglycemic and body weight lowering activity. However, the clinical utility of xGLP/GCG-13 is limited due to its short in vivo half-life. Inspired by the fact that O-GlcNAcylation of intracellular proteins leads to increased stability of secreted proteins, we rationally designed a panel of O-GlcNAcylated xGLP/GCG-13 analogs as potential long-acting GLP-1R/ GCGR dual agonists. One of the synthesized glycopeptides 1f was found to be equipotent to xGLP/GCG-13 in cell-based receptor activation assays. As expected, O-GlcNAcylation effectively improved the stability of xGLP/GCG-13 in vivo. Importantly, chronic administration of 1f potently induced body weight loss and hypoglycemic effects, improved glucose tolerance, and normalized lipid metabolism and adiposity in both db/db and diet induced obesity (DIO) mice models. These results supported the hypothesis that glycosylation is a useful strategy for improving the in vivo stability of GLP-1-based peptides and promoted the development of dual GLP-1R/GCGR agonists as antidiabetic/antiobesity drugs.

Daptomycin versus teicoplanin in the treatment of osteomyelitis: Results of the Göztepe retrospective cohort study.

OBJECTIVES: Daptomycin is highly effective against Gram-positive multidrug-resistant bacteria. Publications on daptomycin in osteomyelitis treatment are limited. PATIENTS AND METHODS: In this multicenter retrospective cohort study, the aim was to evaluate the outcomes of osteomyelitis cases having received daptomycin or teicoplanin. This multicenter retrospective cohort study gathered data from seven centers located in five cities of Turkey. Study inclusion criteria were as follows: (a) magnetic resonance imaging and/or direct X-ray revealed osteomyelitis or biopsy pathologic examination results concomitant with osteomyelitis. Chi-squareand Student t-tests were used for statistical comparison. RESULTS: A total of 72 patients, 38 cases in the daptomycin group and 34 cases in the teicoplanin group diagnosed with osteomyelitis fulfilling the study inclusion criteria, were included in the study. Clinical success at the end of induction therapy was achieved in 32/38 cases in the daptomycin cohort vs. 30/34 cases in the teicoplanin cohort (p: 0.73). CONCLUSION: Although this is a limited experience in a small but well-defined cohort, our data suggest that daptomycin may be a safe alternative to glycopeptides in osteomyelitis treatment. A randomized controlled clinical study involving larger cohorts may increase the available evidence.

CD8+ T-cell percentage increases in diffuse large B-cell lymphoma patients receiving mannatide combined with standard regimens.

WHAT IS KNOWN AND OBJECTIVE: Suppression of antilymphoma effector cells, mainly T cells, is a key prerequisite for tumorigenesis and resistance in diffuse large B-cell lymphoma (DLBCL). The aim of the study was to determine whether mannatide (MT), an immunomodulator, could enhance the immunological response in DLBCL patients receiving standard regimens. METHODS: Patients with aggressive DLBCL treated with first-line standard regimens were included in this single-centre retrospective study. T-cell subtypes were detected using flow cytometry before and after the first cycle of treatment. Patients in MT group were treated with MT combined with standard first-line regimens, and patients in control group with standard first-line regimens. Chi-square test or Fisher's exact tests were used for categorical variables and independent t-tests for continuous variables. RESULTS AND DISCUSSION: Among the 138 DLBCL patients enrolled in this study, 34 (24.64%) were assigned to the MT group, while 104 (75.36%) patients were included in the control group. There were no significant differences in clinicopathological characteristics and baseline T-cell subtypes between the two groups (p > 0.05). After treatment, CD3+ CD8+ T-cell percentage of MT group was significantly higher than that of control group (p = 0.01), while CD3+ CD4+ T-cell percentage of MT group was significantly lower than that of control group (p < 0.01). Thus, the CD4+ /CD8+ ratio of MT group was significantly lower than that of control group (p = 0.03). In the subgroup of DLBCL patients treated with EPOCH/R-EPOCH, significant differences were also found in post-treatment CD3+ CD8+ T-cell percentage (p < 0.01), CD3+ CD4+ T-cell percentage (p = 0.02) and CD4+ /CD8+ ratio (p = 0.01) between MT and control groups. WHAT IS NEW AND CONCLUSION: CD3+ CD8+ T-cell percentage increased in DLBCL patients receiving MT treatment. Further studies are required to determine the clinical benefits of MT.

Impact of pre-transplant use of antibiotics on the graft-versus-host disease in adult patients with hematological malignancies.

OBJECTIVES: Changes in fecal microbiota affect the incidence and extent of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Most patients with hematological malignancies receive antibiotics for the treatment of febrile neutropenia prior to allogeneic HSCT, and pre-transplant use of antibiotics may influence the fecal microbiota and GVHD. METHODS: We retrospectively analysed consecutive adult patients with hematological malignancies who received allogeneic HSCT at Chungnam National University Hospital between 2007 and 2018. Pre-transplant use of antibiotics was defined as the use of antibiotics before conditioning chemotherapy. RESULTS: This study included 131 patients with a median age of 46 (range, 18-71) years: 76 (58%) patients were AML, 28 (21.4%) with ALL, 23 (17.6%) with MDS, and 4 (3.1%) with CML. All patients received calcineurin inhibitors with short-course methotrexate for GVHD prophylaxis. A total of 31 (23.7%) patients received anti-thymocyte globulin. All patients received antibiotics prior to HSCT: 70 (53.4%) patients received glycopeptide, 114 (87.0%) received cefepime, 87 (66.4%) received piperacillin/tazobactam, and 51 (38.9%) received carbapenem. Patients who received glycopeptide had more frequently extensive chronic GVHD (cGVHD) than those who did not (51.1% vs. 28.1% at 5 years) and had more frequently cGVHD of the lung (34.8% vs. 15.8% at 5 years). Pre-transplant use of glycopeptide did not affect the overall survival (OS) or GVHD- and relapse-free survival (GRFS) (median OS; 49 months in glycopeptide group vs. not reached in non-glycopeptide group, p=0.475; median GRFS; 9 months in glycopeptide group vs. 16 months in non-glycopeptide group, p=0.092). CONCLUSION: Pre-transplant use of glycopeptide tends to increase the incidence of extensive cGVHD.

The lysosome: A potential juncture between SARS-CoV-2 infectivity and Niemann-Pick disease type C, with therapeutic implications.

Drug repurposing is potentially the fastest available option in the race to identify safe and efficacious drugs that can be used to prevent and/or treat COVID-19. By describing the life cycle of the newly emergent coronavirus, SARS-CoV-2, in light of emerging data on the therapeutic efficacy of various repurposed antimicrobials undergoing testing against the virus, we highlight in this review a possible mechanistic convergence between some of these tested compounds. Specifically, we propose that the lysosomotropic effects of hydroxychloroquine and several other drugs undergoing testing may be responsible for their demonstrated in vitro antiviral activities against COVID-19. Moreover, we propose that Niemann-Pick disease type C (NPC), a lysosomal storage disorder, may provide new insights into potential future therapeutic targets for SARS-CoV-2, by highlighting key established features of the disorder that together result in an "unfavorable" host cellular environment that may interfere with viral propagation. Our reasoning evolves from previous biochemical and cell biology findings related to NPC, coupled with the rapidly evolving data on COVID-19. Our overall aim is to suggest that pharmacological interventions targeting lysosomal function in general, and those particularly capable of reversibly inducing transient NPC-like cellular and biochemical phenotypes, constitute plausible mechanisms that could be used to therapeutically target COVID-19.

Design and synthesis of glyco-peptides as anti-cancer agents targeting thrombin-protease activated receptor-1 interaction.

Thrombin activates protease-activated receptor-1 (PAR-1) through binding to exosite I and the active site to promote tumor growth. We have developed a new class of anti-cancer glyco-peptides to target exosite I selectively without affecting the active-site-mediated coagulation activity and showed the importance of glycans for the stability and anti-cancer activity of the glyco-peptides.

Synthesis and Immunological Evaluation of Disaccharide Bearing MUC-1 Glycopeptide Conjugates with Virus-like Particles.

Mucin-1 (MUC1) is a highly attractive antigenic target for anticancer vaccines. Naturally existing MUC1 can contain multiple types of O-linked glycans, including the Thomsen-Friedenreich (Tf) antigen and the Sialyl Thomsen-nouveau (STn) antigen. In order to target these antigens as potential anticancer vaccines, MUC1 glycopeptides SAPDT*RPAP (T* is the glycosylation site) bearing the Tf and the STn antigen, respectively, have been synthesized. The bacteriophage Qß carrier is a powerful carrier for antigen delivery. The conjugates of MUC1-Tf and -STn glycopeptides with Qß were utilized to immunize immune-tolerant human MUC1 transgenic (MUC1.Tg) mice, which elicited superior levels of anti-MUC1 IgG antibodies with titers reaching over 2 million units. The IgG antibodies recognized a wide range of MUC1 glycopeptides bearing diverse glycans. Antibodies induced by Qß-MUC1-Tf showed strongest binding, with MUC1-expressing melanoma B16-MUC1 cells, and effectively killed these cells in vitro. Vaccination with Qß-MUC1-Tf first followed by tumor challenge in a lung metastasis model showed significant reductions of the number of tumor foci in the lungs of immunized mice as compared to those in control mice. This was the first time that a MUC1-Tf-based vaccine has shown in vivo efficacy in a tumor model. As such, Qß-MUC1 glycopeptide conjugates have great potential as anticancer vaccines.

A Novel Actin Binding Drug with In Vivo Efficacy.

Occidiofungin is produced by the soil bacterium Burkolderia contaminans MS14 and is structurally similar or identical to the burkholdines, xylocandins, and cepacidines. This study identified the primary cellular target of occidiofungin, which was determined to be actin. The modification of occidiofungin with a functional alkyne group enabled affinity purification assays and localization studies in yeast. Occidiofungin has a subtle effect on actin dynamics that triggers apoptotic cell death. We demonstrate the highly specific localization of occidiofungin to cellular regions rich in actin in yeast and the binding of occidiofungin to purified actin in vitro Furthermore, a disruption of actin-mediated cellular processes, such as endocytosis, nuclear segregation, and hyphal formation, was observed. All of these processes require the formation of stable actin cables, which are disrupted following the addition of a subinhibitory concentration of occidiofungin. We were also able to demonstrate the effectiveness of occidiofungin in treating a vulvovaginal yeast infection in a murine model. The results of this study are important for the development of an efficacious novel class of actin binding drugs that may fill the existing gap in treatment options for fungal infections or different types of cancer.

5-HIAA induces neprilysin to ameliorate pathophysiology and symptoms in a mouse model for Alzheimer's disease.

Serotoninergic activation which decreases brain Aß peptides is considered beneficial in mouse models for Alzheimer's disease (AD), but the mechanisms involved remain unclear. Because growing evidence suggested that the stimulation of proteases digesting Aß, especially the endopeptidase neprilysin (NEP) may be effective for AD therapy/prevention, we explored the involvement of serotonin precursors and derivatives in NEP regulation. We found that 5-hydroxyindolacetic acid (5-HIAA), the final metabolite of serotonin, considered until now as a dead-end and inactive product of serotonin catabolism, significantly reduces brain Aß in the transgenic APPSWE mouse model for AD-related Aß pathology and in the phosphoramidon-induced cerebral NEP inhibition mouse model. 5-HIAA treatment improves memory performance in APPSWE mice. Furthermore, 5-HIAA and its precursors increase NEP level in vivo and in neuroblastoma cells. Inhibition of ERK 1/2 cascade by 5-HIAA or SCH772984 enhanced NEP levels, suggesting MAP-kinase pathway involvement in 5-HIAA-induced regulation of NEP expression. Our results provide the first demonstration that 5-HIAA is an active serotonin metabolite that increases brain Aß degradation/clearance and improves symptoms in the APPSWE mouse model for AD.

Prevention of Cyclophosphamide-Induced Immunosuppression in Mice with the Antimicrobial Peptide Sublancin.

Sublancin is a glycosylated antimicrobial peptide produced by Bacillus subtilis 168 with combined antibacterial and immunomodulatory activities. The purpose of this study was to evaluate the protective effects of sublancin on immunosuppression in cyclophosphamide-treated mice. In normal mice, the phagocytic activity of mouse peritoneal macrophages was significantly enhanced by oral administration of sublancin (1.0 mg/kg body weight) to BALB/c mice for 7 days (P < 0.01). In addition, the mRNA expression of IL-1ß, IL-6, and TNF-α in peritoneal macrophages from sublancin- (1.0 mg/kg body weight) administered mice was significantly increased (P < 0.05). In cyclophosphamide-treated mice, oral sublancin administration accelerated the recovery of peripheral white blood cells, red blood cells, hemoglobins, and platelets and enhanced the macrophage phagocytic activity. Furthermore, sublancin restored the mRNA levels of IL-2, IL-4, and IL-6 in the spleen. Finally, the intestinal absorption of sublancin was poor as detected in the Caco-2 transwell system. Taken together, these findings suggest that sublancin plays a crucial role in the protection against immunosuppression in cyclophosphamide-treated mice and could be a potential candidate for use in immune therapy regimens.

Combatting resistant enterococcal infections: a pharmacotherapy review.

INTRODUCTION: The role of enterococci in infectious diseases has evolved from a gut and urinary commensal to a major pathogen of concern. Few options exist for resistant enterococci, and appropriate use of the available agents is crucial. AREAS COVERED: Herein, the authors discuss antibiotics with clinically useful activity against Enterococcus faecalis and E. faecium. The article specifically discusses: antibiotics active against enterococci and their mechanism of resistance, pharmacokinetic and pharmacodynamic principles, in vitro combinations, and clinical studies which focus on urinary tract, intra-abdominal, central nervous system, and bloodstream infections due to enterococci. EXPERT OPINION: Aminopenicillins are preferred over all other agents when enterococci are susceptible and patients can tolerate them. Daptomycin and linezolid have demonstrated clinical efficacy against vancomycin-resistant enterococci (VRE). Synergistic combinations are often warranted in complex infections of high inoculum and biofilms while monotherapies are generally appropriate for uncomplicated infections. Although active against resistant enterococci, the pharmacokinetics, efficacy and safety of tigecycline and quinupristin/dalfopristin can problematical for severe infections. For cystitis, amoxicillin, nitrofurantoin, or fosfomycin are ideal. Recently, approved agents such as tedizolid and oritavancin have good in vitro activity against VRE but clinical studies against other resistant enterococci are lacking.

Unusual oral mucosal microbiota after hematopoietic cell transplantation with glycopeptide antibiotics: potential association with pathophysiology of oral mucositis.

Severe oral mucositis occurs frequently in patients receiving hematopoietic stem cell transplantation (HCT). Oral mucosal bacteria can be associated with progression of oral mucositis, and systemic infection may occur via ulcerative oral mucositis. However, little information is available regarding the oral microbiota after HCT. Here, PCR-denaturing gradient gel electrophoresis (DGGE) was performed to characterize the oral mucosal microbiota, which can be affected by antibiotics, before and after HCT. Sixty reduced-intensity HCT patients were enrolled. Three patients with the least antibiotic use (quinolone prophylaxis and/or ß-lactam monotherapy group) and three patients with the most antibiotic use (ß-lactam-glycopeptide combination therapy group) were selected. Bacterial DNA samples obtained from the oral mucosa before and after HCT were subjected to PCR-DGGE. The trajectory of oral mucositis was evaluated. The oral mucosal microbiota in the ß-lactam-glycopeptide combination therapy group was different from that in the quinolone prophylaxis and/or ß-lactam monotherapy group, and Staphylococcus spp. and Enterococcus spp. were identified. Lautropia mirabilis was dominant in one patient. Ulcerative oral mucositis was observed only in the ß-lactam-glycopeptide combination therapy group. In conclusion, especially with the use of strong antibiotics, such as glycopeptides, the oral mucosal microbiota differed completely from that under normal conditions and consisted of Staphylococcus spp., Enterococcus spp., and unexpectedly L. mirabilis. The normal oral microbiota consists not only of bacteria, but these unexpected bacteria could be involved in the pathophysiology as well as systemic infection via oral mucositis. Our results can be used as the basis for future studies in larger patient populations.

Comparison of the efficacy of nafcillin and glycopeptides as definitive therapy for patients with methicillin-susceptible Staphylococcus aureus bacteremia: a retrospective cohort study.

BACKGROUND: Studies have shown that the prognosis of the treatment of methicillin-susceptible S. aureus (MSSA) with glycopeptides is inferior compared to treatment with ß-lactam. However, there are only few studies comparing treatment with antistaphylococcal penicillin alone to glycopeptide treatment. The aim of this study was to compare the efficacy of nafcillin, an antistaphylococcal penicillin, with that of glycopeptides as a definitive therapy for MSSA bacteremia. METHODS: Patients with MSSA bacteremia recruited from a tertiary referral hospital were enrolled in this retrospective cohort study. Demographic characteristics, laboratory data, and clinical outcome of the treatment were compared between a group receiving nafcillin and a group receiving glycopeptides. RESULTS: A total of 188 patients with MSSA bacteremia were included in this study. The glycopeptide group had a higher rate of malignancy (28.6 vs. 60.8%, p < 0.001) and proportion of healthcare-associated infections (47.3 vs. 72.2%, p < 0.001) compared to the nafcillin group. The ratio of skin and soft tissue infections (30.0 vs. 16.7%, p = 0.037) and bone and joint infections (17.8 vs. 6.3%, p = 0.022), as well as levels of C-reactive protein (139.60 vs. 107.61 mg/dL, p = 0.022) were higher in the nafcillin group. All-cause 28-day mortality was significantly high in the glycopeptide group (7.7 vs. 20.6%, p = 0.013). CONCLUSION: In patients with MSSA bacteremia, all-cause 28-day mortality rate was higher in a group treated with glycopeptides than in a group treated with nafcillin. Therefore, the use of nafcillin should be considered as a definitive therapy for MSSA bacteremia.

Empirical antibiotics targeting gram-positive bacteria for the treatment of febrile neutropenic patients with cancer.

BACKGROUND: The pattern of infections among neutropenic patients with cancer has shifted in the last decades to a predominance of gram-positive infections. Some of these gram-positive bacteria are increasingly resistant to beta-lactams and necessitate specific antibiotic treatment. OBJECTIVES: To assess the effectiveness of empirical anti-gram-positive (antiGP) antibiotic treatment for febrile neutropenic patients with cancer in terms of mortality and treatment failure. To assess the rate of resistance development, further infections and adverse events associated with additional antiGP treatment. SEARCH METHODS: For the review update we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2017, Issue 2), MEDLINE (May 2012 to 2017), Embase (May 2012 to 2017), LILACS (2012 to 2017), conference proceedings, ClinicalTrials.gov trial registry, and the references of the included studies. We contacted the first authors of all included and potentially relevant trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing one antibiotic regimen versus the same regimen with the addition of an antiGP antibiotic for the treatment of febrile neutropenic patients with cancer. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility and risk of bias, and extracted all data. Risk ratios (RR) with 95% confidence intervals (CIs) were calculated. A random-effects model was used for all comparisons showing substantial heterogeneity (I2 > 50%). Outcomes were extracted by intention-to-treat and the analysis was patient-based whenever possible. MAIN RESULTS: Fourteen trials and 2782 patients or episodes were included. Empirical antiGP antibiotics were tested at the onset of treatment in 12 studies, and for persistent fever in two studies. The antiGP treatment was a glycopeptide in nine trials. Eight studies were assessed in the overall mortality comparison and no significant difference was seen between the comparator arms, RR of 0.90 (95% CI 0.64 to 1.25; 8 studies, 1242 patients; moderate-quality data). Eleven trials assessed failure, including modifications as failures, while seven assessed overall failure disregarding treatment modifications. Failure with modifications was reduced, RR of 0.72 (95% CI 0.65 to 0.79; 11 studies, 2169 patients; very low-quality data), while overall failure was the same, RR of 1.00 (95% CI 0.79 to 1.27; 7 studies, 943 patients; low-quality data). Sensitivity analysis for allocation concealment and incomplete outcome data did not change the results. Failure among patients with gram-positive infections was reduced with antiGP treatment, RR of 0.56 (95% CI 0.38 to 0.84, 5 studies, 175 patients), although, mortality among these patients was not changed.Data regarding other patient subgroups likely to benefit from antiGP treatment were not available. Glycopeptides did not increase fungal superinfection rates and were associated with a reduction in documented gram-positive superinfections. Resistant colonisation was not documented in the studies. AUTHORS' CONCLUSIONS: Based on very low- or low-quality evidence using the GRADE approach and overall low risk of bias, the current evidence shows that the empirical routine addition of antiGP treatment, namely glycopeptides, does not improve the outcomes of febrile neutropenic patients with cancer.

T11TS Treatment Augments Apoptosis of Glioma Associated Brain Endothelial Cells, Hint Toward Anti-Angiogenic Action in Glioma.

Malignant glioma continues to be a clinical challenge with an urgent need for developing curative therapeutic intervention. Apoptosis induction in tumor-associated endothelial cells represent a central mechanism that counteracts angiogenesis in glioma and other solid tumors. We previously demonstrated that intraperitoneal administration of sheep erythrocyte membrane glycopeptide T11-target structure (T11TS) in rodent glioma model inhibits PI3K/Akt pathway and Raf/MEK/ERK signaling in glioma-associated brain endothelial cells. In the present study, we investigated whether T11TS treatment influence apoptosis signaling in vivo in glioma-associated brain endothelial cells. Annexin-V/PI staining showed that T11TS treatment in glioma-induced rats increases apoptosis of glioma-associated endothelial cells within glioma milieu compared to brain endothelial cells in glioma induced and control groups. Flowcytometric JC-1 assay revealed that T11TS administration triggers loss of mitochondrial membrane potential in glioma-associated brain endothelial cells. Flowcytometry, immunoblotting, and in situ immunofluoresecnt imaging were employed to investigate the effect of T11TS on apoptotic regulatory proteins in brain endothelial cells. T11TS treatment-upmodulated expression of p53, Bax, Fas, FasL, and FADD in glioma associated endothelial cells and downregulated Bcl-2 protein. T11TS therapy induced cytochrome-c release into cytosol, activated caspase -9, 8, 3, and cleaved Bid in glioma associated brain endothelial cells. The study demonstrates that T11TS induces apoptosis in glioma-associated brain endothelial cells via p53 accumulation and activation of intrinsic as well as Fas-dependent extrinsic pathway. The pro-apoptotic action of T11TS on glioma-associated endothelial cells provides crucial insight into how T11TS exerts its anti-angiogenic function in glioma. J. Cell. Physiol. 232: 526-539, 2017. © 2016 Wiley Periodicals, Inc.

Large-scale synthesis and structural analysis of a synthetic glycopeptide dendrimer as an anti-cancer vaccine candidate.

Herein, we report a new process that enables the gram-scale production of a fully synthetic anti-cancer vaccine for human use. This therapeutic vaccine candidate, named MAG-Tn3, is a high-molecular-weight tetrameric glycopeptide encompassing carbohydrate tumor-associated Tn antigen clusters and peptidic CD4+ T-cell epitopes. The synthetic process involves (i) the stepwise solid-phase assembly of protected amino acids, including the high value-added Tn building blocks with only 1.5 equivalents, (ii) a single isolated intermediate, and (iii) the simultaneous deprotection of 36 hindered protective groups. The resulting MAG-Tn3 was unambiguously characterized using a combination of techniques, including a structural analysis by nuclear magnetic resonance spectroscopy. The four peptidic chains are flexible in solution, with a more constrained but extended conformation at the Tn3 antigen motif. Finally, we demonstrate that, when injected into HLA-DR1-expressing transgenic mice, this vaccine induces Tn-specific antibodies that mediate the killing of human Tn-positive tumor cells. These studies led to a clinical batch of the MAG-Tn3, currently investigated in breast cancer patients (phase I clinical trial). The current study demonstrates the feasibility of the multigram-scale synthesis of a highly pure complex glycopeptide, and it opens new avenues for the use of synthetic glycopeptides as drugs in humans.

Enhancing the efficacy of cytotoxic agents for cancer therapy using photochemical internalisation.

Photochemical internalisation (PCI) is a technique for improving cellular delivery of certain bioactive agents which are prone to sequestration within endolysosomes. There is a wide range of agents suitable for PCI-based delivery including toxins, oligonucleotides, genes and immunoconjugates which demonstrates the versatility of this technique. The basic mechanism of PCI involves triggering release of the agent from endolysosomes within the target cells using a photosensitiser which is selectively retained with the endolysosomal membranes. Excitation of the photosensitiser by visible light leads to disruption of the membranes via photooxidative damage thereby releasing the agent into the cytosol. This treatment enables the drugs to reach their intended subcellular target more efficiently and improves their efficacy. In this review we summarise the applications of this technique with the main emphasis placed on cancer chemotherapy.

Spectrum of bacteremia in posthematopoietic stem cell transplant patients from an Indian center.

BACKGROUND: Despite the relatively low prevalence of Gram-positive bacteremic infections in Indian oncology patients, glycopeptides are extensively used for empirical management of febrile neutropenia. Our aim was to analyze the spectrum of bacteremia in posthematopoietic stem cell transplant (HSCT) recipients in our center and make a recommendation on glycopeptide use in this patient population. MATERIALS AND METHODS: Retrospective analysis of bacteremic data from HSCT recipients in a tertiary care oncology and transplant center from South India, between 2011 and 2013. RESULTS: In 217 patients, 52 bacteremic episodes were identified. The majority of the isolates were Gram-negatives (88.4%) with very few Gram-positives (7.69%). CONCLUSION: Glycopeptides need not be included in the empirical antibiotic regimen in post-HSCT settings with very low Gram-positive infection rates.