J N C, Guvench O, MacKerell AD, Yamaguchi T, Mallajosyula SS
Journal of chemical theory and computation •
We present a revised version of the Drude polarizable carbohydrate force field (FF), focusing on refining the ring and exocyclic torsional parameters for hexopyranose monosaccharides. This refinement addresses the previously observed discrepancies between calculated and experimental NMR coupling values, particularly in describing ring dynamics and exocyclic rotamer populations within major hexose monosaccharides and their anomers. Specifically, α-MAN, β-MAN, α-GLC, β-GLC, α-GAL, β-GAL, α-ALT, β-ALT, α-IDO, and β-IDO were targeted for optimization. The optimization process involved potential energy scans (PES) of the ring and exocyclic dihedral angles computed using quantum mechanical (QM) methods. The target data for the reoptimization included PES of the inner ring dihedrals (C1-C2-C3-C4, C2-C3-C4-C5, C5-O5-C1-C2, C4-C5-O5-C1, O5-C1-C2-C3, C3-C4-C5-O5) and the exocyclic torsions, other than the pseudo ring dihedrals (O1-C1-O5-C5, O2-C2-C1-O5, and O4-C4-C5-O5) and hydroxyl torsions used in the previous parametrization efforts. These parameters, in conjunction with previously developed Drude parameters for hexopyranose monosaccharides, were validated against experimental observations, including NMR data and conformational energetics, in aqueous environments. The resulting polarizable model is shown to be in good agreement with a range of QM data, experimental NMR data, and conformational energetics of monosaccharides in aqueous solutions. This offers a significant improvement of the Drude carbohydrate force field, wherein the refinement enhances the accuracy of accessing the conformational dynamics of carbohydrates in biomolecular simulations.
This review highlights the causative organisms, clinical features, diagnosis, and treatment of the most common tick-borne illnesses in the United States, including Lyme disease, Rocky Mountain spotted fever, anaplasmosis, ehrlichiosis, tularemia, Powassan virus, and alpha-gal syndrome. Tick bite prevention strategies and some basic tick removal recommendations are also provided.
This phase II trial assessed the activity and tolerability of cetuximab (C225, Erbitux) in combination with carboplatin in patients with relapsed platinum-sensitive ovarian or primary peritoneal carcinoma. Patients were to receive combination therapy with cetuximab (initial dose of 400 mg/m2 intravenously on cycle 1, day 1, followed by weekly infusions of 250 mg/m2) and carboplatin (AUC of 6 on day 1 and every 3 weeks). The primary objectives of this trial were to estimate the anti-tumor activity and adverse events of this combination therapy. Immunohistochemical expression of EGFR was evaluated in tumor specimens from patients enrolled in this trial. Of the 29 patients, 28 (97%) were eligible and evaluable for analysis of the efficacy and toxicity of cetuximab administered in combination with carboplatin. Of the evaluable entries, 26 had EGFR-positive tumors and the response rate in this group of patients was as follows: 9 demonstrated an objective response (3 CR; 6 PR) and 8 had stable disease. The response rate did not meet criteria for opening a second stage of accrual. The median time to progression was 9.4+ months (range: .9-22.2+). The most commonly observed adverse events were dermatologic toxicity (grade 3 in 32%), thrombocytopenia (grade 3 in 14%), and hypersensitivity reactions (grade 3 and 4 in 18%). Cetuximab administered in combination with carboplatin had modest activity in screened patients with EGFR-positive, relapsed platinum-sensitive ovarian or primary peritoneal carcinoma. Cetuximab was associated with an acneiform rash in a majority of patients and occasional serious hypersensitivity reactions.
Safran H, Suntharalingam M, Dipetrillo T, Ng T, Doyle LA, et al.
International journal of radiation oncology, biology, physics •
To determine the feasibility and toxicity of the addition of cetuximab with paclitaxel, carboplatin, and radiation for patients with esophagogastric cancer on a Phase II study. Patients with locoregional esophageal and proximal gastric cancer without distant organ metastases were eligible. All patients received cetuximab, paclitaxel, and carboplatin weekly for 6 weeks with 50.4 Gy radiation. Sixty patients were enrolled, 57 with esophageal cancer and 3 with gastric cancer. Forty-eight had adenocarcinoma and 12 had squamous cell cancer. Fourteen of 60 patients (23%) had Grade 3 dermatologic toxicity consisting of a painful, pruritic acneiform rash on the face outside of the radiation field. The rates of Grades 3 and 4 esophagitis were 12% and 3%, respectively. Three patients had Grade 3/4 cetuximab hypersensitivity reactions and were not assessable for response. Forty of 57 patients (70%) had a complete clinical response after chemoradiation. Cetuximab can be safely administered with chemoradiation for esophageal cancer. Dermatologic toxicity and hypersensitivity reactions were associated with the addition of cetuximab. There was no increase in esophagitis or other radiation-enhanced toxicity.
An efficient chemo-enzymatic synthesis of alpha Gal-conjugated peptide T20 as novel HIV-immuno-targeting agent is described. The synthesis involves chemo-enzymatic preparation of maleimide-functionalized alpha Gal epitope and its chemoselective ligation with the peptide T20. The title compound contains two functional domains: the trisaccharide alpha Gal epitope that binds to human natural anti-Gal antibodies and the 36-amino acid gp41 peptide (T20) that recognizes the gp41 N-terminal ectodomain of the HIV envelope. Biological assays demonstrated that the synthetic conjugate could readily bind to natural anti-Gal antibodies (both IgG and IgM type) in normal human serum and exhibited potent anti-HIV activity even in the absence of human antibodies and complement system. The experimental data suggest that the synthetic alpha Gal-T20 might be valuable for in vivo HIV-immuno-targeting via antibody-mediated cytotoxicity and/or antibody-dependent, complement-mediated lysis of HIV particles and HIV-infected cells, thus providing an additional dimension of HIV intervention.
Escherichia coli strains causing acute pyelonephritis often express multiple fimbrial types and haemolysin, which may contribute to their ability to adhere to, and interact with, kidney epithelial cells. Strain CFT073, a pap+, sfa+, pil+, hly+ pyelonephritis strain, previously established as virulent in the CBA mouse model of ascending urinary tract infection and cytotoxic for cultured human renal epithelial cells, was selected for construction of isogenic strains. From a gene bank of this strain, two distinct copies of the pap operon were isolated. The two P-fimbrial determinants were subcloned into pCVD442, a positive selection suicide vector containing the sacB gene of Bacillus subtilis. Deletion mutations were introduced into each of the two constructs, within papEFG of one operon and papDEFG of the other. Suicide vectors carrying pap deletions were mobilized from E. coli SM10 lambda pir into CFT073 (NalR) and cointegrates were passaged on non-selective medium. The first pap mutation was identified by screening a Southern blot of DNA from sucrose-resistant colonies using a papEFG probe. This mutant retained the MRHA+ phenotype since a second functional copy of pap was still present. A double pap-deletion mutant, UPEC76, confirmed by Southern blotting, was unable to agglutinate human type O erythrocytes or alpha Gal(1-4)beta Gal-coated latex beads. CBA mice (N = 100) were challenged transurethrally with 10(5), 10(6), 10(7), or 10(9) cfu of strains CFT073 or UPEC76. After one week, quantitative cultures of urine, bladder, and kidney were done and histologic changes were examined. No substantive differences in organism concentration or histological findings between parent and mutant were detected in urine, bladder, or kidney at any challenge concentration. We conclude that adherence by P fimbriae of uropathogenic E. coli strain CFT073 plays only a subtle role in the development of acute pyelonephritis in the CBA mouse model.
Recent investigations of immunologic events in systemic sclerosis focus on the identification of which immune system cells are participating in the disease process, what antigens are stimulating the T and B cells, which cytokines are involved, and which cell adhesion molecules promote cell-cell and cell-extracellular matrix interactions. Increased numbers of gamma/delta and activated CD4+ T cells are present in involved skin of line-200 chickens, an animal model of systemic sclerosis. CD4+ T cells from patients with systemic sclerosis are stimulated by human type I collagen, and immunoglobulins from some patients with systemic sclerosis bind retroviral proteins, the terminal galactosyl (alpha 1-3)-galactose disaccharide of laminin, or a 138 amino acid region of the PM-Scl antigen. The development of an anticentromere antibody response in patients with systemic sclerosis appears to require the presence of a polar amino acid at position 26 in the antigen-binding cleft of the HLA-DQB1 molecule. Interleukin-2, interleukin-4, interleukin-6, and transforming growth factor-beta have been implicated as cytokines that may be involved in the pathogenesis of systemic sclerosis. Increased expression of intercellular adhesion molecule 1 (ICAM-1) on systemic sclerosis fibroblasts is responsible for increased binding of T cells to those fibroblasts through ICAM-1/lymphocyte function-associated antigen 1 interactions. beta 1 and beta 2 integrins, ICAM-1, and endothelial leukocyte adhesion molecule 1 all may be involved in the homing of lymphocytes to involved skin in patients with systemic sclerosis.
