bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nonnucleoside Pyrrolopyrimidines with a Unique Mechanism of Action against Human Cytomegalovirus
Authors: Jacobson Jennie G. , Renau Thomas E. , Nassiri M. Reza , Sweier Dominica G. , Breitenbach Julie M. , Townsend Leroy B. , Drach John C. 
Published: October 2018

ABSTRACT

Based upon a prior study which evaluated a series of nonnucleoside pyrrolo[2,3-
d
]pyrimidines as inhibitors of human cytomegalovirus (HCMV), we have selected three active analogs for detailed study. In an HCMV plaque-reduction assay, compounds 828, 951, and 1028 had 50% inhibitory concentrations (IC
50
s) of 0.4 to 1.0 μM. Similar results were obtained when 828 and 951 were examined by HCMV enzyme-linked immunosorbent assay (IC
50
s = 1.9 and 0.4 μM, respectively) and when 828 was tested in a viral DNA-DNA hybridization assay (IC
50
= 1.3 μM). In yield-reduction assays with a low multiplicity of infection (MOI), all three compounds caused multiple log
10
reductions in virus titer, and the activities of these compounds were comparable to the activity of ganciclovir (GCV; IC
90
= 0.2 μM). In contrast to the reduction of viral titers by GCV, the reduction of viral titers by 828, 951, and 1028 decreased with increasing MOI. Cytotoxicity in human foreskin fibroblasts and KB cells ranged from 32 to >100 μM. In addition, 828 (the only compound tested) was less toxic against human bone marrow progenitor cells than GCV. Time-of-addition and time-of-removal studies established that the three pyrrolopyrimidines inhibited HCMV replication before GCV had an effect on viral DNA synthesis but after viral adsorption. Compound 828 was equally effective against GCV-sensitive and GCV-resistant HCMV clinical isolates. Combination studies with 828 and GCV showed that the effects of the two compounds on HCMV were additive but not synergistic. Taken together, the data indicate that these pyrrolopyrimidines target a viral protein that is required in an MOI-dependent manner and that is expressed early in the HCMV replication cycle.
Gastric Penetration of Amoxicillin in a Human
Helicobacter pylori
-Infected Xenograft Model
Authors: Lozniewski Alain , Duprez Adrien , Renault Corinne , Muhale Filipe , Conroy Marie-Christine , Weber Michele , Le Faou Alain , Jehl Francois 
Published: October 2018

ABSTRACT

The delivery of antibiotics into
Helicobacter pylori
-infected human stomachs is still poorly understood. Human embryonic gastric xenografts in nude mice have recently been proposed as a new model for the study of
H. pylori
infection. Using this model, we compared the penetration of amoxicillin, after intraperitoneal administration of a dose of 20 mg/kg of body weight, into the gastric mucosae of infected and uninfected xenografts. The concentrations of this drug in serum and superficial gastric mucosae were determined at 20 min and 1 and 3 h after injection. Ten mice with
H. pylori
-infected grafts (
n
= 5) or uninfected grafts (
n
= 5) were studied. Mucosal samples were obtained by cryomicrotomy. The concentrations in serum were similar to those obtained in the serum of humans after oral administration of 1 g of amoxicillin. The mean area under the tissue concentration-versus-time curve from 0 to 3 h obtained for mice with infected grafts was significantly higher than that obtained for the animals with uninfected grafts (
P
= 0.01). These results suggest that the penetration of amoxicillin into the superficial gastric mucosa may be substantially increased in the case of
H. pylori
infection. Thus, human xenografts in nude mice represent a new, well-standardized model for investigation of systemic delivery of drugs into
H. pylori
-infected gastric mucosa.
Acyclovir Is Phosphorylated by the Human Cytomegalovirus UL97 Protein
Authors: Talarico Christine L. , Burnette Thimysta C. , Miller Wayne H. , Smith Sheila L. , Davis Michelle G. , Stanat Sylvia C. , Ng Teresa I. , He Zuwen , Coen Donald M. , Roizman Bernard , Biron Karen K. 
Published: October 2018

ABSTRACT
Acyclovir (ACV) has shown efficacy in the prophylactic suppression of human cytomegalovirus (HCMV) reactivation in immunocompromised renal transplant patients without the toxicity associated with ganciclovir (GCV). The HCMV UL97 gene product, a protein kinase, is responsible for the phosphorylation of GCV in HCMV-infected cells. This report provides evidence for the phosphorylation of ACV by UL97. Anabolism studies with the HCMV wild-type strain AD169 and with recombinant mutants derived from marker transfer experiments performed by using mutant UL97 DNA from both clinical isolates and a laboratory-derived strain resistant to GCV showed that mutations in the UL97 gene cripple the ability of recombinant virus-infected cells to anabolize both GCV and ACV. These mutant UL97 recombinant viruses were less susceptible to both GCV and ACV than was the wild-type strain. A recombinant herpes simplex virus type 1 strain, in which the thymidine kinase gene is deleted and the UL13 gene is replaced with the HCMV UL97 gene, was able to induce the phosphorylation of ACV in infected cells. Finally, purified UL97 phosphorylated both GCV and ACV to their monophosphates. Our results indicate that UL97 promotes the selective activity of ACV against HCMV.
Antagonism of Azole Activity againstCandida albicansfollowing Induction of Multidrug Resistance Genes by Selected Antimicrobial Agents
Authors: Henry Karl W. , Cruz M. Cristina , Katiyar Santosh K. , Edlind Thomas D. 
Published: October 2018

ABSTRACTAntifungal azoles (e.g., fluconazole) are widely used for prophylaxis or treatment ofCandida albicansinfections in immunocompromised individuals, such as those with AIDS. These individuals are frequently treated with a variety of additional antimicrobial agents. Potential interactions between three azoles and 16 unrelated drugs (antiviral, antibacterial, antifungal, and antiprotozoal agents) were examined in vitro. Two compounds, tested at concentrations achievable in serum, demonstrated an antagonistic effect on azole activity againstC. albicans. At fluconazole concentrations two to four times the 50% inhibitory concentration,C. albicansgrowth (relative to treatment with fluconazole alone) increased 3- to 18-fold in the presence of albendazole (2 μg/ml) or sulfadiazine (50 μg/ml). Antagonism (3- to 78-fold) of ketoconazole and itraconazole activity by these compounds was also observed. Since azole resistance has been correlated with overexpression of genes encoding efflux proteins, we hypothesized that antagonism results from drug-induced overexpression of these same genes. Indeed, brief incubation ofC. albicanswith albendazole or sulfadiazine resulted in a 3-to->10-fold increase in RNAs encoding multidrug transporter Cdr1p or Cdr2p. Zidovudine, trimethoprim, and isoniazid, which were not antagonistic with azoles, did not induce these RNAs. Fluphenazine, a known substrate for Cdr1p and Cdr2p, strongly induced their RNAs and, consistent with our hypothesis, strongly antagonized azole activity. Finally, antagonism was shown to require a functional Cdr1p. The possibility that azole activity againstC. albicansis antagonized in vivo as well as in vitro in the presence of albendazole and sulfadiazine warrants investigation. Drug-induced overexpression of efflux proteins represents a new and potentially general mechanism for drug antagonism.
Evaluation of Low-Dose, Extended-Interval Clindamycin Regimens against
Staphylococcus aureus
and
Streptococcus pneumoniae
Using a Dynamic In Vitro Model of Infection
Authors: Lewis Russell E. , Klepser Michael E. , Ernst Erika J. , Lund Brian C. , Biedenbach Douglas J. , Jones Ronald N. 
Published: October 2018

ABSTRACT

We have previously described the activity of low-dose clindamycin in extended-interval dosing regimens by determination of bactericidal titer in serum. In this study, we used a one-compartment in vitro dynamic infection model to compare the pharmacodynamics of clindamycin in three intravenous-dosing regimens (600 mg every 8 h [q8h], 300 mg q8h, and 300 mg q12h) against three clinical isolates of
Staphylococcus aureus
and two clinical isolates of
Streptococcus pneumoniae
. Test organisms were added to the central compartment of the model to yield a starting inoculum of 10
6
CFU/ml. Clindamycin was injected as a bolus into the central compartment at appropriate times over 48 h to simulate the q8h or q12h dosing regimens. Drug-free culture medium was then pumped through the system to mimic a half-life of 2.4 h. At predetermined time points during the experiment, samples were removed from the central compartments for colony count determination and drug concentration analysis. The rates of killing did not significantly differ among the three clindamycin dosing regimens against either
S. aureus
or
S. pneumoniae
(
P
= 0.88 or 0.998, respectively). Likewise, no significant differences in activities were detected among the three regimens against staphylococci (
P
= 0.677 and 0.667) or pneumococci (
P
= 0.88 and 0.99). Against an
S. aureus
isolate exhibiting inducible macrolide-lincosamide-streptogramin B resistance, none of the three clindamycin regimens prevented regrowth of the resistance phenotype in the model. In this model, clindamycin administered at a low dose in an extended-interval regimen (300 mg q12h) exhibited antibacterial activity equivalent to that of the 300- or 600-mg-q8h regimen.
Quinupristin-Dalfopristin Is Active against
Toxoplasma gondii
Authors: Khan Anis A. , Slifer Teri R. , Araujo Fausto G. , Remington Jack S. 
Published: October 2018

ABSTRACT

Synercid and each of its components (quinupristin and dalfopristin) were examined for their activities against
Toxoplasma gondii
. In vitro, intracellular replication of tachyzoites was inhibited by synercid and each of its two components. The 50% inhibitory concentrations of synercid, quinupristin, and dalfopristin were 1.6, 2.7, and 6.3 μg/ml, respectively. Thus, synercid was markedly more active than its components. Treatment of acutely infected mice with 100 or 200 mg of synercid per kg of body weight per day administered intraperitoneally for 10 days resulted in survival of 50% (
P
= 0.0002) and 100% (
P
< 0.0001) of infected mice, respectively, whereas all control mice died by day 18. In contrast, treatment with 200 mg of either quinupristin and dalfopristin per kg per day alone resulted in only 20% survival; treatment with 50 mg of either drug per kg per day resulted only in the prolongation of time to death. These results suggest that synercid may be useful for treatment of toxoplasmosis in humans.
Role of Permeability in the Activities of β-Lactams against Gram-Negative Bacteria Which Produce a Group 3 β-Lactamase
Authors: Matsumura Naoki , Minami Shinzaburo , Watanabe Yasuo , Iyobe Shizuko , Mitsuhashi Susumu 
Published: October 2018

ABSTRACT

The production of a group 3 β-lactamase permitted
Escherichia coli
to raise the MICs of ceftazidime, cefpirome, and meropenem greatly but those of imipenem and piperacillin only slightly. The ratios of maximum rate of hydrolysis to

K
m

of ceftazidime, cefpirome, and piperacillin were lower than those of meropenem and imipenem for the group 3 β-lactamase. The permeability coefficients for piperacillin and meropenem were higher than those for ceftazidime and cefpirome. Imipenem had the highest permeability coefficient.
Activity of Pleconaril against Enteroviruses
Authors: Pevear Daniel C. , Tull Tina M. , Seipel Martin E. , Groarke James M. 
Published: October 2018

ABSTRACT
The activity of pleconaril in cell culture against prototypic enterovirus strains and 215 clinical isolates of the most commonly isolated enterovirus serotypes was examined. The latter viruses were isolated by the Centers for Disease Control and Prevention during the 1970s and 1980s from clinically ill subjects. Pleconaril at a concentration of ≤0.03 μM inhibited the replication of 50% of all clinical isolates tested. Ninety percent of the isolates were inhibited at a drug concentration of ≤0.18 μM. The most sensitive serotype, echovirus serotype 11, was also the most prevalent enterovirus in the United States from 1970 to 1983. Pleconaril was further tested for oral activity in three animal models of lethal enterovirus infection: coxsackievirus serotype A9 infection in suckling mice, coxsackievirus serotype A21 strain Kenny infection in weanling mice, and coxsackievirus serotype B3 strain M infection in adult mice. Treatment with pleconaril increased the survival rate in all three models for both prophylactic and therapeutic dosing regimens. Moreover, pleconaril dramatically reduced virus levels in target tissues of coxsackievirus serotype B3 strain M-infected animals. Pleconaril represents a promising new drug candidate for potential use in the treatment of human enteroviral infections.
Introduction of a
norA
Promoter Region Mutation into the Chromosome of a Fluoroquinolone-Susceptible Strain of
Staphylococcus aureus
Using Plasmid Integration
Authors: Kaatz Glenn W. , Seo Susan M. , Foster Timothy J. 
Published: October 2018

ABSTRACT

It has been postulated that a mutation 11 bp 3′ to the −10 motif of the
norA
promoter is involved in the increased expression of the gene observed in some strains of
Staphylococcus aureus
exhibiting efflux-related fluoroquinolone resistance. Introduction of this mutation into the chromosome of a fluoroquinolone-susceptible strain by plasmid integration resulted in the minimum inhibitory concentrations of NorA substrates being increased, fluoroquinolone uptake being reduced, and
norA
expression being enhanced. Diffuse hybridization of
norA
and integrating vector probes at a similar molecular weight range, higher than that of the
norA
transcript, was observed in the integrant, suggesting the possibility of a plasmid-based promoter contributing to
norA
expression. The ratio of the quantity of this transcript, which was also observed in the parent strain of the integrant, to the quantity of primary
norA
transcript was 0.14, demonstrating that it was unlikely that this mRNA species contributed significantly to the results observed. It is more likely that the introduced promoter region mutation does affect the expression of
norA.
Immunomodulation of Pneumococcal Pulmonary Infection with

N
G

-Monomethyl-
l
-Arginine
Authors: Bergeron Yves , Ouellet Nathalie , Simard Marie , Olivier Martin , Bergeron Michel G. 
Published: October 2018

ABSTRACT

It has recently become apparent that inflammatory reactions including nitric oxide (NO) release contribute to the outcome of pulmonary infections. To investigate the effect of

N
G

-monomethyl-
l
-arginine (L-NMMA), a NO synthase inhibitor, on the pathogenesis of pneumococcal pneumonia, we inoculated CD
1
Swiss mice with 10
7
CFU of
Streptococcus pneumoniae
. Treatment with two daily subcutaneous injections of 3 mg of L-NMMA per kg of body weight (over a 5-day period) reproducibly delayed mortality, as the number of surviving mice 72, 84, and 96 h after infection was increased by 16.8% (
P
< 0.05), 25.0% (
P
< 0.005), and 11.5% (
P
< 0.05), respectively. In fact, the following chronology of events was noted in L-NMMA-treated infected animals, compared to the untreated infected controls. (i) At 12 to 24 h after infection, larger amounts of leukotriene B
4
in bronchoalveolar lavage (BAL) fluid associated with greater neutrophilia in lung tissue and alveolar spaces and more persistent release of tumor necrosis factor alpha, interleukin-1 alpha (IL-1α), and IL-6 were observed. (ii) At 24 to 72 h, there was better preservation of lung ultrastructure, including reduction of edema in the interstitium and protection of alveolar spaces, despite identical bacterial growth in lungs, in L-NMMA-treated infected animals than in untreated animals. (iii) At 72 to 96 h, the death rate was delayed, despite the absence of antibiotic therapy. In our experiment, partial blockade of NO release was achieved. These data indicate that NO plays an important role in the induction of tissue injury and death during pneumococcal pneumonia and that L-NMMA is helpful for host protection.
Relationship between Pyrazinamide Resistance, Loss of Pyrazinamidase Activity, and Mutations in the
pncA
Locus in Multidrug-Resistant Clinical Isolates of
Mycobacterium tuberculosis
Authors: Mestdagh M. , Fonteyne P. A. , Realini L. , Rossau R. , Jannes G. , Mijs W. , De Smet K. A. L. , Portaels F. , Van den Eeckhout E. 
Published: October 2018

ABSTRACT

Sixty-two
Mycobacterium tuberculosis
isolates were tested for pyrazinamidase activity, and their pyrazinamide susceptibility was determined by the radiometric method. Sequencing of
pncA
genes in the 23 resistant strains revealed mutations in 16 pyrazinamidase-negative strains, 11 of which had not been previously described. Six isolates containing wild-type
pncA
might possess alternative resistance mechanisms.
Palliative care clinicians and online education in India: a survey
Authors: Kiss-Lane Tayler , Spruijt Odette , Day Thomas , Lam Vivian , Ramchandran Kavitha J , Chan Sandy , Hsin Gary , Vallath Nandini , Bhatnagar Sushma , Rajagopal MR , Lorenz Karl A 
Published: October 2018

BackgroundWhether online resources can facilitate spread of palliative care knowledge and skills in India is an urgent question given few providers and a large, ageing population.ObjectivesWe surveyed needs and feasibility regarding e-learning.MethodsIndian, Australian and North American palliative care experts developed an electronic survey using Qualtrics, emailed to all registrants of the 2017 Indian Association of Palliative Care (IAPC) conference and distributed during the conference.ResultsOf 60 respondents (66% men, 60% doctors), most worked in hospitals and had oncology backgrounds, and 35% were from Kerala and Tamil Nadu. Most (90.9%) received palliative care training in India or overseas with 41% trained in a Trivandrum Institute of Palliative Sciences residential course (4–6 weeks). 17% completed the IAPC essential certificate and 22% had undertaken various distance learning courses. Interest in online training was substantial for most aspects of palliative care.ConclusionThere was a high level of interest and reported feasibility in taking a case-based online course. This pilot survey provides support for online case-based education in India, particularly among physicians.
A Multimodal Molecular Imaging Study Evaluates Pharmacological Alteration of the Tumor Microenvironment to Improve Radiation Response
Authors: Takakusagi Yoichi , Naz Sarwat , Takakusagi Kaori , Ishima Masahiro , Murata Hiroshi , Ohta Keisuke , Miura Masahiko , Sugawara Fumio , Sakaguchi Kengo , Kishimoto Shun , Munasinghe Jeeva P. , Mitchell James B. , Krishna Murali C. 
Published: October 2018

Abstract

Hypoxic zones in solid tumors contribute to radioresistance, and pharmacologic agents that increase tumor oxygenation prior to radiation, including antiangiogenic drugs, can enhance treatment response to radiotherapy. Although such strategies have been applied, imaging assessments of tumor oxygenation to identify an optimum time window for radiotherapy have not been fully explored. In this study, we investigated the effects of α-sulfoquinovosylacyl-1,3-propanediol (SQAP or CG-0321; a synthetic derivative of an antiangiogenic agent) on the tumor microenvironment in terms of oxygen partial pressure (pO2), oxyhemoglobin saturation (sO2), blood perfusion, and microvessel density using electron paramagnetic resonance imaging, photoacoustic imaging, dynamic contrast–enhanced MRI with Gd-DTPA injection, and T2*-weighted imaging with ultrasmall superparamagnetic iron oxide (USPIO) contrast. SCCVII and A549 tumors were grown by injecting tumor cells into the hind legs of mice. Five days of daily radiation (2 Gy) combined with intravenous injection of SQAP (2 mg/kg) 30 minutes prior to irradiation significantly delayed growth of tumor xenografts. Three days of daily treatment improved tumor oxygenation and decreased tumor microvascular density on T2*-weighted images with USPIO, suggesting vascular normalization. Acute effects of SQAP on tumor oxygenation were examined by pO2, sO2, and Gd-DTPA contrast-enhanced imaging. SQAP treatment improved perfusion and tumor pO2 (ΔpO2: 3.1 ± 1.0 mmHg) and was accompanied by decreased sO2 (20%–30% decrease) in SCCVII implants 20–30 minutes after SQAP administration. These results provide evidence that SQAP transiently enhanced tumor oxygenation by facilitating oxygen dissociation from oxyhemoglobin and improving tumor perfusion. Therefore, SQAP-mediated sensitization to radiation in vivo can be attributed to increased tumor oxygenation.

Significance:
A multimodal molecular imaging study evaluates pharmacological alteration of the tumor microenvironment to improve radiation response.
Near-Infrared Dye-Labeled Anti-Prostate Stem Cell Antigen Minibody Enables Real-Time Fluorescence Imaging and Targeted Surgery in Translational Mouse Models
Authors: Zhang Mo , Kobayashi Naoko , Zettlitz Kirstin A. , Kono Evelyn A. , Yamashiro Joyce M. , Tsai Wen-Ting K. , Jiang Ziyue K. , Tran Chau P. , Wang Chung , Guan Johnny , Wu Anna M. , Reiter Robert E. 
Published: October 2018

Abstract

Purpose:
The inability to intraoperatively distinguish primary tumor, as well as lymphatic spread, increases the probability of positive surgical margins, tumor recurrence, and surgical toxicity. The goal of this study was to develop a tumor-specific optical probe for real-time fluorescence-guided surgery.

Experimental Design:
A humanized antibody fragment against PSCA (A11 minibody, A11 Mb) was conjugated with a near-infrared fluorophore, IRDye800CW. The integrity and binding of the probe to PSCA were confirmed by gel electrophoresis, size-exclusion chromatography, and flow cytometry, respectively. The ability of the probe to detect tumor-infiltrated lymph nodes and metastatic lesions was evaluated in 2 xenograft models, as well as in transgenic mice expressing human PSCA (hPSCA). An invasive intramuscular model was utilized to evaluate the efficacy of the A11 Mb-IRDye800CW-guided surgery.

Results:
A11 Mb was successfully conjugated with IRDye800CW and retained specific binding to PSCA. In vivo imaging showed maximal signal-to-background ratios at 48 hours. The A11 Mb-IRDye800CW specifically detected PSCA-positive primary tumors, tumor-infiltrated lymph nodes, and distant metastases with high contrast. Fluorescence guidance facilitated more complete tumor resection, reduced tumor recurrence, and improved overall survival, compared with conventional white light surgery. The probe successfully identified primary orthotopic tumors and metastatic lesions in hPSCA transgenic mice.

Conclusions:
Real-time fluorescence image–guided surgery with A11 Mb-IRDye800CW enabled detection of lymph node metastases and positive surgical margins, facilitated more complete tumor removal, and improved survival, compared with white light surgery. These results may be translatable into clinical practice to improve surgical and patient outcomes.