In silico identification of small molecule modulators for disruption of Hsp90-Cdc37 protein-protein interaction interface for cancer therapeutic application.

The protein-protein interactions (PPIs) in the biological systems are important to maintain a number of cellular processes. Several disorders including cancer may be developed due to dysfunction in the assembly of PPI networks. Hence, targeting intracellular PPIs can be considered as a crucial drug target for cancer therapy. Among the enormous and diverse group of cancer-enabling PPIs, the Hsp90-Cdc37 is prominent for cancer therapeutic development. The successful inhibition of Hsp90-Cdc37 PPI interface can be an important therapeutic option for cancer management. In the current study, a set of more than sixty thousand compounds belong to four databases were screened through a multi-steps molecular docking study in Glide against the Hsp90-Cdc37 interaction interface. The Glide-score and Prime-MM-GBSA based binding free energy of DCZ3112, standard Hsp90-Cdc37 inhibitor were found to be -6.96 and -40.46 kcal/mol, respectively. The above two parameters were used as cut-off score to reduce the chemical space from all successfully docked molecules. Furthermore, the in-silico pharmacokinetics parameters, common-feature pharmacophore analyses and the molecular binding interactions were used to wipe out the inactive molecules. Finally, four molecules were found to be important to modulate the Hsp90-Cdc37 interface. The potentiality of the final four molecules was checked through several drug-likeness characteristics. The molecular dynamics (MD) simulation study explained that all four molecules retained inside the interface of Hsp90-Cdc37. The binding free energy of each molecule obtained from the MD simulation trajectory was clearly explained the strong affection towards the Hsp90-Cdc37. Hence, the proposed molecule might be crucial for successful inhibition of the Hsp90-Cdc37 interface.Communicated by Ramaswamy H. Sarma.

Safety of apraclonidine eye drops in diagnosis of Horner syndrome in an outpatient pediatric ophthalmology clinic.

PURPOSE: To describe the efficacy and systemic side effects of apraclonidine drops 0.5% in children clinically suspected of having Horner syndrome. METHODS: The medical records of patients with clinically suspected Horner syndrome who underwent testing with apraclonidine 0.5% eyedrops were reviewed retrospectively. The following data were retrieved from the record: allergic reactions, somnolence, shallow respiration, pallor, or excessive fussiness noted by the examiner or parents. RESULTS: A total of 46 patients presenting with anisocoria and tested with apraclonidine 0.5% were included. Of these, 15 had a positive result, with reversal of anisocoria. The mean age of patients was 3.2 years (median, 0.91; mode, 0.25 years). Twenty-four patients were ≤1 year of age; 19 were ≤6 months. No systemic side effects were noted during the examination or reported by parents in any patients. CONCLUSIONS: The use of topical apraclonidine eyedrops has been described as an effective test for Horner syndrome. However, concerns have been raised regarding the potential systemic side effects in children, especially those under the age of 6 months. In our cohort, no systemic side effects were reported, including in those under 6 months of age.

Antenatal Dexamethasone for Early Preterm Birth in Low-Resource Countries.

BACKGROUND: The safety and efficacy of antenatal glucocorticoids in women in low-resource countries who are at risk for preterm birth are uncertain. METHODS: We conducted a multicountry, randomized trial involving pregnant women between 26 weeks 0 days and 33 weeks 6 days of gestation who were at risk for preterm birth. The participants were assigned to intramuscular dexamethasone or identical placebo. The primary outcomes were neonatal death alone, stillbirth or neonatal death, and possible maternal bacterial infection; neonatal death alone and stillbirth or neonatal death were evaluated with superiority analyses, and possible maternal bacterial infection was evaluated with a noninferiority analysis with the use of a prespecified margin of 1.25 on the relative scale. RESULTS: A total of 2852 women (and their 3070 fetuses) from 29 secondary- and tertiary-level hospitals across Bangladesh, India, Kenya, Nigeria, and Pakistan underwent randomization. The trial was stopped for benefit at the second interim analysis. Neonatal death occurred in 278 of 1417 infants (19.6%) in the dexamethasone group and in 331 of 1406 infants (23.5%) in the placebo group (relative risk, 0.84; 95% confidence interval [CI], 0.72 to 0.97; P = 0.03). Stillbirth or neonatal death occurred in 393 of 1532 fetuses and infants (25.7%) and in 444 of 1519 fetuses and infants (29.2%), respectively (relative risk, 0.88; 95% CI, 0.78 to 0.99; P = 0.04); the incidence of possible maternal bacterial infection was 4.8% and 6.3%, respectively (relative risk, 0.76; 95% CI, 0.56 to 1.03). There was no significant between-group difference in the incidence of adverse events. CONCLUSIONS: Among women in low-resource countries who were at risk for early preterm birth, the use of dexamethasone resulted in significantly lower risks of neonatal death alone and stillbirth or neonatal death than the use of placebo, without an increase in the incidence of possible maternal bacterial infection. (Funded by the Bill and Melinda Gates Foundation and the World Health Organization; Australian and New Zealand Clinical Trials Registry number, ACTRN12617000476336; Clinical Trials Registry-India number, CTRI/2017/04/008326.).

Structure-Based Screening of DNA GyraseB Inhibitors for Therapeutic Applications in Tuberculosis: a Pharmacoinformatics Study.

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (MTB) and considered as serious public health concern worldwide which kills approximately five thousand people every day. Therefore, TB drug development efforts are in gigantic need for identification of new potential chemical agents to eradicate TB from the society. The bacterial DNA gyrase B (GyrB) protein as an experimentally widely accepted effective drug target for the development of TB chemotherapeutics. In the present study, advanced pharmacoinformatics approaches were used to screen the Mcule database against the GyrB protein. Based on a number of chemometric parameters, five molecules were found to be crucial to inhibit the GyrB. A number of molecular binding interactions between the proposed inhibitors and important active site residues of GyrB were observed. The predicted drug-likeness properties of all molecules were indicated that compounds possess characteristics to be the drug-like candidates. The dynamic nature of each molecule was explored through the molecular dynamics (MD) simulation study. Various analyzing parameters from MD simulation trajectory have suggested rationality of the molecules to be potential GyrB inhibitor. Moreover, the binding free energy was calculated from the entire MD simulation trajectories highlighted greater binding free energy values for all newly identified compounds also substantiated the strong binding affection towards the GyrB in comparison to the novobiocin. Therefore, the proposed molecules might be considered as potential anti-TB chemical agents for future drug discovery purposes subjected to experimental validation. Graphical Abstract.

Evaluation of Radiomorphometric Indices in Panoramic Radiograph - A Screening Tool.

BACKGROUND: Mandibular cortical indices, like the mandibular cortical index (MCI), panoramic mandibular index (PMI), mental index (MI), antegonial index (AI) and gonial index (GI) have been developed to assess and quantify the quality of mandibular bone mass. Aim and Objectives : The aim of this pilot study was to measure the radiomorphometric indices in a digital panoramic radiograph and find the inter-relationship of the indices with age and sex of the patients. Materials and Method : A total of 23 randomly selected patients were included in the study. Panoramic radiograph of each patient was taken and radiomorphometric indices were determined. Results : There was 69.57% agreement between MI and PMI which was significant. Similarly 78.26% agreement was seen between AI and MI which was significant. In contrast 30.43%, 52.17% and 56.52% agreement was observed while comparing GI with PMI, MI and AI respectively. Conclusion : MCI, PMI, AI and MI can be effectively measured on a panoramic radiograph, hence could be used as a screening tool for determining osteoporosis. All indices have a negative correlation with age and a significant difference between the younger and older age groups. All indices were significantly lower in females when compared to males of the same age group.

Secondary Metastasis to the Mandible From Breast Carcinoma -A Rare Case Report.

Regardless of the rare occurrence of metastatic lesions to the jaw, it should be taken into consideration in the individuals with a history of malignancy. Early detection requires accurate examination, and microscopic evaluation is essential. In this paper we report a case of breast carcinoma to the mandible as female breast cancer is the most frequent metastatic lesion to the mandible and its metastasis is well documented. The patient's medical history revealed that she had undergone mastectomy on the left breast three years ago. As this condition is infrequently described, documentation of new cases will augment the existing knowledge.

Plication augmentation of the modified Hummelsheim procedure for treatment of large-angle esotropia due to abducens nerve palsy and type 1 Duane syndrome.

BACKGROUND: Multiple procedures have been described to treat a large-angle esodeviation with an associated abduction deficit. We report a plication augmentation of the Hummelsheim procedure for the management of esotropia and severe abduction deficit due to abducens nerve palsy or type 1 Duane syndrome. METHODS: The medical records of patients operated on using the plication augmentation Hummelsheim procedure at two tertiary centers were retrospectively reviewed. The surgery involved ipsilateral lateral rectus plication, half muscle transposition of the vertical rectus muscles to the paralytic plicated lateral rectus, Foster augmentation sutures, and ipsilateral medial rectus recession or botulinum toxin injection if it was found to be tight on intraoperative forced duction testing. Pre- and postoperative deviations, ocular motility findings, and complications were noted. RESULTS: A total of 13 patients were included, all of whom had an esotropia with profound abduction deficit (-4 or more). Postoperative deviations ranged from 14(Δ) of esotropia to 14(Δ) of exotropia, with significant improvement of the abductive motion. No patient developed anterior segment ischemia. CONCLUSIONS: The plication augmentation Hummelsheim procedure resulted in correction of even very large esodeviations and improvement of the abduction force. This procedure may also better preserve the blood supply to the anterior segment compared to other surgical approaches.

Heat shock protein (HSP70) as a marker of epithelial dysplasia in oral dysplastic lesions: A clinicopathological study.

OBJECTIVE: In the present study, expression of heat shock protein (HSP70) was evaluated and compared in oral dysplastic lesions, in particular leukoplakia (study group) and in normal mucosal tissues (control group). Additionally, correlation of HSP70 expression with clinical disease status was investigated. SUBJECTS AND METHODS: A total of 60 fresh tissue specimens were obtained from the oral cavity, consisting of 30 dysplastic cases and 30 normal mucosal tissues. The presence of epithelial dysplasia and its histologic grading was evaluated. Immunohistochemistry was carried out with the monoclonal HSP70 antibodies and expression of cytoplasmic HSP70 within the epithelium was compared between dysplastic and normal mucosal samples using Student's t-test. RESULTS: Expression of HSP70 was detected in 93% of the oral dysplastic tissues and 20% of the normal mucosal tissues. Statistical significant difference in the HSP70 expression was seen between oral dysplastic tissues and normal oral mucosal tissues (P < 0.000). The interexaminer reliability was 93.3%. Statistical significant difference was seen in the HSP70 expression between controls and different grades of dysplasia (mild, moderate and severe). There was no relationship of HSP70 expression with clinical parameters like age, sex, site of the lesion, history of adverse habits and duration of adverse habits. CONCLUSION: In the present study, HSP70 activity was significantly higher in oral dysplastic (leukoplakia) group than in the control group. Further, as the grade of dysplasia increased, the staining intensity and/or distribution increased, indicating that enhanced HSP70 expression occurs during oral carcinogenesis. Hence, it is concluded that increased HSP70 immunoexpression could be an objective marker for the presence of epithelial dysplasia.

Dosimetry in dentistry.

AIM: The purpose of this paper was to review various dosimeters used in dentistry and the cumulative results of various studies done with various dosimeters. MATERIALS AND METHODS: Several relevant PubMed indexed articles from 1999 to 2013 were electronically searched by typing "dosimeters", "dosimeters in dentistry", "properties of dosimeters", "thermoluminescent and optically stimulated dosimeters", "recent advancements in dosimetry in dentistry." The searches were limited to articles in English to prepare a concise review on dental dosimetry. Titles and abstracts were screened, and articles that fulfilled the criteria of use of dosimeters in dental applications were selected for a full-text reading. Article was divided into four groups: (1) Biological effects of radiation, (2) properties of dosimeters, (3) types of dosimeters and (4) results of various studies using different dosimeters. CONCLUSION: The present review on dosimetry based on various studies done with dosimeters revealed that, with the advent of radiographic technique the effective dose delivered is low. Therefore, selection of radiological technique plays an important role in dental dose delivery.

Pleomorphic adenoma of submandibular gland: A case report with review of literature.

Neoplasms that arise in the salivary glands are relatively rare, yet they represent a wide variety of both benign and malignant histologic subtypes. Approximately 70% of the salivary gland tumors affect parotid gland with the submandibular gland being affected in 5-10% of the cases, sublingual gland in 1% and minor glands in 5-15% of the cases. Submandibular gland tumors are relatively rare and very few studies have been reported in the literature that is exclusively conducted on tumors affecting submandibular gland. In this paper, we describe a case of pleomorphic adenoma affecting submandibular gland with brief review of current literature on submandibular gland tumors.

A novel paraboloid intracorporeal lithotripter: computer aided design analysis and in vitro comparison with holmium laser for large renal calculi.

PURPOSE: An intracorporeal lithotripsy probe tip was designed with a paraboloid shaped tip and compared with holmium laser for stone pulverization. MATERIALS AND METHODS: The paraboloid tip concept was developed and designed using computer aided design (CAD), fabricated, and patented. CAD analysis and in vitro comparison (with laser) of pulverization and propulsion dynamics were performed in an underwater hands-free bench arrangement using phantom stones. SPSS analysis for different energy cohorts was performed. RESULTS: CAD analysis: At "point contact" with the tip, the paraboloid lithotripter generated 3590 bars at generator settings of 4 bars. During "follow-up impacts," the tip pressure exponentially decreased (graduated tip pressure) and the lateral/centrifugal forces increased, converting the probe into a side-firing energy source. Bench analysis: At point contact, the paraboloid lithotripter at 2, 3, and 4 bars was comparable to that of a 6, 10, and 15 W laser, respectively (P<0.005). The paraboloid lithotripter showed a statistically significant advantage in breaking the phantoms, as against a laser that always bored through the phantom. Stone propulsion was comparable within all energy cohorts (P>0.05). CONCLUSION: The paraboloid lithotripter generates highly focused impact force with low propulsion, at point contact. As stone pulverization progresses, the tip forces exponentially decrease and the probe converts into a lateral firing energy source resulting in pulverization into larger fragments. Thus, the paraboloid lithotripter has all the advantages of laser at point contact and advantages of pneumatic lithotripter at follow-up hits, akin to being a bimodal energy source.

Biosynthesis of albomycin δ(2) provides a template for assembling siderophore and aminoacyl-tRNA synthetase inhibitor conjugates.

"Trojan horse" antibiotic albomycins are peptidyl nucleosides consisting of a highly modified 4'-thiofuranosyl cytosine moiety and a ferrichrome siderophore that are linked by a peptide bond via a serine residue. While the latter component serves to sequester iron from the environment, the seryl nucleoside portion is a potent inhibitor of bacterial seryl-tRNA synthetases, resulting in broad-spectrum antimicrobial activities of albomycin δ(2). The isolation of albomycins has revealed this biological activity is optimized only following two unusual cytosine modifications, N4-carbamoylation and N3-methylation. We identified a genetic locus (named abm) for albomycin production in Streptomyces sp. ATCC 700974. Gene deletion and complementation experiments along with bioinformatic analysis suggested 18 genes are responsible for albomycin biosynthesis and resistance, allowing us to propose a potential biosynthetic pathway for installing the novel chemical features. The gene abmI, encoding a putative methyltransferase, was functionally assigned in vitro and shown to modify the N3 of a variety of cytosine-containing nucleosides and antibiotics such as blasticidin S. Furthermore, a ΔabmI mutant was shown to produce the descarbamoyl-desmethyl albomycin analogue, supporting that the N3-methylation occurs before the N4-carbamoylation in the biosynthesis of albomycin δ(2). The combined genetic information was utilized to identify an abm-related locus (named ctj) from the draft genome of Streptomyces sp. C. Cross-complementation experiments and in vitro studies with CtjF, the AbmI homologue, suggest the production of a similar 4'-thiofuranosyl cytosine in this organism. In total, the genetic and biochemical data provide a biosynthetic template for assembling siderophore-inhibitor conjugates and modifying the albomycin scaffold to generate new derivatives.

In vitro assessment of a novel spearheaded pneumatic intracorporeal lithotriptor.

BACKGROUND AND PURPOSE: Intracorporeal lithotripsy is an important modality used for stone pulverization. To improve the pulverization properties of intracorporeal lithotriptors, a novel intracorporeal "spearheaded lithotriptor" was designed by our institute. It was compared in vitro with the conventional lithotriptor. MATERIALS AND METHODS: The pulverization and propulsion dynamics were evaluated at various pressure settings on an in vitro bench arrangement with phantom stones. Lateral displacement during pulverization was also compared. RESULTS: The spearheaded lithotriptor had a better first hit (P<0.001) and follow-up hit dynamics (P<0.01). Stone propulsion and lateral displacement were low for the spearheaded lithotriptor at all pressure settings (P<0.05). CONCLUSION: The spearheaded lithotriptor improved stone pulverization without increasing the risk of stone migration. Further clinical evaluation of this novel probe is necessary.

Refractory reverse amblyopia with atropine penalization.

Pharmacological penalization with atropine has been shown to be equally effective as conventional occlusion therapy in the treatment of amblyopia in children. Reverse amblyopia of the sound eye with atropine penalization has been reported before, but is more common in cases where the effect is augmented with optical penalization and is mostly reversible. We report a case of reverse amblyopia with atropine penalization, in a 4-year-old girl, which was refractory to treatment. This report highlights the need for strict monitoring of the vision in the sound eye and regular follow-up in children undergoing amblyopia treatment.

Isolation and characterization of a Nocardiopsis sp. from honeybee guts.

Although actinomycetes are the plant-associated environmental bacteria best known for producing thousands of antibiotics, their presence in the guts of flower-feeding honeybees has rarely been reported. Here, we report on the selective isolation of actinomycetes from the gut microbiota of healthy honeybees, and their inhibitory activity against honeybee indigenous bacteria. More than 70% of the sampled honeybees (N>40) in a season carried at least one CFU of actinomycete. The isolates from bees of one location produced inhibitory bioactivities that were almost exclusively against several bee indigenous Bacillus strains and Gram-positive human pathogens but not Escherichia coli. An antibiotic-producing actinomycete closely related to Nocardiopsis alba was isolated from the guts in every season of the year. A DNA fragment encoding a homologous gene (phzD) involved in phenazine biosynthesis was identified in the isolate. Expression of the phzD detected by reverse transcription-PCR can explain the survival of this organism in anaerobic environments as some redox-active extracellular phenazines are commonly regarded as respiratory electron acceptors. The results raise important questions concerning the roles of the antibiotic-producing actinomycetes and the phenazine-like molecules in honeybee guts and honey.

Characterization of two seryl-tRNA synthetases in albomycin-producing Streptomyces sp. strain ATCC 700974.

The Trojan horse antibiotic albomycin, produced by Streptomyces sp. strain ATCC 700974, contains a thioribosyl nucleoside moiety linked to a hydroxamate siderophore through a serine residue. The seryl nucleoside structure (SB-217452) is a potent inhibitor of seryl-tRNA synthetase (SerRS) in the pathogenic bacterium Staphylococcus aureus, with a 50% inhibitory concentration (IC(50)) of approximately 8 nM. In the albomycin-producing Streptomyces sp., a bacterial SerRS homolog (Alb10) was found to be encoded in a biosynthetic gene cluster in addition to another serRS gene (serS1) at a different genetic locus. Alb10, named SerRS2 herein, is significantly divergent from SerRS1, which shows high homology to the housekeeping SerRS found in other Streptomyces species. We genetically and biochemically characterized the two genes and the proteins encoded. Both genes were able to complement a temperature-sensitive serS mutant of Escherichia coli and allowed growth at a nonpermissive temperature. serS2 was shown to confer albomycin resistance, with specific amino acid residues in the motif 2 signature sequences of SerRS2 playing key roles. SerRS1 and SerRS2 are comparably efficient in vitro, but the K(m) of serine for SerRS2 measured during tRNA aminoacylation is more than 20-fold higher than that for SerRS1. SB-217452 was also enzymatically generated and purified by two-step chromatography. Its IC(50) against SerRS1 was estimated to be 10-fold lower than that against SerRS2. In contrast, both SerRSs displayed comparable inhibition kinetics for serine hydroxamate, indicating that SerRS2 was specifically resistant to SB-217452. These data suggest that mining Streptomyces genomes for duplicated aminoacyl-tRNA synthetase genes could provide a novel approach for the identification of natural products targeting aminoacyl-tRNA synthetases.

Modulated release metoprolol succinate formulation based on ionic interactions: in vivo proof of concept.

A modulated release, multiunit oral drug delivery technology using a system based on ionic interactions of anions of salts with quaternary ammonium ions of the ammoniomethacrylate polymer is described. The system consisted of a drug layered, EUDRAGIT NE-coated salt core which was further coated with EUDRAGIT RS. The relative effects of different anions on the polymer permeability have been investigated by studying their influence on the in vitro drug release. A prototype formulation of metoprolol succinate using this technology was developed and the drug release from the formulation was adjusted to have a release profile which would match the circadian rhythm i.e. a higher amount of drug would be available after an initial lower release (accelerated type of release). The formulation was tested in vivo in 12 healthy human volunteers in an open label, randomized, two-treatment, two-period, single dose crossover bio-study with reference formulation Beloc-zok. The in vivo release demonstrated that compared to the reference, a higher amount of drug was available in the plasma from the 7th hour onwards. A higher AUC of the drug was also observed compared to the reference formulation. An in vitro-in vivo correlation was attempted to identify a bio-relevant in vitro dissolution medium for the formulation.