Development of quantitative structure-activity relationship (QSAR) models to predict the carcinogenic potency of chemicals. II. Using oral slope factor as a measure of carcinogenic potency

The overall risk associated with exposure to a chemical is determined by combining quantitative estimates of exposure to the chemical with their known health effects. For chemicals that cause carcinogenicity, oral slope factors (OSFs) and inhalation unit risks are used to quantitatively estimate the carcinogenic potency or the risk associated with exposure to the chemical by oral or inhalation route, respectively. Frequently, there is a lack of animal or human studies in the literature to determine OSFs. This study aims to circumvent this problem by developing quantitative structure-activity relationship (QSAR) models to predict the OSFs of chemicals. The OSFs of 70 chemicals based on male/female human, rat, and mouse bioassay data were obtained from the United States Environmental Protection Agency's Integrated Risk Information System (IRIS) database. A global QSAR model that considered all 70 chemicals as well as species and/or sex-specific QSARs were developed in this study. Study results indicate that the species and sex-specific QSARs (r(2)>0.8, q(2)>0.7) had a better predictive abilities than the global QSAR developed using data from all species and sexes (r(2)=0.77, q(2)=0.73). The QSARs developed in this study were externally validated, and demonstrated reasonable predictive abilities.     

Diabetic retinopathy among self reported diabetics in southern India: a population based assessment

AIMS: To estimate the prevalence of diabetic retinopathy among self reported diabetics in a population of southern India. METHODS: A cross sectional sample of subjects aged 50 years and older was selected using a cluster sampling technique from Palakkad district of Kerala state. Eligible subjects were identified through a door to door survey. Ocular examinations including visual acuity and anterior and posterior segment examinations were performed at preselected sites within clusters. History of diabetes was elicited, and height, weight, and blood pressure were measured for all subjects. RESULTS: Among the 5212 examined people (92% response rate), 68 (26.2%) of 260 people with self reported history of diabetes had diabetic retinopathy. The age-sex adjusted prevalence of diabetes among people aged 50 years and older was 5.1% (95% CI 3.9, 6.3, deff 4.33) and of diabetic retinopathy among the diabetics was 26.8% (95% CI: 19.2, 34.4, deff 1.99). Non-proliferative diabetic retinopathy (94.1%) was the most common form of retinopathy seen. Two eyes were blind (presenting vision <6/60) as a result of retinopathy. CONCLUSION: Preventive strategies have to be evolved to ensure that blindness due to diabetic retinopathy does not become a public health problem in India. Further studies are required to understand the risk factors for retinopathy and vision loss in this population.     

Periodontal health status of school children in St. Vincent and the Grenadines.

A national oral health survey of school children was conducted in October through November 1991. The objective was to determine the periodontal status of school children in St. Vincent and The Grenadines (SVG), the pattern and severity of periodontal disease, estimate treatment needs and provide information for health planners. The study had a cross-sectional design, and 1646 schoolchildren representing all school districts were selected via multistage, systematic sampling. Examinations were conducted by three examiners using CPITN probe. Periodontal indicators and treatment needs were determined using the CPITN index. Calculus was the most prevalent condition with values ranging from 26 to 83 percent, bleeding was the least prevalent condition, while children with healthy indicator were intermediate in prevalence. Subjects with healthy indicators ranged from a low of 12 percent among 15-19 year olds, to a high of 51 percent among seven-year-olds. The mean number of healthy sextants varied from three to five, and mean number of sextants with bleeding or calculus varied from one to three. Oral hygiene instruction (OHI) was the most common treatment need, ranging from 49 to 88 percent. The need for prophylaxis was associated with increase in age, with the highest prophylaxis treatment needs of 83 percent, among 15-19 year olds. No significant differences were observed in periodontal status between gender, and also between urban and rural children. A high prevalence of calculus and bleeding was observed among SVG school children. Study recommends initiation of primary prevention programs in form of health promotion and health education.     

Canadian Consensus for Biomarker Testing and Treatment of TRK Fusion Cancer in Pediatric Patients

Neurotrophic tyrosine receptor kinase gene fusions (NTRK) are oncogenic drivers present at a low frequency in most tumour types (<5%), and at a higher frequency (>80%) in a small number of rare tumours (e.g., infantile fibrosarcoma [IFS]) and considered mutually exclusive with other common oncogenic drivers. Health Canada recently approved two tyrosine receptor kinase (TRK) inhibitors, larotrectinib (for adults and children) and entrectinib (for adults), for the treatment of solid tumours harbouring NTRK gene fusions. In Phase I/II trials, these TRK inhibitors have demonstrated promising overall response rates and tolerability in patients with TRK fusion cancer who have exhausted other treatment options. In these studies, children appear to have similar responses and tolerability to adults. In this report, we provide a Canadian consensus on when and how to test for NTRK gene fusions and when to consider treatment with a TRK inhibitor for pediatric patients with solid tumours. We focus on three pediatric tumour types: non-rhabdomyosarcoma soft tissue sarcoma/unspecified spindle cell tumours including IFS, differentiated thyroid carcinoma, and glioma. We also propose a tumour-agnostic consensus based on the probability of the tumour harbouring an NTRK gene fusion. For children with locally advanced or metastatic TRK fusion cancer who have either failed upfront therapy or lack satisfactory treatment options, TRK inhibitor therapy should be considered.     

In vitro screen of a small molecule inhibitor drug library identifies multiple compounds that synergize with oncolytic myxoma virus against human brain tumor-initiating cells

Background

Brain tumor-initiating cells (BTICs) are stem-like cells hypothesized to form a disease reservoir that mediates tumor recurrence in high-grade gliomas. Oncolytic virotherapy uses replication-competent viruses to target and kill malignant cells and has been evaluated in clinic for glioma therapy with limited results. Myxoma virus (MyxV) is a safe and highly effective oncolytic virus (OV) in conventional glioma models but, as seen with other OVs, is only modestly effective for patient-derived BTICs. The objective of this study was to determine whether MyxV treatment against human BTICs could be improved by combining chemotherapeutics and virotherapy.

Methods

A 73-compound library of drug candidates in clinical use or preclinical development was screened to identify compounds that sensitize human BTICs to MyxV treatment in vitro, and synergy was evaluated mathematically in lead compounds using Chou-Talalay analyses. The effects of combination therapy on viral gene expression and viral replication were also assessed.

Results

Eleven compounds that enhance MyxV efficacy were identified, and 6 were shown to synergize with the virus using Chou-Talalay analyses. Four of the synergistic compounds were shown to significantly increase viral gene expression, indicating a potential mechanism for synergy. Three highly synergistic compounds (axitinib, a VEGFR inhibitor; rofecoxib, a cyclooxygenase-2 inhibitor; and pemetrexed, a folate anti-metabolite) belong to classes of compounds that have not been previously shown to synergize with oncolytic viruses in vitro.

Conclusions

This study has identified multiple novel drug candidates that synergistically improve MyxV efficacy in a preclinical BTIC glioma model.     

Filamentous fungal infections of the cornea: a global overview of epidemiology and drug sensitivity

Fungal keratitis is a serious suppurative, usually ulcerative corneal infection which may result in blindness or reduced vision. Epidemiological studies indicate that the occurrence of fungal keratitis is higher in warm, humid regions with agricultural economy. The most frequent filamentous fungal genera among the causal agents are Fusarium, Aspergillus and Curvularia. A more successful therapy of fungal keratitis relies on precise identification of the pathogen to the species level using molecular tools. As the sequence analysis of the internal transcribed spacer (ITS) region of the ribosomal RNA gene cluster (rDNA) is not discriminative enough to reveal a species‐level diagnosis for several filamentous fungal species highly relevant in keratitis infections, analysis of other loci is also required for an exact diagnosis. Molecular identifications may also reveal the involvement of fungal species which were not previously reported from corneal infections. The routinely applied chemotherapy of fungal keratitis is based on the topical and systemic administration of polyenes and azole compounds. Antifungal susceptibility testing of the causal agents is of special importance due to the emergence and spread of resistance. Testing the applicability of further available antifungals and screening for new, potential compounds for the therapy of fungal keratitis are of highlighted interest.     

A Case of Candida albicans Endophthalmitis with No Predisposing Risk Factors and a Distant Source of Infection

Purpose

To report a case of Candida albicans endophthalmitis with no identifiable predisposing risk factors.

Case Report

A 57-year-old male presented with a 3-day history of worsening floaters and reduced visual acuity. Fundoscopy and optical coherence tomography showed presence of fluffy white preretinal and intraretinal infiltrates. With no past medical history or evidence of immunosuppression but having travelled abroad and suffered from diarrhoea, fungal aetiology was thought to be unlikely and as a result, treatment was commenced for toxoplasma. Despite treatment, his vision did not improve. Initial investigations including inflammatory markers, serology for toxoplasmosis, blood culture, chest radiograph and aqueous sampling could not identify a source of infection. However, polymerase chain reaction results from vitreous sampling revealed C. albicans. As a result, the patient was treated with intravenous voriconazole and intravitreal amphotericin B. As initial clinical improvement was limited, a vitrectomy was performed with further intravitreal amphotericin B. Clinical improvement was rapid following vitrectomy. After repeated Gram staining and culture of infected toenails, Gram-positive yeast cells were isolated.

Conclusion

Although C. albicans is a frequent cause of endogenous endophthalmitis, patients often have one or more predisposing systemic condition assisting the diagnosis. The present case illustrates that (1) even in the absence of any predisposing risk factors, C. albicans should be considered as a possible differential diagnosis in recalcitrant uveitis, and (2) endogenous candida endophthalmitis can be a result of fungal infections from distant sites such as the toenails.Key Words: Candida albicans, Endophthalmitis, Amphotericin B, Voriconazole     

Episcleral plaque brachytherapy using 'BARC I-125 Ocu-Prosta seeds' in the treatment of intraocular tumors: a single-institution experience in India

Context:

To analyze the results of episcleral plaque brachytherapy using indigenous Bhabha Atomic Research Centre (BARC) Iodine-125 Ocu-Prosta seeds for the management of intraocular tumors from a single institute.

AIM:

To report our initial experience and learning curve on the use of ‘BARC I-125 Ocu-Prosta seeds’ for the management of intraocular tumors such as choroidal melanomas, retinoblastomas and vasoproliferative tumors (VPT).

Materials and Methods:

We retrospectively reviewed 13 eyes of 13 patients who underwent ophthalmic brachytherapy between May 2008 to March 2012. Nine cases had choroidal melanomas; three had retinoblastomas while one case had VPT.

Results:

For choroidal melanomas the average apical diameter before brachytherapy was 7.6 mm and average largest basal diameter was 12.1 mm, respectively, which reduced to 4.2 mm and 7.7 mm after the procedure at an average follow-up of 24 months (range 10-43 months). Retinoblastoma and VPT also showed good regression after brachytherapy.

Conclusion:

Plaque radiotherapy using ¹²⁵I seeds can be performed under peribulbar anesthesia and provides a viable option for the management of intraocular cancer with minimal invasiveness and surgical complications. Patients in our studies experienced excellent local tumor control. With the availability of indigenous ‘BARC I-125 Ocu-Prosta seeds’ locally, cost effective ophthalmic brachytherapy can be performed in India.