Melatonin in pathogenesis and therapy of cancer.

Melatonin is a neuroendocrine hormone secreted by the pineal gland to transduce the body's circadian rhythms. An internal 24 hour time keeping system (biological clock) regulated by melatonin, controls the sleep-wake cycle. Melatonin production is a highly conserved evolutionary phenomenon. The indole hormone is synthesized in the pinealocytes derived from photoreceptors. Altered patterns and/or levels of melatonin secretion have been reported to coincide with sleep disorders, jetlag, depression, stress, reproductive activities, some forms of cancer and immunological disorders. Lately, the physiological and pathological role of melatonin has become a priority area of investigation, particularly in breast cancer, melanoma, colon cancer, lung cancer and leukemia. According to the 'melatonin hypothesis' of cancer, the exposure to light at night (LAN) and anthropogenic electric and magnetic fields (EMFs) is related to the increased incidence of breast cancer and childhood leukaemia via melatonin disruption. Melatonin's hypothermic, antioxidant and free radical scavenging properties, attribute it to an immunomodulator and an oncostatic agent as well. Many clinical studies have envisaged the potential therapeutic role of melatonin in various pathophysiological disorders, particularly cancer. A substantial reduction in risk of death and low adverse effects were reported from various randomized controlled trials of melatonin treatment in cancer patients. This review summarizes the physiological significance of melatonin and its potential role in cancer therapy. Furthermore, the article focuses on melatonin hypothesis to represent the cause-effect relationship of the three aspects: EMF, LAN and cancer.

Clinical relevance of alternative splicing.

The unique phenomenon of alternative splicing is gathering concern due to its promising therapeutic potential. The human genome sequencing project suggests approximately 20,000-25,000 genes. Among these, about 35-60% of genes generate multiple mRNAs by alternative splicing mechanism and contribute to the diversity of the proteomic world. This 'gene shortfall' has ignited considerable interest in alternative RNA splicing. This process leads to expression of a single gene responsible for the transcription of different mRNA isoforms that might have multiple biological functions. The disruption of splicing pattern can produce aberrant splice variants, which are implicated in more than 50% of genetic disorders including cancer. Altered splice sites in neoplastic cell contribute to the development, progression and/or maintenance of tumorous growth. The repertoire of tumor-specific variant represents a potential marker in pharmacogenomic diagnostic relevance. Alternative splice isoforms have been analyzed serendipitously by qualitative gene profiling with in silico gene prediction software. Computational approach in identifying exonic splicing enhancers in genomic DNA and focus on microarray technology will elucidate differential expression of alternative splice variants. The antisense oligonucleotides modulate alternative splicing and engender the production of therapeutic gene products. Oligonucleotides have the potential to silence the mutations caused by aberrant splicing. The efficacy of the antisense oligonucleotides lies in the chemical configuration, affinity and delivery strategies. Hence the therapeutic potential of antisense oligonucleotides as modulators of aberrant alternative splicing would be a major challenge to the upcoming proteomic era.

(CTG)n expansion at DMPK locus seen only in muscle tissue: a novel case.

Triplet repeat expansion in 3 untranslated region of myotonic dystrophy protein kinase (DMPK) gene has been implicated as causative in myotonic dystrophy (DM). In cases of DM, high levels of somatic instability have been reported, in which inter-tissue repeat length differences as large as 3000 repeats have been observed. This study highlights the inter-tissue (CTG)n expansion variability at the DMPK locus. Molecular analysis of DMPK gene, encompassing the triplet repeat expansion, was carried out in 31 individuals (11 clinically identified DM patients, 20 controls). All controls showed a 2.1kb band (upto 35 CTG repeats), while four cases exhibited an expansion (>50 repeats). A novel observation was made in one case, wherein the DNA from lymphocytes showed a normal 2.1kb band while the muscle tissue DNA from the same patient was heterozygous for normal and 4.3 kb band (>700 repeats). Our results suggested that because inter-tissue variability existed in the (CTG)n repeat number at DMPK locus, an attempt should be made to evaluate affected tissue along with blood wherever possible prior to making a final diagnosis. This is important not only for diagnosis and prenatal analysis, but also while providing genetic counseling to families.

In vitro effects of low-level, low-frequency electromagnetic fields on DNA damage in human leucocytes by comet assay.

The sources for the effects of electromagnetic fields (EMFs) have been traced to time-varying as well as steady electric and magnetic fields, both at low and high to ultra high frequencies. Of these, the effects of low-frequency (50/60 HZ) magnetic fields, directly related to time-varying currents, are of particular interest as exposure to some fields may be commonly experienced. In the present study, investigations have been carried out at low-level (mT) and low-frequency (50 Hz) electromagnetic fields in healthy human volunteers. Their peripheral blood samples were exposed to 5 doses of electromagnetic fields (2,3,5,7 and 10mT at 50 Hz) and analysed by comet assay. The results were compared to those obtained from unexposed samples from the same subjects. 50 cells per treatment per individual were scored for comet-tail length which is an estimate of DNA damage. Data from observations among males were pooled for each flux density for analysis. At each flux density, with one exception, there was a significant increase in the DNA damage from the control value. When compared with a similar study on females carried out by us earlier, the DNA damage level was significantly higher in the females as compared to the males for each flux density.

Genotoxic Effects On Photocopying Workers : A Statistical Investigation.

Photocopiers are a source of employment for a large number of people. The personnel working with photocopiers are commonly exposed to toners and their by-products during reloading and running of the machines. The main components of these toners are carbon black, styrene, resins, formaldehyde and polycyclic aromatic hydrocarbons (PAHs) and they are known to be genotoxic. For possible genotoxic effects of occupational exposure to photocopying machines, the present study was undertaken on 29 exposed and 26 control subjects. DNA damage war studied on their peripheral blood leukocytes, using comet assay. DNA repair studies were also undertaken on 10 exposed and 10 control subjects. 50 cells per treatment per individual were scored for comet tail length which is an estimate of DNA damage. The control and the exposed groups show clear difference in the mean tail length of the comets and the standard deviations. The scatter in the individual measurements is also high in the exposed group as compared to the control group.

A Study On The Genetics Of Sense Of Humour.

An attempt was made to assess the role of genetic factors in the expression of humour. The IPAT Humour Test was used to evaluate humour as a quantitative parameter. Correlation coefficients were calculated between pairs of first degree relatives. Variation in mean scores obtained for each of the 13 components of humour for the comparable pairs was high, and the correlations in general were poor. Our results may be explained on the basis of cultural and environmental influences.