Local Translation in Primary Afferent Fibers Regulates Nociception

Recent studies have demonstrated the importance of local protein synthesis for neuronal plasticity. In particular, local mRNA translation through the mammalian target of rapamycin (mTOR) has been shown to play a key role in regulating dendrite excitability and modulating long-term synaptic plasticity associated with learning and memory. There is also increased evidence to suggest that intact adult mammalian axons have a functional requirement for local protein synthesis in vivo. Here we show that the translational machinery is present in some myelinated sensory fibers and that active mTOR-dependent pathways participate in maintaining the sensitivity of a subpopulation of fast-conducting nociceptors in vivo. Phosphorylated mTOR together with other downstream components of the translational machinery were localized to a subset of myelinated sensory fibers in rat cutaneous tissue. We then showed with electromyographic studies that the mTOR inhibitor rapamycin reduced the sensitivity of a population of myelinated nociceptors known to be important for the increased mechanical sensitivity that follows injury. Behavioural studies confirmed that local treatment with rapamycin significantly attenuated persistent pain that follows tissue injury, but not acute pain. Specifically, we found that rapamycin blunted the heightened response to mechanical stimulation that develops around a site of injury and reduced the long-term mechanical hypersensitivity that follows partial peripheral nerve damage - a widely used model of chronic pain. Our results show that the sensitivity of a subset of sensory fibers is maintained by ongoing mTOR-mediated local protein synthesis and uncover a novel target for the control of long-term pain states

A higher degree of expression of DNA methyl transferase 1 in cervical cancer is associated with poor survival outcome

Chandrika J Piyathilake,1 Suguna Badiga,1 Samuel G Borak,2 Janaka Weragoda,1 Sejong Bae,3 Roland Matthews,4 Walter C Bell,2 Edward E Partridge5 1Department of Nutrition Sciences, 2Department of Pathology, 3Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL, 4Department of Obstetrics and Gynecology, Morehouse School of Medicine, Atlanta, GA, 5Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, AL, USA Background: Even though novel therapies based on aberrant DNA methylation could be of particular importance for the treatment of cervical cancer (CC) because the oncoproteins E6/E7 of high-risk human papillomaviruses, the causative agents for developing CC, have the capacity to bind and upregulate DNA methyltransferases (DNMTs), to our knowledge, no previous studies have evaluated the expression of this enzyme in CC in relation to survival outcomes. The purpose of the study was to evaluate the expression of DNMT1 in CC and its association with survival outcomes.Methods: The study population consisted of 76 women treated for primary CC and followed up by the University of Alabama at Birmingham (UAB) cancer registry. The expression of DNMT1 was examined using immunohistochemistry, and the degree of expression of DNMT1 was expressed as a percentage of cells positive for DNMT1 and its intensity. Cox proportional hazards model was used to assess the relationship between the degree of expression of DNMT1 and overall survival after adjusting for relevant covariates.Results: The expression of DNMT1 was significantly higher in CC cells compared to that in the normal cervical epithelium. A higher percentage of cells positive for DNMT1 and a higher intensity score for DNMT1 were significantly associated with poor survival outcome (hazard ratio [HR] =4.3, P=0.03 and HR =4.9, P=0.02, respectively).Conclusion: Our findings suggested that the degree of expression of DNMT1 could be considered as a target in the epigenetic treatment of CC. Replication of our results in other study populations with CC could create the opportunity of using DNMT inhibitors to treat CC. Keywords: DNMT1, cervical cancer, survival outcome&nbsp

Risk Assessment of Trace Element Contamination in Drinking Water and Agricultural Soil: A Study in Selected Chronic Kidney Disease of Unknown Etiology (CKDu) Endemic Areas in Sri Lanka

Unexplained or unclear etiology of chronic kidney disease (CKDu) has been reported in Sri Lanka’s North Central Province (NCP) for more than two decades. Meanwhile, high exposure to heavy metals/metalloids and their accumulation are recognized as the origin of many acute and chronic diseases in certain vulnerable human tissues including kidneys. This study evaluates the contamination status of heavy metals/metalloids of the drinking water and agricultural soil in two CKDu endemic areas compared with a reference area in Sri Lanka based on common indexes and attribute of the commonly used fertilizers evaluated to identify the basic sources of toxic metals in the agricultural soil. Mean concentrations of heavy metals/metalloids such as Mn, Co, As, Cd, Pb, Cu, Zn, and Fe in drinking water of CKDu endemic areas were far below Sri Lankan water quality standards (permissible limits). In addition, all sampling locations dropped below the medium range of the heavy metal pollution index of water (HPI 15–40). Geoaccumulation indexes (Igeo) of soil reveal that paddy soil in CKDu endemic areas is being moderately polluted with toxic metals/metalloids such as As, Pb, Cu, Ni, Cr, Zn, and Cd. On the other hand, the application of fertilizers, which contained a high dose of toxic metals, could be the driving force for agricultural soil pollution, and limitless application of low-quality fertilizer would lead to more soil contamination with heavy metals. Hence, hazardous metals can be incorporated into the food chains via contaminated paddy soil