Valproic acid and butyrate induce apoptosis in human cancer cells through inhibition of gene expression of Akt/protein kinase B

BACKGROUND: In eukaryotic cells, the genomic DNA is packed with histones to form the nucleosome and chromatin structure. Reversible acetylation of the histone tails plays an important role in the control of specific gene expression. Mounting evidence has established that histone deacetylase inhibitors selectively induce cellular differentiation, growth arrest and apoptosis in variety of cancer cells, making them a promising class of anticancer drugs. However, the molecular mechanisms of the anti-cancer effects of these inhibitors have yet to be understood. RESULTS: Here, we report that a key determinant for the susceptibility of cancer cells to histone deacetylase inhibitors is their ability to maintain cellular Akt activity in response to the treatment. Also known as protein kinase B, Akt is an essential pro-survival factor in cell proliferation and is often deregulated during tumorigenesis. We show that histone deacetylase inhibitors, such as valproic acid and butyrate, impede Akt1 and Akt2 expression, which leads to Akt deactivation and apoptotic cell death. In addition, valproic acid and butyrate induce apoptosis through the caspase-dependent pathway. The activity of caspase-9 is robustly activated upon valproic acid or butyrate treatment. Constitutively active Akt is able to block the caspase activation and rescues cells from butyrate-induced apoptotic cell death. CONCLUSION: Our study demonstrates that although the primary target of histone deacetylase inhibitors is transcription, it is the capacity of cells to maintain cellular survival networks that determines their fate of survival

Using Patient Registries to Identify Triggers of Rare Diseases

Mapping the distribution of patients and analyzing disease clusters is an effective method in epidemiology, where the non-random aggregation of patients is carefully investigated. This can aid in the search for clues to the etiology of diseases, particularly the rare ones. Indeed, with the increased incidence of rare diseases in certain populations and/or geographic areas and with proper analysis of common exposures, it is possible to identify the likely promoters/triggers of these diseases at a given time. In this chapter, we will highlight the appropriate methodology and demonstrate several examples of cluster analyses that lead to the recognition of environmental, occupational and communicable preventable triggers of several rare diseases

National trends in incidence and geographic distribution of melanoma and keratinocyte carcinoma in the Russian Federation

Keratinocyte Carcinomas (KC), including basal cell and cutaneous squamous cell carcinomas, are the most common skin cancers in Fitzpatrick phototype I-III individuals, while melanoma is one of the deadliest skin cancer types. The incidence of both melanoma and KC is increasing in Russia. KCs’ incidence increases from north-to-south across the Russian Federation. In contrast, while melanoma’s incidence increases from north-to-south in the eastern part of the country, in the west of Russia a reverse latitude gradient trend is noted, where northern more affluent regions of Russia display higher rates of melanoma than the southern jurisdictions. Furthermore, our detailed analysis of incidence by jurisdiction highlights that affluent northern capital cities have higher rates of melanoma than the surrounding regions. The observed melanoma incidence trends in the western portion of Russia are similar to the findings in the western Europe and opposite of the findings in Canada

Environmental and Other Extrinsic Risk Factors Contributing to the Pathogenesis of Cutaneous T Cell Lymphoma (CTCL)

The applications of disease cluster investigations in medicine have developed rather rapidly in recent decades. Analyzing the epidemiology of non-random aggregation of patients with a particular disease fostered identification of environmental and external exposures as disease triggers and promoters. Observation of patient clusters and their association with nearby exposures, such as Dr. John Snow's astute mapping analysis in the mid-1800's, which revealed proximity of cholera patients in London to a contaminated water pump infected with Vibrio cholerae, have paved the way for the field of epidemiology. This approach enabled the identification of triggers for many human diseases including infections and cancers. Cutaneous T-cell lymphomas (CTCL) represent a group of non-Hodgkin lymphomas that primarily affect the skin. The detailed pathogenesis by which CTCL develops remains largely unknown. Notably, non-random clustering of CTCL patients was reported in several areas worldwide and this rare malignancy was also described to affect multiple members of the same family. These observations indicate that external factors are possibly implicated in promoting CTCL lymphomagenesis. Here, we review the epidemiology of CTCL worldwide and the clinical characteristics of CTCL patients, as revealed by global epidemiological data. Further, we review the known risk factors including sex, age, race as well as environmental, infectious, iatrogenic and other exposures, that are implicated in CTCL lymphomagenesis and discuss conceivable mechanisms by which these factors may trigger this malignancy

New-onset of pemphigus following COVID-19 infection: A case report

COVID-19 has been implicated in various cutaneous autoimmune diseases. Pemphigus is a group of autoimmune blistering diseases that target the desmosomal complexes. Pemphigus triggered by COVID-19 has been seldom reported in the literature and remains both a diagnostic and therapeutic challenge. We report a case of COVID-19-induced pemphigus that responded well to prednisone and mycophenolate mofetil after 9 months from initial presentation. On histologic examination, both intercellular and basement membrane staining were noted. Indirect immunofluorescence staining was positive against the intercellular cement of the stratified epithelium from monkey esophagus. We hypothesize that COVID-19 stimulated the release of multiple pemphigus antigens, which resulted in the unusual histologic pattern reported in the present case. Although malignancy should be suspected when features of paraneoplastic pemphigus, such as basement membrane staining on direct immunofluorescence, are noted, it may also be a histologic pattern of pemphigus secondary to COVID-19 that clinicians may consider

A novel nonsense mutation in exon 9 in the extracellular matrix protein 1 gene associated with lipoid proteinosis: A case report

Lipoid proteinosis is a rare autosomal recessive genodermatosis that is caused by loss-of-function mutations in the extracellular matrix protein 1 gene. This study identifies a novel nonsense mutation in exon 9 of the extracellular matrix protein 1 gene associated with lipoid proteinosis, contributing to recent advances in our understanding of the molecular genetics underlying this disease. It is important to identify the mutations in the extracellular matrix protein 1 gene that are associated with lipoid proteinosis and how these affect protein function. Understanding the molecular basis for such genetic disorders may lead to novel therapeutic approaches for treating hereditary genodermatoses