Epigenetic Mechanisms of Metal Carcinogenicity

Many metals exhibit genotoxic and/or carcinogenic effects. These toxic metals can be found ubiquitously – in drinking water, food, air, general use products, in everyday and occupational settings. Exposure to such carcinogenic metals can result in serious health disorders, including cancer. Arsenic, cadmium, chromium, nickel, and their compounds have already been recognized as carcinogens by the International Agency for Research on Cancer. This review summarizes a wide range of epigenetic mechanisms contributing to carcinogenesis induced by these metals, primarily including, but not limited to, DNA methylation, miRNA regulation, and histone posttranslational modifications. The mechanisms are described and discussed both from a metal-centric and a mechanism-centric standpoint. The review takes a broad perspective, putting the mechanisms in the context of real-life exposure, and aims to assist in guiding future research, particularly with respect to the assessment and control of exposure to carcinogenic metals and novel therapy development

Occupational Therapy After Breast Cancer Treatment: A Guidebook for Hispanic Women

This project aims to understand the needs of Hispanic women post-breast cancer treatment and offer a guidebook with educational resources in both English and Spanish.https://soar.usa.edu/otdcapstonesspring2024/1004/thumbnail.jp

A Metabolomic Signature of Acute Caloric Restriction

Context: The experimental paradigm of acute caloric restriction followed by refeeding can be used to study the homeostatic mechanisms that regulate energy homeostasis, which are relevant to understanding the adaptive response to weight loss. Objective: Metabolomics, the measurement of hundreds of small molecule metabolites, their precursors, derivatives, and degradation products, has emerged as a useful tool for the study of physiology and disease and was used here to study the metabolic response to acute caloric restriction. Participants, Design and Setting: We used four ultra high performance liquid chromatography-tandem mass spectrometry methods to characterize changes in carbohydrates, lipids, amino acids and steroids in eight normal weight men at baseline, after 48 hours of caloric restriction (CR; 10% of energy requirements) and after 48 hours of ad libitum refeeding in a tightly-controlled environment. Results: We identified a distinct metabolomic signature associated with acute CR characterized by the expected switch from carbohydrate to fat utilization with increased lipolysis and beta-fatty acid oxidation. We found an increase in omega-fatty acid oxidation and levels of endocannabinoids which are known to promote food intake. These changes were reversed with refeeding. Several plasmalogen phosphatidylethanolamines (endogenous anti-oxidants) significantly decreased with CR (all p≤0.0007). Additionally, 48 acute CR was associated with an increase in the branched chain amino acids (all p≤1.4x10-7) and dehydroepiandrosterone sulfate (p=0.0006). Conclusions We identified a distinct metabolomic signature associated with acute CR. Further studies are needed to characterise the mechanisms that mediate these changes and their potential contribution to the adaptive response to dietary restriction.This work was supported by the Wellcome Trust (to I.S.F.), the NIHR Cambridge Biomedical Research Centre, the European Research Council, the Bernard Wolfe Health Neuroscience Fund (all to I.S.F.), the Swiss National Science Foundation (P3SMP3-155318, PZ00P3-167826, to T.H.C.), and the Uehara Memorial Foundation (to T.S.). This work was supported by the NIHR Rare Diseases Translational Research Collaboration and the NeuroFAST consortium, which is funded by the European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no 245009

Evidence of chikungunya virus disease in Pakistan since 2015 with patients demonstrating involvement of the central nervous system

Several arboviruses are endemic to and co-circulate in Pakistan. In recent years, Pakistan has observed a rise in arboviral infections. A cross-sectional study for arboviral diseases, which included screening for Chikungunya virus (CHIKV), was initiated in 2015 to determine which pathogens were causing disease in patients presenting to health care services. Exposure to CHIKV was verified via detection of viral nucleic acids or virus-specific IgM with virus-specific neutralizing antibodies. Out of 997 enrolled patients presenting with clinical features suggestive of arboviral disease, 102 patients were positive for CHIKV IgM antibodies and 60 patients were positive for CHIKV nucleic acids or neutralizing antibodies. The data presented here show that CHIKV has been circulating in Pakistan since April of 2015. CHIKV infections were detected in study subjects up to the conclusion of our enrollment period in July 2017. Syndromic and clinical data show that arthralgia was associated with CHIKV as was rash, fever greater than 38°C, and lymphopenia. Neurological symptoms were reported in 49% of CHIKV suspect patients and in 46.6% of confirmed infections. Acute disseminated encephalomyelitis was diagnosed in 5% of confirmed infection and various manifestation of encephalitis diagnosed in an additional 16.6% of patients with confirmed CHIKV infections. CHIKV-exposed patients were just as likely to present with neurological symptoms and encephalitis as patients with West Nile Virus infections but were 4.57 times more likely to have lymphopenia. This proportion of neurological symptoms may be a complicating factor in countries where WNV and/or JEV co-circulate with CHIKV

Comparison of clinical presentation and out-comes of chikungunya and dengue virus infections in patients with acute undifferentiated febrile illness from the Sindh region of Pakistan

Background: Arboviruses are a cause of acute febrile illness and outbreaks worldwide. Recent outbreaks of Chikungunya virus (CHIKV) in dengue endemic areas have alarmed clinicians as unique clinical features differentiating CHIKV from Dengue virus (DENV) are limited. This has complicated diagnostic efforts especially in resource limited countries where lab testing is not easily available. Therefore, it is essential to analyse and compare clinical features of laboratory confirmed cases to assist clinicians in suspecting possible CHIKV infection at time of clinical presentation.Methodology: A prospective point prevalence study was conducted, with the hypothesis that not all patients presenting with clinical suspicion of dengue infections at local hospitals are suffering from dengue and that other arboviruses such as Chikungunya, West Nile viruses, Japanese Encephalitis virus and Zika virus are co-circulating in the Sindh region of Pakistan. Out-patients and hospitalized (in-patients) of selected district hospitals in different parts of Sindh province of Pakistan were recruited. Patients with presumptive dengue like illness (Syndromic diagnosis) by the treating physicians were enrolled between 2015 and 2017. Current study is a subset of larger study mentioned above. Here-in we compared laboratory confirmed cases of CHIKV and DENV to assess clinical features and laboratory findings that may help differentiate CHIKV from DENV infection at the time of clinical presentation.Results: Ninety-eight (n = 98) cases tested positive for CHIKV, by IgM and PCR and these were selected for comparative analysis with DENV confirmed cases (n = 171). On multivariable analysis, presence of musculoskeletal [OR = 2.5 (95% CI:1.6-4.0)] and neurological symptoms [OR = 4.4 (95% CI:1.9-10.2)], and thrombocytosis [OR = 2.2 (95% CI:1.1-4.0)] were associated with CHIKV infection, while atypical lymphocytes [OR = 8.3 (95% CI:4.2-16.7)] and thrombocytopenia [OR = 8.1 (95% CI:1.7-38.8)] were associated with DENV cases at time of presentation. These findings may help clinicians in differentiating CHIKV from DENV infection.Conclusion: CHIKV is an important cause of illness amongst patients presenting with acute febrile illness in Sindh region of Pakistan. Arthralgia and encephalitis at time of presentation among patients with dengue-like illness should prompt suspicion of CHIKV infection, and laboratory confirmation must be sought

From monogenic to polygenic obesity: recent advances

The heritability of obesity and body weight in general is high. A small number of confirmed monogenic forms of obesity—the respective mutations are sufficient by themselves to cause the condition in food abundant societies—have been identified by molecular genetic studies. The elucidation of these genes, mostly based on animal and family studies, has led to the identification of important pathways to the disorder and thus to a deeper understanding of the regulation of body weight. The identification of inborn deficiency of the mostly adipocyte-derived satiety hormone leptin in extremely obese children from consanguineous families paved the way to the first pharmacological therapy for obesity based on a molecular genetic finding. The genetic predisposition to obesity for most individuals, however, has a polygenic basis. A polygenic variant by itself has a small effect on the phenotype; only in combination with other predisposing variants does a sizeable phenotypic effect arise. Common variants in the first intron of the ‘fat mass and obesity associated’ gene (FTO) result in an elevated body mass index (BMI) equivalent to approximately +0.4 kg/m² per risk allele. The FTO variants were originally detected in a genome wide association study (GWAS) pertaining to type 2 diabetes mellitus. Large meta-analyses of GWAS have subsequently identified additional polygenic variants. Up to December 2009, polygenic variants have been confirmed in a total of 17 independent genomic regions. Further study of genetic effects on human body weight regulation should detect variants that will explain a larger proportion of the heritability. The development of new strategies for diagnosis, treatment and prevention of obesity can be anticipated

Human west nile virus disease outbreak in Pakistan, 2015–2016

Like most of the world, Pakistan has seen an increase in mosquito-transmitted diseases in recent years. The magnitude and distribution of these diseases are poorly understood as Pakistan does not have a nation-wide system for reporting disease. A cross-sectional study to determine which flaviviruses were causing of arboviral disease in Pakistan was instituted. West Nile virus (WNV) is a cause of seasonal fever with neurotropic findings in countries that share borders with Pakistan. Here, we describe the active and persistent circulation of WNV in humans in the southern region of Pakistan. This is the first report of WNV causing neurological disease in human patients in this country. Of 997 enrolled patients presenting with clinical features suggestive of arboviral disease, 105 were positive for WNV IgM antibodies, and 71 of these patients possessed WNV-specific neutralizing antibodies. Cross-reactivity of WNV IgM antibodies with Japanese encephalitis virus(JEV) occurred in 75 of these 105 patients. WNV co-infections with Dengue viruses were not a contributing factor for the severity of disease. Nor did prior exposure to dengue virus contribute to incidence of neurological involvement in WNV-infected patients. Patients with WNV infections were more likely to present with altered mental status, seizures, and reduced Glasgow Coma scores when compared with JEV-infected patients. Human WNV cases and vector numbers exhibited a temporal correlation with climate

Canopy and Ear Traits Associated With Avoidance of Fusarium Head Blight in Wheat

Doubled haploid and elite wheat genotypes were ground inoculated in three field experiments and head spray inoculated in two glasshouse experiments, using mixed Fusarium and Microdochium species, to identify crop canopy and ear traits associated with Fusarium head blight (FHB) disease. In all experiments, flag leaf length and tiller number were consistently identified as the most significant canopy traits contributing to progression of FHB caused by Fusarium graminearum, F. culmorum, and F. avenaceum. The influence of ear traits was greater for F. poae that may possess more diverse routes for transmission and spread. Consistently, spikelet density was associated with increased disease severity in the field. F. graminearum, F. culmorum, and F. langsethiae were the main mycotoxin producers and their respective toxins were significantly related to fungal biomass and number of spikelets per ear. Genotypes with lower tiller numbers, shorter flag leaves and less dense ears may be able to avoid FHB disease caused by F. graminearum, F. culmorum, F. avenaceum, or Microdochium species however selection for these canopy and ear architectural traits to enable disease avoidance in wheat is likely to result in a potential trade-off with grain yield and therefore only moderately advantageous in susceptible genotypes