5-Fluorouracil signaling through a calcium-calmodulin-dependent pathway is required for p53 activation and apoptosis in colon carcinoma cells

5-Fluorouracil (5-FU) is an anti-metabolite that is in clinical use for treatment of several cancers. In cells, it is converted into three distinct fluoro-based nucleotide analogs, which interfere with DNA synthesis and repair, leading to genome impairment and, eventually, apoptotic cell death. Current knowledge states that in certain cell types, 5-FU-induced stress is signaling through a p53-dependent induction of tumor necrosis factor-receptor oligomerization required for death-inducing signaling complex formation and caspase-8 activation. Here we establish a role of calcium (Ca 2+) as a messenger for p53 activation in response to 5-FU. Using a combination of pharmacological and genetic approaches, we show that treatment of colon carcinoma cells stimulates entry of extracellular Ca 2+ through long lasting-type plasma membrane channels, which further directs posttranslational phosphorylation of at least three p53 serine residues (S15, S33 and S37) by means of calmodulin (CaM) activity. Obstructing this pathway by the Ca 2+ -chelator BAPTA (1,2-bis(o-aminophenoxy)ethane- N,N,N',N'-tetraacetic acid) or by inhibitors of CaM efficiently reduces 5-FU-induced caspase activities and subsequent cell death. Moreover, ectopic expression of p53 S15A in HCT116 p53 -/- cells confirmed the importance of a Ca 2+ -CaM-p53 axis in 5-FU-induced extrinsic apoptosis. The fact that a widely used therapeutic drug, such as 5-FU, is operating via this pathway could provide new therapeutic intervention points, or specify new combinatorial treatment regimes. © 2013 Macmillan Publishers Limited.Swedish Science Foundation; Swedish and Stockholm Cancer Societies; Swedish Childhood Cancer Foundation; EC-FP-6 (Chemores); EC-FP-7 (APO-SYS

A hemophagocytic lymphohistiocytosis case with newly defined UNC13D (C.175G>C; p.Ala59Pro) mutation and a rare complication

Hemophagocytic lymphohistiocytosis (HLH) represents a severe hyperinflammatory condition with cardinal symptoms of prolonged fever, cytopenias, hepatosplenomegaly, and hemophagocytosis by activated, morphologically benign macrophages with impaired function of natural killer cells and cytotoxic T lymphocytes. A 2-month-old girl, who was admitted with fever, was diagnosed with HLH and her genetic examination revealed a newly defined mutation in the UNC13D (c.175G>C; p.Ala59Pro) gene. She was treated with dexamethasone, etoposide, and intrathecal methotrexate. During the second week of treatment, after three doses of etoposide, it was noticed that there was a necrotic plaque lesion on the soft palate. Pathologic examination of debrided material in PAS and Grocott staining revealed lots of septated hyphae, which was consistent with aspergillosis infection. Etoposide was stopped and amphotericin B treatment was given for six weeks. HLH 2004 protocol was completed to eight weeks with cyclosporine A orally. There was no patient with invasive aspergillosis infection as severe as causing palate and nasal septum perforation during HLH therapy. In immuncompromised patients, fungal infections may cause nasal septum perforation and treatment could be achieved by antifungal therapy and debridement of necrotic tissue. © 2015 Turkish Society of Hematology. All rights reserved

Work-related injuries sustained by emergency medical technicians and paramedics in Turkey

BACKGROUND: Evaluated in the present study were locations, descriptions, and results of work-related injuries (WRIs) sustained by emergency medical technicians (EMTs) and paramedics in Turkey’s most crowded city, İstanbul. METHODS: After the present study had been accepted by the urban health authority, a questionnaire was emailed to the healthcare personnel of İstanbul’s 195 ambulance stations. RESULTS: Included in the present study were the responses of 901 members of staff (660 EMTs and 241 paramedics), with a mean age of 29.5±6.1 (min: 18; max: 61). The majority of participants (94.9%) had encountered verbal abuse from the public, and 39.8% had encountered physical violence from patients’ relatives. Levels of satisfaction with work in emergency medical services (EMS) was also evaluated, and 510 participants (57.6%) were unhappy. Regarding gender, female employees were more likely to be verbally attacked (p=0.01), while males were more likely to be physically attacked (p=0.001). It was reported that motor vehicle accidents (MVAs) were the most common cause of WRIs (81.4%), followed by needle-stick injuries (52.2%), ocular exposure to blood and other fluids (30.9%), and sharp injuries (22.5%). Only 10.5% (n=95) of WRIs were reported to authorities; 488 (54.2%) of participants just attended to the practice to prevent possible WRIs. CONCLUSION: For paramedics and EMTs, risk of WRI is obviously high. Strategies to decrease and prevent verbal and physical violence should be developed. © 2016 TJTES

The Impact of Dementia on Women Internationally: an Integrative Review

Women are disproportionately affected by dementia, both in terms of developing dementia and becoming caregivers. We conducted an integrative review of English language literature of the issues affecting women in relation to dementia from an international perspective. The majority of relevant studies were conducted in high income countries, and none were from low-income countries. The effects of caregiving on health, wellbeing and finances are greater for women; issues facing women, particularly in low and middle-income countries need to be better understood. Research should focus on building resilience to help people adjust and cope long term

Supplementary File for Capturing wheat phenotypes at the genome level

Supplementary S1: Yield and related traits in bread wheat. Table S1: Examples of genomic regions, candidate and cloned genes for yield and related traits in bread wheat. Supplementary S2: Drought tolerance. Table S2: Examples of genomic regions and candidate genes for drought tolerance. Supplementary S3: Heat tolerance. Table S3. Examples of genomic regions and candidate genes for heat tolerance. Supplementary S4: salinity tolerance in bread wheat. Table S4. Examples of genomic regions and candidate genes for salinity tolerance in bread wheat. Supplementary S5: Frost tolerance. Supplementary S6: Disease resistance. Table S5. Examples of genomic regions, candidate and cloned genes mapped for disease resistance in wheat species. Supplementary S7 insect and mite resistance. Table S6. Examples of genomic regions and candidate genes mapped for insect and mite resistance. Supplementary S8: Quality traits. Table S7. Examples of genomic regions, candidate and cloned genes for quality traits.Recent technological advances in next-generation sequencing (NGS) technologies have dramatically reduced the cost of DNA sequencing, allowing species with large and complex genomes to be sequenced. Although bread wheat (Triticum aestivum L.) is one of the world’s most important food crops, efficient exploitation of molecular marker-assisted breeding approaches has lagged behind that achieved in other crop species, due to its large polyploid genome. However, an international public–private effort spanning 9 years reported over 65% draft genome of bread wheat in 2014, and finally, after more than a decade culminated in the release of a gold-standard, fully annotated reference wheat-genome assembly in 2018. Shortly thereafter, in 2020, the genome of assemblies of additional 15 global wheat accessions was released. As a result, wheat has now entered into the pan-genomic era, where basic resources can be efficiently exploited. Wheat genotyping with a few hundred markers has been replaced by genotyping arrays, capable of characterizing hundreds of wheat lines, using thousands of markers, providing fast, relatively inexpensive, and reliable data for exploitation in wheat breeding. These advances have opened up new opportunities for marker-assisted selection (MAS) and genomic selection (GS) in wheat. Herein, we review the advances and perspectives in wheat genetics and genomics, with a focus on key traits, including grain yield, yield-related traits, end-use quality, and resistance to biotic and abiotic stresses. We also focus on reported candidate genes cloned and linked to traits of interest. Furthermore, we report on the improvement in the aforementioned quantitative traits, through the use of (i) clustered regularly interspaced short-palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9)-mediated gene-editing and (ii) positional cloning methods, and of genomic selection. Finally, we examine the utilization of genomics for the next-generation wheat breeding, providing a practical example of using in silico bioinformatics tools that are based on the wheat reference-genome sequence.Peer reviewe