Oesophageal cancer among the Turkomans of northeast Iran

A Caspian Littoral Cancer Registry survey in the early 1970s established northern Iran as one of the highest oesophageal cancer incidence regions of the world. To verify this, an oesophageal cancer survey was carried out between 1995 and 1997 in the Turkoman Plain at the southeastern corner of the Caspian Sea. Oesophageal balloon cytology screening was carried out on 4192 asymptomatic adults above age 30 years in one town and three adjoining villages with a total population of 20 392 people at risk. Oesophagoscopy was performed on 183 patients with abnormal cytological findings. The discovery of two asymptomatic small squamous cell cancers and one ‘carcinoma- suspect’ implied a prevalence ranging from 47.7 per 100 000 to 71.5 per 100 000. During a 1-year active surveillance, 14 patients were found with clinically advanced oesophageal squamous cell cancer, yielding age-standardized incidence rates of 144.09 per 100 000 for men and 48.82 per 100 000 for women. The very high frequency of oesophageal cancer reported for northern Iran 25 years ago stands confirmed. Differences in incidence rates, then and now, can be attributed to survey methods used and diagnostic criteria applied, but not to socioeconomic factors, which have remained relatively stable. Oesophageal balloon cytology is a practical method of mass screening for oesophageal cancer in Iran. © 2000 Cancer Research Campaig

Two novel human cytomegalovirus NK cell evasion functions target MICA for lysosomal degradation

NKG2D plays a major role in controlling immune responses through the regulation of natural killer (NK) cells, αβ and γδ T-cell function. This activating receptor recognizes eight distinct ligands (the MHC Class I polypeptide-related sequences (MIC) A andB, and UL16-binding proteins (ULBP)1–6) induced by cellular stress to promote recognition cells perturbed by malignant transformation or microbial infection. Studies into human cytomegalovirus (HCMV) have aided both the identification and characterization of NKG2D ligands (NKG2DLs). HCMV immediate early (IE) gene up regulates NKGDLs, and we now describe the differential activation of ULBP2 and MICA/B by IE1 and IE2 respectively. Despite activation by IE functions, HCMV effectively suppressed cell surface expression of NKGDLs through both the early and late phases of infection. The immune evasion functions UL16, UL142, and microRNA(miR)-UL112 are known to target NKG2DLs. While infection with a UL16 deletion mutant caused the expected increase in MICB and ULBP2 cell surface expression, deletion of UL142 did not have a similar impact on its target, MICA. We therefore performed a systematic screen of the viral genome to search of addition functions that targeted MICA. US18 and US20 were identified as novel NK cell evasion functions capable of acting independently to promote MICA degradation by lysosomal degradation. The most dramatic effect on MICA expression was achieved when US18 and US20 acted in concert. US18 and US20 are the first members of the US12 gene family to have been assigned a function. The US12 family has 10 members encoded sequentially through US12–US21; a genetic arrangement, which is suggestive of an ‘accordion’ expansion of an ancestral gene in response to a selective pressure. This expansion must have be an ancient event as the whole family is conserved across simian cytomegaloviruses from old world monkeys. The evolutionary benefit bestowed by the combinatorial effect of US18 and US20 on MICA may have contributed to sustaining the US12 gene family

Human cytomegalovirus interactome analysis identifies degradation hubs, domain associations and viral protein functions

Human cytomegalovirus (HCMV) extensively modulates host cells, downregulating >900 human proteins during viral replication and degrading ≥133 proteins shortly after infection. The mechanism of degradation of most host proteins remains unresolved, and the functions of many viral proteins are incompletely characterised. We performed a mass spectrometry-based interactome analysis of 169 tagged, stably-expressed canonical strain Merlin HCMV proteins, and two non-canonical HCMV proteins, in infected cells. This identified a network of >3,400 virus-host and >150 virus-virus protein interactions, providing insights into functions for multiple viral genes. Domain analysis predicted binding of the viral UL25 protein to SH3 domains of NCK Adaptor Protein-1. Viral interacting proteins were identified for 31/133 degraded host targets. Finally, the uncharacterised, non-canonical ORFL147C protein was found to interact with elements of the mRNA splicing machinery, and a mutational study suggested its importance in viral replication. The interactome data will be important for future studies of herpesvirus infection

Design and psychometric analysis of the safety harness usability and comfort assessment tool (SH UCAT)

sections in 2022. The research steps included field interviews, an expert panel, and compiling the questionnaires for assessing the comfort and usability of the harness. The items of tools were designed based on the qualitative part of the research and review of the literature. The face and content validity of the instrument were assessed. Its reliability was also evaluated using the test-retest method. Results: Two tools were developed including a comfort questionnaire with 13 questions and a usability questionnaire with 10 questions. The Cronbach's alpha coefficients of these instruments were 0.83 and 0.79, respectively. Additionally, the content and face validity indices were 0.97 and 3.89 for the comfort questionnaire and 0.991 and 4 for the usability questionnaire, respectively. Conclusions: The designed tools showed appropriate validity and reliability and could be used to evaluate the comfort and usability of safety harnesses. On the other hand, the criteria used in the designed tools could be employed in user-centered harness designs. © 2023 The Author

Design and psychometric analysis of the safety harness usability and comfort assessment tool (SH UCAT)

whether deferoxamine (DFO) can prevent acute cardiotoxicity in children with cancer who were treated with DOX as part of their chemotherapy. Results: Sixty-two newly-diagnosed pediatric cancer patients aged 2–18 years with DOX as part of their treatment regimens were assigned to three groups: group 1 (no intervention, n = 21), group II (Deferoxamine (DFO) 10 times DOX dose, n = 20), and group III (DFO 50 mg/kg, n = 21). Patients in the intervention groups were pretreated with DFO 8-h intravenous infusion in each chemotherapy course during and after completion of DOX infusion. Conventional and tissue Doppler echocardiography, serum concentrations of human brain natriuretic peptide (BNP), and cardiac troponin I (cTnI) were checked after the last course of chemotherapy. Sixty patients were analyzed. The level of cTnI was < 0.01 in all patients. Serum BNP was significantly lower in group 3 compared to control subjects (P = 0.036). No significant differences were observed in the parameters of Doppler echocardiography. Significant lower values of tissue Doppler late diastolic velocity at the lateral annulus of the tricuspid valve were noticed in group 3 in comparison with controls. By using Pearson analysis, tissue Doppler systolic velocity of the septum showed a marginally significant negative correlation with DOX dose (P = 0.05, r = − 0.308). No adverse effect was reported in the intervention groups. Conclusions: High-dose DFO (50 mg/kg) may serve as a promising cardioprotective agent at least at the molecular level in cancer patients treated with DOX. Further multicenter trials with longer follow-ups are needed to investigate its protective role in delayed DOX-induced cardiac damage. Trial registration IRCT, IRCT2016080615666N5. Registered 6 September 2016

Efficacy of a trivalent influenza vaccine against seasonal strains and against 2009 pandemic H1N1: a randomized, placebo-controlled trial

Background: Before pandemic H1N1 vaccines were available, the potential benefit of existing seasonal trivalent inactivated influenza vaccines (IIV3s) against influenza due to the 2009 pandemic H1N1 influenza strain was investigated, with conflicting results. This study assessed the efficacy of seasonal IIV3s against influenza due to 2008 and 2009 seasonal influenza strains and against the 2009 pandemic H1N1 strain. Methods: This observer-blind, randomized, placebo-controlled study enrolled adults aged 18–64 years during 2008 and 2009 in Australia and New Zealand. Participants were randomized 2:1 to receive IIV3 or placebo. The primary objective was to demonstrate the efficacy of IIV3 against laboratory-confirmed influenza. Participants reporting an influenza-like illness during the period from 14 days after vaccination until 30 November of each study year were tested for influenza by real-time reverse transcription polymerase chain reaction. Results: Over a study period of 2 years, 15,044 participants were enrolled (mean age ± standard deviation: 35.5 ± 14.7 years; 54.4% female). Vaccine efficacy of the 2008 and 2009 IIV3s against influenza due to any strain was 42% (95% confidence interval [CI]: 30%, 52%), whereas vaccine efficacy against influenza due to the vaccine-matched strains was 60% (95% CI: 44%, 72%). Vaccine efficacy of the 2009 IIV3 against influenza due to the 2009 pandemic H1N1 strain was 38% (95% CI: 19%, 53%). No vaccine-related deaths or serious adverse events were reported. Solicited local and systemic adverse events were more frequent in IIV3 recipients than placebo recipients (local: IIV3 74.6% vs placebo 20.4%, p < 0.001; systemic: IIV3 46.6% vs placebo 39.1%, p < 0.001). Conclusions: The 2008 and 2009 IIV3s were efficacious against influenza due to seasonal influenza strains and the 2009 IIV3 demonstrated moderate efficacy against influenza due to the 2009 pandemic H1N1 strain

Genome-Scale Networks Link Neurodegenerative Disease Genes to α-Synuclein through Specific Molecular Pathways

Numerous genes and molecular pathways are implicated in neurodegenerative proteinopathies, but their inter-relationships are poorly understood. We systematically mapped molecular pathways underlying the toxicity of alpha-synuclein (α-syn), a protein central to Parkinson's disease. Genome-wide screens in yeast identified 332 genes that impact α-syn toxicity. To “humanize” this molecular network, we developed a computational method, TransposeNet. This integrates a Steiner prize-collecting approach with homology assignment through sequence, structure, and interaction topology. TransposeNet linked α-syn to multiple parkinsonism genes and druggable targets through perturbed protein trafficking and ER quality control as well as mRNA metabolism and translation. A calcium signaling hub linked these processes to perturbed mitochondrial quality control and function, metal ion transport, transcriptional regulation, and signal transduction. Parkinsonism gene interaction profiles spatially opposed in the network (ATP13A2/PARK9 and VPS35/PARK17) were highly distinct, and network relationships for specific genes (LRRK2/PARK8, ATXN2, and EIF4G1/PARK18) were confirmed in patient induced pluripotent stem cell (iPSC)-derived neurons. This cross-species platform connected diverse neurodegenerative genes to proteinopathy through specific mechanisms and may facilitate patient stratification for targeted therapy. Keywords: alpha-synuclein; iPS cell; Parkinson’s disease; stem cell; mRNA translation; RNA-binding protein; LRRK2; VPS35; vesicle trafficking; yeas