Introducing molecular biology to medical physicists

Molecular biology helps us understand how genetic information is converted to functional proteins, how proteins interact through complex networks to determine the fate and function of a cell and how mutations lead to diseases. In the era of molecular medicine and ommissionin medicine, medical physicists need to acquire basic knowledge of molecular biology in order to communicate and collaborate with clinical and life science colleagues. This article documents our experience in introducing molecular biology as an academic module in a regional training course for educators held in Kuala Lumpur, Nov 2019. The module consists of didactic lectures, simulation, group exercises, etc. From the positive feedbacks that we received, the participants benefited from the exposure and we plan to produce some learning materials for future courses

Genome-Wide Association Study of Hepatocellular Carcinoma in Southern Chinese Patients with Chronic Hepatitis B Virus Infection

One of the most relevant risk factors for hepatocellular carcinoma (HCC) development is chronic hepatitis B virus (HBV) infection, but only a fraction of chronic HBV carriers develop HCC, indicating that complex interactions among viral, environmental and genetic factors lead to HCC in HBV-infected patients. So far, host genetic factors have incompletely been characterized. Therefore, we performed a genome-wide association (GWA) study in a Southern Chinese cohort consisting of 95 HBV-infected HCC patients (cases) and 97 HBV-infected patients without HCC (controls) using the Illumina Human610-Quad BeadChips. The top single nucleotide polymorphisms (SNPs) were then validated in an independent cohort of 500 cases and 728 controls. 4 SNPs (rs12682266, rs7821974, rs2275959, rs1573266) at chromosome 8p12 showed consistent association in both the GWA and replication phases (ORcombined = 1.31–1.39; pcombined = 2.71×10−5–5.19×10−4; PARcombined = 26–31%). We found a 2.3-kb expressed sequence tag (EST) in the region using in-silico data mining and verified the existence of the full-length EST experimentally. The expression level of the EST was significantly reduced in human HCC tumors in comparison to the corresponding non-tumorous liver tissues (P<0.001). Results from sequence analysis and in-vitro protein translation study suggest that the transcript might function as a long non-coding RNA. In summary, our study suggests that variations at chromosome 8p12 may promote HCC in patients with HBV. Further functional studies of this region may help understand HBV-associated hepatocarcinogenesis

Effects of varying blood flow rate during peripheral veno-arterial extracorporeal membrane oxygen (V-A ECMO) on left ventricular function measured by two-dimensional strain

BackgroundWe evaluated the effects of varying blood flow rate during peripheral veno-arterial extracorporeal membrane oxygen (V-A ECMO) on left ventricular function measured by two-dimensional strain.MethodsAdult patients who were supported by peripheral V-A ECMO were recruited. Serial hemodynamic and cardiac performance parameters were measured by transthoracic echocardiogram within the first 48 h after implementation of V-A ECMO. Measurements at 100%, 120%, and 50% of target blood flow (TBF) were compared.ResultsA total of 54 patients were included and the main indications for V-A ECMO were myocardial infarction [32 (59.3%)] and myocarditis [6 (11.1%)]. With extracorporeal blood flow at 50% compared with 100% TBF, the mean arterial pressure was lower [66 ± 19 vs. 75 ± 18 mmHg, p &lt; 0.001], stroke volume was greater [23 (12–34) vs. 15 (8–26) ml, p &lt; 0.001], and cardiac index was higher [1.2 (0.7–1.7) vs. 0.8 (0.5–1.3) L/min/m2, p &lt; 0.001]. Left ventricular contractile function measured by global longitudinal strain improved at 50% compared with 100% TBF [−2.8 (−7.6- −0.1) vs. −1.2 (−5.2–0) %, p &lt; 0.001]. Similarly, left ventricular ejection fraction increased [24.4 (15.8–35.5) vs. 16.7 (10.0–28.5) %, p &lt; 0.001] and left ventricular outflow tract velocity time integral increased [7.7 (3.8–11.4) vs. 4.8 (2.5–8.5) cm, p &lt; 0.001]. Adding echocardiographic parameters of left ventricular systolic function to the Survival After Veno-arterial ECMO (SAVE) score had better discriminatory value in predicting eventual hospital mortality (AUROC 0.69, 95% CI 0.55–0.84, p = 0.008) and successful weaning from V-A ECMO (AUROC 0.68, 95% CI 0.53–0.83, p = 0.017).ConclusionIn the initial period of V-A ECMO support, measures of left ventricular function including left ventricular ejection fraction and global longitudinal strain were inversely related to ECMO blood flow rate. Understanding the heart-ECMO interaction is vital to interpretation of echocardiographic measures of the left ventricle while on ECMO

Molecular landscape of IDH-mutant primary astrocytoma Grade IV/glioblastomas

WHO 2016 classified glioblastomas into IDH-mutant and IDH-wildtype with the former having a better prognosis but there was no study on IDH-mutant primary glioblastomas only, as previous series included secondary glioblastomas. We recruited a series of 67 IDH-mutant primary glioblastomas/astrocytoma IV without a prior low-grade astrocytoma and examined them using DNA-methylation profiling, targeted sequencing, RNA sequencing and TERT promoter sequencing, and correlated the molecular findings with clinical parameters. The median OS of 39.4 months of 64 cases and PFS of 25.9 months of 57 cases were better than the survival data of IDH-wildtype glioblastomas and IDH-mutant secondary glioblastomas retrieved from datasets. The molecular features often seen in glioblastomas, such as EGFR amplification, combined +7/-10, and TERT promoter mutations were only observed in 6/53 (11.3%), 4/53 (7.5%), and 2/67 (3.0%) cases, respectively, and gene fusions were found only in two cases. The main mechanism for telomere maintenance appeared to be alternative lengthening of telomeres as ATRX mutation was found in 34/53 (64.2%) cases. In t-SNE analyses of DNA-methylation profiles, with an exceptional of one case, a majority of our cases clustered to IDH-mutant high-grade astrocytoma subclass (40/53; 75.5%) and the rest to IDH-mutant astrocytoma subclass (12/53; 22.6%). The latter was also enriched with G-CIMP high cases (12/12; 100%). G-CIMP-high status and MGMT promoter methylation were independent good prognosticators for OS (p = 0.022 and p = 0.002, respectively) and TP53 mutation was an independent poor prognosticator (p = 0.013) when correlated with other clinical parameters. Homozygous deletion of CDKN2A/B was not correlated with OS (p = 0.197) and PFS (p = 0.278). PDGFRA amplification or mutation was found in 16/59 (27.1%) of cases and was correlated with G-CIMP-low status (p = 0.010). Aside from the three well-known pathways of pathogenesis in glioblastomas, chromatin modifying and mismatch repair pathways were common aberrations (88.7% and 20.8%, respectively), the former due to high frequency of ATRX involvement. We conclude that IDH-mutant primary glioblastomas have better prognosis than secondary glioblastomas and have major molecular differences from other commoner glioblastomas. G-CIMP subgroups, MGMT promoter methylation, and TP53 mutation are useful prognostic adjuncts

Measurement of the cross-section and charge asymmetry of WW bosons produced in proton-proton collisions at s=8\sqrt{s}=8 TeV with the ATLAS detector

This paper presents measurements of the $W^+ \rightarrow \mu^+\nu$ and $W^- \rightarrow \mu^-\nu$ cross-sections and the associated charge asymmetry as a function of the absolute pseudorapidity of the decay muon. The data were collected in proton--proton collisions at a centre-of-mass energy of 8 TeV with the ATLAS experiment at the LHC and correspond to a total integrated luminosity of 20.2~\mbox{fb^{-1}}. The precision of the cross-section measurements varies between 0.8% to 1.5% as a function of the pseudorapidity, excluding the 1.9% uncertainty on the integrated luminosity. The charge asymmetry is measured with an uncertainty between 0.002 and 0.003. The results are compared with predictions based on next-to-next-to-leading-order calculations with various parton distribution functions and have the sensitivity to discriminate between them.Comment: 38 pages in total, author list starting page 22, 5 figures, 4 tables, submitted to EPJC. All figures including auxiliary figures are available at https://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/STDM-2017-13