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The diagnostic role of Isocitrate Dehydrogenase (IDH) mutation status in adult lower grade astrocytomas was first formally presented within the WHO Classification of Tumours of the Central Nervous System (2016). IDH-mutant astrocytomas are not as common as IDH-wildtype astrocytomas but are of better prognosis. Our previous study provided an evident that IDH-mutant lower grade astrocytomas is not a homogeneous group and could be further stratified by PDGFRA amplification, CDK4 amplification and CDKN2A deletion. In this study, we detected the expressions of DNA mismatch repair (MMR) proteins (PMS2, MLH1, MSH2, MSH6) and PD-L1 by immunohistochemistry in 147 IDH-mutant lower grade astrocytomas and explored their clinical relevance. The loss of was identified in 28.6%, 1.4%, 8.8% and 13.6%, respectively. PD-L1 expression was detected in 1.4% of this cohort. Survival analysis revealed that loss of PMS2 was correlated with shorter OS (p < 0.001) and PFS (p = 0.005). Loss of PMS2 or MLH1 was associated with shorter OS (p < 0.001) and PFS (p = 0.008). In IDH-mutant lower grade astrocytomas without CDKN2A deletion, loss of PMS2 was associated with poorer OS (p < 0.001) and PFS (p = 0.001). Furthermore, among IDH-mutant lower grade astrocytomas lacking the three biomarkers (PDGFRA, CDK4 and CDKN2A), loss of PMS2 was also associated with a poorer OS (p < 0.001) and PFS (p = 0.003). Our data illustrated the potential application of MMR genes in stratification of IDH-mutant lower grade astrocytomas without PDGFRA, CDK4 and CDKN2A copy number alterations., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Protein-protein interactions (PPIs) are increasingly important targets for drug discovery. Efficient fragment-based drug discovery approaches to tackle PPIs are often stymied by difficulties in the production of stable, unliganded target proteins. Here, we report an approach that exploits protein engineering to "humanise" thermophilic archeal surrogate proteins as targets for small-molecule inhibitor discovery and to exemplify this approach in the development of inhibitors against the PPI between the recombinase RAD51 and tumour suppressor BRCA2. As human RAD51 has proved impossible to produce in a form that is compatible with the requirements of fragment-based drug discovery, we have developed a surrogate protein system using RadA from Pyrococcus furiosus. Using a monomerised RadA as our starting point, we have adopted two parallel and mutually instructive approaches to mimic the human enzyme: firstly by mutating RadA to increase sequence identity with RAD51 in the BRC repeat binding sites, and secondly by generating a chimeric archaeal human protein. Both approaches generate proteins that interact with a fourth BRC repeat with affinity and stoichiometry comparable to human RAD51. Stepwise humanisation has also allowed us to elucidate the determinants of RAD51 binding to BRC repeats and the contributions of key interacting residues to this interaction. These surrogate proteins have enabled the development of biochemical and biophysical assays in our ongoing fragment-based small-molecule inhibitor programme and they have allowed us to determine hundreds of liganded structures in support of our structure-guided design process, demonstrating the feasibility and advantages of using archeal surrogates to overcome difficulties in handling human proteins., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This study aims to investigate the impacts of ethyl lactate (EL) based Fenton treatment on soil quality for polycyclic aromatic hydrocarbons (PAHs)-contaminated soils. Accumulation of oxygenated-polycyclic aromatic hydrocarbons (oxy-PAHs) was observed, but quantitative measurement on the most abundant compound 9,10-anthraquinone (ATQ) showed lower accumulation of the compound than that reported for ethanol (ET) based Fenton treatment. In general, as compared to conventional water (CW) based Fenton treatment, the EL based Fenton treatment exerted either a lower or higher negative impact on soil physicochemical properties depending on the property type and shared the main disadvantage of reduced soil pH. For revegetation, EL based Fenton treatment was most appropriately adopted for soil with native pH >/~ 6.2 in order to obtain a final soil pH >/~ 4.9 subject to the soil buffering capacity., (Copyright © 2013 Elsevier B.V. All rights reserved.)

This work focuses on the remediation of polycyclic aromatic hydrocarbon (PAH)-contaminated soil using modified Fenton (MF) treatment coupled with a novel chelating agent (CA), a more effective technique among currently available technologies. The performance of MF treatment to promote PAH oxidation in artificially contaminated soil was investigated in a packed column with a hydrogen peroxide (H(2)O(2)) delivery system simulating in-situ soil flushing which is more representative of field conditions. The effectiveness of process parameters H(2)O(2)/soil, Fe(3+)/soil, CA/soil weight ratios and reaction time were studied using a 2(4) three level factorial design experiments. An optimised operating condition of the MF treatment was observed at H(2)O(2)/soil 0.05, Fe(3+)/soil 0.025, CA/soil 0.04 and 3h reaction time with 79.42% and 68.08% PAH removals attainable for the upper and lower parts of the soil column respectively. The effects of natural attenuation and biostimulation process as post-treatment in the remediation of the PAH-contaminated soil were also studied. In all cases, 3-aromatic ring PAH (phenanthrene) was more readily degraded than 4-aromatic ring PAH (fluoranthene) regardless of the bioremediation approach. The results revealed that both natural attenuation and biostimulation could offer remarkable enhancement of up to 6.34% and 9.38% in PAH removals respectively after 8 weeks of incubation period. Overall, the results demonstrated that combined inorganic CA-enhanced MF treatment and bioremediation serves as a suitable strategy to enhance soil quality particularly to remediate soils heavily contaminated with mixtures of PAHs., (Copyright © 2012 Elsevier B.V. All rights reserved.)

A brief review is conducted on the application of vegetable oils in the treatment of PAH-contaminated soils. Three main scopes of treatment strategies are discussed in this work including soil washing by oil, integrated oil-biological treatment and integrated oil-non-biological treatment. For each of these, the arguments supporting vegetable oil application, the applied treatment techniques and their efficiencies, associated factors, as well as the feasibility of the techniques are detailed. Additionally, oil regeneration, the environmental impacts of oil residues in soil and comparison with other commonly employed techniques are also discussed., (Copyright (c) 2009 Elsevier B.V. All rights reserved.)

The placenta has arisen relatively recently and is among the most rapidly evolving tissues in mammals. Several different placental barrier and structure types appear to have independently evolved common functional features. Specific patterns of gene expression that determine placental development in humans are predicted to be accompanied by specific profiles of epigenetic modification. However, the stratification of epigenetic modifications into those involved in conserved aspects of placental function, versus those involved in divergent placental features, has yet to begin. As a first step towards this goal, we have investigated the methylation status of a small number of gene-specific methylation events recently identified in human placenta, in a panel of placental tissue from baboon, marmoset, cow, cat, guinea pig and mouse. These represent disparate placental barrier types and structures. In this study we hypothesized that specific epigenetic markings may be associated with placental barrier type or function, independent of phylogeny. However, in contrast to our predictions, the majority of gene-specific methylation appears to track with phylogeny, independent of placental barrier type or other structural features. This suggests that despite the likelihood of epigenetic modification playing a role in the functioning and evolution of different placental subtypes, there is no evidence for an involvement of the gene-specific methylation profiles we have identified, in specifying these differences. Further studies, examining larger numbers of epigenetic modifications across phylogeny, are required to define the role of specific epigenetic modifications in the evolution of distinct placental structures., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Polycyclic aromatic hydrocarbons (PAHs) are carcinogenic micropollutants which are resistant to environmental degradation due to their highly hydrophobic nature. Concerns over their adverse health effects have resulted in extensive studies on the remediation of soils contaminated with PAHs. This paper aims to provide a review of the remediation technologies specifically for PAH-contaminated soils. The technologies discussed here include solvent extraction, bioremediation, phytoremediation, chemical oxidation, photocatalytic degradation, electrokinetic remediation, thermal treatment and integrated remediation technologies. For each of these, the theories are discussed in conjunction with comparative evaluation of studies reported in the specialised literature.

Array comparative genomic hybridization (CGH) is useful to assess genome-wide chromosomal imbalance, but the requirement for relatively large amounts of DNA can be a limitation, in particular for samples extracted from small tumor areas on paraffin sections. Whole genome amplification (WGA) can be performed before array CGH to obtain sufficient DNA, but the possibility of artifacts attributable to biased amplification cannot be excluded. We optimized the WGA protocol to generate sufficient DNA with minimum amplification bias. Using formalin-fixed, paraffin-embedded histological sections of tumors carrying known TP53 mutations, LOH 1p, LOH 10q, LOH 19q, and EGFR amplification, we first optimized the protocol so that these genetic alterations were detected after WGA. We found that a ligation step before WGA is important because it allows a short reaction time with Phi29 to generate WGA-DNA with greatly decreased amplification bias. Using template >150 ng of DNA, a ligation step before WGA, and a short reaction time with Phi29 DNA polymerase (<1.5 hours), we obtained WGA-DNA (>4 mug) with minimum amplification bias (less than threefold). Using this protocol, we performed array CGH (Agilent 105K) before and after WGA. Pearson correlation analysis indicated a significant positive correlation in array CGH results between DNA before and after WGA (P < 0.0001). These results suggest that genetic analyses are possible using WGA-DNA extracted from paraffin sections, but that they should be performed with a carefully optimized and controlled protocol.

Objective: (1) To determine and compare the rates of cognitive change using global and executive psychometric measures between lacunar stroke patients and matched controls and; (2) to identify features associated with cognitive changes in patients., Methods: Sixty-one lacunar stroke patients and 35 demographically-matched controls were followed-up for 28.6 months (range 19.4-45.9 months) with psychometric assessments performed at baseline and follow-up., Results: Lacunar stroke patients were more impaired than controls in general and executive functions at both time points. Both groups had similar stability in all psychometric tests. Patients, but not controls, exhibited a trend for improvement in general cognitive functions overtime (interaction term, p=0.084). No patient who was non-demented at baseline became demented during the study period. Two (5.7%) and five (8.2%) incident cerebrovascular events occurred among the controls and patients, respectively. Linear regression analyses performed upon patients failed to identify any predictor for the cognitive change., Conclusion: Similar to controls, cognition in lacunar stroke patients is stable during the first 2-3 years after the stroke. There maybe a spontaneous improvement in general cognition overtime, but this awaits confirmation by future studies.

Objective: To investigate how categorizing body mass index (BMI) into weight classes can impact the assessment of the relationship between BMI and in-hospital mortality after coronary artery bypass graft (CABG) surgery., Study Design and Setting: BMI-mortality (in-hospital) relationship was assessed in 5,762 patients who underwent isolated CABG at Baylor University Medical Center (Dallas, TX) from January 1, 1997 to November 30, 2003. Different ways of modeling BMI were used to investigate this association in a propensity-adjusted model, controlling for risk factors identified by the Society of Thoracic Surgeons (STS) and other clinical/nonclinical details., Results: A highly significant (P=0.003) association between BMI (modeled with a restricted cubic spline) and mortality was found. Reduced risk of in-hospital mortality was observed for subjects with BMI in the low-30s as compared with patients with BMI in the mid-20s or over 40 kg/m(2). Results were strongly affected by the way BMI was specified in the multivariable model. Only five of the 10 BMI categorizations considered produced significant results, and these results did not fully determine the effect of BMI on mortality., Conclusions: BMI categorization critically impacts study results. Conceivably, findings of other studies investigating BMI and adverse outcomes after CABG may be similarly affected. Investigators should consider smoothing techniques to avoid categorization.

In this study, we have elucidated the chromosomal imbalances in the multistep pathogenesis and delineated several critical tumor suppressor gene (TSG) loci in multiple myeloma (MM). By using comparative genomic hybridization, allelotyping, and multicolor interphase fluorescence in situ hybridization, 5 MM cell lines and bone marrow CD138+ plasma cells from 88 Chinese patients with monoclonal gammopathy of undetermined significance (MGUS) and early and advanced stages of MM were investigated. In all MGUS and MM samples, chromosome copy number abnormalities were detected. A higher number of chromosomal imbalances and specific genetic alterations are involved in MGUS to MM transition (-6q, +3p, and +1p) and MM progression (+2p and +9q). In addition to -13q, we first found high frequencies (42% to 46%) of -4q involving high percentages (70% to 74%) of clonal plasma cells in both MGUS and MM, suggesting that inactivation of TSG in this region is also a potentially critical genetic event in MM tumorigenesis. By high-resolution allelotyping, we defined a common deletion region on 4q13.3 and found that a candidate TSG, platelet factor 4, was frequently silenced by promoter hypermethylation in MM (15 of 28) and MM cell lines (5 of 5). These data have opened up a new approach in the molecular targeting therapy and provide novel insights into MM tumorigenesis.

Apoptosis of glioma may represent a promising intervention for tumor treatment. Macrophages are able to induce apoptosis in a number of tumor cells, including glioma. It is known that apoptosis of cells is executed on either a death receptor-dependent or independent pathway. Whether and how apoptosis of glioma cells induced by activated macrophages is involved in these two pathways simultaneously are not known. Using in vitro and in vivo experimental models, we investigated Bcl-2 system and Fas/FasL channel, representing the death receptor-dependent and independent pathways, respectively, in glioma cells treated with the supernatant from the activated macrophages, which was rich in tumor necrosis factor-alpha and interferon-gamma. We found that levels of Fas and FasL were up-regulated both in vitro and in vivo, accompanying an increase in the expression of caspase-8. The number of apoptotic cells was also increased significantly, although the percentage of death cells exceeded the number of tumor cells positive for Fas or FasL. It was also evident that the expression of Bax was increased, whereas the level of Bcl-2 was decreased, in glioma cells treated with the supernatant from the activated macrophages. The alteration of molecules related to both death pathways led to apoptosis of glioma and the inhibition of xenograft glioma growth in mice. Apoptosis of glioma induced by the activated macrophage is executed by way of both death receptor-dependent and independent pathways, and such an apoptosis-induced approach can effectively inhibit the growth of glioma in vivo.

Although cerebrospinal fluid spread by malignant brain tumors is well recognised, cases of drop metastasis to spinal cord by intracranial oligodendroglial tumors have only been rarely described. We described a 61-year-old man who developed diffuse spinal metastases and cord compression 20 months after resection of a frontal lobe anaplastic oligodendrogliomas. To our knowledge, this represents the eighth recorded case in the literature.

Although diffuse axonal injury (DAI) has been described as a major form of primary damage to the brain in blunt head injury, there has been no systematic study of the pathological changes in different regions of the brain. In this study, 22 cases of DAI were comprehensively examined histologically in the following areas: corpus callosum, internal capsule, superior cerebellar peduncles, cerebral white matter, fornix, rostral brain stem and globus pallidus, with a total of 17 standard blocks in each case. Sections were stained for axons with Glees and Marsland and neurofilament immunostaining and myelin with luxol fast blue and myelin basic protein immunostaining, and axonal retraction balls and myelin globoids were counted. Neurofilament immunostaining was superior to Glees and Marsland in both the positivity rates and the actual scores. Small myelin globoids were identified by the myelin stains, probably as a form of myelin damage secondary to axonal disruption. Such acute myelin damage was previously undescribed. There was no significant difference in both positivity rates and the scores obtained for luxol fast blue and myelin basic protein. Of all the regions of the brain examined, the internal capsule, corpus callosum and superior cerebellar peduncles yielded the highest counts of axonal balls as well as the highest incidences. It is recommended that in cases of DAI, these three regions of the brain should be examined most profitably with neurofilament immunostaining supplemented with a myelin stain.

Primary amoebic meningoencephalitis due to Naegleria fowleri was found in a 38-year-old Chinese man living in Hong Kong who presumably acquired the infection from swimming in a hot spring in neighbouring China. Amoebic cysts were identified in tissue taken from a brain abscess. The patient responded to surgical drainage and a 6-week course of amphotericin B, rifampicin and chloramphenicol. This is one of 6 cases of successful treatment of primary amoebic meningoencephalitis documented in the medical literature.

We studied, with echocardiography as the main tool, the incidence of congenital heart disease in newborn babies in Hong Kong. The population examined was the 20,928 babies who were born alive in the Prince of Wales Hospital from January 1987 to December 1989. All had a thorough physical examination by a paediatrician after birth, and an estimated 95% of the babies who were discharged from hospital received another routine physical examination at one of the five local Maternal and Child Health Centres within two months of birth. All babies with either suspected congenital heart disease or multiple congenital abnormalities were referred to the paediatric cardiologists in the Prince of Wales Hospital for further cardiovascular assessment that included echocardiographic examination. In all, 492 babies had Doppler and cross-sectional echocardiographic studies. Various abnormalities of the cardiovascular system were diagnosed in 216 babies. Almost all the babies who died within two months of life underwent autopsy. This proved the presence of congenital cardiac malformations in 15 babies, of whom 10 had correct echocardiographic diagnoses during life. One had a patent arterial duct which was missed by the echocardiography. The other four babies did not have echocardiographic examination while alive, either because of early death or absence of clinical suspicion. In total, congenital cardiac malformations were confirmed in 221 babies by echocardiographic examination and autopsy. Excluding 82 premature babies with patency of the arterial duct, and 6 babies with transient tricuspid regurgitation, there were 133 cases of structural cardiac malformation in the studied population, giving an incidence of 6.35 per thousand live births.(ABSTRACT TRUNCATED AT 250 WORDS)

A 38-year-old man experienced severe neck pain while playing badminton. This was followed by symptoms of vertebrobasilar ischaemia, seizure and coma. Autopsy showed bilateral vertebral artery dissection and cystic medial necrosis.