Graphite oxide (GO) samples were prepared by a simplified Brodie method. Hydroxyl, epoxide, carboxyl, and some alkyl functional groups are present in the GO, as identified by solid-state 13C NMR, ...Fourier-transform infrared spectroscopy, and X-ray photoemission spectroscopy. Starting with pyrolytic graphite (interlayer separation 3.36 Å), the average interlayer distance after 1 h of reaction, as determined by X-ray diffraction, increased to 5.62 Å and then increased with further oxidation to 7.37 Å after 24 h. A smaller signal in 13C CPMAS NMR compared to that in 13C NMR suggests that carboxyl and alkyl groups are at the edges of the flakes of graphite oxide. Other aspects of the chemical bonding were assessed from the NMR and XPS data and are discussed. AB stacking of the layers in the GO was inferred from an electron diffraction study. The elemental composition of GO prepared using this simplified Brodie method is further discussed.
The phosphoinositol-3 kinase (PI3K) pathway is highly dysregulated in squamous cell carcinoma of the head and neck (SCCHN). While inhibitors of the PI3K/AKT pathway are being developed in cancer, ...their efficacy does not appear to be related to the presence of mutations or amplification in pathway genes. The PI3K pathway is a major regulator of macro-autophagy, an evolutionarily conserved catabolic process that degrades cellular materials to promote cellular homeostasis and survival under stress. Employing a panel of SCCHN cell lines, we observed a significant correlation between the activity of PI3K/AKT inhibitors and their ability to induce autophagy. More specifically, resistance to these inhibitors was associated with accumulation of p62/SQSTM1, a pleotropic protein that is consumed during autophagy, while loss of autophagy was, for the first time, found to be due to silencing of an essential autophagy gene, ATG7. Moreover, modulating ATG7 and p62/SQSTM1 could regulate sensitivity to PI3K/AKT inhibitors, underscoring a mechanistic link between autophagy and drug sensitivity. Analysis of human tissues revealed progressive accumulation of p62/SQSTM1 in a significant proportion of cancer samples compared to normal tissue, suggesting that defective autophagy has relevance to SCCHN. These findings are further validated by analysis of TCGA data confirming homozygous deletion and mRNA down-regulation of ATG7 in 10.0% of SCCHN samples. Taken together, these data indicate that p62/SQSTM1 levels modulate sensitivity to PI3K/AKT inhibitors; cancers vary in their capacity to undergo autophagy through epigenetic modification and, when deficient, accumulate p62/SQSTM1; and expression of autophagy-related proteins may serve as markers for resistance to PI3K/AKT inhibitors in SCCHN.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Management options are limited for patients with radioactive iodine refractory, locally advanced, or metastatic differentiated thyroid carcinoma. Prior to 2015, sorafenib, a multitargeted tyrosine ...kinase inhibitor, was the only approved treatment and was associated with a median progression-free survival (PFS) of 11 months and overall response rate (ORR) of 12% in a phase III trial. Lenvatinib, a multikinase inhibitor with high potency against VEGFR and FGFR demonstrated encouraging results in phase II trials. Recently, the pivotal SELECT trial provided the basis for the FDA approval of lenvatinib as a second targeted therapy for these patients. Median PFS of 18.3 months in the lenvatinib group was significantly improved from 3.6 months in the placebo group, with an HR of 0.21 (95% confidence interval, 0.4-0.31; P < 0.0001). ORR was also significantly increased in the lenvatinib arm (64.7%) compared with placebo (1.5%). In this article, we will review the molecular mechanisms of lenvatinib, the data from preclinical studies to the recent phase III clinical trial, and the biomarkers being studied to further guide patient selection and predict treatment response.
Using the Pseudomonas aeruginosa Genome Project as a test case, we have developed a database and submission system to facilitate a community-based approach to continually updated genome annotation ...(http://www.pseudomonas.com). Researchers submit proposed annotation updates through one of three web-based form options which are then subjected to review, and if accepted, entered into both the database and log file of updates with author acknowledgement. In addition, a coordinator continually reviews literature for suitable updates, as we have found such reviews to be the most efficient. Both the annotations database and updates-log database have Boolean search capability with the ability to sort results and download all data or search results as tab-delimited files. To complement this peer-reviewed genome annotation, we also provide a linked GBrowse view which displays alternate annotations. Additional tools and analyses are also integrated, including PseudoCyc, and knockout mutant information. We propose that this database system, with its focus on facilitating flexible queries of the data and providing access to both peer-reviewed annotations as well as alternate annotation information, may be a suitable model for other genome projects wishing to use a continually updated, community-based annotation approach. The source code is freely available under GNU General Public Licence.
Background
Pre-treatment tumour-associated lymphocytes (TILs) and stromal lymphocytes (SLs) are independent predictive markers of future pathological complete response (pCR) in HER2-positive breast ...cancer. Whilst studies have correlated baseline lymphocyte levels with subsequent pCR, few have studied the impact of neoadjuvant therapy on the immune environment.
Methods
We performed TIL analysis and T-cell analysis by IHC on the pretreatment and ‘On-treatment’ samples from patients recruited on the Phase-II TCHL (NCT01485926) clinical trial. Data were analysed using the Wilcoxon signed-rank test and the Spearman rank correlation.
Results
In our sample cohort (
n
= 66), patients who achieved a pCR at surgery, post-chemotherapy, had significantly higher counts of TILs (
p
= 0.05) but not SLs (
p
= 0.08) in their pre-treatment tumour samples. Patients who achieved a subsequent pCR after completing neo-adjuvant chemotherapy had significantly higher SLs (
p
= 9.09 × 10
–3
) but not TILs (
p
= 0.1) in their ‘On-treatment’ tumour biopsies. In a small cohort of samples (
n
= 16), infiltrating lymphocyte counts increased after 1 cycle of neo-adjuvant chemotherapy only in those tumours of patients who did not achieve a subsequent pCR. Finally, reduced CD3 + (
p
= 0.04, rho = 0.60) and CD4 + (
p
= 0.01, rho = 0.72) T-cell counts in 'On-treatment' biopsies were associated with decreased residual tumour content post-1 cycle of treatment; the latter being significantly associated with increased likelihood of subsequent pCR (
p
< 0.01).
Conclusions
The immune system may be ‘primed’ prior to neoadjuvant treatment in those patients who subsequently achieve a pCR. In those patients who achieve a pCR, their immune response may return to baseline after only 1 cycle of treatment. However, in those who did not achieve a pCR, neo-adjuvant treatment may stimulate lymphocyte influx into the tumour.
Background: Matrix metalloproteinase (MMP)1, interleukin(IL)6 and vitamin D receptor (VDR) have been implicated in the biological cascade of events initiated by particulate wear debris and bacterial ...infection, resulting in periprosthetic bone loss around loosened total hip replacements (THRs). The individual responses to such stimuli may be dictated by genetic variation. Objective: To study the effect of single-nucleotide polymorphisms (SNPs) within these candidate genes. Methods: A case–control study of the MMP1, IL6 and VDR genes was performed for possible association with deep sepsis or aseptic loosening. All cases included in the study were Caucasian patients with osteoarthritis who had received a cemented Charnley total hip arthroplasty (THA) and polyethylene acetabular cup. Cases consisted of 91 patients with early aseptic loosening and 71 patients with microbiological evidence of deep infection on surgery. Controls consisted of 150 patients with THAs that were clinically asymptomatic for over 10 years and showed no radiographic features of aseptic loosening. DNA samples from all individuals were genotyped using Taqman allelic discrimination. Results: The C allele (p = 0.001; OR = 3.27; 95% CI 2.21 to 4.83) and C/C genotype (p = 0.001) for the MMP1 SNP were highly associated with aseptic failure when compared with controls. No statistically significant relationships were found between aseptic loosening and the MMP2, MMP4, IL6 –174 or VDRL SNPs. The T allele (p = 0.007; OR = 1.76; 95% CI 1.16 to 2.66) and T/T genotype (p = 0.028) for VDR-T were statistically associated with osteolysis owing to deep infection as compared with controls. No statistically significant relationship was found between septic failure and any of the other SNPs examined in this study. Conclusions: Aseptic loosening and possibly deep infection of THR may be due to the genetic influence of candidate susceptibility genes. SNP markers may serve as predictors of implant survival and aid in pharmacogenomic prevention of THR failure.
Colorectal cancer (CRC) is one of the most common cancers in the Western world. 5-Fluorouracil (5FU)-based chemotherapy (CT) remains the mainstay treatment of CRC in the advanced setting, and ...activates executioner caspases in target cells. Executioner caspases are key proteins involved in cell disassembly during apoptosis. Activation of executioner caspases also has a role in tissue regeneration and repopulation by stimulating signal transduction and cell proliferation in neighbouring, non-apoptotic cells as reported recently. Tissue microarrays (TMAs) consisting of tumour tissue from 93 stage II and III colon cancer patients were analysed by immunohistochemistry. Surprisingly, patients with low levels of active Caspase-3 had an increased disease-free survival time. This was particularly pronounced in patients who received 5FU-based adjuvant CT. In line with this observation, lower serum levels of active Caspase-3 were found in patients with metastasised CRC who revealed stable disease or tumour regression compared with those with disease progression. The role of Caspase-3 in treatment responses was explored further in primary human tumour explant cultures from fresh patient tumour tissue. Exposure of explant cultures to 5FU-based CT increased the percentage of cells positive for active Caspase-3 and Terminal Deoxynucleotidyl Transferase dUTP Nick end Labelling (TUNEL), but also the expression of regeneration and proliferation markers β-Catenin and Ki-67, as well as cyclooxygenase-2 (COX-2). Of note, selective inhibition of Caspase-3 with Ac-DNLD-CHO, a selective, reversible inhibitor of Caspase-3, significantly reduced the expression of proliferation markers as well as COX-2. Inhibition of COX-2 with aspirin or celecoxib did not affect Caspase-3 levels but also reduced Ki-67 and β-Catenin levels, suggesting that Caspase-3 acted via COX-2 to stimulate cell proliferation and tissue regeneration. This indicates that low levels of active Caspase-3 may represent a new predictor of CT responsiveness, and inhibition of Caspase-3, or antagonising downstream effectors of Caspase-3 paracrine signalling, such as COX-2 may improve patient outcomes following CT in advanced CRC.
This report describes the complication of pulmonary vein stenosis with resultant severe pulmonary hypertension that developed in 2 patients after successful catheter ablation of chronic atrial ...fibrillation.
Three months after successful catheter ablation of atrial fibrillation, both patients developed progressive dyspnea and pulmonary hypertension. Both were found to have severe stenosis of all 4 pulmonary veins near the junction with the left atrium. Balloon dilation of the stenotic pulmonary veins was performed in these patients, with improvement in dyspnea and pulmonary hypertension.
The complication of pulmonary vein stenosis is potentially life-threatening, and the application of radiofrequency current within the pulmonary veins with standard catheter technology should be avoided. This complication can be treated with balloon dilation, although the long-term course is unknown.
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