Lung cancer is the leading cause of cancer deaths, and effective treatments are urgently needed. Loss-of-function mutations in the DNA damage response kinase ATM are common in lung adenocarcinoma but ...directly targeting these with drugs remains challenging. Here we report that ATM loss-of-function is synthetic lethal with drugs inhibiting the central growth factor kinases MEK1/2, including the FDA-approved drug trametinib. Lung cancer cells resistant to MEK inhibition become highly sensitive upon loss of ATM both in vitro and in vivo. Mechanistically, ATM mediates crosstalk between the prosurvival MEK/ERK and AKT/mTOR pathways. ATM loss also enhances the sensitivity of KRAS- or BRAF-mutant lung cancer cells to MEK inhibition. Thus, ATM mutational status in lung cancer is a mechanistic biomarker for MEK inhibitor response, which may improve patient stratification and extend the applicability of these drugs beyond RAS and BRAF mutant tumours.
Hyoscyamus muticus
L. is a traditional medicine used as antispasmodic and sedative. Herein, we aimed to determine the phytochemical constituents and for the first time its anti-cancer activities. The ...phytochemical constituents of the different extracts were evaluated by calorimetric methods. The anti-cancer activities of the extracts were tested against leukemia, breast, renal, and prostate cancers cell lines. 4, 6-Diamidino-2-phenylindole (DAPI) staining, flow cytometric analysis, knockdown of ASK1, and reactive oxygen species (ROS) production were evaluated to clarify the mechanism of action. Phytochemical screening confirmed the presence of wide range of phytoconstituents.
Hyoscyamus muticus
methanolic extracts (HMME) showed the highest anti-cancer activities against leukemia, breast, renal, and prostate cancers as compared to ethanol and aqueous extracts. Specifically, HMME exerted cytotoxic effect against the MDA-MB-231 and MDA-MB-468 triple-negative breast cancer (TNBC) cell lines with IC
50
values of 8.75 and 7.25 μg/mL, respectively. Mechanistically, DAPI staining and flow cytometric analysis revealed that HMME induces apoptosis via the death receptor, FAS, but not the mitochondrial pathway. Moreover, ASK1 and p38 were rapidly activated in response to HMME, and knockdown of ASK1 by a small interference of RNA specific to Ask1 attenuated p38 and caspase-3 activation and suppressed apoptosis, implying that HMME-induced apoptosis relies on the ASK1-p38-caspase-3 pathway. Furthermore, we confirmed that cellular ROS generation was a critical mediator in HMME-induced apoptosis because the ROS-scavenger N-acetyl cysteine significantly decreased the phosphorylation of ASK1 and HMME-induced apoptosis. Our results confirmed HMME cytotoxic effects in TNBCs via ROS-dependent activation of the Fas/FasL-ASK1-p38 axis.
This work describes an approach for the development of two bacteria biosensors based on surface plasmon resonance (SPR) technique. The first biosensor was based on functionalized gold substrate and ...the second one on immobilized gold nanoparticles. For the first biosensor, the gold substrate was functionalized with acid–thiol using the self-assembled monolayer technique, while the second one was functionalized with gold nanoparticles immobilized on modified gold substrate. A polyclonal anti-
Escherichia coli antibody was immobilized for specific (
E. coli) and non-specific (
Lactobacillus) bacteria detection. Detection limit with a good reproducibility of 10
4 and 10
3
cfu
mL
−1 of
E. coli bacteria has been obtained for the first biosensor and for the second one respectively. A refractive index variation below 5
×
10
−3 due to bacteria adsorption is able to be detected. The refractive index of the multilayer structure and of the
E. coli bacteria layer was estimated with a modeling software.
Background and Aims: Currently, liver biopsy is the gold standard method for diagnosis of non-alcoholic fatty liver severity. It is critical to develop non-invasive diagnostic method to diagnose ...nonalcoholic fatty liver rather than invasive techniques. Our casecontrol study was to address the value of circulating miRNA-122 and serum pro-neurotensin as a potential non-invasive biomarker for the diagnosis of non-alcoholic fatty acid diseases. Methods: Clinical assessment, laboratory investigations, and anthropometric measurements were reported for 157 patients with proven NAFLD. Apparently, healthy participants (n=100) were enrolled as a control group. Serum samples were tested for micro-RNAs-122 and pro-neurotensin. Results: Compared with the control subjects, both mi-RNA-122 and serum proneurotensin levels were increased in NAFLD (p<0.001) and at a cut-off greater than or equal to6.83, mi-RNA-122 had 51.0% sensitivity, 70.0% specificity to differentiate NAFLD from healthy controls, while serum proneurotensin had 80.0% sensitivity and 80.0% specificity at a cutoff greater than or equal to108. Conclusion: The circulating pro-neurotensin might be used as a novel biomarker for diagnosis of patients with NAFLD, wherefore the integration of a circulating mi-RNA-122 and serum pro-neurotensin could be beneficial to diagnose NAFLD cases. Large-scale studies are needed to investigate the possible role of mi-RNA-122 and pro-neurotensin in the development, progression, and prognosis of NAFLD and NASH. Keywords: nonalcoholic fatty liver disease, NAFLD, metabolic associated fatty liver disease, MAFLD, biomarker, proneurotensin, micro-RNA-122, noninvasive, diagnosis, fatty liver
In the present work, we compare the use of antibodies (Ab) and phages as bioreceptors for bacteria biosensing by Electrochemical Impedance Spectroscopy (EIS). With this aim, both biocomponents have ...been immobilised in parallel onto interdigitated gold microelectrodes. The produced surfaces have been characterised by EIS and Fourier Transform Infra-Red (FTIR) Spectroscopy and have been applied to bacteria detection. Compared to immunocapture, detection using phages generates successive dual signals of opposite trend over time, which consist of an initial increase in impedance caused by bacteria capture followed by impedance decrease attributed to phage-induced lysis. Such dual signals can be easily distinguished from those caused by non-specific adsorption and/or crossbinding, which helps to circumvent one of the main drawbacks of reagentless biosensors based in a single target-binding event. The described strategy has generated specific detection of
Escherichia coli in the range of 10
4–10
7
CFU
mL
−1 and minimal interference by non-target
Lactobacillus. We propose that the utilisation of phages as capture biocomponent for bacteria capture and EIS detection allows in-chip signal confirmation.
After surgical resection of pancreatic ductal adenocarcinoma (PDAC), patients are predominantly treated with adjuvant chemotherapy, commonly consisting of gemcitabine (GEM)-based regimens or the ...modified FOLFIRINOX (mFFX) regimen. While mFFX regimen has been shown to be more effective than GEM-based regimens, it is also associated with higher toxicity. Current treatment decisions are based on patient performance status rather than on the molecular characteristics of the tumor. To address this gap, the goal of this study was to develop drug-specific transcriptomic signatures for personalized chemotherapy treatment.
We used PDAC datasets from preclinical models, encompassing chemotherapy response profiles for the mFFX regimen components. From them we identified specific gene transcripts associated with chemotherapy response. Three transcriptomic artificial intelligence signatures were obtained by combining independent component analysis and the least absolute shrinkage and selection operator-random forest approach. We integrated a previously developed GEM signature with three newly developed ones. The machine learning strategy employed to enhance these signatures incorporates transcriptomic features from the tumor microenvironment, leading to the development of the ‘Pancreas-View’ tool ultimately clinically validated in a cohort of 343 patients from the PRODIGE-24/CCTG PA6 trial.
Patients who were predicted to be sensitive to the administered drugs (n = 164; 47.8%) had longer disease-free survival (DFS) than the other patients. The median DFS in the mFFX-sensitive group treated with mFFX was 50.0 months stratified hazard ratio (HR) 0.31, 95% confidence interval (CI) 0.21-0.44, P < 0.001 and 33.7 months (stratified HR 0.40, 95% CI 0.17-0.59, P < 0.001) in the GEM-sensitive group when treated with GEM. Comparatively patients with signature predictions unmatched with the treatments (n = 86; 25.1%) or those resistant to all drugs (n = 93; 27.1%) had shorter DFS (10.6 and 10.8 months, respectively).
This study presents a transcriptome-based tool that was developed using preclinical models and machine learning to accurately predict sensitivity to mFFX and GEM.
•Transcriptomic signatures were developed for key pancreatic cancer drugs to enable personalized treatment.•The Pancreas-View tool integrates four drug signatures to assist informed therapeutic decisions.•Signatures accurately identify high responder patients, indicative of improved DFS and cancer-specific survival.•Clinical validation involving a cohort of 343 patients confirms the efficacy of this signature approach.•Transcriptomic signatures that integrate predictors from preclinical models and machine learning offer a rationalized treatment strategy.
Abstract
Introduction
Post-ST elevation myocardial infarction (STEMI) course can be complicated with mitral regurgitation (MR) which has significant impact on in-patient outcomes and post-discharge ...course. MR in the setting of STEMI can be due to left ventricular dilatation, papillary muscle rupture or chordal rupture.
Purpose
In this retrospective study, we aimed to evaluate the impact of MR on readmission within one year after percutaneous coronary intervention (PCI) in STEMI patients.
Methods
We conducted a single-center retrospective observation cohort study. We included all patients admitted to the hospital with diagnosis of STEMI, underwent PCI during the same admission (index admission) and discharged alive in the period between Jan 1st, 2016 and Sep 30th, 2018. Factors associated with readmission due to heart failure within 1 year of discharge were evaluated using multivariate logistic regression and results were reported as odds ratio (OR) with p-value <0.05 indicating statistical significance.
Results
A total of 1257 patients were included in our retrospective analysis. The mean age of the study population was 51±10 years. Around 16% (n=206) of the study population had mitral regurgitation (MR) during their admission for STEMI. Among them, 195 patients had newly discovered MR. MR severity was mild in 196 (95%) patients with MR. Unplanned readmission due to cardiac reasons within 1 year of discharge occurred in 103 (8.2%) patients. Among them, 37 (3%) were readmitted due to heart failure. MR was found to increase the likelihood of readmission due to heart failure within one year after PCI among patients with STEMI by three times (aOR=3.13, 95% CI 1.39–7.03; p-value 0.006). As demonstrated in table 1, other positive predictors for readmission due to heart failure were female gender (aOR=3.80, 95% CI 1.22–11.86; p-value 0.021), chronic kidney disease (aOR=4.56, 95% CI 1.22–17.03; p-value 0.024), and clinical heart failure during the index admission (aOR=4.82, 95% CI 1.53–15.15; p-value 0.007). Interestingly, reduced left ventricular ejection fraction was not a significant predictor of heart failure readmission.
Conclusion
Mitral regurgitation is relatively common in STEMI and most frequently presents with mild severity. In our study, MR was found to be a strong predictor for readmission due to heart failure within one year after PCI among patients with STEMI, which may warrant frequent follow-up for these patients and proper initiation of and titration of guideline-directed medical therapy (GDMT).
Funding Acknowledgement
Type of funding sources: None.
Abstract
Introduction and aim
Unplanned readmission after percutaneous coronary intervention (PCI) in patients with ST-elevation myocardial infarction (STEMI) has a significant impact on the ...healthcare system. Nevertheless, most of the previous literature evaluated readmission within one month only post PCI without assessing the long-term readmission rates and predictors post-PCI. Therefore, we conducted a retrospective observational study to determine the rates, causes, and predictors of readmission post PCI among patients with STEMI over 1-year follow-up.
Methods
We conducted a single-center retrospective observation cohort study. Study population included all patients who were admitted to the hospital with diagnosis of STEMI and underwent PCI during the same admission (index admission) and discharged alive in the period between Jan 1st, 2016 and Sep 30th, 2018. Patients were divided into two groups: those who had one or more unplanned readmission within one year after PCI and those who were not readmitted. Rates and causes of readmission within one year following PCI were reported. Predictors of readmission post-PCI were assessed using multivariate logistic regression and reported as odds ratio (OR) with p<0.05 indicating statistical significance.
Results
A total of 1257 patients were included in our retrospective analysis. Most of the patients were male (95.9%). The mean age of the study population was 51±10. The most frequent culprit vessel was left anterior descending artery (LAD) in 56.3%. The median troponin T upon presentation was 47 ng/L interquartile range: 171, with 25th percentile of 17 ng/L and 75th percentile of 2197 ng/L. Although around 70% of patients had reduced ejection fraction during the index admission, only 13.4% of the study population had clinical heart failure (HF). The unplanned readmission rate within one year post PCI was 11.5%, with 8.2% due to cardiac readmission while the remaining 3.3% due to non-cardiac causes. The most common cardiac causes for readmission were acute coronary syndrome and HF as shown in Table 1. As demonstrated in Table 2, positive predictors for all-cause readmission within one year after PCI among patients with STEMI were female gender (aOR= 4.14, 95% CI 2.10–8.18; p-value<0.001), chronic kidney disease (aOR= 2.76, 95% CI 1.07–7.08; p-value= 0.035), PCI using more than one stent (aOR= 1.66, 95% CI 1.09–2.55; p-value= 0.019) and clinical HF during index admission (aOR= 2.36, 95% CI 1.49–3.74; p-value<0.001).
Conclusion
The rate of one-year unplanned readmissions after PCI among patients with STEMI was 11.5%, with acute coronary syndrome and HF as most common causes of cardiac readmission. We found that female gender, chronic kidney disease, PCI with more than one stent and clinical HF were associated with a significantly increased likelihood of readmission after PCI among patients with STEMI which may warrant close and frequent follow-up for these populations.
Funding Acknowledgement
Type of funding sources: None.
Summary
Background
Accepted ‘standard practice’ for the diagnosis of immunobullous disease is a perilesional sample for direct immunofluorescence (DIF).
Objectives
To compare diagnostic outcomes of a ...normal buccal punch biopsy (NBPB) with a perilesional biopsy (PLB) for mucous membrane pemphigoid (MMP) and pemphigus vulgaris (PV).
Methods
A retrospective analysis of 251 DIF‐positive patients with MMP and 77 DIF‐positive patients with PV was undertaken. Parameters analysed included the intraoral sites of involvement and histopathological, DIF and indirect immunofluorescence (IIF) findings.
Results
For MMP, PLB was positive in 134 of 143 (93·7%) samples, compared with 129 of 144 (89·6%) by NBPB. The diagnostic sensitivities for PLB (81%, 39 of 48) and NBPB (77%, 37 of 48) among 48 patients who underwent both techniques were not significantly different (P = 0·62). In gingival‐only MMP, PLB was positive in 63 of 69 (91%) and NBPB was positive in 63 of 75 (84%). For multisite MMP, PLB was positive in 71 of 74 (96%) and NBPB was positive in 66 of 69 (96%). In gingival‐only MMP, biopsies from reflected alveolar mucosa in 17 consecutive patients were positive in 17 of 17 cases (100%). For PV, PLB was positive in 42 of 43 (98%), compared with 42 of 42 (100%) by NBPB. Histopathology was diagnostic in 93 of 134 (69·4%) cases of MMP and 38 of 41 (93%) cases of PV. IIF was positive in 126 of 197 (64·0%) MMP and 68 of 74 (92%) PV patient sera.
Conclusions
In the largest series of combined oral DIF results in patients with MMP and PV, we have shown that NBPB is equivalent to PLB for the diagnosis of PV and multisite MMP, and is more sensitive than both histology and IIF.
What's already known about this topic?
The variation in sensitivity of oral biopsy sites for direct immunofluorescence (DIF) in the diagnosis of oral MMP and PV has not been studied in detail in large series of patients.
Biopsy can be challenging due to difficult access and fragility of the oral mucosa. The diagnostic biopsy technique is therefore critical.
What does this study add?
We have shown that a normal buccal punch biopsy (NBPB) from uninvolved oral mucosa is as sensitive as a perilesional biopsy (PLB) for diagnosis of oral PV, and superior to serology and histology.
For multisite MMP, NBPB is equivalent to PLB and is more sensitive than serology and histology.
The oral punch biopsy technique on uninvolved buccal mucosa tissue is a simple and safe practical method for diagnosing oral PV and MMP.
Linked Comment: Maglie and Hertl. Br J Dermatol 2020; 182:539–540.
Plain language summary available online
PDF
