Acquired BRAF/MAPK/extracellular signal‒regulated kinase inhibitor resistance in melanoma results in a new transcriptional state associated with an increased risk of metastasis. In this study, we ...identified noncanonical ephrin receptor (Eph) EphA2 signaling as a driver of the resistance-associated metastatic state. We used mass spectrometry‒based proteomic and phenotypic assays to demonstrate that the expression of active noncanonical EphA2-S897E in melanoma cells led to a mesenchymal-to-amoeboid transition driven by Cdc42 activation. The induction of mesenchymal-to-amoeboid transition promoted melanoma cell invasion, survival under shear stress, adhesion to endothelial cells under continuous-flow conditions, increased permeability of endothelial cell monolayers, and stimulated melanoma transendothelial cell migration. In vivo, melanoma cells expressing EphA2-S897E or active Cdc42 showed superior lung retention after tail-vain injection. Analysis of BRAF inhibitor‒sensitive and ‒resistant melanoma cells demonstrated resistance to be associated with a mesenchymal-to-amoeboid transition switch, upregulation of Cdc42 activity, increased invasion, and transendothelial migration. The drug-resistant metastatic state was dependent on histone deacetylase 8 activity. Silencing of histone deacetylase 8 led to the inhibition of EphA2 and protein kinase B phosphorylation, reduced invasion, and impaired melanoma cell-endothelial cell interactions. In summary, we have demonstrated that the metastatic state associated with acquired BRAF inhibitor resistance is dependent on noncanonical EphA2 signaling, leading to increased melanoma-endothelial cell interactions and enhanced tumor dissemination.
Leptomeningeal disease (LMD) is a devastating complication caused by seeding malignant cells to the cerebrospinal fluid (CSF) and the leptomeningeal membrane. LMD is diagnosed in 5-15% of patients ...with systemic malignancy. Management of LMD is challenging due to the biological and metabolic tumor microenvironment of LMD being largely unknown. Patients with LMD can present with a wide variety of signs and/or symptoms that could be multifocal and include headache, nausea, vomiting, diplopia, and weakness, among others. The median survival time for patients with LMD is measured in weeks and up to 3-6 months with aggressive management, and death usually occurs due to progressive neurologic dysfunction. In melanoma, LMD is associated with a suppressive immune microenvironment characterized by a high number of apoptotic and exhausted CD4
T-cells, myeloid-derived suppressor cells, and a low number of CD8
T-cells. Proteomics analysis revealed enrichment of complement cascade, which may disrupt the blood-CSF barrier. Clinical management of melanoma LMD consists primarily of radiation therapy, BRAF/MEK inhibitors as targeted therapy, and immunotherapy with anti-PD-1, anti-CTLA-4, and anti-LAG-3 immune checkpoint inhibitors. This review summarizes the biology and anatomic features of melanoma LMD, as well as the current therapeutic approaches.
A national referendum to legalise recreational cannabis use and supply in New Zealand via the Cannabis Legalisation and Control Bill (CLCB) was recently narrowly defeated. Understanding the ...underlying factors for this result can inform the cannabis legalisation debate in other countries.
To investigate predictors of voter support for and opposition to the CLCB.
A representative population panel of 1,022 people completed an online survey of intended voting on the CLCB referendum, which included questions on demographics, drug use history, medicinal cannabis, perceptions of the health risk and moral views of cannabis use, political affiliation, religiosity, community size and reading of the CLCB. Regression models were developed to predict support for the CLCB, with additional predictor variables added over successive iterations.
The most robust predictors of support for the CLCB were use of and policy support for medicinal cannabis use, voting for a left-wing political party, having a positive moral view of cannabis use, living in a small town and having read the CLCB. Predictors of opposing the CLCB were voting for right-wing parties, considering “frequent” cannabis use to be a high health risk, and lifetime use of other drugs. Age, ethnicity, education, employment status, religiosity and lifetime cannabis use were not significant predictors after controlling for other variables.
Support for cannabis legalization was not based on broad demographics, but rather specific views concerning the medicinal benefit, morality of cannabis use, health risk of frequent cannabis use, political party affiliation, and knowledge of the proposed regulatory controls of the CLCB. The influence of moral views of cannabis use on voting behaviour suggest the need to debate the right to use cannabis. The importance of knowledge of the proposed regulatory controls of the CLCB on voting underlines the need to raise awareness of proposed regulatory controls during debate.
New families of salts, based on quaternary ammonium, 1-methyl-3-alkylimidazolium or -methyl--alkylpyrrolidinium organic cations together with the dicyanamide (dca, N(CN)) anion are reported. The ...salts are low melting compounds, all those reported are liquid at room temperature, for example 1-methyl-3-ethylimidazolium dicyanamide (mp -21 degreeC) and -methyl--ethylpyrrolidinium dicyanamide (mp -10 degreeC). Some of the salts exhibit multiple crystalline phases below their melting points. Above their melting points they are stable to at least 200 degreeC. Many of the salts were found to be glass forming when cooled rapidly to -100 degreeC. The room-temperature liquids exhibit very low viscosities, for example ethylmethylimidazolium dicyanamide: = 21 cP at ambient temperature (25 degreeC).
The presence of contrast enhancement in a brain tumor is often regarded as a sign of malignancy. The authors identified 314 patients with malignant and low-grade supratentorial glial neoplasms in an ...unselected population, 58 of which lacked contrast enhancement on preoperative neuroimaging. Nonenhancing gliomas were malignant in approximately one third of cases, especially in older patients. Histologic confirmation of the diagnosis is therefore important in all patients suspected of harboring a primary glial neoplasm.
Background
Low muscularity and malnutrition at intensive care unit (ICU) admission have been associated with negative clinical outcomes. There are limited data available evaluating the validity of ...bedside techniques to measure muscle mass in critically ill adults. We aimed to compare bedside methods for muscle mass assessment bioimpedance spectroscopy (BIS), arm anthropometry and subjective physical assessment against reference technology computed tomography (CT) at ICU admission.
Methods
Adults who had CT scanning at the third lumbar area <72 h after ICU admission were prospectively recruited. Bedside methods were performed within 48 h of the CT scan. Pearson’s correlation compared CT muscle area with BIS‐derived fat‐free mass (FFM) (kg) and FFM‐Chamney (kg) (adjusted for overhydration), mid‐upper arm circumference (cm) and mid‐arm muscle circumference (cm). Depleted muscle stores were determined using published thresholds for each method. Cohen’s kappa (κ) was used to evaluate the agreement between bedside and CT assessment of muscularity status (normal or low).
Results
Fifty participants were enrolled. There were strong correlations between CT muscle area and FFM values and mid‐arm muscle circumference (P < 0.001). Using FFM‐Chamney, all six (100%) participants with low CT muscle area were detected (κ = 0.723). FFM‐BIS, arm anthropometry and subjective physical assessment methods detected 28%–38% of participants with low CT muscle area.
Conclusions
BIS‐derived FFM using an adjustment algorithm for overhydration was correlated with CT muscle area and had good agreement with muscularity status assessed by CT image analysis. Arm anthropometry and subjective physical assessment techniques were not able to reliably detect participants with low CT muscle area.
Melanomas can adopt multiple transcriptional states. Little is known about the epigenetic drivers of these cell states, limiting our ability to regulate melanoma heterogeneity. Here, we identify ...stress-induced HDAC8 activity as driving melanoma brain metastasis development. Exposure of melanocytes and melanoma cells to multiple stresses increases HDAC8 activation leading to a neural crest-stem cell transcriptional state and an amoeboid, invasive phenotype that increases seeding to the brain. Using ATAC-Seq and ChIP-Seq we show that increased HDAC8 activity alters chromatin structure by increasing H3K27ac and enhancing accessibility at c-Jun binding sites. Functionally, HDAC8 deacetylates the histone acetyltransferase EP300, causing its enzymatic inactivation. This, in turn, increases binding of EP300 to Jun-transcriptional sites and decreases binding to MITF-transcriptional sites. Inhibition of EP300 increases melanoma cell invasion, resistance to stress and increases melanoma brain metastasis development. HDAC8 is identified as a mediator of transcriptional co-factor inactivation and chromatin accessibility that drives brain metastasis.
Lewis base ionic liquids MacFarlane, Douglas R; Pringle, Jennifer M; Johansson, Katarina M ...
Chemical communications (Cambridge, England),
01/2006
18
Journal Article
Recenzirano
Ionic liquids which are (weak) Lewis bases have a number of interesting and useful properties different to those of traditional ionic liquids, including volatility and the possibility of being ...distillable in some cases, a base catalysis effect in others and enhancement of the acidity of dissolved acids.
Due to recent concerns about the toxicity of trastuzumab emtansine (T-DM1) with stereotactic radiation, we assessed our institutional outcomes treating HER2-positive breast cancer brain metastases ...(BCBM) with T-DM1 and stereotactic radiation.
This is a single institution series of 16 patients with HER2-positive breast cancer who underwent 18 stereotactic sessions to 40 BCBM from 2013 to 2019 with T-DM1 delivered within 6 months. The Kaplan-Meier method was used to calculate overall survival (OS), local control (LC), distant intracranial control (DIC), and systemic progression-free survival (sPFS) from the date of SRS. A neuro-radiologist independently reviewed follow-up imaging.
One patient had invasive lobular carcinoma, and 15 patients had invasive ductal carcinoma. All cases were HER2-positive, while 10 were hormone receptor (HR) positive. Twenty-four lesions were treated with stereotactic radiosurgery (SRS) to a median dose of 21 Gy (14-24 Gy). Sixteen lesions were treated with fractionated stereotactic radiation (FSRT) with a median dose of 25 Gy (20-30Gy) delivered in 3 to 5 fractions. Stereotactic radiation was delivered concurrently with T-DM1 in 19 lesions (48%). Median follow up time was 13.2 months from stereotactic radiation. The 1-year LC, DIC, sPFS, and OS were 75, 50, 30, and 67%, respectively. There was 1 case of leptomeningeal progression and 1 case (3%) of symptomatic radionecrosis.
We demonstrate that stereotactic radiation and T-DM1 is well-tolerated and effective for patients with HER2-positive BCBM. An increased risk for symptomatic radiation necrosis was not noted in our series.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Planning and undertaking elective surgery in people with haemophilia (PWH) is most effective with the involvement of a specialist and experienced multidisciplinary team (MDT) at a haemophilia ...treatment centre. However, despite extensive best practice guidelines for surgery in PWH, there may exist a gap between guidelines and practical application. For this consensus review, an expert multidisciplinary panel comprising surgeons, haematologists, nurses, physiotherapists and a dental expert was assembled to develop practical approaches to implement the principles of multidisciplinary management of elective surgery for PWH. Careful preoperative planning is paramount for successful elective surgery, including dental examinations, physical assessment and prehabilitation, laboratory testing and the development of haemostasis and pain management plans. A coordinator may be appointed from the MDT to ensure that critical tasks are performed and milestones met to enable surgery to proceed. At all stages, the patient and their parent/caregiver, where appropriate, should be consulted to ensure that their expectations and functional goals are realistic and can be achieved. The planning phase should ensure that surgery proceeds without incident, but the surgical team should be ready to handle unanticipated events. Similarly, the broader MDT must be made aware of events in surgery that may require postoperative plans to be changed. Postoperative rehabilitation should begin soon after surgery, with attention paid to management of haemostasis and pain. Surgery in patients with inhibitors requires even more careful preparation and should only be undertaken by an MDT experienced in this area, at a specialized haemophilia treatment centre with a comprehensive care model.
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