Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene that impair the function of CFTR, an epithelial chloride channel required for proper function of ...the lung, pancreas, and other organs. Most patients with CF carry the F508del CFTR mutation, which causes defective CFTR protein folding and processing in the endoplasmic reticulum, resulting in minimal amounts of CFTR at the cell surface. One strategy to treat these patients is to correct the processing of F508del-CFTR with small molecules. Here we describe the in vitro pharmacology of VX-809, a CFTR corrector that was advanced into clinical development for the treatment of CF. In cultured human bronchial epithelial cells isolated from patients with CF homozygous for F508del, VX-809 improved F508del-CFTR processing in the endoplasmic reticulum and enhanced chloride secretion to approximately 14% of non-CF human bronchial epithelial cells (EC50, 81 ± 19 nM), a level associated with mild CF in patients with less disruptive CFTR mutations. F508del-CFTR corrected by VX-809 exhibited biochemical and functional characteristics similar to normal CFTR, including biochemical susceptibility to proteolysis, residence time in the plasma membrane, and single-channel open probability. VX-809 was more efficacious and selective for CFTR than previously reported CFTR correctors. VX-809 represents a class of CFTR corrector that specifically addresses the underlying processing defect in F508del-CFTR.
Introduction
The management of glioblastoma at the time of progression is an important facet of all physicians involved in neuro-oncology. This is an update of the evidence-based guidelines for ...management of progressive glioblastoma published by the Congress of Neurological Surgeons and American Association of Neurological Surgeons in 2014.
Methods
The medical literature from July 1, 2012 through March 31, 2019 was searched in MEDLINE® and Embase® and the Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Registry, and Cochrane Database of Abstracts of Reviews of Effects to determine if information was available to update, modify or create new recommendations related to imaging, cytoreductive surgery, neuropathology, radiotherapy, cytotoxic chemotherapy, targeted therapy, and immunotherapy.
Results
The writing group utilized the information from the updated literature search to formulate recommendations that were exclusively evidence based and not founded on potentially biased consensus or expert opinion.
Conclusion
The series of guideline documents provides an update of the information and recommendations that could be derived in the 2014 version. It sets a benchmark as to what we really know about the management of this difficult disease. It also provides clues to key investigations that are necessary to move us toward truly effective disease control.
Target population
These recommendations apply to adult patients (18 years of age and above) with progressive/recurrent glioblastoma multiforme (pGBM) after first line combined multimodality ...treatment.
Question
Can re-irradiation (by using conventional radiotherapy, fractionated radiosurgery, or single fraction radiosurgery) be used in patients with pGBM after the first adjuvant combined multimodality treatment with radiation and chemotherapy?
Recommendation
Level III:
When the target tumor is amenable for additional radiation, re-irradiation is recommended as it provides improved local tumor control, as measured by best imaging response. Such re-irradiation can take the form of conventional fractionation radiotherapy, fractionated radiosurgery, or single fraction radiosurgery.
Level III:
Re-Irradiation is recommended in order to maintain or improve a patient’s neurological status and quality of life prior to any further tumor progression.
Abstract
TARGET POPULATION
These recommendations apply to adult patients with new or recurrent solitary or multiple brain metastases from solid tumors as detailed in each section.
QUESTION 1
Should ...patients with newly diagnosed metastatic brain tumors undergo stereotactic radiosurgery (SRS) compared with other treatment modalities?
RECOMMENDATIONS
Level 3: SRS is recommended as an alternative to surgical resection in solitary metastases when surgical resection is likely to induce new neurological deficits, and tumor volume and location are not likely to be associated with radiation-induced injury to surrounding structures.
Level 3: SRS should be considered as a valid adjunctive therapy to supportive palliative care for some patients with brain metastases when it might be reasonably expected to relieve focal symptoms and improve functional quality of life in the short term if this is consistent with the overall goals of the patient.
QUESTION 2
What is the role of SRS after open surgical resection of brain metastasis?
RECOMMENDATION
Level 3: After open surgical resection of a solitary brain metastasis, SRS should be used to decrease local recurrence rates.
QUESTION 3
What is the role of SRS alone in the management of patients with 1 to 4 brain metastases?
RECOMMENDATIONS
Level 3: For patients with solitary brain metastasis, SRS should be given to decrease the risk of local progression.
Level 3: For patients with 2 to 4 brain metastases, SRS is recommended for local tumor control, instead of whole brain radiotherapy, when their cumulative volume is < 7 mL.
QUESTION 4
What is the role of SRS alone in the management of patients with more than 4 brain metastases?
RECOMMENDATION
Level 3: The use of stereotactic radiosurgery alone is recommended to improve median overall survival for patients with more than 4 metastases having a cumulative volume < 7 mL. The full guideline can be found at: https://www.cns.org/guidelines/guidelines-treatment-adults-metastatic-brain-tumors/chapter_4
Glioblastomas (GBMs), neoplasms derived from glia and neuroglial progenitor cells, are the most common and lethal malignant primary brain tumors diagnosed in adults, with a median survival of 14 ...months. GBM tumorigenicity is often driven by genetic aberrations in receptor tyrosine kinases, such as amplification and mutation of EGFR.
Using a
glioma model and human patient-derived GBM stem cells and xenograft models, we genetically and pharmacologically tested whether the YAP and TAZ transcription coactivators, effectors of the Hippo pathway that promote gene expression via TEA domain (TEAD) cofactors, are key drivers of GBM tumorigenicity downstream of oncogenic EGFR signaling.
YAP and TAZ are highly expressed in EGFR-amplified/mutant human GBMs, and their knockdown in EGFR-amplified/mutant GBM cells inhibited proliferation and elicited apoptosis. Our results indicate that YAP/TAZ-TEAD directly regulates transcription of
,
, and
itself to create a feedforward loop to drive survival and proliferation of human GBM cells. Moreover, the benzoporphyrin derivative verteporfin, a disruptor of YAP/TAZ-TEAD-mediated transcription, preferentially induced apoptosis of cultured patient-derived EGFR-amplified/mutant GBM cells, suppressed expression of YAP/TAZ transcriptional targets, including EGFR, and conferred significant survival benefit in an orthotopic xenograft GBM model. Our efforts led us to design and initiate a phase 0 clinical trial of Visudyne, an FDA-approved liposomal formulation of verteporfin, where we used intraoperative fluorescence to observe verteporfin uptake into tumor cells in GBM tumors in human patients.
Together, our data suggest that verteporfin is a promising therapeutic agent for EGFR-amplified and -mutant GBM.
Interstitial lung disease (ILD) is a common pulmonary manifestation of rheumatoid arthritis. There is lack of clarity around predictors of mortality and disease behaviour over time in these ...patients.We identified rheumatoid arthritis-related interstitial lung disease (RA-ILD) patients evaluated at National Jewish Health (Denver, CO, USA) from 1995 to 2013 whose baseline high-resolution computed tomography (HRCT) scans showed either a nonspecific interstitial pneumonia (NSIP) or a "definite" or "possible" usual interstitial pneumonia (UIP) pattern. We used univariate, multivariate and longitudinal analytical methods to identify clinical predictors of mortality and to model disease behaviour over time.The cohort included 137 subjects; 108 had UIP on HRCT (RA-UIP) and 29 had NSIP on HRCT (RA-NSIP). Those with RA-UIP had a shorter survival time than those with RA-NSIP (log rank p=0.02). In a model controlling for age, sex, smoking and HRCT pattern, a lower baseline % predicted forced vital capacity (FVC % pred) (HR 1.46; p<0.0001) and a 10% decline in FVC % pred from baseline to any time during follow up (HR 2.57; p<0.0001) were independently associated with an increased risk of death.Data from this study suggest that in RA-ILD, disease progression and survival differ between subgroups defined by HRCT pattern; however, when controlling for potentially influential variables, pulmonary physiology, but not HRCT pattern, independently predicts mortality.
Background The cornerstone of hypersensitivity pneumonitis (HP) management is having patients avoid the inciting antigen (IA). Often, despite an exhaustive search, an IA cannot be found. The ...objective of this study was to examine whether identifying the IA impacts survival in patients with chronic HP. Methods We used the Kaplan-Meier method to display, and the log-rank test to compare, survival curves of patients with well-characterized chronic HP stratified on identification of an IA exposure. A Cox proportional hazards (PH) model was used to identify independent predictors in time-to-death analysis. Results Of 142 patients, 67 (47%) had an identified IA, and 75 (53%) had an unidentified IA. Compared with survivors, patients who died (n = 80, 56%) were older, more likely to have smoked, had lower total lung capacity % predicted and FVC % predicted, had higher severity of dyspnea, were more likely to have pulmonary fibrosis, and were less likely to have an identifiable IA. In a Cox PH model, the inability to identify an IA (hazard ratio HR, 1.76; 95% CI, 1.01–3.07), older age (HR, 1.04; 95% CI, 1.01–1.07), the presences of pulmonary fibrosis (HR, 2.43; 95% CI, 1.36–4.35), a lower FVC% (HR, 1.36; 95% CI, 1.10–1.68), and a history of smoking (HR, 2.01; 95% C1, 1.15–3.50) were independent predictors of shorter survival. After adjusting for mean age, presence of fibrosis, mean FVC%, mean diffusing capacity of the lung for carbon monoxide (%), and history of smoking, survival was longer for patients with an identified IA exposure than those with an unidentified IA exposure (median, 8.75 years vs 4.88 years; P = .047). Conclusions Among patients with chronic HP, when adjusting for a number of potentially influential predictors, including the presence of fibrosis, the inability to identify an IA was independently associated with shortened survival.
Ubiquitination governs oscillation of cyclin-dependent kinase (CDK) activity through a periodic degradation of cyclins for orderly cell cycle progression; however, the mechanism that maintains the ...constant CDK protein levels throughout the cell cycle remains unclear. Here we show that CDK6 is modified by small ubiquitin-like modifier-1 (SUMO1) in glioblastoma, and that CDK6 SUMOylation stabilizes the protein and drives the cell cycle for the cancer development and progression. CDK6 is also a substrate of ubiquitin; however, CDK6 SUMOylation at Lys 216 blocks its ubiquitination at Lys 147 and inhibits the ubiquitin-mediated CDK6 degradation. Throughout the cell cycle, CDK1 phosphorylates the SUMO-specific enzyme, ubiquitin-conjugating enzyme9 (UBC9) that in turn mediates CDK6 SUMOylation during mitosis; CDK6 remains SUMOylated in G1 phase and drives the cell cycle through G1/S transition. Thus, SUMO1-CDK6 conjugation constitutes a mechanism of cell cycle control and inhibition of this SUMOylation pathway may provide a strategy for treatment of glioblastoma.
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