Histone demethylase LSDl (KDMlA) belongs to the flavin adenine dinucleotide (FAD) dependent family of monoamine oxidases and is vital in regulation of mammalian biology. Dysregulation and ...overexpression of LSD1 are hallmarks of a number of human diseases, particularly cancers that are characterized as morphologically poorly differentiated. As such, inhibitors of LSD1 have potential to be beneficial as a cancer therapy. The most clinically advanced inhibitors of LSDl are covalent inhibitors derived from tranylcypromine (TCP). Herein, we report the discovery of a novel series of reversible and selective LSDl inhibitors. Exploration of structure–activity relationships (SARs) and optimization of ADME properties resulted in the identification of clinical candidate CC-90011. CC-90011 exhibits potent on-target induction of cellular differentiation in acute myeloid leukemia (AML) and small cell lung cancer (SCLC) cell lines, and antitumor efficacy in patient-derived xenograft (PDX) SCLC models. CC-90011 is currently in phase 2 trials in patients with first line, extensive stage SCLC (ClinicalTrials.gov identifier: NCT03850067).
Adoptive immunotherapy using chimeric antigen receptor (CAR) expressing T cells targeting the CD19 B lineage receptor has demonstrated marked success in relapsed pre-B-cell acute lymphoblastic ...leukaemia (ALL). Persisting CAR-T cells generate sustained pressure against CD19 that may drive unique mechanisms of resistance. Pre-B ALL originates from a committed pre-B cell or an earlier progenitor, with potential to reprogram into other hematopoietic lineages. Here we report changes in lineage markers including myeloid conversion in patients following CD19 CAR therapy. Using murine ALL models we study the long-term effects of CD19 CAR-T cells and demonstrate partial or complete lineage switch as a consistent mechanism of CAR resistance depending on the underlying genetic oncogenic driver. Deletion of Pax5 or Ebf1 recapitulates lineage reprogramming occurring during CD19 CAR pressure. Our findings establish lineage switch as a mechanism of CAR resistance exposing inherent plasticity in genetic subtypes of pre-B-cell ALL.
Varying coefficient regression models are known to be very useful tools for analysing the relation between a response and a group of covariates. Their structure and interpretability are similar to ...those for the traditional linear regression model, but they are more flexible because of the infinite dimensionality of the corresponding parameter spaces. The aims of this paper are to give an overview on the existing methodological and theoretical developments for varying coefficient models and to discuss their extensions with some new developments. The new developments enable us to use different amount of smoothing for estimating different component functions in the models. They are for a flexible form of varying coefficient models that requires smoothing across different covariates' spaces and are based on the smooth backfitting technique that is admitted as a powerful technique for fitting structural regression models and is also known to free us from the curse of dimensionality.
Abstract
Background
Local response prediction for brain metastases (BM) after stereotactic radiosurgery (SRS) is challenging, particularly for smaller BM, as existing criteria are based solely on ...unidimensional measurements. This investigation sought to determine whether radiomic features provide additional value to routinely available clinical and dosimetric variables to predict local recurrence following SRS.
Methods
Analyzed were 408 BM in 87 patients treated with SRS. A total of 440 radiomic features were extracted from the tumor core and the peritumoral regions, using the baseline pretreatment volumetric post-contrast T1 (T1c) and volumetric T2 fluid-attenuated inversion recovery (FLAIR) MRI sequences. Local tumor progression was determined based on Response Assessment in Neuro-Oncology‒BM criteria, with a maximum axial diameter growth of >20% on the follow-up T1c indicating local failure. The top radiomic features were determined based on resampled random forest (RF) feature importance. An RF classifier was trained using each set of features and evaluated using the area under the receiver operating characteristic curve (AUC).
Results
The addition of any one of the top 10 radiomic features to the set of clinical features resulted in a statistically significant (P < 0.001) increase in the AUC. An optimized combination of radiomic and clinical features resulted in a 19% higher resampled AUC (mean = 0.793; 95% CI = 0.792–0.795) than clinical features alone (0.669, 0.668–0.671).
Conclusions
The increase in AUC of the RF classifier, after incorporating radiomic features, suggests that quantitative characterization of tumor appearance on pretreatment T1c and FLAIR adds value to known clinical and dosimetric variables for predicting local failure.
Middle East respiratory syndrome (MERS) coronavirus causes a highly fatal lower-respiratory tract infection. There are as yet no licensed MERS vaccines or therapeutics. This study (WRAIR-2274) ...assessed the safety, tolerability, and immunogenicity of the GLS-5300 MERS coronavirus DNA vaccine in healthy adults.
This study was a phase 1, open-label, single-arm, dose-escalation study of GLS-5300 done at the Walter Reed Army Institute for Research Clinical Trials Center (Silver Spring, MD, USA). We enrolled healthy adults aged 18–50 years; exclusion criteria included previous infection or treatment of MERS. Eligible participants were enrolled sequentially using a dose-escalation protocol to receive 0·67 mg, 2 mg, or 6 mg GLS-5300 administered by trained clinical site staff via a single intramuscular 1 mL injection at each vaccination at baseline, week 4, and week 12 followed immediately by co-localised intramuscular electroporation. Enrolment into the higher dose groups occurred after a safety monitoring committee reviewed the data following vaccination of the first five participants at the previous lower dose in each group. The primary outcome of the study was safety, assessed in all participants who received at least one study treatment and for whom post-dose study data were available, during the vaccination period with follow-up through to 48 weeks after dose 3. Safety was measured by the incidence of adverse events; administration site reactions and pain; and changes in safety laboratory parameters. The secondary outcome was immunogenicity. This trial is registered at ClinicalTrials.gov (number NCT02670187) and is completed.
Between Feb 17 and July 22, 2016, we enrolled 75 individuals and allocated 25 each to 0·67 mg, 2 mg, or 6 mg GLS-5300. No vaccine-associated serious adverse events were reported. The most common adverse events were injection-site reactions, reported in 70 participants (93%) of 75. Overall, 73 participants (97%) of 75 reported at least one solicited adverse event; the most common systemic symptoms were headache (five 20% with 0·67 mg, 11 44% with 2 mg, and seven 28% with 6 mg), and malaise or fatigue (five 20% with 0·67 mg, seven 28% with 2 mg, and two 8% with 6 mg). The most common local solicited symptoms were administration site pain (23 92% with all three doses) and tenderness (21 84% with all three doses). Most solicited symptoms were reported as mild (19 76% with 0·67 mg, 20 80% with 2 mg, and 17 68% with 6 mg) and were self-limiting. Unsolicited symptoms were reported for 56 participants (75%) of 75 and were deemed treatment-related for 26 (35%). The most common unsolicited adverse events were infections, occurring in 27 participants (36%); six (8%) were deemed possibly related to study treatment. There were no laboratory abnormalities of grade 3 or higher that were related to study treatment; laboratory abnormalities were uncommon, except for 15 increases in creatine phosphokinase in 14 participants (three participants in the 0·67 mg group, three in the 2 mg group, and seven in the 6 mg group). Of these 15 increases, five (33%) were deemed possibly related to study treatment (one in the 2 mg group and four in the 6 mg group). Seroconversion measured by S1-ELISA occurred in 59 (86%) of 69 participants and 61 (94%) of 65 participants after two and three vaccinations, respectively. Neutralising antibodies were detected in 34 (50%) of 68 participants. T-cell responses were detected in 47 (71%) of 66 participants after two vaccinations and in 44 (76%) of 58 participants after three vaccinations. There were no differences in immune responses between dose groups after 6 weeks. At week 60, vaccine-induced humoral and cellular responses were detected in 51 (77%) of 66 participants and 42 (64%) of 66, respectively.
The GLS-5300 MERS coronavirus vaccine was well tolerated with no vaccine-associated serious adverse events. Immune responses were dose-independent, detected in more than 85% of participants after two vaccinations, and durable through 1 year of follow-up. The data support further development of the GLS-5300 vaccine, including additional studies to test the efficacy of GLS-5300 in a region endemic for MERS coronavirus.
US Department of the Army and GeneOne Life Science.
We report our experience in salvaging spinal metastases initially irradiated with stereotactic body radiation therapy (SBRT), who subsequently progressed with imaging-confirmed local tumor ...progression, and were re-irradiated with a salvage second SBRT course to the same level.
From a prospective database, 56 metastatic spinal segments in 40 patients were identified as having been irradiated with a salvage second SBRT course to the same level. In addition, 24 of 56 (42.9%) segments had initially been irradiated with conventional external beam radiation therapy before the first course of SBRT. Local control (LC) was defined as no progression on magnetic resonance imaging at the treated segment, and calculated according to the competing risk model. Overall survival (OS) was evaluated for each patient treated by use of the Kaplan-Meier method.
The median salvage second SBRT total dose and number of fractions was 30 Gy in 4 fractions (range, 20-35 Gy in 2-5 fractions), and for the first course of SBRT was 24 Gy in 2 fractions (range, 20-35 Gy in 1-5 fractions). The median follow-up time after salvage second SBRT was 6.8 months (range, 0.9-39 months), the median OS was 10.0 months, and the 1-year OS rate was 48%. A longer time interval between the first and second SBRT courses predicted for better OS (P=.02). The crude LC was 77% (43/56), the 1-year LC rate was 81%, and the median time to local failure was 3.0 months (range, 2.7-16.7 months). Of the 13 local failures, 85% (11/13) and 46% (6/13) showed progression within the epidural space and paraspinal soft tissues, respectively. Absence of baseline paraspinal disease predicted for better LC (P<.01). No radiation-induced vertebral compression fractures or cases of myelopathy were observed.
A second course of spine SBRT, most often with 30 Gy in 4 fractions, for spinal metastases that failed initial SBRT is a feasible and efficacious salvage treatment option.
The development of unmanned aerial vehicles (UAVs) is expected to become one of the most commercialized research areas in the world over the next decade. Globally, unmanned aircraft have been ...increasingly used for safety surveillance in the construction industry and civil engineering fields. This paper presents an aerial image-based approach using UAVs to inspect cracks and deformations in buildings. A state-of-the-art safety evaluation method termed SMART SKY EYE (Smart building safety assessment system using UAV) is introduced; this system utilizes an unmanned airplane equipped with a thermal camera and programmed with various surveying efficiency improvement methods, such as thermography, machine-learning algorithms, and 3D point cloud modeling. Using this method, crack maps, crack depths, and the deformations of structures can be obtained. Error rates are compared between the proposed and conventional methods.
Heterozygous germline mutations in the zinc finger transcription factor GATA2 have recently been shown to underlie a range of clinical phenotypes, including Emberger syndrome, a disorder ...characterized by lymphedema and predisposition to myelodysplastic syndrome/acute myeloid leukemia (MDS/AML). Despite well-defined roles in hematopoiesis, the functions of GATA2 in the lymphatic vasculature and the mechanisms by which GATA2 mutations result in lymphedema have not been characterized. Here, we have provided a molecular explanation for lymphedema predisposition in a subset of patients with germline GATA2 mutations. Specifically, we demonstrated that Emberger-associated GATA2 missense mutations result in complete loss of GATA2 function, with respect to the capacity to regulate the transcription of genes that are important for lymphatic vessel valve development. We identified a putative enhancer element upstream of the key lymphatic transcriptional regulator PROX1 that is bound by GATA2, and the transcription factors FOXC2 and NFATC1. Emberger GATA2 missense mutants had a profoundly reduced capacity to bind this element. Conditional Gata2 deletion in mice revealed that GATA2 is required for both development and maintenance of lymphovenous and lymphatic vessel valves. Together, our data unveil essential roles for GATA2 in the lymphatic vasculature and explain why a select catalogue of human GATA2 mutations results in lymphedema.
We report mature outcomes for a cohort of patients with no prior radiation (de novo) to the spine treated with 24 Gy in 2 daily fractions for metastases, which represents the same stereotactic body ...radiation therapy (SBRT) regimen under evaluation in the current Symptom Control-24 phase 3 randomized trial (NCT02512965).
The cohort consisted of 279 de novo spinal metastases in 145 consecutive patients treated with 24 Gy in 2 SBRT fractions, identified from a prospective single-institution database. The endpoints were overall survival (OS), imaging-based local failure (LF), and cumulative risk of vertebral compression fractures (VCF).
The median follow-up per treated metastasis was 15.0 months (range, 0.1-71.6). The 1-year and 2-year OS rates were 73.1% and 60.7%, respectively. Presence of epidural disease (P < .0001), lung (P = .0415), and renal cell (P < .0001) primary histologies and baseline diffuse metastases (P = .0034) were significant prognostic factors for OS. The 1-year and 2-year LF rates were 9.7% and 17.6%, respectively, and the median time to LF was 9.2 month (range, 0.4-31.3 months). Only the presence of epidural disease predicted for LF (P < .0001). The cumulative risk of VCF at 1 and 2 years was 8.5% and 13.8%, respectively. Lytic (P = .0143) or mixed lytic/blastic (P = .0214) lesions, spinal malalignment (P = .0121), and the dose to 90% of the planning target volume (P = .0085) were significant predictors for VCF.
Twenty-four Gray in 2 daily fractions is safe and effective in achieving high tumor control rates for de novo spinal metastases. These outcomes will serve as a benchmark for the ongoing Symptom Control-24 randomized trial comparing 24 Gy in 2 SBRT fractions to 20 Gy delivered in 5 daily conventional fractions.
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