tbuckley/cabot-search huggingface dataset:
NIMG-22. HIGH-GRADE GLIOMA OUTCOMES IN THE PHASE 1 BXQ-350 TRIAL OF CANCER-SELECTIVE SapC-DOPS NANOVESICLES
Authors: Vinay Puduvalli, John Villano, Trisha Wise-Draper, John Morris, Olivier Rixe, Angela Johnson, Pierre Giglio, Jose Otero
Journal: Neuro-Oncology (2018)

Saposin C-dioleylphosphatidylserine (SapC-DOPS) is a novel blood-brain barrier penetrant nanoliposomal agent that targets externalized phosphatidylserine overexpressed on tumor cell membranes. A recent Phase 1a BXQ-350 trial (NCT02859857) reported SapC-DOPS was well tolerated in both solid tumor and high-grade glioma (HGG) patients with potential for treating clinically challenging gliomas, including their diffuse infiltrative components. We evaluated the HGG subset of the ongoing Phase 1 study of IV BXQ-350 administered on Days 1–5, 8, 10, 12, 15, 22 (cycle 1) and each 28 day cycles thereafter. MRI neuroimaging (e.g. Axial T1-post-contrast Ax SE T1 POST-FC and medically necessary views) at Days 29, 57, 113, and 171 (or withdrawal) were completed. RANO assessment, functional neurological deficits, ECOG Performance Status, and safety were assessed. The HGG patients (9/17) were dosed at 0.7 (N = 1), 1.1 (N = 1), 1.4 (N = 2), 1.8 (N = 2), or 2.4 (N = 3) mg/kg, with 8/9 completing a full cycle before withdrawal (7 due to progression, 1 voluntary withdrawal). BXQ-350 was not linked to dose limiting toxicities or severe adverse reactions. Functional neurological deficits and ECOG decline were proportional to radiological progression, with ECOG scores declining from a baseline 0–1 in 2/9 (22%) to 3. One patient completing 6 cycles (>12 months) of BXQ-350 therapy (0.7 mg/kg) exhibited stable disease, -7% lesion size, and no significant progressive functional neurological deficits. Three patients underwent surgery for progression while on treatment. CONCLUSIONS: BXQ-350 was well tolerated by GBM patients with promising best response apparent in neuroimaging, suggesting therapeutic benefit warranting further trials. Updates from the ongoing trial will be presented.
CSIG-03. CYCLIC DEPSIPEPTIDE LIGANDS TO TARGET CO-TRANSLATIONAL TRANSLOCATION AND ER PROTEOSTASIS IN GLIOBLASTOMA CELLS
Authors: Jane Ishmael, Xuemei Wan, Soheila Kazemi, Kerry McPhail
Journal: Neuro-Oncology (2018)

Coibamide A, is a rare cytotoxic N-methyl-stabilized cyclopeptide originally isolated from a cyanobacterium growing within the marine reserve of Coiba National Park, Panama. We have recently determined that this natural product targets the co-translational translocation machinery and potently inhibits expression of secreted, resident endoplasmic reticulum (ER) and membrane-bound proteins. This mechanism of coibamide A action leads to a pattern of cellular consequences including inhibition of glucose regulated protein 78 (GRP78) expression and a specific pattern of cell stress and death signaling in cultured glioblastoma cells. Exposure to nanomolar concentrations of coibamide A, or the related cyclic depsipeptide natural product apratoxin A, promotes proteasomal degradation of GRP78 and a compensatory upregulation of cytosolic heat shock proteins 40 and 70 that precedes cell death. Co-translational translocation is mediated by the Sec61 translocation channel, which comprises a conserved hetero-oligomeric protein composed of a main pore-forming Sec61alpha subunit plus beta and gamma subunits. Sec61 also signals directly with the protein folding machinery of the ER lumen to maintain proteostasis. The Sec61 translocon channel is not a direct target of any currently approved or experimental drug, however, several natural product structures are now known to target the Sec61 channel and inhibit the co-translational translocation process. Pharmacological inhibitors of Sec61 may be valuable tools to probe GBM biology as SEC61gamma has previously been identified as a proto-oncogene, and Sec61gamma overexpression reported in high versus low grade glioma or normal astrocytes. Natural products have historically been important sources of new chemical structures, particularly for cancer and infectious disease, rather than providing the final drug entity. Although preliminary, the discovery of natural product ligands to target the ER translocation machinery reveals a distinct mechanism to perturb proteostasis in aggressive CNS cancers characterized by high expression of GRP78 and therapeutic resistance.
CADD-23. PD-L1 CHECKPOINT BLOCKADE USING A SINGLE-CHAIN VARIABLE FRAGMENT TARGETING PD-L1 DELIVERED BY RETROVIRAL REPLICATING VECTOR (TOCA 521) ENHANCES ANTI-TUMOR EFFECT IN CANCER MODELS
Authors: Amy Lin, Kader Yagiz, Andrew Hofacre, Anthony Munday, Fernando Lopez Espinoza, Daniel Mendoza, Cynthia Burrascano, Harry Gruber, Leah Mitchell, Douglas Jolly
Journal: Neuro-Oncology (2018)

Conventional interventions for treating glioblastoma (GBM) patients has had limited success, with a median overall survival of 15–17 months. Recently, immune checkpoint inhibitors (CPIs) showed long-term response rates from 20–30% in some tumors, but no consistent clinical benefit with these agents has been demonstrated so far in GBM patients. We propose and provide preliminary evidence for a strategy using retroviral replicating vectors (RRV) to deliver CPI agents selectively to cancer cells that may circumvent such issues. An RRV encoding a single-chain variable fragment targeting PD-L1 (RRV-scFv-PDL1, Toca 521) binds to both mouse and human PD-L1 by competitive ELISA and competes for target occupancy with a commercially available monoclonal antibody against cell surface PD-L1. A dose-dependent bystander effect is observed with scFv PD-L1 protein expressed from RRV-scFv-PDL1 infected tumor cells showing saturated receptor binding to the cell surface PD-L1 of bystander cells when co-cultured with as low as 10% scFv PD-L1 expressing cells. In addition, the immune functional activity of scFv PD-L1 to reverse PD-1/PD-L1 mediated immune suppression was observed in a co-culture system in vitro and further supported by in vivo mouse models. Such models included a syngeneic orthotopic glioma showing that tumors infected with RRV-scFv-PDL1 conferred robust and durable immune-mediated antitumor activity superior to systemically administered anti-PD-1/anti-PD-L1 monoclonal antibodies. These results support the concept that RRV-scFv-PDL1 CPI strategy may provide an improved safety and efficacy profile compared to systemic monoclonal antibodies. The superior anti-tumor activity of RRV-scFv-PDL1 may be due to consistent high levels of scFv PD-L1 within the tumor microenvironment. This localized delivery approach with less concern for autoimmune adverse events may be therapeutically beneficial as an immuno-oncology agent either alone or in combination.
SAT0493 Plasma levels of hsp90 are increased in interstitial lung disease and skin fibrosis in patients with systemic sclerosis
Authors: H. Storkanova, S. Oreska, M. Spiritovic, B. Hermankova, K. Pavelka, J. Vencovsky, J.H. Distler, L. Senolt, R. Becvar, M. Tomcik
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Our previous study demonstrated that Heat shock protein 90 (Hsp90) is overexpressed in the skin of patients with systemic sclerosis (SSc), in cultured SSc fibroblasts and preclinical models of SSc in a TGF-β dependent manner. We showed that Hsp90 is a regulator of TGF-β signalling and its inhibition prevents the stimulatory effects of TGF-β on collagen synthesis and dermal fibrosis in three preclinical models of SSc<sup>1</sup>. <h3>Objectives</h3> The aim of this study was to evaluate Hsp90 in the circulation of SSc patients and characterise its potential association with skin changes and SSc-related features. <h3>Methods</h3> A total of 91 patients (78 females; mean age 52.7; disease duration 6.0 years; diffuse cutaneous (dc)SSc/limited cutaneous (lc)SSc=38/53) who met the ACR/EULAR 2013 classification criteria for SSc and 85 age-/sex- matched healthy individuals were included. Plasma Hsp90 was measured by ELISA (eBioscience, Vienna, Austria). Data are presented as median (IQR, 25.–75. percentile). <h3>Results</h3> Plasma Hsp90 levels were increased in SSc patients compared to healthy controls [12.5 (9.6–17.9) vs. 9.9 (7.9–12.6) ng/mL, p=0.001], but no difference between lcSSc and dcSSc was detected [13.1 (9.4–18.1) vs. 11.5 (9.5–17.5) ng/mL, p=0.316]. Hsp90 levels in all patients positively correlated with CRP (r=0.313, p=0.006). Furthermore, Hsp90 was increased in patients with interstitial lung disease (ILD) compared to those without ILD [12.8 (10.2–17.9) vs. 10.3 (8.6–16.6) ng/mL, p=0.045] and was negatively associated with functional parameters of ILD: FVC (r=−0.299, p=0.011), FEV1 (r=−0.256, p=0.031), DLCO (r=−0.303, p=0.009) and SpO<sub>2</sub> (r=−0.317, p=0.038). In addition, only in patients with dcSSc, Hsp90 levels positively correlated with the mRSS (r=0.437, p=0.006). Hsp90 concentrations were not significantly affected by other main clinical parameters of SSc. <h3>Conclusions</h3> We demonstrated higher plasma levels of Hsp90 in SSc patients compared to healthy controls. Concentrations of extracellular Hsp90 increase with higher inflammatory activity, with deteriorated lung functions in ILD and also with the extent and severity of the skin involvement in patients with diffuse cutaneous SSc. These data further highlight the role of Hsp90 as a significant regulator of fibroblast activation and tissue fibrosis in SSc. <h3>Reference</h3> [1] Tomcik M, et al. Ann Rheum Dis2014;73(6):1215–22. <h3>Acknowledgements</h3> Supported by AZV – 16–33542A and SVV – 2 60 373. <h3>Disclosure of Interest</h3> None declared
Recurrent mutations at estrogen receptor binding sites alter chromatin topology and distal gene expression in breast cancer
Authors: Jiekun Yang, Xiaolong Wei, Turan Tufan, Cem Kuscu, Hayrunnisa Unlu, Saadia Farooq, Elif Demirtas, Bryce M. Paschal, Mazhar Adli
Journal: Genome biology (2018)

The mutational processes underlying non-coding cancer mutations and their biological significance in tumor evolution are poorly understood. To get better insights into the biological mechanisms of mutational processes in breast cancer, we integrate whole-genome level somatic mutations from breast cancer patients with chromatin states and transcription factor binding events. We discover that a large fraction of non-coding somatic mutations in estrogen receptor (ER)-positive breast cancers are confined to ER binding sites. Notably, the highly mutated estrogen receptor binding sites are associated with more frequent chromatin loop contacts and the associated distal genes are expressed at higher level. To elucidate the functional significance of these non-coding mutations, we focus on two of the recurrently mutated estrogen receptor binding sites. Our bioinformatics and biochemical analysis suggest loss of DNA-protein interactions due to the recurrent mutations. Through CRISPR interference, we find that the recurrently mutated regulatory element at the LRRC3C-GSDMA locus impacts the expression of multiple distal genes. Using a CRISPR base editor, we show that the recurrent C→T conversion at the ZNF143 locus results in decreased TF binding, increased chromatin loop formation, and increased expression of multiple distal genes. This single point mutation mediates reduced response to estradiol-induced cell proliferation but increased resistance to tamoxifen-induced growth inhibition. Our data suggest that ER binding is associated with localized accumulation of somatic mutations, some of which affect chromatin architecture, distal gene expression, and cellular phenotypes in ER-positive breast cancer.
Meeting the Criteria of Medication Therapy Management
Authors: Jean Y. Moon, Stephanie Walek, Kyle Walburg
Journal: JAMA Internal Medicine (2018)

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STEM-27. THE ALTERATION OF IMMUNOSUPPRESSIVE FUNCTION IN GLIOBLASTOMA WITH UNDIFFERENTIATED TRANSFORMATION
Authors: Shun Yamamuro, Yuya Hanashima, Sodai Yoshimura, Emiko Sano, Takuya Ueda, Atsuo Yoshino
Journal: Neuro-Oncology (2018)

Glioma stem-like cells (GSCs) are strongly related to the treatment resistance in glioblastoma (GBM). GSCs differentiate into differentiated glioma cells (non-GSCs), and lose the stem cell features such as self-renewal, pluripotency and tumorigenesis. However, several study have demonstrated that GSCs and non-GSCs could convert between each other. Recently, immunotherapy has been attracting attention as a new GBM therapy. Indoleamine 2,3-dioxygenase (IDO), the enzyme for Tryptophan metabolism, is involved in the ability of GBM to escape from immune surveillance, and show immunosuppressive function. In this study, we investigated the difference of IDO expression between GSCs and non-GSCs to search a new therapeutic target for GBM. We used the human malignant glioma cell lines U-251MG and Rev-U-251MG, which was established by culturing U-251MG cells in serum-free media. Rev-U-251MG formed spheres with increased level of Nestin and Nanog expression. We regarded Rev-U-251MG as a GSCs cell line model and investigated the expression of IDO. The expression levels of IDO mRNA and protein were increased in Rev-U-251MG compared to the expression in U-251MG. The expression levels of IDO1 mRNA were analyzed by the quantitative reverse transcription PCR (p<0.01, n=6), and IDO1 protein were analyzed by Western blotting. These results suggest that the GSCs strongly escape from immune surveillance while producing more IDO compared to non-GSCs. It is important to know about the alteration of immunosuppressive function between GSCs and non-GSCs to establish a new treatment strategy for GBM. The possibility was suggested that GSCs immunosuppressive function via expression of IDO could be a new target for the GBM therapy.
SAT0302 Evaluation of subclinical gut inflammation using faecal calprotectin level and colonic mucosal biopsy in patients with psoriasis and psoriatic arthritis
Authors: M. B. Adarsh, S. K. Sinha, S. Dogra, K. Vaiphei, C. Vaishnavi, A. Sharma
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> The association between gut inflammation and ankylosing spondylitis is well established, while it is not so in psoriatic arthritis(PsA). <h3>Objectives</h3> To study the prevalence of subclinical gut inflammation in PsA and Psoriasis(PsO) patients using faecal calprotectin levels and colonic mucosal biopsies and its correlation with disease phenotypes and activity scores. <h3>Methods</h3> Fifty patients with active PsA and hundred with active PsO were recruited.Faecal calprotectin levels of more than 43.2 µgm/gm by ELISA was considered positive.Sigmoidoscopy and multiple colonic mucosal biopsies were done in twenty PsA patients and eight PsO patients.Thirty consecutive patients with irritable bowel syndrome(IBS)according to ROME III criteria were disease control population.Mann Whitney u test and Kruskal Wallis H test were used. <h3>Results</h3> Baseline characteristics are given in table 1.Faecal calprotectin level was elevated in 29 (58%) PsA patients and 26 (26%) PsO patients (p=0.000). The mean value of faecal calprotectin was higher in PsA patients than PsO(86.6±81.5 µgm/gm vs 32.9±48.1 µgm/gm,p=0.000).The Odds for a positive faecal calprotectin level in PsA was 3.9 (95% CI 1.9–8.0) in comparison to PsO. Faecal calprotectin levels were significantly higher in PsA patients with high body surface area(BSA) and psoriasis area and severity index(PASI) scores.Those with axial phenotype had higher calprotectin levels and the levels correlated with BASDAI. Mean faecal calprotectin level was 22.0±18.5 µgm/gmin IBS patients which was significantly lower than PsA patients (0.002)but was comparable with that of PsO patients(p=0.8). Sigmoidoscopy was normal in all PsO patients while two PsA patients had mucosal erythema. Fifteen PsA and all PsO patients showed increased lymphoplasmocytic infiltration of lamina propria. Evidence of active colitis with cryptitis was seen in two and collagenous colitis was seen in seven PsApatients (figure 1). No PsO patient had active or collagenous colitis. <h3>Conclusions</h3> Subclinical gut inflammation was significantly higher in PsA patients in comparison to PsO patients and is more prevalent among those with axial phenotype. <h3>Acknowledgements</h3> IRA <h3>Disclosure of Interest</h3> None declared
Subtype-specific regulatory network rewiring in acute myeloid leukemia
Authors: Salam A. Assi, Maria Rosaria Imperato, Daniel J. L. Coleman, Anna Pickin, Sandeep Potluri, Anetta Ptasinska, Paulynn Suyin Chin, Helen Blair, Pierre Cauchy, Sally R. James, Joaquin Zacarias-Cabeza, L. Niall Gilding, Andrew Beggs, Sam Clokie, Justin C. Loke, Phil Jenkin, Ash Uddin, Ruud Delwel, Stephen J. Richards, Manoj Raghavan, Michael J. Griffiths, Olaf Heidenreich, Peter N. Cockerill, Constanze Bonifer
Journal: Nature Genetics (2018)
Abstract P226: Higher Calcium Density in Abdominal Aortic Calcium (AAC) and Coronary Artery Calcium (CAC) Does Not Increase Risk for Cardiovascular Disease (CVD) Events: The Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Nketi I Forbang, Joachim Ix, Rosemay Remigo-Baker, Matthew Allison, Robyn McClelland, Veit Sandfort, Erin Michos
Journal: Circulation (2016)

Background: AAC and CAC independently and similarly predict CVD events, but only AAC independently predicts all-cause mortality (ACM). The standard calcified plaque score, the Agatston method, up-weights for greater calcium density, thus modeling higher calcium density associated with increased CVD risk. We evaluated this model by comparing associations of density and volume separately of AAC and CAC for incident coronary heart disease (CHD, defined as myocardial infarction, and resuscitated cardiac arrest), CVD (defined as CHD plus stroke and stroke death), and ACM. Methods: Cox-proportional hazard model was used to compare independent associations of AAC and CAC density and volume to CHD, CVD, and ACM, with adjustments for the General Framingham Risk Score (composite of CVD risk factors, predicts 10 year CVD risk), ethnicity and statin therapy. Density was calculated as: Density = Agatston / (volume, mm 3 / CT scan slice thickness, mm). Agatston = area, mm 2 X density. Results: In 997 participants with prevalent AAC and CAC, mean age was 66 ± 9 years, mean AAC density 3.10 ± 0.58, and mean CAC density was 2.75 ± 0.72, 58% were men, 46% were European-, 24% were Hispanic-, 16% were African-, and 13% were Chinese-Americans. Over a mean follow-up of 9 years, there were 77 CHD, 118 CVD, and 169 ACM. Compared to the 0-50 th , the &gt;75 th percentile of AAC density was non-significantly associated with lower ACM but not CHD or CVD (Table). Also, the &gt;75 th percentile of CAC density was non-significantly associated with lower CHD and CVD, but not ACM. In contrast, compared to the 0-50 th , the &gt;75 th percentile of AAC volume was significantly associated with higher CHD, CVD, ACM, and the &gt;75 th percentile of CAC volume was significantly associated with higher CHD, CVD, but not ACM. Conclusion: In mutually adjusted models, although volume of AAC and CAC increased CVD risk, density of AAC and CAC did not. Thus, the Agatston method of up-weighting calcium scores for greater density, in CVD risk prediction, may be inappropriate for the aorta and coronary arteries.
<i>Notes from the Field</i>: Increase in Coccidioidomycosis — Arizona, October 2017–March 2018
Authors: Carla P. Bezold, Mohammed A. Khan, Guillermo Adame, Shane Brady, Rebecca Sunenshine, Ken Komatsu
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

Beginning in October 2017, the Arizona Department of Health Services (ADHS) noted an increase in the number of reported cases of coccidioidomycosis (Figure).According to provisional data (not finalized), the incidence in December 2017 (17.2 per 100,000 population) represented the highest monthly rate in the last 5 years, surpassing the previous peak of 14.2 cases per 100,000 population in September 2015.In total, 4,827 cases of coccidioidomycosis were reported to ADHS during October 2017-March 2018.Whereas case counts typically increase during these months, this particular period represented a 58.3% increase over the 3,050 cases reported during the same months the previous year and a 50.3% increase over the 6-month average of 3,211 cases reported during October-March for the years 2013-2017.Coccidioidomycosis (Valley fever) is an infectious disease caused by inhalation of Coccidioides spores; approximately 40% of infected persons experience signs and symptoms including fever, cough, fatigue, chest pain, shortness of breath, and rash.Coccidioides is endemic in soil in the southwestern United States (1).The majority of reported U.S. coccidioidomycosis cases occur in Arizona (2), and incidence is seasonal: the highest number of reported cases in Arizona typically occurs during the fall and winter months.*Because of the high number of cases in Arizona and the high predictive value of a positive laboratory result, Arizona's coccidioidomycosis case definition requires only laboratory evidence to confirm a case (3).Laboratory evidence can include detection of anticoccidioidal immunoglobulin M (IgM) or immunoglobulin G (IgG) antibodies; culture, histopathologic, or molecular evidence of Coccidioides spp.; or coccidioidal skin test conversion after illness onset.During October 2017-March 2018, the median age of persons with reported coccidioidomycosis was 56 years (interquartile range [IQR] = 39-69 years); approximately half (50.5%) of patients were male.Age and sex distributions were similar to those observed during October 2016-March 2017, with a median age of 57 years, (IQR = 40-69); 51.2% of patients were male.Approximately 90% of persons with reported coccidioidomycosis in Arizona reside in the three most populous counties (Maricopa, Pima, and Pinal).