tbuckley/cabot-search huggingface dataset:
Impact of body composition on outcomes from anti-PD1 +/− anti-CTLA-4 treatment in melanoma
Authors: Arissa C Young, Henry T Quach, Haocan Song, Elizabeth J Davis, Javid J Moslehi, Fei Ye, Grant R Williams, Douglas B Johnson
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Immune checkpoint inhibitors (ICIs) have transformed treatment for melanoma, but identifying reliable biomarkers of response and effective modifiable lifestyle factors has been challenging. Obesity has been correlated with improved responses to ICI, although the association of body composition measures (muscle, fat, etc) with outcomes remains unknown. Methods We performed body composition analysis using Slice-o-matic software on pretreatment CT scans to quantify skeletal muscle index (SMI=skeletal muscle area/height 2 ), skeletal muscle density (SMD), skeletal muscle gauge (SMG=SMI × SMD), and total adipose tissue index (TATI=subcutaneous adipose tissue area + visceral adipose tissue area/height 2 ) of each patient at the third lumbar vertebrae. We then correlated these measures to response, progression-free survival (PFS), overall survival (OS), and toxicity. Results Among 287 patients treated with ICI, body mass index was not associated with clinical benefit or toxicity. In univariable analyses, patients with sarcopenic obesity had inferior PFS (HR 1.4, p=0.04). On multivariable analyses, high TATI was associated with inferior PFS (HR 1.7, p=0.04), which was particularly strong in women (HR 2.1, p=0.03). Patients with intermediate TATI and high SMG had the best outcomes, whereas those with low SMG/high TATI had inferior PFS and OS (p=0.02 for both PFS and OS). Conclusions Body composition analysis identified several features that correlated with improved clinical outcomes, although the associations were modest. As with other studies, we identified sex-specific associations that warrant further study.
Correspondence to ‘Gender gap in rheumatology: speaker representation at annual conferences’ by Monga and Liew—gender discrepancies at annual EULAR congresses: towards the gap narrowing
Authors: Paola Conigliaro, Silvia Laura Bosello, Cristina Iannuccelli, Elisa Gremese, Francesca Romana Spinelli, Marta Vadacca, Maria Sole Chimenti
Journal: Annals of the Rheumatic Diseases (2020)

We read with interest the letter entitled ‘Gender gap in rheumatology: speaker representation at annual conferences’ by Kanika Monga and Jean Liew published in the Annals of the Rheumatic Diseases .1

The authors highlight the issue of a gender gap among speakers and moderators at the academic conferences investigating female representation at the American College of Rheumatology (ACR) in 2017 and 2018. Overall, the proportion of female speakers and moderators was 42.8%–47% and the gap was higher in the clinician sessions presentations compared with basic science ones (45.8% vs 40.5%). The highest proportion of female representation was detected in Alliance for Human Research Protection sessions (65.3%), and the lowest in Meet the Professors and workshop sessions (34.4% and 28.7%). Indeed, the gender gap was narrower as compared with other conferences.2 Recently, European League Against Rheumatism (EULAR) established a task force on gender equity …
Abstract B12: PAX3 translocations co-opt super enhancers and intrinsically disordered fusion partners in rhabdomyosarcoma
Authors: Berkley E. Gryder, Marco Wachtel, Winston Ewert, Kenneth Chang, Osama El Demerdash, Young Song, Beat W Schäfer, Christopher R. Vakoc, Javed Khan
Journal: Cancer Research (2020)

Abstract Chromosomal translocations drive many types of childhood cancer. Fusion-positive rhabdomyosarcoma (FP-RMS) tumors are found most frequently with a fusion between PAX3 and FOXO1, but less frequent translocation partners have been discovered, including INO80D and NCOA1. We hypothesized that all FP-RMS translocations are selecting simultaneously for (1) enhancers active in a myoblast-like epigenome and (2) protein partners with high-levels of intrinsic disorder to give PAX3 enhanced transcriptional strength. Analysis of primary tumors revealed these diverse PAX3 fusions recapitulate a near-identical transcriptome, suggesting uniform underlying molecular mechanisms. ChIP-seq evidence from cell lines and primary tumors suggested that in all FP-RMS tumors, large super-enhancer (SE) elements were present near each chosen translocation partner (distal to FOXO1, INO80D, or NCOA1). Using tools to determine the 3-D folding of chromatin (3C, 4C-seq, and HiChIP), we discovered an extensive network of hijacked FOXO1 enhancers and a SE that physically interact together and with the PAX3 promoter, only in PAX3-FOXO1 positive cells. Furthermore, pooled CRISPR tiling of cis-regulatory elements revealed special dependence on the FOXO1 SE, or certain CTCF boundary elements that facilitate enhancer interactions. ChIP-seq paired to short-term CRISPR experiments shows PAX3-FOXO1 transcription depends on an extended network of related enhancers distal to FOXO1. We find these enhancers are unique to early myoblast stages of differentiation and are bound by myogenic TFs in RMS, suggesting miswiring of normal myogenic enhancer logic. While many SE-driven genes exist in FP-RMS, most are never selected for translocation partners. We found that FOXO1, INO80D, and NCOA1 are all highly disordered proteins, a theme they hold in common despite having no amino acid sequence homology. Initial evidence suggests that PAX3-FOXO1 enables the formation of phase condensates in the nucleus that recruit high-levels of transcriptional machinery such as BRD4. Ongoing work is exploring the mechanistic chemical determinants of these interactions, and how phase condensates are manipulated by drugs that block PAX3-FOXO1’s transcriptional output. Together our studies are illuminating new paradigms for understanding how fusion transcription factors drive cancer. Citation Format: Berkley E. Gryder, Marco Wachtel, Winston Ewert, Kenneth Chang, Osama El Demerdash, Young Song, Beat W Schäfer, Christopher R. Vakoc, Javed Khan. PAX3 translocations co-opt super enhancers and intrinsically disordered fusion partners in rhabdomyosarcoma [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B12.
Diagnosing adrenal insufficiency using ACTH stimulation test
Authors: Alexandra M. Nanzer, Grainne D'Ancona, Philip A. Kelly, David J. Jackson
Journal: European Respiratory Journal (2020)

We acknowledge B. Lipworth's work and significant contribution in highlighting the metabolic consequences of steroid therapy in airways disease over the past decades. In their letter he and colleagues refer to a post-synthetic adrenocorticotropic hormone (ACTH, Synacthen) cortisol level of 500 nmol·L−1 as the accepted cut-off to diagnose impaired adrenal function. These diagnostic values were derived using older cortisol assays; however, the cortisol levels in our report relate specifically to the newer Roche Elecsys II Cortisol assay used at our centre that gives, on average, 25% lower serum cortisol values, with a cut-off of ≥420 nmol·L−1 for the 250 µg intramuscular short Synacthen test (SST) at 30 or 60 min [1]. The median cortisol level after SST was 490 nmol·L−1 (interquartile range (IQR) 453–620 nmol·L−1) in patients who passed the SST; in those who failed the SST the cortisol level after SST was 262 nmol·L−1 (IQR 130–310 nmol·L−1). When to wean? Steroid stewardship in the biologic era <https://bit.ly/3cOL94R>
The Design of Vaccines Based on the Shielding of Antigenic Site Ø of a Respiratory Syncytial Virus Fusion Protein Immunogen
Authors: Steven J. Frey, Chad Varner, Ammar Arsiwala, Michael G. Currier, Martin L. Moore, Ravi S. Kane
Journal: Advanced Healthcare Materials (2020)

Abstract Respiratory syncytial virus (RSV), for which there is currently no licensed vaccine, displays a fusion (F) protein that is considered a vaccine target. This protein has an antigenic site called site Ø, which has been shown to elicit potent, neutralizing antibodies and has therefore been considered important in the formulation of RSV vaccines. However, this site is also the least conserved region on the F protein across RSV subtypes. Therefore, directing the immune response away from site Ø and refocusing it toward more conserved parts of the RSV F protein might serve to better elicit broadly neutralizing antibodies. To demonstrate that directing the immune response away from site Ø is a viable approach, a prefusion F‐based vaccine based on an F protein with a shielded site Ø is generated. Sera from mice immunized with multivalent scaffolds presenting this immunogen is capable of neutralizing RSV of both subtypes. This result may have application in the development of an effective and broadly protective RSV vaccine.
Abstract A60: Transcriptional profile of CD56negCD16pos Natural Killer cells within endemic Burkitt lymphoma
Authors: Catherine S. Forconi, Cliff Oduor, John M. Ong’echa, Jeff Bailey, Ann M. Moormann
Journal: Cancer Research (2020)

Abstract Endemic Burkitt lymphoma (eBL), the most common pediatric cancer in equatorial Africa, has long been associated with two etiologic agents: Epstein-Barr virus (EBV) and Plasmodium falciparum malaria. On the other hand, Natural Killer (NK) cells are essential in the clearance of infected cells as well as play a critical role in tumor immunosurveillance. Despite chronic viral infections as HIV, HCV, which have been found to promote the expansion of a CD56 (negative) NK cell subset with impaired effector function, previous cancer studies have been limited to investigations of CD56dimCD16pos NK cells. We previously published that eBL children had significantly more CD56negCD16pos NK cells compared to age-matched healthy children from a low and high malaria transmission area. Here, we characterized this CD56negCD16pos NK subset using histology staining, multicolor flow cytometry, and RNA-sequencing. We found CD56negCD16pos NK cells to be morphologically similar to CD56dimCD16pos NK cells but had higher expression of FCGR3B (CD16b) (p=0.000008) and MPEG1 (Perforin 2) (p=0.0000007), and lower expression of KLRF1 (NKp80), IL18RAP and IL18R1 (IL18 receptor) (p=0.000003, p=0.000003 and p=0.00005, respectively). Phenotypically, CD56negCD16pos NK cells share characteristics of adaptive NK cells; however, they differ from “memory-like” NK cells, with consistent expression of NKG2C/CD57, lower expression of NKp46 and CD160, and higher expression of KIR3DL1 compared to CD56dimCD16pos NK cells. Finally, higher plasma levels of IL-12p70 and IL-2 (known to help NK cell activation and proliferation) and IL-6 and MIP1a were found in healthy compared to eBL children. Together, these findings suggest that the expansion of CD56negCD16pos NK cells could help explain diminished tumor immunosurveillance and might be a mechanism by which EBV-infected cells evades NK-cell mediated immunity. Citation Format: Catherine S. Forconi, Cliff Oduor, John M. Ong’echa, Jeff Bailey, Ann M. Moormann. Transcriptional profile of CD56negCD16pos Natural Killer cells within endemic Burkitt lymphoma [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A60.
A Seven Gene Signature to Distinguish Bortezomib- and Lenalidomide-Responsive Myeloma: Rnaseq from the Padimac Study
Authors: Michael Chapman, Jonathan Sive, John Ambrose, Claire Roddie, Nicholas Counsell, Paul Smith, Nivette Braganza, Toyin Adedayo, Rakesh Popat, James D Cavenagh, Matthew J. Streetly, Roger G. Owen, Stephen Schey, Mickey Koh, Josephine Crowe, Michael F. Quinn, Shirley D'Sa, Andres E. Virchis, Gordon Cook, Charles R Crawley, Guy Pratt, Mark Cook, Laura Clifton-Hadley, Javier Herrero, Kwee Yong
Journal: Blood (2017)
Abstract A43: Effects of transcriptional dysregulation on the DNA damage response in Ewing’s sarcoma
Authors: Matthew G. Rollins, Jacob C. Schwartz
Journal: Cancer Research (2020)

Abstract Ewing’s sarcoma is a soft-tissue bone malignancy characterized by a translocation event wherein the N-terminal low complexity domain of EWSR1 is fused with the DNA binding domain of the ETS transcription factor Fli1. The resulting EWS-Fli1 fusion protein drives expression of oncogenes and knockdown of tumor-suppressor proteins. More specifically, EWS-Fli1 acts as transcriptional regulator by helping recruit RNA Pol II to promoter regions, which is subsequently phosphorylated by CDK9 to escape initiation into elongation. Interestingly, Ewing’s sarcoma is particularly susceptible to chemotherapy compared to other cancers; however, the underlying reason for this sensitivity to DNA damage has not been elucidated. Given EWS-Fli1’s role in disrupting transcription, it was hypothesized that EWS-Fli1 is concurrently disrupting the DNA damage response. Here, a combination of CDK9 inhibition with DNA damage was found to drastically diminish cell viability in Ewing’s cell lines but not in non-Ewing’s osteosarcoma or HEK293 cells. Ordinarily, after DNA damage γH2A.X phosphorylation occurs on histones near sites of damaged DNA early during the DNA damage response to signal DNA damage repair initiation. Further work has shown Ewing’s cells undergoing the combination treatment above have a marked decrease in the DNA damage marker γH2A.X as compared to non-Ewing’s cells. Together, these results suggest Ewing’s sarcoma cells are sensitized to DNA damage due in part to transcriptional dysregulation. Citation Format: Matthew G. Rollins, Jacob C. Schwartz. Effects of transcriptional dysregulation on the DNA damage response in Ewing’s sarcoma [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A43.
A multilayered epithelial mucosa model of head neck squamous cell carcinoma for analysis of tumor-microenvironment interactions and drug development
Authors: Leonie Gronbach, Christopher Wolff, Konrad Klinghammer, Johannes Stellmacher, Philipp Jurmeister, Ulrike Alexiev, Monika Schäfer-Korting, Ingeborg Tinhofer, Ulrich Keilholz, Christian Zoschke
Journal: Biomaterials (2020)
Lactoferrin-mediated macrophage targeting delivery and patchouli alcohol-based therapeutic strategy for inflammatory bowel diseases
Authors: Yuge Zhao, Yuting Yang, Jiaxin Zhang, Rong Wang, Biyun Cheng, Dipika Kalambhe, Yingshu Wang, Zeyun Gu, Dongying Chen, Bing Wang, Yongzhuo Huang
Journal: Acta Pharmaceutica Sinica B (2020)

Inflammatory bowel diseases (IBD) are the incurable chronic recurrent gastrointestinal disorders and currently lack in safe and effective drugs. In this study, patchouli alcohol, a main active compound of traditional Chinese herb patchouli, was developed into biomimetic liposomes for macrophage-targeting delivery for IBD treatment. The developed lactoferrin-modified liposomes (LF-lipo) can specifically bind to LRP-1 expressed on the activated colonic macrophages and achieve cell-targeting anti-inflammatory therapy. LF-lipo reduced the levels of inflammatory cytokines and ROS and suppressed the MAPK/NF-κB pathway. LF-lipo also suppressed the formation of NLRP3 inflammasome and the consequent IL-1β activation. LF-lipo showed improved therapeutic efficacy in a DSS-induced colitis murine model, evidenced by the reduced disease activity index, the improved colon functions, and the downregulated inflammatory cytokines in the colon. LF-lipo provided an effective and safe macrophage-targeting delivery and therapeutic strategy for addressing the unmet medical need in IBD management.
Diagnosing adrenal insufficiency using ACTH stimulation test
Authors: Brian Lipworth, Rory Chan, Chris RuiWen Kuo
Journal: European Respiratory Journal (2020)

We read with interest the real-world data of Nanzer et al. [1], looking at adrenal insufficiency (AI) in severe asthma patients taking oral corticosteroid-sparing anti-interleukin (IL)-5 therapy. They reported that 43% of patients apparently failed a short adrenocorticotropic hormone (ACTH) stimulation test associated with a median baseline morning serum cortisol of 86 nmol·L−1 and a median prednisolone dose of 5 mg. We would be interested to know the mean cortisol level after ACTH, as well as the percentage of patients who failed to achieve a post-ACTH level of 500 nmol·L−1 which is the accepted cut-off for impaired response [2, 3]. Low dose ACTH stimulation test is more likely to detect adrenal insuffiency in patients being weaned off oral corticosteroids <https://bit.ly/2XsMA3i>
Avoiding duodenal biopsy in investigating coeliac disease during covid-19
Authors: Ian L P Beales
Journal: BMJ (2020)

<b>Objective</b> This study9s purpose was to obtain a quantitative natural history of the cerebrovascular involvement in Fabry disease. <b>Background</b> Fabry disease is an X-linked recessive disorder due to a-galactosidase A deficiency. Progressive accumulation of ceramidetrihexoside within the intima and media of cerebral blood vessels causes ischemic lesions in the majority of affected patients. Determination of the natural history of the cerebral vasculopathy in Fabry disease is important to assess the effects of therapeutic intervention in this disorder. <b>Methods</b> A longitudinal MRI study of 50 patients who had a total of 129 MRI scans was performed. The burden of cerebrovascular disease was determined using direct linear measurement. <b>Results</b> On T2-weighted MRI scans, 32% of the patients had no lesions (mean age, 33 years), 16% had gray matter lesions only (mean age, 36 years), 26% had lesions in white matter only (mean age, 43 years), and 26% had lesions in white and gray matter (mean age, 47 years). Disease burden increased with age, but no patient younger than 26 had lesions on MRI. All patients older than 54 had cerebrovascular involvement. The distribution of MRI-detectable lesions was typical of a small-vessel disease. Only 37.5% of patients with cerebral lesions had neurologic symptoms. <b>Conclusion</b> These findings provide a predictable outcome measure to assess the effect of molecular interventions on the cerebrovascular circulation in Fabry disease.
Asthma among hospitalized patients with COVID-19 and related outcomes
Authors: Stephanie Lovinsky-Desir, Deepti R. Deshpande, Aliva De, Laurie Murray, Jeanette A. Stingone, Angela Chan, Neha Patel, Nooralam Rai, Emily DiMango, Joshua Milner, Meyer Kattan
Journal: Journal of Allergy and Clinical Immunology (2020)
Characteristics and Outcome of Philadelphia(Ph) Negative Myeloproliferative Neoplasms(MPN) in Patients Younger Than 45 Years - a Multicenter Retrospective Study
Authors: Merav Barzilai, Ilya Kirgner, Martin Ellis, Irit Avivi, Najib Dally, Uri Rozovski, Noa Lavi
Journal: Blood (2017)
Abstract A65: Alveolar soft part sarcoma in children and adolescents: A single-institute retrospective analysis
Authors: Se Na Kang, Jung Yoon Choi, Bo Kyung Kim, Hong Yul Ahn, Kyung Taek Hong, Hyoung Jin Kang, Han Soo Kim, Jung Eun Cheon, Sung Hye Park, Hee Young Shin
Journal: Cancer Research (2020)

Abstract Background: Alveolar soft part sarcoma (ASPS) is a rare soft tissue tumor that typically affects young patients. Because of the rarity of the disease, the standard treatment is not established. The aim of this study is to evaluate the clinical characteristics and treatment outcomes of pediatric ASPS. Method: A retrospective study was conducted on children and adolescents treated for ASPS at a single center between 2000 and 2018. Results: A total number of 11 patients were evaluated. Median age at diagnosis was 12.6 (range 3.8-16.3) years. Nine (82%) were female. The most common primary sites were limbs (64%). IRS postsurgical clinical group (IRS CG) was I in 2 (18%), III in 3 (27%), and IV in 6 (55%) patients. Of 9 patients with IRS CG III and IV who received chemotherapy, one had a complete response, two had a partial response, and six had progressive disease. One patient showed SD to sunitinib. The 5-year event-free survival (EFS) and overall survival (OS) rates were 31% and 88%, respectively. The 5-year EFS rate by primary site was 50% for the 7 patients with extremity and 0% for the 4 patients with head and neck (P-value = 0.001). The 5-year OS rate by the primary site was 100% for the 7 patients with extremity and 50% for the 4 patients with head and neck (P-value = 0.027). Conclusion: Localized ASPS has a good prognosis after total resection. If the primary site is head and neck, the prognosis is poor due to difficulty in surgical resection. Chemotherapy and radiation therapy have limitations in the cure for patients with metastatic disease. Further studies of ASPS need to achieve development in treatment. Citation Format: Se Na Kang, Jung Yoon Choi, Bo Kyung Kim, Hong Yul Ahn, Kyung Taek Hong, Hyoung Jin Kang, Han Soo Kim, Jung Eun Cheon, Sung Hye Park, Hee Young Shin. Alveolar soft part sarcoma in children and adolescents: A single-institute retrospective analysis [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A65.
Trends in Female Representation on NCCN Guideline Panels
Authors: Pranammya Dey, Angela K. Green, Michael Haddadin, Peter B. Bach, Aaron P. Mitchell
Journal: Journal of the National Comprehensive Cancer Network (2020)

NCCN produces highly influential disease-specific oncology clinical practice guidelines. Because the number of women in academic oncology has increased, we assessed whether the composition of NCCN Guidelines Panels reflected this trend.Using historical guidelines requested from NCCN, we investigated time trends for female representation on 21 NCCN Guidelines Panels and analyzed the trends for female-predominant cancers (breast, ovarian, uterine, and cervical) compared with all cancers.From 2013 to 2019, there was an increase from 123 women of 541 total panelists (22.7%) to 175 women of 542 panelists (32.3%). Within the 4 female-predominant cancers, the increase was more rapid: from 30 of 101 total panelists (29.7%) to 66 of 118 panelists (56.4%). Excluding female-predominant cancers, increases were minimal.There could be multiple explanations for these differing trends, including the possibility of more rapid increases in the underlying pool of female physician-scientists in female-predominant specialties or more efforts to increase the representation of women in decisions about the standard of care in cancers predominantly affecting women.
Extracorporeal CO<sub>2</sub> removal for stable hypercapnic COPD: is it really worth it?
Authors: Marieke L Duiverman, Peter J Wijkstra
Journal: Thorax (2020)

daytime or nocturnal NIV.Taking this into account, maybe in the future, with advances in the technology, ECCO 2 R would gain its place in a selected group of advanced stable
Abstract 10833: Small Dense Low-density Lipoprotein Cholesterol as a Predictor for Rapid Progression of Non-culprit Lesion in Patients With Acute Coronary Syndrome
Authors: Teruo Sekimoto, Shinji Koba, Toshiro Shinke, Ken Arai, Yousuke Oishi, Kunihiro Ogura, Hiroaki Tsujita, Seita Kondo, Hideaki Tanaka, Makoto Shoji
Journal: Circulation (2019)

Background: It remains unclear whether small dense low-density lipoprotein cholesterol (sd-LDL-C), highly atherogenic LDL can predict rapid progression (RP) of coronary artery disease in patients u...
Extreme Vulnerability of Home Care Workers During the COVID-19 Pandemic—A Call to Action
Authors: Theresa A. Allison, Anna Oh, Krista L. Harrison
Journal: JAMA Internal Medicine (2020)

Madeline R. Sterling, MD, MPH, MS; Emily Tseng, MS; Anthony Poon, BS; Jacklyn Cho, BS; Ariel C. Avgar, PhD; Lisa M. Kern, MD, MPH; Claire K. Ankuda, MD, MPH; Nicola Dell, PhD