tbuckley/cabot-search huggingface dataset:
Comparison of Remission and Lupus Low Disease Activity State in Damage Prevention in a United States Systemic Lupus Erythematosus Cohort
Authors: Michelle Petri, Laurence S. Magder
Journal: Arthritis & Rheumatology (2018)

Objective One objective in the treatment of systemic lupus erythematosus ( SLE ) disease activity is to reduce long‐term rates of organ damage. We undertook this study to analyze data from a large clinical SLE cohort to compare patients achieving different levels of disease activity with respect to rates of long‐term damage. Methods We analyzed data from 1,356 SLE patients in the Hopkins Lupus Cohort, followed up quarterly, with 77,105 person‐months observed from 1987 to 2016. Three outcome measures were considered: clinical remission with no treatment, clinical remission on treatment, and lupus low disease activity state ( LLDAS ). Results Patients achieved LLDAS in 50% of their follow‐up months. They achieved clinical remission with no treatment or clinical remission on treatment in only 13% and 27%, respectively, of their follow‐up visits. The rates of damage consistently declined with increased percentage of prior time in either LLDAS or clinical remission on treatment. Spending a short proportion of prior time (&lt;25%) in clinical remission on treatment was associated with a relatively low rate of damage compared to never achieving that condition (1.01 events per 10 person‐years versus 1.82 events per 10 person‐years; rate ratio 0.54, P &lt; 0.0001). Those patients who experienced LLDAS at least 50% of the time had relatively low rates of damage (rate ratio 0.39–0.47, P &lt; 0.0001). Conclusion LLDAS is an easier target to achieve than clinical remission on treatment and results in reduced risk of long‐term damage. However, even a small percentage of time in clinical remission on treatment was associated with reduced damage.
Skin Wound Healing: Micelle‐Coated, Hierarchically Structured Nanofibers with Dual‐Release Capability for Accelerated Wound Healing and Infection Control (Adv. Healthcare Mater. 11/2018)
Authors: Victoria Albright, Meng Xu, Anbazhagan Palanisamy, Jun Cheng, Mary Stack, Beilu Zhang, Arul Jayaraman, Svetlana A. Sukhishvili, Hongjun Wang
Journal: Advanced Healthcare Materials (2018)

Healing of chronic wounds is challenging because of the imbalance of growth factors and common occurrence of infection. In article 1800132, Svetlana A. Sukhishvili and co-workers develop a dual-releasing, multiscale system of biodegradable nanofibers to simultaneously accelerate wound healing and mitigate bacterial infection. A unique strategy of submicron topography provided by the surface-bound polymer micelles enables accelerated wound healing and supported localized delivery of antibiotics. Cover image designed and produced by Victor Selin.
Notch-Induced Myeloid Reprogramming in Spontaneous Pancreatic Ductal Adenocarcinoma by Dual Genetic Targeting
Authors: Phyllis F. Cheung, Florian Neff, Christian Neander, Anna Bazarna, Konstantinos Savvatakis, Sven-Thorsten Liffers, Kristina Althoff, Chang-Lung Lee, Everett J. Moding, David G Kirsch, Dieter Saur, Alexandr V. Bazhin, Marija Trajkovic-Arsic, Mathias F. Heikenwalder, Jens T. Siveke
Journal: Cancer Research (2018)

Despite advances in our understanding of the genetics of pancreatic ductal adenocarcinoma (PDAC), the efficacy of therapeutic regimens targeting aberrant signaling pathways remains highly limited. Therapeutic strategies are greatly hampered by the extensive desmoplasia that comprises heterogeneous cell populations. Notch signaling is a contentious pathway exerting opposite roles in tumorigenesis depending on cellular context. Advanced model systems are needed to gain more insights into complex signaling in the multilayered tumor microenvironment. In this study, we employed a dual recombinase-based in vivo strategy to modulate Notch signaling specifically in myeloid cells to dissect the tumorigenic role of Notch in PDAC stroma. Pancreas-specific KrasG12D activation and loss of Tp53 was induced using a Pdx1-Flp transgene, whereas Notch signaling was genetically targeted using a myeloid-targeting Lyz2-Cre strain for either activation of Notch2-IC or deletion of Rbpj. Myeloid-specific Notch activation significantly decreased tumor infiltration by protumorigenic M2 macrophages in spontaneous endogenous PDAC, which translated into significant survival benefit. Further characterization revealed upregulated antigen presentation and cytotoxic T effector phenotype upon Notch-induced M2 reduction. This approach is the first proof of concept for genetic targeting and reprogramming of myeloid cells in a complex disease model of PDAC and provides evidence for a regulatory role of Notch signaling in intratumoral immune phenotypes.Significance: This study provides insight into the role of myeloid-dependent NOTCH signaling in PDAC and accentuates the need to dissect differential roles of signaling pathways in different cellular components within the tumor microenvironment. Cancer Res; 78(17); 4997-5010. ©2018 AACR.
Efficacy of sacituzumab govitecan (anti-Trop-2-SN-38 antibody-drug conjugate) for treatment-refractory hormone-receptor positive (HR+)/HER2- metastatic breast cancer (mBC).
Authors: Aditya Bardia, Jennifer Robinson Diamond, Linda T. Vahdat, Sara M. Tolaney, Joyce O'Shaughnessy, Rebecca L. Moroose, Ingrid A. Mayer, Vandana Gupta Abramson, Dejan Juric, Robert M. Sharkey, Sarah A. Washkowitz, William A. Wegener, David M. Goldenberg, Kevin Kalinsky
Journal: Journal of Clinical Oncology (2018)

1004 Background: Sacituzumab govitecan is a novel antibody-drug conjugate consisting of SN-38, the active metabolite of irinotecan, conjugated to a humanized mAb targeting Trop-2 (trophoblastic antigen-2), which is highly expressed in many epithelial cancers. A phase I/II basket trial (NCT01631552) investigated its activity in patients (pts) with advanced cancers, and we previously reported on pts with triple-negative mBC. Results in HR+/ HER2 negative (as per ASCO/CAP guidelines) mBC pts who had ≥ 1 prior hormonal therapy are presented here. Methods: Pts received sacituzumab govitecan at a dose of 10 mg/kg on days 1 & 8 of a 21-day cycle until progression or unacceptable toxicity. Eligibility included ≥ 1 prior line of standard therapy for metastatic disease, measurable disease by CT or MRI. Efficacy was assessed locally by RECIST 1.1. Adverse events (AE) were evaluated according to CTCAE v4.0, Results: Fifty-four pts with HR+/HER2- mBC (all female; median age 54 yrs, range 33-79) were accrued between 2/2015 and 6/2017. For metastatic disease, all pts received at least 2 prior treatments, with a median of 3 prior hormonal agents and 2 prior chemotherapy regimens. Prior treatments in any setting included taxane (93%), anthracycline (69%) and CDK 4/6 inhibitors (69%). 16 pts have died, 27 are in long-term follow-up and 11 still on treatment. The median number of doses was 11 (range 1-74). Treatment was generally well tolerated, with no treatment-related deaths. Based on currently available AE data, grade ≥ 3 toxicity (≥10%) included neutropenia and leukopenia; there was 1 case each of grade ≥ 3 diarrhea and febrile neutropenia. As of 12/31/2017 data cutoff, the overall response rate (ORR) was 31% (17 PRs/54) by local assessment, and the clinical benefit rate (CBR: PR+SD > 6 months) was 48%. For pts who received CDK inhibitors, ORR was 24% (9 PRs/37). Maturing durability of response and progression-free survival to be presented at the meeting. Conclusions: Sacituzumab govitecan as a single agent induced objective responses in heavily pre-treated HR+/HER2neg mBC, and was well tolerated with a safety profile consistent with previous reports. Clinical trial information: NCT01631552.
Molecular, biologic and clinical profiling of chromosomal instable, hormone receptor positive, invasive ductal breast cancer (IDBC).
Authors: David Demanse
Journal: Journal of Clinical Oncology (2018)

e12524 Background: The relationship between sporadic breast cancer and the accumulation of molecular abnormalities resulting from estrogens and other carcinogens is well established. The spectrum of molecular changes is diverse, including numerical or structural chromosomal abnormalities, gene expression alterations and epigenetic changes. The objective of this study was to determine the molecular profile of the subpopulation of ER and/or PR positive, HER2 negative IDBCs of the METABRIC collection (N = 1.104) characterized by high chromosomal instability (25%). Methods: Clinical-pathologic and genomic variables (oncogenic mutations/CNVs, gene expression) were used to develop a parsimonious prognostic model for disease free survival using a robust, innovative statistics approach combined with cross-validation methodology. The predictive accuracy of the different sets of information was assessed using time-dependent ROC curves. Results: Common molecular features of this IDBC subpopulation include RB deficiency, TP53 loss-of-function mutation (41%), 11q13-14 (30%) and/or 8p11-12 (25%) amplification and PIK3CA gain-of-function mutation (32%). Hallmarks include high proliferation activity, defect apoptosis, epithelial-mesenchymal- transformation (EMT), BRCA-ness, multiple-drug resistance (MDR) and early relapse. Classification based on clinical-pathologic baseline variables revealed a subgroup of tumors with low (35%) and another one with high distant recurrence risk at 5 years (65%). The estimated relapse-free-survival rate at 5 years of the whole group of chromosomal instable, ER and/or PR positive, HER2 negative IDBCs was statistically significantly shorter compared to chromosomal stable luminal IDBCs (77% [95%CI: 72; 82] vs 91% [89; 93]) and comparable to the group of triple negative IDBCs of the METABRIC collection (70% [95%CI: 65; 76]). Conclusions: Collectively our data suggest that chromosomal instable, luminal IDBCs represent a novel and unique entity of luminal breast cancers of very high medical need. Implications for the molecular diagnosis of this entity of luminal breast cancers and their treatment will be discussed.
Comment on: ‘Aberrant tRNA processing causes an autoinflammatory syndrome responsive to TNF inhibitors’ by Giannelou <i>et al</i>: mutations in <i>TRNT1</i> result in a constitutive activation of type I interferon signalling
Authors: Marie-Louise Frémond, Isabelle Melki, Sven Kracker, Vincent Bondet, Darragh Duffy, Gillian I Rice, Yanick J Crow, Brigitte Bader-Meunier
Journal: Annals of the Rheumatic Diseases (2018)

We read with great interest the paper of Giannelou et al 1 reporting, for the first time, the efficacy of tumour necrosis factor (TNF) inhibitors in sideroblastic anaemia with immunodeficiency, fevers and developmental delay (SIFD). These authors also demonstrated high levels of interleukin (IL)-6, IL-12p40, IL-18, interferon (IFN)-γ and IFN-induced chemokines (IP-10 and MIG) in two patients. Herein, we wish to highlight that an activation of the type I IFN pathway may also be observed in SIFD.

Patient 1 (P1) was a 12-month-old girl referred because of recurrent attacks of fever from the age of 2 months, with or without documented infections, and failure to thrive. C-reactive protein (CRP) levels were elevated during each episode. Infections consisted of recurrent septicaemias. Aseptic febrile manifestations included vulvitis, parotiditis, adenitis and neutrophilic panniculitis. A chronic microcytic anaemia and low levels of serum IgG, IgA and IgM were noted from 2 months of age. She developed progressive lymphopenia with undetectable levels of B lymphocytes and CD27+ B memory cells by age 15 months, so that intravenous immunoglobulin (IVIG) (400 mg/kg/month) was initiated at this time. At last follow-up, aged 6 years, her height and development were normal and she was no longer subject to …
Integrative Modeling Identifies Key Determinants of Inhibitor Sensitivity in Breast Cancer Cell Lines
Authors: Katarzyna Jastrzebski, Bram Thijssen, Roelof J.C. Kluin, Klaas de Lint, Ian J. Majewski, Roderick L. Beijersbergen, Lodewyk F.A. Wessels
Journal: Cancer Research (2018)

Abstract Cancer cell lines differ greatly in their sensitivity to anticancer drugs as a result of different oncogenic drivers and drug resistance mechanisms operating in each cell line. Although many of these mechanisms have been discovered, it remains a challenge to understand how they interact to render an individual cell line sensitive or resistant to a particular drug. To better understand this variability, we profiled a panel of 30 breast cancer cell lines in the absence of drugs for their mutations, copy number aberrations, mRNA, protein expression and protein phosphorylation, and for response to seven different kinase inhibitors. We then constructed a knowledge-based, Bayesian computational model that integrates these data types and estimates the relative contribution of various drug sensitivity mechanisms. The resulting model of regulatory signaling explained the majority of the variability observed in drug response. The model also identified cell lines with an unexplained response, and for these we searched for novel explanatory factors. Among others, we found that 4E-BP1 protein expression, and not just the extent of phosphorylation, was a determinant of mTOR inhibitor sensitivity. We validated this finding experimentally and found that overexpression of 4E-BP1 in cell lines that normally possess low levels of this protein is sufficient to increase mTOR inhibitor sensitivity. Taken together, our work demonstrates that combining experimental characterization with integrative modeling can be used to systematically test and extend our understanding of the variability in anticancer drug response. Significance: By estimating how different oncogenic mutations and drug resistance mechanisms affect the response of cancer cells to kinase inhibitors, we can better understand and ultimately predict response to these anticancer drugs. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/15/4396/F1.large.jpg. Cancer Res; 78(15); 4396–410. ©2018 AACR.
T cells establish and maintain CNS viral infection in HIV-infected humanized mice
Authors: Jenna B. Honeycutt, Baolin Liao, Christopher C. Nixon, Rachel A. Cleary, William O. Thayer, Shayla L. Birath, Michael D. Swanson, Patricia Sheridan, Oksana Zakharova, Francesca Prince, JoAnn Kuruc, Cynthia L. Gay, Chris Evans, Joseph J. Eron, Angela Wahl, J. Victor Garcia
Journal: Journal of Clinical Investigation (2018)

The human brain is an important site of HIV replication and persistence during antiretroviral therapy (ART). Direct evaluation of HIV infection in the brains of otherwise healthy individuals is not feasible; therefore, we performed a large-scale study of bone marrow/liver/thymus (BLT) humanized mice as an in vivo model to study HIV infection in the brain. Human immune cells, including CD4+ T cells and macrophages, were present throughout the BLT mouse brain. HIV DNA, HIV RNA, and/or p24+ cells were observed in the brains of HIV-infected animals, regardless of the HIV isolate used. HIV infection resulted in decreased numbers of CD4+ T cells, increased numbers of CD8+ T cells, and a decreased CD4+/CD8+ T cell ratio in the brain. Using humanized T cell–only mice (ToM), we demonstrated that T cells establish and maintain HIV infection of the brain in the complete absence of human myeloid cells. HIV infection of ToM resulted in CD4+ T cell depletion and a reduced CD4+/CD8+ T cell ratio. ART significantly reduced HIV levels in the BLT mouse brain, and the immune cell populations present were indistinguishable from those of uninfected controls, which demonstrated the effectiveness of ART in controlling HIV replication in the CNS and returning cellular homeostasis to a pre-HIV state.
Abstract 12295: Utilization of Whole-Exome Sequencing to Identify Causative Mutations in Familial Congenital Heart Disease
Authors: Stephanie LaHaye, Don Corsmeier, Jessica L Bowman, Sara Fitzgerald-Butt, Gloria Zender, Kevin Bosse, Kim L McBride, Peter White, Vidu Garg
Journal: Circulation (2015)

Congenital heart disease (CHD) is the most common type of birth defect, affecting ~8 out of every 1,000 live births, but there remains a limited understanding of the etiology for the majority of cases of CHD. Familial and population based studies have identified a strong genetic component to CHD, and familial cases of almost every type of CHD have been reported. The goal of this study was to identify pathogenic segregating variants in multiplex CHD families by whole-exome sequencing (WES). Target capture was performed using the Agilent SureSelectXT Target Enrichment kit, followed by WES on an Illumina HiSeq2500, on members from 9 families with Mendelian inherited CHD. Sequence alignment, post alignment processing, variant calling, and genotyping was performed with the Churchill pipeline. Tertiary analysis and annotation consisted of identifying rare (&lt;1% mean allele frequency in the population) segregating variants, prioritizing by matching to a CHD gene list, and predicting pathogenicity via 12 different utilities. This strategy utilized a list of 69 CHD genes selected under strict criteria and allowed for prioritization of the variants. Predicted pathogenic mutations were identified in 3 of the 9 families. A splice donor site mutation was identified in MYH11 (c.4599+1delC) in a family with autosomal dominant patent ductus arteriosus that is predicted to cause a 71 amino acid deletion, affecting functionality of the coiled-coil tail domain. A GATA4 mutation, p.G115W , was identified in a family with autosomal dominant atrial septal defects (ASD) and is predicted to affect the transactivation ability of GATA4 . A p.I263V mutation in TLL1 was identified in a family with autosomal dominant ASD; as this mutation was located in the astacin-like metalloprotease catalytic domain it is predicted to affect the enzymatic efficacy of TLL1 . In summary, our findings demonstrate the clinical utility of WES to successfully identify causative mutations in familial CHD and support the use of a CHD candidate gene list to allow for a more streamlined approach that enables rapid prioritization and identification of pathogenic variants from large WES data sets.
AZD5363 plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (PAKT): A randomised, double-blind, placebo-controlled, phase II trial.
Authors: Peter Schmid, Jacinta Abraham, Stephen Chan, Duncan Wheatley, Murray Brunt, Gia Nemsadze, Richard Baird, Yeon Hee Park, Peter Hall, Timothy Perren, Robert C. Stein, Mangel László, Jean-Marc Ferrero, Melissa Phillips, John Conibear, Shah-Jalal Sarker, Aaron Prendergast, Hayley Cartwright, Kelly Mousa, Nicholas C. Turner
Journal: Journal of Clinical Oncology (2018)

1007 Background: The PI3K/AKT signalling pathway is frequently activated in triple-negative breast cancer (TNBC). AZD5363 is a highly-selective, oral, small molecule AKT inhibitor. The PAKT trial investigated the addition of AZD5363 to paclitaxel as 1st-line therapy for TNBC. Methods: This investigator-led, double-blind, placebo-controlled, randomised phase II trial, recruited women with previously untreated, metastatic TNBC at 42 sites in 6 countries. Patients were randomly assigned (1:1) to paclitaxel 90mg/m2 (days 1, 8, & 15) with either AZD5363 (400mg BD) or placebo (days 2-5, 9-12, 16-19) every 28 days until disease progression or unacceptable toxicity. The primary endpoint was progression‐free survival (PFS). Secondary endpoints included overall survival (OS), PFS in the subgroup with PIK3CA/AKT1/PTEN-alterations, response, and safety. Results: Between 05/2014 and 06/2017, 140 patients were randomised to paclitaxel + AZD5363 (n = 70) or paclitaxel + placebo (n = 70). Median duration of follow-up was 18.2 months (95% CI, 13.6 to 24.0). In the ITT analysis, median PFS was 5.9 months (m) for AZD5363 compared to 4.2m for placebo (hazard ratio [HR], 0.75; 95% CI, 0.52 to 1.08; one-sided p = 0.06; two-sided p = 0.11 [predefined significance level of 0.10, one-sided]). Median OS was 19.1m for AZD5363 compared to 12.6m for placebo (HR, 0.64; 95% CI, 0.40 to 1.01; one-sided p = 0.02; two-sided p = 0.04). Results for the subgroup with PIK3CA/AKT1/PTEN-altered tumours will be presented. Most common grade 3 or worse adverse events were diarrhoea (12% [8/68] of AZD5363-treated patients vs 1% [1/70] of placebo-treated patients), infection (4% vs 1%), neutropenia (3% vs 3%), rash (4% vs 0) and fatigue (4% vs 0). Conclusions: The trial met its primary endpoint. Addition of AZD5363 to 1st-line paclitaxel therapy for TNBC resulted in significantly longer PFS and OS. AZD5363 warrants further investigation for the treatment of TNBC. Clinical trial information: NCT02423603.
ER Lipid Defects in Neuropeptidergic Neurons Impair Sleep Patterns in Parkinson’s Disease
Authors: Jorge S. Valadas, Giovanni Esposito, Dirk Vandekerkhove, Katarzyna Miskiewicz, Liesbeth Deaulmerie, Susanna Raitano, Philip Seibler, Christine Klein, Patrik Verstreken
Journal: Neuron (2018)
Vibrational spectroscopy: a promising approach to discriminate neurodegenerative disorders
Authors: Maria Paraskevaidi, Pierre L. Martin-Hirsch, Francis L. Martin
Journal: Molecular Neurodegeneration (2018)

Neurodegenerative diseases are a growing burden in modern society, thus crucially calling for the development of accurate diagnostic strategies. These diseases are currently incurable, a fact which has been attributed to their late diagnosis, after brain damage has already become widespread. An earlier and improved diagnosis is necessary for the enrolment of patients into clinical trials and can pave the way for the development of therapeutic tactics. Novel analytical techniques, such as mass spectrometry and vibrational spectroscopy, have been able to successfully detect and characterise neurodegenerative disorders. It is critical to globally support and make use of innovative basic research and techniques, which could ultimately lead to the creation of a cost-effective diagnostic test. Minimally invasive samples, such as biological fluids, have also been shown to reveal information for these diseases; utilising them could simplify sample collection/analysis and be more preferable to patients.