tbuckley/cabot-search huggingface dataset:
Distinct Gene Expression Signatures Characterize Strong Clinical Responders Versus Nonresponders to Canakinumab in Children With Systemic Juvenile Idiopathic Arthritis
Authors: Emely L. Verweyen, Alex Pickering, Alexei A. Grom, Grant S. Schulert
Journal: Arthritis & Rheumatology (2021)

Canakinumab is a human anti-interleukin-1β (anti-IL-1β) blocking agent that effectively neutralizes IL-1β-mediated signaling for treatment of systemic juvenile idiopathic arthritis (JIA). While many patients have dramatic clinical response to IL-1 blockade, approximately one-third fail to respond, but there are currently no validated clinical or immunologic predictors of response. We undertook this study to characterize distinct gene signatures for treatment response and nonresponse to canakinumab in systemic JIA patients.We performed a secondary analysis of whole-blood gene expression microarrays using blood samples obtained from healthy controls and systemic JIA patients at baseline and on day 3 after canakinumab treatment (GEO accession no. GSE80060). Patients were considered strong clinical responders if they met the ACR90 response (exhibited ≥90% improvement in the American College of Rheumatology [ACR] JIA response criteria; nonresponders were those who met ACR30 [exhibiting ≤30% improvement in the ACR JIA response criteria]). A random-effects model with patient identity as the random variable was used for differential expression analysis.We identified a distinct gene expression signature in patients with a strong clinical response to canakinumab treatment as compared to nonresponders, mediated by up-regulation of neutrophil- and IL-1-associated genes and characterized by increasing divergence from control transcriptomes with increasing clinical response. We also identified a signature including up-regulated CD163 expression that was associated with canakinumab nonresponse. Intriguingly, canakinumab treatment induced either up- or down-regulation of type I interferon (IFN) genes, independent of clinical response.Here, we identify a gene signature in systemic JIA patients prior to receiving treatment that distinguishes strong responders to canakinumab from nonresponders. Further prospective studies are needed to assess the utility of these insights for treatment decisions in systemic JIA and to track the association of up-regulated type I IFN signatures with systemic JIA complications.
Abstract 12250: Prediction of Patients With Chronic Heart Failure at Risk for Sudden Cardiac Death by Combination of Cardiac I-123 Metaiodobenzylguanidine Imaging and Long Runs of Non-Sustained Ventricular Tachycardia:a Serial Evaluation Study
Authors: Masashi Ishimi, Takahisa Yamada, Takashi Morita, Yoshio Furukawa, Shunsuke Tamaki, Yusuke Iwasaki, Masato Kawasaki, Atsushi Kikuchi, Takumi Kondo, Masatake Fukunami
Journal: Circulation (2015)

Background: Identification of patients (pts) with chronic heart failure (CHF) at risk for sudden cardiac death (SCD) is an important objective. Cardiac I-123 metaiodobenzylguanidine (MIBG) imaging provides prognostic information in pts with CHF. On the other hand, long runs of non-sustained ventricular tachycardia (high-grade NSVT) has been associated with an increased risk of SCD in pts with coronary artery disease. However, there is little information available on the comparison of the prognostic significance for SCD between MIBG and high grade-NSVT in patients with CHF. Methods and Results: We studied 105 consecutive outpatients (NYHA class: 2.1±0.6), with LVEF 27%.High-grade NSVT was defined as consecutive 6 or more beats and more than 100 bpm. All pts underwent 24-hour ECG Holter monitoring and MIBG at the entry and every year after entry for three years. In the serial Holter monitoring, 32 pts had high-grade NSVT. At the last evaluation of MIBG study, 51 pts had abnormal WR. During the mean follow-up period of 5.1±3.5 years, 22 pts had SCD. A multivariate Cox analysis revealed that both abnormal WR and high-grade NSVT were significantly and independently associated with SCD (abnormal WR; hazard ratio 3.4 [95%CI 1.2-10.0], p = 0.025, high-grade NSVT; hazard ratio 3.3[95%Cl 1.3-8.2], p = 0.012). Pts with both abnormal WR and high-grade NSVT and those with either abnormal WR or high-grade NSVT had a significantly higher SCD risk than those with none of these parameters (47 [9/47] % vs 29 [13/45] % vs 0 [0/41] %, p&lt;0.0001). Conclusion: The combination of abnormal WR and high-grade NSVT would be more strongly associated with an increased risk of SCD in CHF pts.
Abstract 16236: Hyperthyroidism Does Not Negatively Impact the Outcomes of Patients Admitted for Atrial Fibrillation: Analysis of the National Inpatient Sample
Authors: Hafeez Shaka, Emmanuel Akuna, Iriagbonse Asemota, Ehizogie Edigin, Precious O Eseaton, Precious Nwachukwu, Mavi Rivera Pavon
Journal: Circulation (2020)

Introduction: Hyperthyroidism is a well-established risk factor for developing Atrial fibrillation (AF). The impact of hyperthyroidism in patients admitted for AF is unclear. This study aims to compare the outcomes of patients primarily admitted for AF with and without a secondary diagnosis of hyperthyroidism. Methods: We queried the National Inpatient Sample (NIS) 2016 and 2017 database. The NIS is the largest inpatient hospitalization database in the United States (US). The NIS was searched for hospitalization of adult patients with AF as a principal diagnosis with and without hyperthyroidism as a secondary diagnosis using ICD-10 codes. The primary outcome was inpatient mortality while the secondary outcomes were hospital length of stay (LOS), rate of ablation and electrical cardioversion. STATA software was used for analysis. Multivariate logistic and linear regression analysis was used accordingly to adjust for confounders. Results: There were over 71 million discharges in the combined 2016 and 2017 NIS database. Out of 821,629 AF hospitalizations, 1.8% had hyperthyroidism. Hospitalization for AF with hyperthyroidism had similar inpatient mortality (0.5% vs 0.9%, AOR 0.61, CI 0.36-1.04, P=0.069), longer LOS (3.6 vs 3.4 days, p&lt;0.0001), with lower rates of ablation (2.8% vs 4.2%, AOR 0.62, CI 0.49-0.78, P&lt;0.0001) and electrical cardioversion (14.6% vs 17.6%, AOR 0.82, CI 0.73-0.91, P&lt;0.0001) compared to those without hyperthyroidism. Conclusion: Hospitalizations for AF with hyperthyroidism had similar inpatient mortality, decreased LOS and less rates of ablation and electrical cardioversion compared to those without hyperthyroidism. Although, hyperthyroidism increases the risk of AF, hyperthyroidism does not negatively impact outcomes of patients admitted for AF based on US national hospital billing database.
Learning from the First Wave of the Pandemic in England, Wales, and Northern Ireland
Authors: David Pilcher, Matthew Durie
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

ICS treatment are sicker (13).Similarly, those with a history of more exacerbations showed a larger reduction in mortality with 320 BGF.It is becoming clearer that the effect of either starting or stopping ICS on exacerbation risk is influenced by the blood eosinophil count (14, 15).In ETHOS, this appears to be true for mortality as well, with patients with a higher eosinophil count being at greater risk of dying when receiving GFF compared with 320 BGF.Further analysis of this potentially important observation is needed.Several important lessons come from these positive studies of ICS and COPD mortality.First, large studies allow for more complex analyses than small ones, but to properly test their primary hypothesis, trialists need to focus on patient groups at the greatest risk of experiencing the events under study.Treatment that reduces mortality will only be seen to work in patients who are at risk of dying.Second, neither the drug, the delivery system, nor the dosage regime is crucial to preventing death with ICS-LAMA-LABA treatment, but the dose of the corticosteroid chosen may be.Finally, mortality is not different from other endpoints in COPD studies, and a therapy that decreases exacerbations is likely to reduce mortality if sufficient numbers of the right kind of patient are studied.So, belatedly, the flame lit by TORCH is burning brightly again and does offer hope to all those who have COPD after all.
Pathological Evidence for SARS-CoV-2 as a Cause of Myocarditis
Authors: Rika Kawakami, Atsushi Sakamoto, Kenji Kawai, Andrea Gianatti, Dario Pellegrini, Ahmed Nasr, Bob Kutys, Liang Guo, Anne Cornelissen, Masayuki Mori, Yu Sato, Irene Pescetelli, Matteo Brivio, Maria Romero, Giulio Guagliumi, Renu Virmani, Aloke V. Finn
Journal: Journal of the American College of Cardiology (2021)
A three dimensional collagen gel model for investigating potential chemopreventive agents against development of early breast cancer
Authors: Raghu Sinha, J. Stanley Smith, Nicole D. Facompre, Ronald Grenko, Rena Kass, Tonya King, Karam El-Bayoumy
Journal: Cancer Research (2006)

686   Breast cancer is the second leading cause of cancer-related death in women. It is estimated that 211,240 women will be diagnosed with invasive breast cancer in 2005, and 40,410 will die of the disease. In addition, 58,490 cases of carcinoma  in situ  (early stage of breast cancer) are expected to occur in 2005. The causes of breast cancer remain obscure, and there are no established primary prevention strategies; moreover, advances in therapy are limited. Thus, there is an urgent need for developing novel cancer chemopreventive agents and appropriate models to test their efficacies. The use of naturally occurring or synthetic agents (e.g., selenium compounds) that can inhibit the early events, before the occurrence of clinically detectable cancer, is an appropriate approach for breast cancer prevention and control. We are developing a three-dimensional (3-D) collagen gel model that replicates characteristics of human ductal carcinoma  in situ  (DCIS) and / or atypical ductal hyperplasia (ADH). This model will provide a suitable environment to examine the efficacy of promising chemopreventive agents. To develop this model, tissues obtained from biopsy of suspected cases of DCIS and / or ADH are selectively excised, digested in enzymes, and the separated clusters of cells placed in collagen gels. The cells grow and spread out into tube-like structures similar to those seen in a human breast. These characteristic features are confirmed by laboratory staining techniques. These tube-like structures growing in collagen have been examined for responsiveness to Se-methylselenocysteine (MSC) and methylseleninic acid (MSeA); chemopreventive agents known to inhibit breast cancer in laboratory animals. Both these compounds also inhibit growth of human breast cancer cells growing on collagen and on plastic as evidenced by Cell Death ELISA. This model will prove useful in testing other effective agents against development of early breast cancer. Support: Penn State Cancer Institute Funds.
Analysis of structural components of decellularized scaffolds in renal fibrosis
Authors: Rui Zhang, Junqun Jiang, Yaling Yu, Fangfang Wang, Niuniu Gao, Yingjie Zhou, Xinlong Wan, Zhibin Wang, Peng Wei, Jin Mei
Journal: Bioactive Materials (2021)

Chronic kidney disease has been recognized as a major public health problem worldwide and renal fibrosis is a common pathological process occurring in chronic renal failure. It is very promising to find the strategies to slow or even prevent the progression of fibrosis. This study focused on whether renal fibrosis decellularized scaffolds has the potential to be a model of cellular mechanisms of tissue fibrosis or donors for tissue engineering. In order to evaluate the feasibility of decellularized scaffolds derived from pathological kidneys, histology, proteomics and ELISA will be used to analysis the changes in the structure and main components of fibrotic tissue. The fibrosis model in this paper was induced by adenine-fed and the results showed that the structure of fibrotic scaffold was changed and some protein were up-regulated or down-regulated, but the cytokines associated with renal regeneration after injury were remained. In cell experiments, endothelial progenitor cells proliferated well, which proved that the fibrotic scaffolds have non-cytotoxic. All these conclusions indicate that the renal fibrosis decellularized scaffolds model has the ability to study fibrosis mechanism and the potential to be engineering donors as well as normal scaffolds.
Targeting AURKA in Cancer: molecular mechanisms and opportunities for Cancer therapy
Authors: Ruijuan Du, Chuntian Huang, Kangdong Liu, Xiang Li, Zigang Dong
Journal: Molecular Cancer (2021)

Abstract Aurora kinase A (AURKA) belongs to the family of serine/threonine kinases, whose activation is necessary for cell division processes via regulation of mitosis. AURKA shows significantly higher expression in cancer tissues than in normal control tissues for multiple tumor types according to the TCGA database. Activation of AURKA has been demonstrated to play an important role in a wide range of cancers, and numerous AURKA substrates have been identified. AURKA-mediated phosphorylation can regulate the functions of AURKA substrates, some of which are mitosis regulators, tumor suppressors or oncogenes. In addition, enrichment of AURKA-interacting proteins with KEGG pathway and GO analysis have demonstrated that these proteins are involved in classic oncogenic pathways. All of this evidence favors the idea of AURKA as a target for cancer therapy, and some small molecules targeting AURKA have been discovered. These AURKA inhibitors (AKIs) have been tested in preclinical studies, and some of them have been subjected to clinical trials as monotherapies or in combination with classic chemotherapy or other targeted therapies.
Dendritic Cells Revisited
Authors: Mar Cabeza-Cabrerizo, Ana Cardoso, Carlos M. Minutti, Mariana Pereira da Costa, Caetano Reis e Sousa
Journal: Annual Review of Immunology (2021)

Dendritic cells (DCs) possess the ability to integrate information about their environment and communicate it to other leukocytes, shaping adaptive and innate immunity. Over the years, a variety of cell types have been called DCs on the basis of phenotypic and functional attributes. Here, we refocus attention on conventional DCs (cDCs), a discrete cell lineage by ontogenetic and gene expression criteria that best corresponds to the cells originally described in the 1970s. We summarize current knowledge of mouse and human cDC subsets and describe their hematopoietic development and their phenotypic and functional attributes. We hope that our effort to review the basic features of cDC biology and distinguish cDCs from related cell types brings to the fore the remarkable properties of this cell type while shedding some light on the seemingly inordinate complexity of the DC field.
Informed Consent: What Must Be Disclosed and What Must Be Understood?
Authors: Joseph Millum, Danielle Bromwich
Journal: The American Journal of Bioethics (2021)

Over the last few decades, multiple studies have examined the understanding of participants in clinical research. They show variable and often poor understanding of key elements of disclosure, such as expected risks and the experimental nature of treatments. Did the participants in these studies give valid consent? According to the standard view of informed consent they did not. The standard view holds that the recipient of consent has a duty to disclose certain information to the profferer of consent because valid consent requires that information to be understood. The contents of the understanding and disclosure requirements are therefore conceptually linked. In this paper, we argue that the standard view is mistaken. The disclosure and understanding requirements have distinct grounds tied to two different ways in which a token of consent can be rendered invalid. Analysis of these grounds allows us to derive the contents of the two requirements. It also implies that it is sometimes permissible to enroll willing participants who have not understood everything that they ought to be told about their clinical trials.
Estrogen Receptor β-Mediated Inhibition of Actin-Based Cell Migration Suppresses Metastasis of Inflammatory Breast Cancer
Authors: Christoforos Thomas, Ilias V. Karagounis, Ratnesh K. Srivastava, Nicholas Vrettos, Fotis Nikolos, Noëlle Francois, Menggui Huang, Siliang Gong, Qi Long, Sushil Kumar, Constantinos Koumenis, Savitri Krishnamurthy, Naoto T. Ueno, Rumela Chakrabarti, Amit Maity
Journal: Cancer Research (2021)

Abstract Inflammatory breast cancer (IBC) is a highly metastatic breast carcinoma with high frequency of estrogen receptor α (ERα) negativity. Here we explored the role of the second ER subtype, ERβ, and report expression in IBC tumors and its correlation with reduced metastasis. Ablation of ERβ in IBC cells promoted cell migration and activated gene networks that control actin reorganization, including G-protein–coupled receptors and downstream effectors that activate Rho GTPases. Analysis of preclinical mouse models of IBC revealed decreased metastasis of IBC tumors when ERβ was expressed or activated by chemical agonists. Our findings support a tumor-suppressive role of ERβ by demonstrating the ability of the receptor to inhibit dissemination of IBC cells and prevent metastasis. On the basis of these findings, we propose ERβ as a potentially novel biomarker and therapeutic target that can inhibit IBC metastasis and reduce its associated mortality. Significance: These findings demonstrate the capacity of ERβ to elicit antimetastatic effects in highly aggressive inflammatory breast cancer and propose ERβ and the identified associated genes as potential therapeutic targets in this disease.
SAT0025 Evolution of psoriatic arthritis with distal interphalangeal joints involvement at onset
Authors: CA Montilla, CM González, FJ López-Longo, R Castillo, N Caro, C González-Montagut, L Cebrián, S Gómez, E Carmona, I Monteagudo, L Carreño
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Distal interphalangeal joints (DIP) arthritis described by Moll and Wright as a psoriatic arthritis (Psa) pattern is now considered an evolutionary step towards other classification patterns. <h3>Objectives</h3> To study the clinical and radiological evolution of a group of patients with arthritis limited to the DIP as onset of Psa. <h3>Methods</h3> We have studied the clinical and radiological evolution of 204 patients diagnosed with Psa (Moll and Wright criteria) during the first year of the disease selecting those patients whose initial clinical features were exclusively arthritis of the DIP. The radiological findings after one-year follow-up were classified into stages according to Steinbrocker´s criteria. <h3>Results</h3> Arthritis of DIP as onset of the disease was found in 19/204 (9.3%) of the patients. The mean age at onset was 49 years (range: 34–64). Psoriasis before arthritis onset was present in 8/19 (42.1%) and in 9/19 (47.3%) the onset of arthritis and psoriasis was simultaneous. Onychodystrophy (pitting) was present in 7/19 (36.8%). After one-years 9/19 (47.3%) patients continued with arthritis as the only manifestations of Psa, 8/19 (42.1%) patients evolved toward other arthritis patterns (5 asymmetrical oligoarthritis and 3 symmetrical polyarthritis). The joints more commonly involved along with the DIP were metacarpophalangeal (75%) and proximal interphalangeal (62.5%). 2/19 patients (10.4%) did not show DIP arthritis after one year. At the end of the one-year study 9/19 (47,3%) of the patients were classified into III stage radiological criteria, 2/19 (10.4%) were at the stage I and in the remaining patients radiological was considered as normal. <h3>Conclusion</h3> Almost half of the patients with DIP arthritis as Psa onset evolve within one year towards others arthritis patterns. Half of the patients revealed an aggressive radiological progression during the first year of the disease.
Results of a phase II trial of ramucirumab plus irinotecan as second-line treatment for patients with advanced gastric cancer (HGCSG 1603).
Authors: Yasuyuki Kawamoto, Satoshi Yuki, Kentaro Sawada, Michio Nakamura, Osamu Muto, Susumu Sogabe, Yoshiaki Shindo, Atsushi Ishiguro, Atsushi Sato, Yasushi Tsuji, Masayoshi Dazai, Hiroyuki Okuda, Takahide Sasaki, Kazuaki Harada, Shintaro Nakano, Hiroshi Nakatsumi, Mari Sekiguchi, Yuh Sakata, Naoya Sakamoto, Yoshito Komatsu
Journal: Journal of Clinical Oncology (2021)

217 Background: Ramucirumab (RAM) is a fully human IgG1 monoclonal vascular endothelial growth factor receptor-2 (VEGFR-2) antibody. The RAINBOW trial showed RAM plus paclitaxel (PTX) increased overall survival (OS) compared with PTX alone for advanced gastric cancer (AGC) in second-line treatment. WJOG 4007 trial demonstrated equivalent efficacy between irinotecan (IRI) and PTX. We conducted this trial to examine the efficacy and safety of RAM plus IRI combination therapy in the second-line treatment for AGC. Methods: This non-randomized, single arm, phase 2 trial was carried out at 22 institutes in Japan. AGC patients with refractory or intolerance to primary chemotherapy were eligible. RAM 8 mg/kg and IRI 150 mg/m 2 combination therapy administered every two weeks were continued until progression or emergence of adverse events requiring discontinuation. The primary endpoint was progression-free survival (PFS) rate at six-month, the target was set as 16% with an expected threshold of 39%. A total of 35 cases are planned for registration. The secondary endpoints were OS, PFS, response rate (RR) and safety. This trial was registered with Japan Registry of Clinical Trials, number jRCTs011180029. Results: Between Jan 2018 and Sept 2019, 35 patients were enrolled. Median age was 70 (range, 47-80); female/male were 10/25; ECOG PS 0/1, 22/13. PFS rate at six months was 26.5% (95%C.I., 13.2-41.8%, p = 0.1353). Median PFS and OS were 4.2 (95%C.I., 2.5-5.4 months) and 9.6 months (95%C.I., 6.5-16.6 months), respectively. RR was 26% and disease control rate was 85%. Grade 3 or higher adverse events that occurred in more than 5% of patients were neutropenia (51%), leucopenia (43%), anemia (20%), anorexia (14%), febrile neutropenia (11%), diarrhea (9%), hypertension (9%), proteinuria (9%), hypokalemia (9%), hypoalbuminemia (9%), thrombocytopenia (6%), and hyponatremia (6%). No death and new safety signals with a causal relation to study treatment were observed. Conclusions: Although the primary endpoint was not achieved statistically, the results are clinically encouraging, especially take into account that more elderly patients enrolled in this trial. The combination of RAM plus IRI has anti-cancer activity and manageable safety profile in second-line treatment for patients with AGC. Clinical trial information: jRCTs011180029.
A Phase I Study of a Novel Fully Human BCMA-Targeting CAR (CT103A) in Patients with Relapsed/Refractory Multiple Myeloma
Authors: Di Wang, Jue Wang, Guang Hu, Wen Wang, Yi Xiao, Haodong Cai, Lijun Jiang, Li Meng, Yongkun Yang, Xiaoxi Zhou, Zhenya Hong, Zheng Yao, Min Xiao, Liting Chen, Xia Mao, Li Zhu, Jin Wang, Lugui Qiu, Chunrui Li, Jianfeng Zhou
Journal: Blood (2021)