tbuckley/cabot-search huggingface dataset:
Antibody targeting tumor-derived soluble NKG2D ligand sMIC reprograms NK cell homeostatic survival and function and enhances melanoma response to PDL1 blockade therapy
Authors: Fahmin Basher, Payal Dhar, Xin Wang, Derek A. Wainwright, Bin Zhang, Jeffrey Sosman, Zhe Ji, Jennifer D. Wu
Journal: Journal of Hematology & Oncology (2020)

Melanoma patients who have detectable serum soluble NKG2D ligands either at the baseline or post-treatment of PD1/PDL1 blockade exhibit poor overall survival. Among families of soluble human NKG2D ligands, the soluble human MHC I chain-related molecule (sMIC) was found to be elevated in melanoma patients and mostly associated with poor response to PD1/PDL1 blockade therapy.In this study, we aim to investigate whether co-targeting tumor-released sMIC enhances the therapeutic outcome of PD1/PDL1 blockade therapy for melanoma. We implanted sMIC-expressing B16F10 melanoma tumors into syngeneic host and evaluated therapeutic efficacy of anti-sMIC antibody and anti-PDL1 antibody combination therapy in comparison with monotherapy. We analyzed associated effector mechanism. We also assessed sMIC/MIC prevalence in metastatic human melanoma tumors.We found that the combination therapy of the anti-PDL1 antibody with an antibody targeting sMIC significantly improved animal survival as compared to monotherapies and that the effect of combination therapy depends significantly on NK cells. We show that combination therapy significantly increased IL-2Rα (CD25) on NK cells which sensitizes NK cells to low dose IL-2 for survival. We demonstrate that sMIC negatively reprograms gene expression related to NK cell homeostatic survival and proliferation and that antibody clearing sMIC reverses the effect of sMIC and reprograms NK cell for survival. We further show that sMIC/MIC is abundantly present in metastatic human melanoma tumors.Our findings provide a pre-clinical proof-of-concept and a new mechanistic understanding to underscore the significance of antibody targeting sMIC to improve therapeutic efficacy of anti-PD1/PDL1 antibody for MIC/sMIC+ metastatic melanoma patients.
FRI0172 THE INFLUENCE OF CALCINEURIN INHIBITORS ON DEVELOPMENT OF CANCER IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS: A RETROSPECTIVE OBSERVATIONAL STUDY IN THE LUNA REGISTRY
Authors: K. Ichinose, T. Igawa, M. Okamoto, A. Takatani, N. Yajima, K. E. Sada, R. Yoshimi, Y. Shimojima, S. Ono, H. Kajiyama, S. Sato, M. Fujiwara, A. Kawakami
Journal: Annals of the Rheumatic Diseases (2020)

Background: It has been reported that the incidence of cancer in patients with systemic lupus erythematosus (SLE) is higher than that in healthy individuals, but the findings are inconsistent 1 . In the transplantation field, a few studies indicated an association between the use of immunosuppressants and an increased risk of cancer 2 . Calcineurin inhibitors (CNIs), which include cyclosporine and tacrolimus, have been used for &gt;30 years to treat renal and extrarenal manifestations of SLE, but the effects of exposure to CNIs among SLE patients have not been established. Objectives: We investigated the incidence of various cancers (including cervical dysplasia) among SLE patients registered in the LUpus registry of NAtionwide institution (LUNA). We also investigate whether the registrants’ exposure to CNIs increased the risk of cancer. Methods: We calculated the standardized incidence ratio (SIR) of cancer among SLE patients based on the age-standardized incidence rate of cancer reported by Japan’s Ministry of Health, Labour and Welfare. A multivariate analysis of the risk of cancer was performed using the covariates of age, smoking history, CNI treatment history, maximum steroid dose in the past, and Systemic Lupus International Collaboration Clinics/American College of Rheumatology Damage Index [SDI]) value (excluding the occurrence of cancer) at the time of the patient’s registration. Results: We studied 714 patients (663 females; 88.9%).The median age at registry was 44 [interquartile range (IQR): 35–56] years. The median past max. steroid dose was 40 mg/day (IQR: 30–60 mg/day), and the SDI at registration was 1 (IQR 0–2). Smoking history was present in 248 patients (34.9%), and 53 patients (7.4%) experienced cancer complications. Gynecologic malignancies accounted for 71% of all cancers, including 12 cervical dysplasia cases. The standardized incidence rate of cancer in these SLE patients was 1.46 (95%CI: 1.07–1.85, p&lt;0.01). The multivariate analysis showed that a CNI treatment history was not a risk factor for the development of cancer (OR 1.76, 95%CI: 0.63–4.88, p=0.30). After the covariance was adjusted for the propensity score, the risk of cancer in the CNIs group was not increased compared to the non-CNIs group (adjusted OR 2.46, 95%CI: 0.68–8.91, p=0.20). Conclusion: The incidence of cancer in SLE was higher in the LUNA cohort than in the general population. Our results suggest that CNI treatment for individuals with SLE is not a risk factor for the development of cancer. References: [1]Ladouceur A. et.al, Expert Rev Clin Immunol. 2018 Oct;14(10):793-802. [2]Gutierrez-Dalmau A. et.al, Drugs 2007;67(8):1167-98. Disclosure of Interests: None declared
PET/CT of COVID-19 as an Organizing Pneumonia
Authors: Jaime Alonso Sanchez, Julia García Prieto, Alvaro Galiana Morón, John Patrick Pilkington-Woll
Journal: Clinical Nuclear Medicine (2020)

Abstract An 85-year-old woman with history of melanoma is referred for a follow-up 18 F-FDG PET/CT. 18 F-FDG PET/CT scan showed bilateral and peripheral ground-glass opacities in upper and lower pulmonary lobes surrounded by consolidations of crescent shape with increased FDG uptake, findings compatible with organizing pneumonia. Following further inquiry, the patient reported low-grade fever, sore throat, and fatigue for the past 6 days. Because of the ongoing COVID-19 pandemic, the patient was tested for SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), which resulted positive.
Alteration in gut microbiota is associated with dysregulation of cytokines and glucocorticoid therapy in systemic lupus erythematosus
Authors: Mengchen Guo, Huixia Wang, Sixie Xu, Yaoyao Zhuang, Jingang An, Chuan Su, Yankai Xia, Jingyun Chen, Zhenjiang Zech Xu, Qisha Liu, Jianwei Wang, Zhou Dan, Kun Chen, Xiaoting Luan, Zhi Liu, Kangjian Liu, Faming Zhang, Yumin Xia, Xingyin Liu
Journal: Gut Microbes (2020)

A growing corpus of evidence implicates the involvement of the commensal microbiota and immune cytokines in the initiation and progression of systemic lupus erythematosus (SLE). Glucocorticoids have been widely used in the treatment of SLE patients, however, glucocorticoid treatment carries a higher risk of other diseases. Using the 16S rRNA technique, we investigated the differences between the gut microbiota associated with the immune cytokines of SLE and relevant glucocorticoid treatment in a female cohort of 20 healthy control subjects (HC), 17 subjects with SLE (SLE-G), and 20 SLE patients having undergone glucocorticoid treatment (SLE+G). We observed that the diversity and structure of the microbial community in SLE+G patients were significantly changed compared to that of SLE-G patients, whereas the gut microbial community of the SLE+G group showed a similarity with the HC group, which implicate that the shift in the gut microbiome could represent a return to homeostasis. Furthermore, the up-regulations of immune cytokines in SLE-G were identified as closely related to gut dysbiosis, which indicates that the overrepresented genera in SLE patients may play roles in regulating expression level of these immune cytokines. This associated analysis of gut microbiota, glucocorticoid therapy, and immune factors might provide novel and insightful clues revealing the pathogenesis of SLE patients.
Beijing proposes law to ban criticism of traditional Chinese medicine
Authors: Owen Dyer
Journal: BMJ (2020)

A law proposed by the Beijing municipality could criminalise statements critical of traditional Chinese medicine, at a time when China's government is claiming, without clear evidence, that many traditional medicines are effective against covid-19.The draft law, which is open for public comment until 28 June, would ban making exaggerated claims for traditional medicines' efficacy but also outlaws "denigrating or defaming traditional Chinese medicine."That could place critics of traditional Chinese medicine at odds with a government that officially promotes its use and recommends six traditional recipes for the prevention or treatment of covid-19.The six medicines, each a mixture of several herbs, are Jinhua Qinggan granules, Lianhua Qingwen capsules, Xuebijing injection, lung cleansing, and detoxifying decoction, Huashi Baidu formula, and Xuanfei Baidu granules.They have been recommended by China's state media, which provides a few details from studies of their efficacy against covid-19.
Abstract 13262: Impaired Myocardial Perfusion Reserve is Associated With Adverse Cardiovascular Events in Patients With Dilated Cardiomyopathy
Authors: Daniel Hammersley, Brian Halliday, Ankur Gulati, Tevfik F Ismail, Aamir Ali, Li-Yueh Hsu, Richard Jones, Upasana Tayal, Amrit Lota, Rick Wage, Peter Gatehouse, David Firmin, Dominique Auger, Ruth Owen, Dudley J Pennell, Andrew E Arai, Sanjay K Prasad
Journal: Circulation (2019)

Introduction: Stress perfusion cardiovascular magnetic resonance (CMR) and PET data suggest the presence of microvascular dysfunction in non-ischaemic dilated cardiomyopathy (DCM) but its impact on...
Abstract B62: Wholesome non-invasive liquid biopsies for pharmacodiagnostic work-up in breast cancer
Authors: Dadasaheb Akolkar
Journal: Clinical Cancer Research (2020)

Abstract Background: Diagnosis and treatment of breast cancers is based on histopathological analysis of tumor tissue obtained by invasive biopsies. However invasive biopsies cause pain, anxiety and carry the risk of needle seeding. Though Immunocytochemistry (ICC) profiling of Circulating Tumor Cells (CTCs, defined as EpCAM+, panCK+, CD45-) has been previously attempted for diagnosis, these efforts have been unsuccessful. We used an epigenetically modified medium for enrichment of sufficient viable CTCs. These CTCs were used for diagnosis and characterization. Methods: We obtained 15 ml of venous blood draw from 2500 patients with confirmed diagnosis of breast cancer. CTCs were enriched from PBMCs fraction using an epigenetically acting enrichment process that is lethal towards normal (non-malignant) cells, but confers survival privilege on apoptosis-resistant CTCs. Harvested CTCs were confirmed by immunostaining for EpCAM and pan-CK. Deep ICC profiling of these CTCs was performed with organ specific marker GCDFP15. Theranostic ICC Profiling was performed with ER and Her2. Results: CTCs could be obtained from 2232 samples (89.3%) out of 2500. A subset of 100 samples were characterised by deep ICC profiling, among which 80% of samples were positive for GCDFP15. 14 and 17 samples out of 100 were positive for ER and Her2 respectively. Conclusions: Our results show that ICC based characterization of CTCs can provide necessary diagnostic information non-invasively to substitute conventional procedures dependent on tissue extraction. Citation Format: Dadasaheb Akolkar. Wholesome non-invasive liquid biopsies for pharmacodiagnostic work-up in breast cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr B62.
High Expression of NEK2 and PIM1, but Not PIM3, Is Linked to an Aggressive Phenotype of Bronchopulmonary Neuroendocrine Neoplasms
Authors: Ewelina Motylewska, Marcin Braun, Henryk Stępień
Journal: Endocrine Pathology (2020)

Abstract Dysregulations of the NEK2 and PIM1-3 kinase signaling axes have been implicated in the pathogenesis of several cancers, including those with a neuroendocrine phenotype. However, their impact on bronchopulmonary neuroendocrine neoplasms (BP-NENs) has not been investigated. The aim of this pilot study was to determine mRNA and protein levels of NEK2, PIM1, and PIM3 in a group of 49 patients with BP-NENs: 11 typical carcinoids, 5 atypical carcinoids, 11 large cell neuroendocrine carcinomas, 22 small cell lung carcinomas (SCLC). The expression was measured using TaqMan-based RT-PCR and immunohistochemistry. NEK2 and PIM1 mRNA levels were higher in the SCLC patients than in the other BP-NEN groups ( p &lt; 0.001). There was an association between NEK2 mRNA and protein expression ( p = 0.023) and elevated NEK2 mRNA levels were related to reduced survival in BP-NEN patients ( p = 0.015). Patients with higher PIM1 protein expression had also diminished survival comparing with those with weak or no PIM1 expression ( p = 0.037). Elevated NEK2 and PIM1 expression were related to aggressive tumor phenotype and indirectly affected the overall survival of BP-NEN patients. Our pilot study supports the need for future investigation of the biological function of NEK2 and PIM1 in BP-NEN transformation to verify the clinical value of our findings.
SARS-CoV-2 RNA detection in tears and conjunctival secretions of COVID-19 patients with conjunctivitis
Authors: Noemi Güemes-Villahoz, Barbara Burgos-Blasco, Ana Arribi-Vilela, Pedro Arriola-Villalobos, Beatriz Vidal-Villegas, Rosalia Mendez-Fernandez, Alberto Delgado-Iribarren, Julian Garcia-Feijoo
Journal: Journal of Infection (2020)
Erratum: Corrigendum: Genome-wide CRISPR screens reveal a Wnt–FZD5 signaling circuit as a druggable vulnerability of RNF43-mutant pancreatic tumors
Authors: Zachary Steinhart, Zvezdan Pavlovic, Megha Chandrashekhar, Traver Hart, Xiaowei Wang, Xiaoyu Zhang, Mélanie Robitaille, Kevin R Brown, Sridevi Jaksani, René Overmeer, Sylvia F Boj, Jarrett Adams, James Pan, Hans Clevers, Sachdev Sidhu, Jason Moffat, Stéphane Angers
Journal: Nature Medicine (2017)
AB0225 THE NATURAL COURSE OF EARLY RA WITH LATE ONSET IN EVERYDAY CLINICAL PRACTICE ACCORDING TO THE RUSSIAN RA PATIENT REGISTER OREL
Authors: A. Satybaldyev, N. Demidova, G. Gridneva, N. Nikishina, H. Gerasimova, K. Kasumova, A. Misiyuk, O. Rumyantseva, E. Strebkova, E. Nasonov
Journal: Annals of the Rheumatic Diseases (2020)

Background: The opinion about the severity and prognosis of rheumatoid arthritis (RA) with late onset balanced between more favorable and more severe over various periods of rheumatology development. We studied this group of patients according to the Russian RA Patient Register OREL. Objectives: To study clinical, laboratory and radiological characteristics in patients with early RA with late onset of the disease (50 years and older) who are DMARD (disease modifying antirheumatic drugs), biological DMARD and glucocorticoid (GC) (systemic administration) – naive. Methods: All patients were included in the OREL register in the period from 01.01.2014 to 12.31.2018. There were 151 patients in the study (M:41, W:110; average age 60 ± 7.0 years). There were 73 patients (48%) with the duration of RA up to 3 months, 45 (30%) - 4-6 months, 33 (22%) - 7-12 months. The ratio of men and women was only 1: 2.8 (50 -64 years = 1:3.8; 64 years and older = 1: 1.8). Results: 99/151 (66%) patients had high disease activity (according to DAS-28), 52/151 (34%) – medium activity. 22/151 (15%) patients had II functional class (FC), 103 (68%) – III FC, 26 (17%) – IV FC. Table 1 illustrates that with an increase in the duration of the disease, a gradual increase in the frequency of detection of radiological erosion in the hands and distal parts of the feet is noted: 1.5 - 3 months - 33/73 (45%) patients; 4-6 months - 22/45 (49%) patients and in the period 7-12 months - 23/33 (70%) patients. Table 1. X-ray Stage and RA duration X-ray Stage Duration of disease (months) &lt;3 4 5 6 7-12 Total Non Erosive RA I 11(1*) 6(1*) 3(1*) 1 5 26(3*) II 29(1*) 5 5 3 5 47(1*) Erosive II 31 8 7 4 20 70 RA III 2 1 1 1 3 8 IV - Total 73(2*) 20(1*) 16(1*) 9 33 151(4*) * - Erosion according to MRI of the hands Table 1. illustrates higher incidence of joint erosions in the presence of RF and / or anti-CPA antibodies (ACPA) compared to patients who are seronegative for RF and ACPA. Таблица 2. X-ray-Stage and RF and ACPA Detection Frequency X-ray-Stage The frequency of RF and AСPA detection RF (+) ACPA (+) RF (+) ACPA (-) RF (-) ACPA (+) RF (-) ACPA (-) Non-erosive RA: Stages I and II 30% 20% 22% 58% Erosive RA: II, III and IV stages 70% 80% 78% 42% The frequency of RF and AСPA detection in non-erosive patients, in all patients with radiological erosion and in patients with advanced stages only (III and IV) was 67% (RF) -78% (ACPA), 75% -90% and 100% -100%, respectively. Conclusion: Everyday clinical practice (OREL register) shows that in patients aged 50 years and older with early clinical stage of RA who are naive about the treatment of DMARD, biological DMARD and GC, the detection of RF, ACPA and erosive changes in the joints are often observed in the onset of the disease. RF and ACPA are markers of early joint destruction. Disclosure of Interests: None declared
Abstract MP029: Higher Television Viewing Relates to Less Exercise in a Representative Sample of Irish 9 Year Olds
Authors: Deirdre Harrington, Peter T Katzmarzyk
Journal: Circulation (2012)

INTRODUCTION: Television (TV) viewing is blamed as a contributor to low physical activity levels in children, yet it is unclear if such a sedentary behavior actually displaces exercise. HYPOTHESIS: Children who engage in higher levels of TV viewing will be less active than children who watch &lt;1 hour of TV/day. METHODS: This study utilized the ‘Growing up in Ireland’ (2008) first wave of data which is a longitudinal study of a representative sample of over 8,000 9 year olds. The main caregiver reported the number of hours/day the child spent watching TV/video/DVDs and responses were then classified as: &lt;1, 1-3 and &gt;3 hours. The number of days out of the previous 14 that the child had engaged in ‘hard’ and ‘light’ exercise for at least 20 minutes was also reported. Responses were classified as ≥9 days (highest possible answer) or ≤8 days out of 14. Odds ratios were calculated using logistic regression. RESULTS: The sample consisted of 3956 male and 4152 female 9 year olds. Overall, 12.4% of males and 14.1% of females, 32.0% of males and 32.6% of females and 4.4% of males and 4.5% of females watched &lt;1 hour, 1-3 hours and &gt;3 hours of TV/day respectively. Compared to children who watched less than 1 hour of TV/day, children who watched 1-3 or &gt;3 hours/day had significantly lower odds of engaging in exercise ( Table 1 ). Table 1. Odds ratios (95% Confidence Intervals) for TV viewing and likelihood of engaging in 20 minutes of ‘hard’ and ‘light’ exercise on 9 or greater days out of 14 days. Hours of TV/Video/DVD ‘Hard Exercise’ ‘Light Exercise’ Male Female Male Female &lt;1 Referent Referent Referent Referent 1 to 3 0.8 (0.7-0.9) 0.7 (0.6-0.9) 0.7 (0.6-0.8) 0.8 (0.7-0.9) &gt;3 0.4 (0.3-0.6) 0.5 (0.4-0.6) 0.4 (0.3-0.5) 0.5 (0.4-0.6) Analysis controlled for social class (defined from the parent’s occupation and categorized under professional managers, non-manual/skilled manual and semi-skilled/unskilled manual) CONCLUSION: Children with higher levels of TV viewing were less likely to engage in hard or light exercise. These findings support the displacement hypothesis where sedentary behaviors reduce children’s amount of exercise.
Abstract 13919: Fibrillation Cycle Length in Surface Electrocardiogram Predicts Cardiovascular Event in Patients With Long-standing Persistent Atrial Fibrillation
Authors: Hironori Nakamura, Shinichi Niwano, Hidehira Fukaya, Jun Kishihara, Akira Satoh, Jun Oikawa, Tazuru Igarashi, Naruya Ishizue, Tamami Fujiishi, Ryo Nishinarita, Ai Horiguchi, Junya Ako
Journal: Circulation (2017)

Introduction: Atrial fibrillation (AF) is associated with a high risk of heart failure, stroke, and death. However, the risk factors for cardiovascular events in AF patients remain poorly understoo...
There is no stopping covid-19 without stopping racism
Authors: Abraar Karan, Ingrid Katz
Journal: BMJ (2020)

Siva-1 is a death domain-containing proapoptotic protein identified as an intracellular ligand of CD27 and of the glucocorticoid-induced TNFR family-related gene, which are two members of the TNFR family expressed on lymphoid cells. Although Siva-1 expression is up-regulated in multiple pathological processes, little is known about the signaling pathway underlying the Siva-induced apoptosis. In this study, we investigated the mechanism of the proapoptotic activity of Siva-1 and an alternative splice form lacking the death domain of Siva-1, Siva-2, in T lymphocytes in which Siva proteins, CD27, and glucocorticoid-induced TNFR family-related gene are primarily expressed. Overexpression of Siva proteins triggers a typical apoptotic process manifested by cell shrinkage and surface exposure of phosphatidylserine, and confirmed by ultrastructural features. Siva-induced apoptosis is related to the CD27-mediated apoptotic pathway and results in activation of both initiator and effector caspases. This pathway involves a mitochondrial step evidenced by activation of Bid and cytochrome <i>c</i> release, and is modulated by overexpression of Bcl-2 or Bcl-x<sub>L</sub>. The determinants for Siva-induced apoptosis are not contained within the death domain found in the central part of Siva-1, but rather in both the N-terminal and C-terminal regions shared by both Siva proteins. The N-terminal region also participates in the translocation of both Siva proteins into the nuclear compartment. These results indicate that Siva-1 and Siva-2 mediate apoptosis in T lymphocytes via a caspase-dependent mitochondrial pathway that likely involves both cytoplasmic and nuclear events.
Nectin4 is a novel TIGIT ligand which combines checkpoint inhibition and tumor specificity
Authors: Adi Reches, Yael Ophir, Natan Stein, Inbal Kol, Batya Isaacson, Yoav Charpak Amikam, Afek Elnekave, Pinchas Tsukerman, Paola Kucan Brlic, Tihana Lenac, Barbara Seliger, Stipan Jonjic, Ofer Mandelboim
Journal: Journal for ImmunoTherapy of Cancer (2020)

The use of checkpoint inhibitors has revolutionized cancer therapy. Unfortunately, these therapies often cause immune-related adverse effects, largely due to a lack of tumor specificity.We stained human natural killer cells using fusion proteins composed of the extracellular portion of various tumor markers fused to the Fc portion of human IgG1, and identified Nectin4 as a novel TIGIT ligand. Next, we generated a novel Nectin4 blocking antibody and demonstrated its efficacy as a checkpoint inhibitor in killing assays and in vivo.We identify Nectin4 to be a novel ligand of TIGIT. We showed that, as opposed to all other known TIGIT ligands, which bind also additional receptors, Nectin4 interacts only with TIGIT. We show that the TIGIT-Nectin4 interaction inhibits natural killer cell activity, a critical part of the innate immune response. Finally, we developed blocking Nectin4 antibodies and demonstrated that they enhance tumor killing in vitro and in vivo.We discovered that Nectin4 is a novel ligand for TIGIT and demonstrated that specific antibodies against it enhance tumor cell killing in vitro and in vivo. Since Nectin4 is expressed almost exclusively on tumor cells, our Nectin4-blocking antibodies represent a combination of cancer specificity and immune checkpoint activity, which may prove more effective and safe for cancer immunotherapy.