tbuckley/cabot-search huggingface dataset:
M1<sup>hot</sup>tumor-associated macrophages boost tissue-resident memory T cells infiltration and survival in human lung cancer
Authors: Eva M Garrido-Martin, Toby W P Mellows, James Clarke, Anusha-Preethi Ganesan, Oliver Wood, Angelica Cazaly, Gregory Seumois, Serena J Chee, Aiman Alzetani, Emma V King, Catherine C Hedrick, Gareth Thomas, Peter S Friedmann, Christian Hermann Ottensmeier, Pandurangan Vijayanand, Tilman Sanchez-Elsner
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background The role of tumor-associated macrophages (TAMs) in determining the outcome between the antitumor effects of the adaptive immune system and the tumor’s anti-immunity stratagems, is controversial. Macrophages modulate their activities and phenotypes by integration of signals in the tumor microenvironment. Depending on how macrophages are activated, they may adopt so-called M1-like, antitumor or M2-like, protumor profiles. In many solid tumors, a dominance of M2-like macrophages is associated with poor outcomes but in some tumor types, strong M1-like profiles are linked to better outcomes. We aimed to investigate the interrelationship of these TAM populations to establish how they modulate the efficacy of the adaptive immune system in early lung cancer. Methods Macrophages from matched lung (non-tumor-associated macrophages (NTAMs)) and tumor samples (TAMs) from resected lung cancers were assessed by bulk and single-cell transcriptomic analysis. Protein expression of genes characteristic of M1-like (chemokine (C-X-C motif) ligand 9) or M2-like (matrix metallopeptidase 12) functions was confirmed by confocal microscopy. Immunohistochemistry related the distribution of TAM transcriptomic signatures to density of CD8 + tissue-resident memory T cells (T RM ) in tumors and survival data from an independent cohort of 393 patients with lung cancer. Results TAMs have significantly different transcriptomic profiles from NTAMs with &gt;1000 differentially expressed genes. TAMs displayed a strong M2-like signature with no significant variation between patients. However, single-cell RNA-sequencing supported by immuno-stained cells revealed that additionally, in 25% of patients the M2-like TAMs also co-expressed a strong/hot M1-like signature (M1 hot ). Importantly, there was a strong association between the density of M1 hot TAMs and T RM cells in tumors that was in turn linked to better survival. Our data suggest a mechanism by which M1 hot TAMs may recruit T RM cells via CXCL9 expression and sustain them by making available more of the essential fatty acids on which T RM depend. Conclusions We showed that in early lung cancer, expression of M1-like and M2-like gene signatures are not mutually exclusive since the same TAMs can simultaneously display both gene-expression profiles. The presence of M1 hot TAMs was associated with a strong T RM tumor-infiltrate and better outcomes. Thus, therapeutic approaches to re-program TAMs to an M1 hot phenotype are likely to augment the adaptive antitumor responses.
Tumor Subtype Determines Therapeutic Response to Chimeric Polypeptide Nanoparticle–based Chemotherapy in <i>Pten</i>-deleted Mouse Models of Sarcoma
Authors: Rebecca D. Dodd, Amanda Scherer, Wesley Huang, Gavin R. McGivney, Wade R. Gutierrez, Emily A. Laverty, Kathleen A. Ashcraft, Victoria R. Stephens, Parisa Yousefpour, Soumen Saha, Vickie Knepper-Adrian, Warren Floyd, Mark Chen, Yan Ma, Eric M. Mastria, Diana M. Cardona, William C. Eward, Ashutosh Chilkoti, David G. Kirsch
Journal: Clinical Cancer Research (2020)

Nanoparticle-encapsulated drug formulations can improve responses to conventional chemotherapy by increasing drug retention within the tumor and by promoting a more effective antitumor immune response than free drug. New drug delivery modalities are needed in sarcomas because they are often chemoresistant cancers, but the rarity of sarcomas and the complexity of diverse subtypes makes it challenging to investigate novel drug formulations.New drug formulations can be tested in animal models of sarcomas where the therapeutic response of different formulations can be compared using mice with identical tumor-initiating mutations. Here, using Cre/loxP and CRISPR/Cas9 techniques, we generated two distinct mouse models of Pten-deleted soft-tissue sarcoma: malignant peripheral nerve sheath tumor (MPNST) and undifferentiated pleomorphic sarcoma (UPS). We used these models to test the efficacy of chimeric polypeptide doxorubicin (CP-Dox), a nanoscale micelle formulation, in comparison with free doxorubicin.The CP-Dox formulation was superior to free doxorubicin in MPNST models. However, in UPS tumors, CP-Dox did not improve survival in comparison with free doxorubicin. While CP-Dox treatment resulted in elevated intratumoral doxorubicin concentrations in MPNSTs, this increase was absent in UPS tumors. In addition, elevation of CD8+ T cells was observed exclusively in CP-Dox-treated MPNSTs, although these cells were not required for full efficacy of the CP nanoparticle-based chemotherapy.These results have important implications for treating sarcomas with nanoparticle-encapsulated chemotherapy by highlighting the tumor subtype-dependent nature of therapeutic response.
Efficacy in non-Hodgkin’s lymphoma xenograft models of PNT225X, a chemically unmodified DNA oligonucleotide directed against the BCL2 locus
Authors: Neal Goodwin, J. McGovren, Wendi Rodrigueza, Ayad Al-Katib, Omar Kameel, Ramzi Mohammad
Journal: Cancer Research (2007)

4889  Non-Hodgkin’s lymphoma (NHL) incidence and mortality have been steadily increasing over the past 30 years. While rituximab-containing combination regimens are efficacious in patients with diffuse large cell lymphoma (DLCL) and other subtypes, relapse rates are high and new therapies are still needed. PNT225X was designed to target a specific non-coding region within the BCL2 locus, thereby initiating a cell death program in malignant cells. PNT225X consists of a chemically unmodified, DNA oligonucleotide encapsulated in a novel liposomal formulation for intravenous (IV) use that protects the oligo from degradation by circulating nucleases. Antitumor efficacy in vivo was investigated in 2 NHL models: 1) In SCID mice bearing advanced, subcutaneous (SC) implants of the WSU-DLCL2 xenograft model of DLCL, an IV daily x 5 regimen at an optimal dose of 10 mg/kg of PNT225X produced 4/8 complete regressions (CR), 1/8 partial regressions (PR), and a 131% median tumor growth delay (TGD) (p=0.0002), with 2/8 tumor-free survivors (TFS) at study termination (day 81). There were no treatment-related deaths and mean nadir weight loss was   Based on its single-agent and combination efficacy in NHL models, PNT225X is in preclinical development in preparation for clinical trials.
AB0137 DIVERSITY ANALYSIS OF INTESTINAL FLORA IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS
Authors: Z. Mingxing, X. F. Yin
Journal: Annals of the Rheumatic Diseases (2020)

Background: Systemic lupus erythematosus (SLE) is a multiple systemic autoimmune disease and its pathogenesis is still not fully understanding. In recent years, there has been reports on the relationship between SLE and intestinal flora. Objectives: To study the diversity and the intestinal flora intestinal microbes in patients with SLE and further provide new ideas for clinical treatment. Methods: The stool samples of 28 patients with SLE and 125 normal healthy adults were collected. The 16S rRNA in the specimen was sequenced using the Roche/45 high-throughput sequencing platform, and the differences between the two groups were compared at the level of the phylum and genus. Results: In SLE patients, as the picture show, the levels of fusobacteria, proteobacteria and TM7 were significantly higher (P&lt;0.05) and the number of firmicutes was significantly decreased (P&lt;0.05) than that of healthy controls at the phylum level.The percentage of bifidobacterium, collinsella, enterococcus, leuconostoc, streptococcus, bilophila were significantly higher (P&lt;0.05) and the number of lachnospira, roseburia, gemmiger, devosia, desulfovibrio were significantly decreased (P&lt;0.05) than that of healthy participants at the genus level. Figure 1. the differences between patients with SLE and normal healthy adults were compared at the level of the phylum Figure 2. the differences between patients with SLE and normal healthy adults were compared at the level of the genus Conclusion: The diversity of intestinal flora in patients with SLE altered from that of normal population. The differences are likely to be one of the pathogenesis of lupus, which might provide theoretical foundation for the regulation of intestinal flora to treat autoimmune diseases such as lupus. Disclosure of Interests: None declared
Abstract 13877: Inflammatory Activity Correlates With Severity of Heart Failure - The Association of High Sensitive CRP With Left Ventricular Ejection Fraction, ProBNP and NYHA-Class in a Real-World Cohort
Authors: Alexander Peikert, Klaus Kaier, Lucas Steffens, Andreas Clemens, Christoph Bode, Andreas Zirlik, Peter Stachon
Journal: Circulation (2019)

Introduction: Inflammatory mechanisms play a critical role in pathogenesis and maintenance of heart failure. Growing experimental and clinical evidence suggests anti-inflammatory interventions as p...
FRI0204 Trigeminal sensory neuropathy in systemic sclerosis
Authors: YV Grachov, NG Guseva, VM Grinin, ML Kukushkin, AV Syrovegin, VF Guravlev
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> Systemic sclerosis (SSc) is one of the few somatic disorders which induce isolated or combined trigeminal sensory neuropathy (TSN). <h3>Methods</h3> A screening of 101 patients with SSc hospitalised at the Institute of Rheumatology over a period of six months in 2000 revealed that eight patients (7,9%) had TSN (all of them were females aged 42–69 with a clinical history of SSc of 1 to 12 years). In two cases, SSc was associated with the SJÖGREN'S syndrome; one case was associated with polymyositis. All the patients with TSN underwent rheumatological and neurological examinations including the recording of blink reflex. <h3>Results</h3> The main clinical manifestation of TSN was bilateral asymmetric numbness in all the three divisions of the trigeminal nerve, especially in the perioral area. Five patients had qualitative taste disorders including «oral astereognosis», i.e., monotypical sensations in the oral cavity on taking up foods of different kinds and tastes. In two cases, TSN was manifested as constant and constant or «neuralgia-like» facial pains. Irrespective of remissions (which could be spontaneous), in each case facial pain was one of the most significant manifestations of SSc. All the patients had disturbances in surface sensitivity (hyper- or hypoesthesia) in the distal parts of the upper and lower extremities. In three cases, early symptomes of TSN (e.g., facial paraesthesia, numbness and hyperesthesia) developed simultaneously with the changes in the skin colour (especially of fingers), skin oedema, arthralgias and malaise. In the rest of the patients, TSN developed within 6 months to 3 years after the Raynaud's syndrome, sclerodactyly and other manifestations of SSc. The blink reflex records revealed modest prolongation of ipsilateral R1 responses. Specific therapy of TSN included administration of vasoactive drugs (e.g., pentoxifylline, vazaprostan) and group B vitamins. The elimination of facial pain presented a problem. The use of NSAID resulted in short-term attenuation of pain; in one case, topical application of ibuprofen (in the form of a cream) was more effective. Patients with paroxysmal manifestations of pain received additionally carbamazepine (300–400 mg/d). The efficiency of physio- and reflexotherapy in patients with acute facial pain syndrome is open to question. <h3>Conclusion</h3> TSN is a typical neurological sign of SSc (with frequency 7,9% of cases), which is manifested as facial numbness, qualitative taste disorders including «oral astereognosis», pain and paraesthesiae. Most often, TSN develops within 6 months to 3 years after the appearance of other characteristic features of SSc. A combination of bilateral sensory disturbances in the facial area and distal parts of the upper and lower extremities suggests that TSN can be regarded as a partial form of generalised sensory polyneuropathy.
Abstract 13895: Screening for Atrial Fibrillation in Native Americans Using Smartphone-Based ECG
Authors: Khaled Elkholey, Marty M Lofgren, Karrie Q Meeks, Zain Ul Abideen Asad, Ben Freedman, Stavros Stavrakis
Journal: Circulation (2019)

Background: Screening for silent atrial fibrillation (AF), a major risk factor for stroke, with subsequent initiation of anticoagulation in at-risk individuals, may decrease stroke incidence. Nativ...
Abstract 15684: Local Plaque Morphology Predicts Cardiovascular Events in Patients With Peripheral Arterial Disease; Angioscopic Analysis
Authors: Kenji Yamaji, Masafumi Ueno, Kazuhiro Kobuke, Yoshitaka Iwanaga, Shunich Miyazaki
Journal: Circulation (2017)

Background: Angioscopic evaluations in coronary arteries showed that plaques with higher grade of yellow color or adherent thrombus may be associated with the vulnerability leading to cardiovascula...
COX-2 inhibition promotes IFNγ-dependent enhancement of anti-tumor immunity and vaccine response in lung cancer models
Authors: Seok-Chul Yang, Li Zhu, Brian Gardner, Karen Reckamp, Robert M. Strieter, Raj K. Batra, Min Huang, Sherven Sharma, Steven M. Dubinett
Journal: Cancer Research (2005)

6056  Despite the identification of a repertoire of tumor antigens, hurdles persist for successful immune-based therapies. The active immune suppression induced by the tumor itself is a problem of paramount importance. In previous studies, we have demonstrated an immune suppressive network in non-small cell lung cancer that is due to over expression of tumor cyclooxygenase 2 (COX-2). In this study, we assessed the vaccination response to tumor challenge following pharmacological or genetic inhibition of COX-2 in a murine lung cancer model. Treatment of naive mice with the COX-2 inhibitor, SC-58236, skewed splenocytes toward a Type 1 cytokine response, inducing IFNγ, IL-12 and IP-10. Fifty percent of mice receiving SC-58236 and a sub-optimal irradiated tumor cell vaccine completely rejected tumors on rechallenge. In contrast, all mice vaccinated with either irradiated tumor cells alone or receiving SC-58236 alone showed progressive tumor growth. Studies performed in CD4 and CD8 knockout mice revealed a requirement for CD4 T lymphocyte subset for complete rejection of tumors following SC-58236 and a sub-optimal irradiated tumor cell vaccine administration. To determine the role of COX-2 expression on the vaccination responses, studies were performed in COX-2 gene knockout mice. Compared to control littermates, COX-2 -/- mice showed a significant reduction in tumor growth following vaccination with a sub-optimal dose of irradiated tumor cells. Compared to homozygous COX-2 -/- knockout mice, heterozygous COX-2 -/+ vaccinated mice had an intermediate reduction in tumor growth. In vivo depletion of IFNγ abrogated the COX-2 inhibitor-mediated vaccination effect. These findings provide a strong rationale for further evaluation of COX-2 inhibition in tumor immunity and its use to enhance vaccination responses against cancer.
Associations between a smoke-free homes intervention and childhood admissions to hospital in Scotland: an interrupted time-series analysis of whole-population data
Authors: Steve Turner, Daniel Mackay, Smita Dick, Sean Semple, Jill P Pell
Journal: The Lancet Public Health (2020)

BackgroundMany children are exposed to second-hand smoke in the home and are at increased risk of asthma and other respiratory conditions. In Scotland, a public health mass-media campaign was launched on March 24, 2014, called Take it Right Outside (TiRO), with a focus on reducing the exposure of children to domestic second-hand smoke. In this study, our aim was to establish whether the TiRO campaign was followed by a decrease in hospital admissions for childhood asthma and other respiratory conditions related to second-hand smoke exposure across Scotland.MethodsFor an interrupted time-series analysis, data were obtained on all hospital admissions in Scotland between 2000 and 2018 for children aged younger than 16 years. We studied changes in the monthly incidence of admissions for conditions potentially related to second-hand smoke exposure (asthma, lower respiratory tract infection, bronchiolitis, croup, and acute otitis media) per 1000 children following the 2014 TiRO campaign, while considering national legislation banning smoking in public spaces from 2006. We considered asthma to be the primary condition related to second-hand smoke exposure, with monthly asthma admissions as the primary outcome. Gastroenteritis was included as a control condition. The analysis of asthma admissions considered subgroups stratified by age and area quintile of the Scottish Index of Multiple Deprivations (SIMD).Findings740 055 hospital admissions were recorded for children. 138 931 (18·8%) admissions were for respiratory conditions potentially related to second-hand smoke exposure, of which 32 342 (23·3%) were for asthma. After TiRO in 2014, we identified a decrease relative to the underlying trend in the slope of admissions for asthma (−0·48% [–0·85 to −0·12], p=0·0096) in younger children (age <5 years), but not in older children (age 5–15 years). Asthma admissions did not change after TiRO among children 0–15 years of age when data were analysed according to area deprivation quintile. Following the 2006 legislation, independent of TiRO, asthma admissions decreased in both younger children (−0·36% [–0·67 to −0·05], p=0·021) and older children (−0·68% [–1·00 to −0·36], p<0·0001), and in children from the most deprived (SIMD 1; −0·49% [–0·87 to −0·11], p=0·011) and intermediate deprived (SIMD 3; −0·70% [–1·17 to −0·23], p=0·0043) area quintiles, but not in those from the least deprived (SIMD 5) area quintile.InterpretationOur findings suggest that smoke-free home interventions could be an important tool to reduce asthma admissions in young children, and that smoke-free public space legislation might improve child health for many years, especially in the most deprived communities.FundingUniversity of Aberdeen Research Excellence Framework 2021 Impact Support Award Scheme.
E3 ligase ZFP91 inhibits Hepatocellular Carcinoma Metabolism Reprogramming by regulating PKM splicing
Authors: De Chen, Yanjie Wang, Ruixun Lu, Xiaofeng Jiang, Xinhui Chen, Nan Meng, Min Chen, Shan Xie, Guang-Rong Yan
Journal: Theranostics (2020)

Rationale: Hepatocellular carcinoma (HCC) is one of the most lethal cancers, and few molecularly targeted anticancer therapies have been developed to treat it. Thus, the identification of new therapeutic targets is urgent. Metabolic reprogramming is an important hallmark of cancer. However, how ubiquitin ligases are involved in the regulation of cancer metabolism remains poorly understood. Methods: RT-PCR, western blot and IHC were used to determine ZFP91 expression. RNAi, cell proliferation, colony formation and transwell assays were used to determine the in vitro functions of ZFP91. Mouse xenograft models were used to study the in vivo effects of ZFP91. Co-IP together with mass spectrometry or western blot was utilized to investigate protein-protein interaction. Ubiquitination was analyzed using IP together with western blot. RNA splicing was assessed by using RT-PCR followed by restriction digestion. Lactate production and glucose uptake assays were used to analyze cancer metabolism. Results: We identified that an E3 ligase zinc finger protein 91 (ZFP91) suppressed HCC metabolic reprogramming, cell proliferation and metastasis in vitro and in vivo. Mechanistically, ZFP91 promoted the Lys48-linked ubiquitination of the oncoprotein hnRNP A1 at lysine 8 and proteasomal degradation, thereby inhibiting hnRNP A1-dependent PKM splicing, subsequently resulting in higher PKM1 isoform formation and lower PKM2 isoform formation and suppressing HCC glucose metabolism reprogramming, cell proliferation and metastasis. Moreover, HCC patients with lower levels of ZFP91 have poorer prognoses, and ZFP91 is an independent prognostic factor for patients with HCC. Conclusions: Our study identifies ZFP91 as a tumor suppressor of hepatocarcinogenesis and HCC metabolism reprogramming and proposes it as a novel prognostic biomarker and therapeutic target of HCC.
Response to: ‘Comment on Ye<i>et al ‘</i>Presence of respiratory failure of COVID-19 infection in patients with rheumatism in Wuhan, China’’ by Chen<i>et al</i>
Authors: Jixin Zhong, Cong Ye, Shaozhe Cai, Lingli Dong
Journal: Annals of the Rheumatic Diseases (2020)

We appreciate the valuable comments from Chen et al on our recent study about the clinical characteristics of COVID-19 cases with rheumatic disease.1 They highlight an important point about the sample size of patients with rheumatism infected with COVID-19 in our study. We agree that the sample size was relatively small, although we have included all such cases in Tongji Hospital, the hospital that admitted the most patients with COVID-19 in China. We acknowledged this limitation in the discussion of the paper.2 With the urgent pandemic of COVID-19, the aim of this study is to provide a timely report to present the clinical features of patients with rheumatism infected with COVID-19. The clinical manifestation of COVID-19 cases with rheumatic disease in Wuhan, the first COVID-19 epicentre in the world, may provide important information for disease management in patients with rheumatic disease in other areas of the world. In our report, we noticed that respiratory failure was more common in patients with rheumatism (38% vs 10%, p<0.001) infected with COVID-19, although the duration of hospital stay and mortality were similar between patients with rheumatic disease and those without rheumatic disease.2 These results were confirmed by subsequent studies in other areas of the world.3 4 An …
TWIST1 Drives Smooth Muscle Cell Proliferation in Pulmonary Hypertension via Loss of GATA-6 and BMPR2
Authors: Ye Fan, Xia Gu, Jing Zhang, Katharina Sinn, Walter Klepetko, Na Wu, Vasile Foris, Philip Solymosi, Grazyna Kwapiszewska, Wolfgang M. Kuebler
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Rationale: The bHLH (basic helix-loop-helix) transcription factor TWIST1 (Twist-related protein 1) controls cell proliferation and differentiation in tissue development and disease processes. Recently, endothelial TWIST1 has been linked to pulmonary hypertension (PH) and endothelial-to-mesenchymal transition, yet the role of TWIST1 in smooth muscle cells (SMCs) remains so far unclear.Objectives: To define the role of TWIST1 in SMCs in the pathogenesis of PH.Methods: SMC-specific TWIST1-deficient mice, SMC-specific TWIST1 silencing in rats, mass spectrometry, immunoprecipitation, and chromatin immunoprecipitation were used to delineate the role of SMC TWIST1 in PH.Measurements and Main Results: In pulmonary vessels from patients with PH and rodent PH models, TWIST1 expression was markedly increased and predominantly localized to SMCs. SMC-specific TWIST1 deficiency or silencing attenuated the development of PH and distal vessel muscularization in chronically hypoxic mice and in monocrotaline-treated rats. In vitro, TWIST1 inhibition or silencing prevented pulmonary artery SMC proliferation and migration. Mechanistically, the observed effects were mediated, at least in part, by TWIST1-dependent degradation of GATA-6 (GATA-binding protein 6). BMPR2 (bone morphogenetic protein receptor-2) was identified as a novel downstream target of GATA-6, which directly binds to its promoter. Inhibition of TWIST1 promoted the recruitment of GATA-6 to the BMPR2 promoter and restored BMPR2 functional expression.Conclusions: Our findings identify a key role for SMC TWIST1 in the pathogenesis of lung vascular remodeling and in PH that is partially mediated via reduced GATA-6–dependent BMPR2 expression. Inhibition of SMC TWIST1 may constitute a new therapeutic strategy for the treatment of PH.