tbuckley/cabot-search huggingface dataset:
Human Mammalian Enabled (hMena) is a marker of tumor progression in human colorectal cancer
Authors: Akihiro Toyoda, Hidetada Kawana, Kouji Azuhata, Jianyong Yu, Aya Omata, Hirohisa Kishi, Morihiro Higashi, Kenichi Harigaya
Journal: Cancer Research (2008)

2883    Human isotype of mammalian enabled (hMena), a family of enabled/vasodilator-stimulated phosphoprotein, is an actin regulatory protein involved in the regulation of cell motility and adhesion. It does this by protecting actin filaments from capping protein at their barbed ends. Increasing evidence suggests that hMena may have a role in human carcinogenesis. It has been shown that hMena is overexpressed in human breast tumor tissue, and that there is a correlation between the malignant potential of tumors and the intensity of hMena expression in human breast tumors (Modugno et al; 2006). This study aimed to evaluate hMena expression in human colorectal tumors and to examine the relationship between the histological features of tumors and their intensity of hMena expression.    Human total RNA master panel (Clontech), human mammary gland total RNA(Clontech) and 6 surgically resected fresh colorectal samples (tumor and its normal counterpart) were assessed by real-time polymerase chain reaction (PCR) for the messenger RNA (mRNA) expression of hMena. Twenty-six paraffin-embedded colorectal tumors were analyzed immunohistochemically to detect hMena protein expression. Histological grading and the intensity of hMena staining were examined by two experienced pathologists.    We assayed the mRNA expression of hMena using real-time PCR and found that hMena mRNAs were expressed in all human tissue examined, but were most abundant in human central nervous system, colon, and breast tissue. PCR demonstrated that there was a significant increase of hMena mRNA in colorectal cancer tissue compared with its normal counterpart. Immunohistochemical analysis showed that hMena staining was strong in colorectal cancer but showed weak or no staining in normal counterpart tissue. In adenomas, stronger hMena staining was observed in high- compared to low-grade dysplasia, suggesting that higher hMena expression correlated with malignant potential. Furthermore, hMena staining tended to show higher positive reaction at the invasive front of tumors than in their centers. These observations raise the possibility that increased hMena expression may have a role in both carcinogenesis and invasiveness of human colorectal cancer.
Abstract 13473: Macrophage Migration Inhibitory Factor Knockout Exacerbates Doxorubicin-Induced Cardiomyopathy: Role of Autophagy
Authors: Xihui Xu, Jun Ren
Journal: Circulation (2012)

Background: The cardioprotective function of macrophage migration inhibitory factor (MIF) against ischemia/reperfusion has been attributed to activation of AMPK pathway. Autophagy (activated or inh...
Dendritic cell recognition by group 3 innate lymphoid cells through DNAX accessory molecule 1 triggers proinflammatory reciprocal cell activation
Authors: Stefania Campana, Emma Di Carlo, Claudia De Pasquale, Chiara Barberi, Daniela Oliveri, Giacomo Sidoti Migliore, Serafinella Patrizia Cannavò, Bruno Galletti, Daniela Pende, Paolo Carrega, Guido Ferlazzo
Journal: Journal of Allergy and Clinical Immunology (2019)
Reversible Inactivation of Different Millimeter-Scale Regions of Primate IT Results in Different Patterns of Core Object Recognition Deficits
Authors: Rishi Rajalingham, James J. DiCarlo
Journal: Neuron (2019)

Extensive research suggests that the inferior temporal (IT) population supports visual object recognition behavior. However, causal evidence for this hypothesis has been equivocal, particularly beyond the specific case of face-selective subregions of IT. Here, we directly tested this hypothesis by pharmacologically inactivating individual, millimeter-scale subregions of IT while monkeys performed several core object recognition subtasks, interleaved trial-by trial. First, we observed that IT inactivation resulted in reliable contralateral-biased subtask-selective behavioral deficits. Moreover, inactivating different IT subregions resulted in different patterns of subtask deficits, predicted by each subregion's neuronal object discriminability. Finally, the similarity between different inactivation effects was tightly related to the anatomical distance between corresponding inactivation sites. Taken together, these results provide direct evidence that the IT cortex causally supports general core object recognition and that the underlying IT coding dimensions are topographically organized.
Disruption of Long Noncoding RNAs Targets Cancer Hallmark Pathways in Lung Tumorigenesis
Authors: Veronica Davalos, Manel Esteller
Journal: Cancer Research (2019)

Advances in high-throughput genomic and epigenomic technologies have revealed the tremendous complexity of the transcriptional landscape. Beyond protein-coding RNAs (derived from only ∼1.5% of the genome), noncoding RNAs (ncRNA) are emerging as versatile key regulators of gene information involved in multiple major biological processes. Accordingly, deregulation of ncRNA expression has been associated with multiple diseases, including cancer. In this issue of Cancer Research, Shahabi and colleagues characterize LINC00261 as a tumor suppressor long ncRNA epigenetically silenced in lung cancer. They provide crucial mechanistic insights to explain its role in lung tumorigenesis, demonstrating that deregulation of the LINC00261/FOXA2 locus disrupts DNA damage repair signaling, cell-cycle control, and cell proliferation.See related article by Shahabi et al., p. 3050.
Effectiveness and safety of sofosbuvir/velpatasvir/voxilaprevir in patients with chronic hepatitis C previously treated with DAAs
Authors: Jordi Llaneras, Mar Riveiro-Barciela, Sabela Lens, Moisés Diago, Alba Cachero, Javier García-Samaniego, Isabel Conde, Ana Arencibia, Juan Arenas, Francisco Gea, Xavier Torras, José Luis Calleja, José Antonio Carrión, Inmaculada Fernández, Rosa María Morillas, José Miguel Rosales, Isabel Carmona, Conrado Fernández-Rodríguez, Manuel Hernández-Guerra, Susana Llerena, Vanesa Bernal, Juan Turnes, Jesús M. González-Santiago, Silvia Montoliu, Blanca Figueruela, Ester Badia, Manuel Delgado, Miguel Fernández-Bermejo, Mercedes Iñarrairaegui, Juan Manuel Pascasio, Rafael Esteban, Zoe Mariño, Maria Buti
Journal: Journal of Hepatology (2019)
Abstract 17105: Higher Maximum Temperatures Associated With Worse Outcomes in Patients With Pyrexia Following Rewarming From Post-arrest Targeted Temperature Management
Authors: Anne V Grossestreuer, David F Gaieski, Magda B Wernovsky, Douglas J Wiebe, Benjamin S Abella
Journal: Circulation (2015)

Background: Post-arrest pyrexia has been associated with worse outcomes in recent clinical studies. While TTM serves as prophylaxis against pyrexia during active temperature management, it remains unknown to what extent the degree of post-TTM pyrexia relates to survival and neurologic outcomes. We sought to evaluate the association between outcomes and maximum temperature (Tmax) within 72 hours post-rewarming in patients who had Tmax≥38 °C. Hypothesis: We hypothesized that increased Tmax a patient with pyrexia reaches in 72h after TTM discontinuation is associated with worse neurologic and survival outcomes. Methods: We identified 382 TTM-treated patients treated at 14 hospitals between 2005-2014 who had out-of-hospital arrests and serial temperatures recorded during the 72h after returning to normothermia (≥36.5 °C) post-TTM. Our primary outcome was neurologic status (Cerebral Performance Category (CPC) score dichotomized into “good” (1-2) and “poor” (3-5)). Highest recorded temperature in 72h post-TTM after returning to a temperature ≥36.5°C was Tmax. Multiple imputation was used to manage covariate missingness. Results: 147 (39%) patients had documented pyrexia within 72h post-rewarming. In patients with pyrexia, 60% were male, 44% had initial pulseless rhythm of VF/VT, median duration of arrest was 20 (IQR: 13, 30) mins, 49% survived to hospital discharge, and 52 (36%) had a CPC score 1-2 at hospital discharge. Tmax ranged from 38.0-42.2°C, with mean Tmax of 38.7±0.7°C. Median time to Tmax was 19h (IQR: 8, 42). In univariate analysis, higher Tmax was associated with worse neurologic outcomes (OR: 0.38 (95% CI: 0.18-0.80); p=0.01) and survival (OR: 0.41 (95% CI: 0.22-0.79); p=0.01). When controlling for year of arrest, hospital, initial rhythm, sex, witnessed arrest, arrest duration, and age, this relationship was still significant, with each increase in 1°C corresponding to 77% reduction in odds of having good neurologic outcome (aOR: 0.23 (95% CI: 0.08-0.67); p=0.007) and 65% reduction in odds of surviving to hospital discharge (aOR: 0.35 (95% CI: 0.15-0.82); p=0.015). Conclusion: Increased maximum temperature in patients with pyrexia post-rewarming is associated with increased likelihood of poor neurologic and survival outcomes.
AB0999 TREATMENT FOLLOW UP AFTER TRANSITION FROM PAEDIATRIC TO ADULT RHEUMATOLOGY CARE
Authors: Brigita Koren, Maja Tomazin, Vojko Berce, Artur Pahor, Iztok Holc
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Many juvenile onset rheumatic diseases continue to have activity in adulthood. Therefore, a continuous uninterrupted healthcare of these patients is needed. <h3>Objectives</h3> To determine whether and how therapy has changed in patients after transition from paediatric to adult rheumatology service in our medical centre. <h3>Methods</h3> A retrospective single centre study was performed. Patients seen at least once at both paediatric and adult rheumatology outpatient service were enrolled. Data was collected from patients medical records. <h3>Results</h3> A total of 50 patients were included. Most of them were female (82%). Average age at transition was 19,6 years (range 18- 27 years). Mean time of follow up was 44 months (range 2- 119 months). Juvenile idiopathic arthritis (JIA) was the most common juvenile onset chronic rheumatic disease. The medications used either as monotherapy or in combination before transition at last visit at paediatric rheumatology outpatient unit were nonsteroidal anti-inflammatory drugs (NSAIDs) (14%), corticosteroids (6%), synthetic disease modifying antirheumatic drugs (DMARDs) (18%), biologic DMARDs (2%). After transition 34% of patients used NSAIDs, 16% corticosteroids, 24% synthetic DMARDs, 8% biologic DMARDs. Without any medication before and after transition were 66% and 48% of patients, respectively. After transition 36% of patients had their therapy changed. 30% needed escalation of therapy because their disease was still active or they experienced exacerbation. Most changes in therapy occurred in the first year after transition. <h3>Conclusion</h3> We confirmed that many patients with juvenile onset rheumatic disease had changes in their therapy after transition, especially escalations of therapy. Most changes occurred in the first year after transition which is a vulnerable period in a young adult life. <h3>References</h3> [1] Foster H, et al. EULAR/PReS standards and recommendations for the transitional care of young people with juvenile- onset rheumatic diseases. Ann Rheum Dis2017;76:639-46. [2] Jensen PT, et al. Quantitative evaluation of a pediatric rheumatology transition program. Pediatric Rheumatology 2015; 13:17. [3] Kanakoudi-Tsakalidou F. The art of transitioning pediatric patients with rheumatic diseases to adult rheumatologists. Mediterr J Rheumatol 2016;27(2):55-8. [4] Luque Ramos A. Transition to adult rheumatology care is necessary to maintain DMARD therapy in young people with juvenile idiopathic arthritis. Semin Arthritis Rheum2017;47(2):269-75. <h3>Disclosure of Interests</h3> None declared
Prevention of Child Maltreatment as an Unexpected Benefit of Social Policies
Authors: Kristine Campbell
Journal: JAMA Network Open (2019)

Emily C. B. Brown, MD, MS; Michelle M. Garrison, PhD, MPH; Hao Bao, PhD; Pingping Qu, PhD; Carole Jenny, MD, MBA; Ali Rowhani-Rahbar, MD, MPH, PhD
METTL3 facilitates tumor progression via an m6A-IGF2BP2-dependent mechanism in colorectal carcinoma
Authors: Ting Li, Pei-Shan Hu, Zhixiang Zuo, Jin-Fei Lin, Xingyang Li, Qi-Nian Wu, Zhan-Hong Chen, Zhao-Lei Zeng, Feng Wang, Jian Zheng, Demeng Chen, Bo Li, Tie-Bang Kang, Dan Xie, Dongxin Lin, Huai-Qiang Ju, Rui-Hua Xu
Journal: Molecular Cancer (2019)

Colorectal carcinoma (CRC) is one of the most common malignant tumors, and its main cause of death is tumor metastasis. RNA N6-methyladenosine (m6A) is an emerging regulatory mechanism for gene expression and methyltransferase-like 3 (METTL3) participates in tumor progression in several cancer types. However, its role in CRC remains unexplored. Western blot, quantitative real-time PCR (RT-qPCR) and immunohistochemical (IHC) were used to detect METTL3 expression in cell lines and patient tissues. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and transcriptomic RNA sequencing (RNA-seq) were used to screen the target genes of METTL3. The biological functions of METTL3 were investigated in vitro and in vivo. RNA pull-down and RNA immunoprecipitation assays were conducted to explore the specific binding of target genes. RNA stability assay was used to detect the half-lives of the downstream genes of METTL3. Using TCGA database, higher METTL3 expression was found in CRC metastatic tissues and was associated with a poor prognosis. MeRIP-seq revealed that SRY (sex determining region Y)-box 2 (SOX2) was the downstream gene of METTL3. METTL3 knockdown in CRC cells drastically inhibited cell self-renewal, stem cell frequency and migration in vitro and suppressed CRC tumorigenesis and metastasis in both cell-based models and PDX models. Mechanistically, methylated SOX2 transcripts, specifically the coding sequence (CDS) regions, were subsequently recognized by the specific m6A "reader", insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2), to prevent SOX2 mRNA degradation. Further, SOX2 expression positively correlated with METTL3 and IGF2BP2 in CRC tissues. The combined IHC panel, including "writer", "reader", and "target", exhibited a better prognostic value for CRC patients than any of these components individually. Overall, our study revealed that METTL3, acting as an oncogene, maintained SOX2 expression through an m6A-IGF2BP2-dependent mechanism in CRC cells, and indicated a potential biomarker panel for prognostic prediction in CRC.
5,10-methylenetetrahydrofolate/5-fluorouracil combination therapy shows enhanced antitumor activity and lower systemic toxicity with a broad range of cytotoxic drugs
Authors: Mark J. Cantwell, Joan M. Robbins
Journal: Cancer Research (2005)

5107  Although 5-fluorouracil (5-FU)/leucovorin (LV) has historically been the treatment mainstay for colorectal and pancreatic cancers, the development of new cytotoxic agents such as CPT-11, oxaliplatin, bevacizumab, and gemcitabine has expanded the therapeutic options available to patients afflicted with these diseases. While combination drug regimens using these new chemotherapeutic agents with 5-FU/LV have been shown to be advantageous, they still are generally not curative and often only show modest treatment benefits over previous treatment options. Furthermore, increased toxicity associated with combination drug regimens is a consequence that must be considered. Thus, methods to enhance anti-tumor activity and/or decrease toxicity of 5-FU-based treatments are still needed. LV, which is a common component to the 5-FU-based drug combinations, is inactive directly and must undergo several metabolic transformations to its active metabolite, thus limiting its full activity. 5,10-methylenetetrahydrofolate (CoFactor™), the active metabolite of LV, promotes 5-FU-mediated anti-tumor activity. Concurrently, CoFactor appears to induce less toxicity than LV, thus making 5-FU/CoFactor a promising therapy for solid tumors. As such, we hypothesized combining 5-FU/CoFactor with newer classes of cytotoxic drugs might have therapeutic advantages over 5-FU/LV. Using in vivo human tumor xenotransplant models for colorectal and pancreatic cancer in athymic nude mice, we examined the antitumor efficacy of 5-FU/CoFactor in combination with the aforementioned cytotoxic agents. We observed that CoFactor-containing combination regimens induced either equivalent or better antitumor responses, as noted by slower tumor growth and increased mouse survival, compared to LV-containing combinations for all drug types tested. Simultaneously, in an in vivo Balb/c systemic toxicity model, 5-FU/CoFactor induced less systemic toxicity than 5-FU/LV either alone or in combination drug regimens. Specifically, we observed lower hematological toxicity including less thrombocytopenia, neutropenia, and lymphopenia. Furthermore, weight loss, a common side-effect associated with 5-FU/LV-based treatments, was quantitatively less severe with drug treatments containing CoFactor. For example, while 5-FU/LV/gemcitabine induced >25% weight loss in 91% of mice, significantly less (p
Abstract 19613: Ventricular Repolarization in Transient Apical And Midventricular Ballooning
Authors: Hendrik Bonnemeier, Sarah Sandrock, Thomas Demming
Journal: Circulation (2012)

The aim of the present study was to assess potential differences in cardiac repolarization dynamics in patients with transient left ventricular apical ballooning syndrome (AB) and the midventricular variant (MB). Even though repolarization abnormalities and QT interval prolongation in the surface electrocardiogram (ECG) have been consistently reported, repolarization dynamics have not yet been investigated in the AB and MB variants. We hypothesized that differences in regional sympathetic denervation may induce differential effects on cardiac repolarization. METHODS: In a prospective single-center study, 49 consecutive patients with transient left ventricular dysfunction syndrome underwent 3-channel-Holter-ECG-recording on the third day after admission. A total of 27 recordings of patients with AB and 10 recordings of patients with MB were valid for beat-to-beat-QT-interval-analyses. RESULTS: There were no significant differences in baseline clinical characteristics between AB and MB patients. Patients with MB showed significantly lower values for mean RR interval (835 ± 104 vs. 908 ± 118 ms; P&lt;.05). Both, Bazett- and Fridericia-corrected QT-intervals were significantly longer in MB patients (QTcB 441.9 ± 38 vs. 483.4 ± 40ms; P&lt;.05; QTcF 435.0 ± 36 vs.469.4 ± 36.5 ms; P&lt;.05). Parameters of QT-interval variability (QTSD) and QT-interval dynamicity (QT/RR-slope) also exhibited significant differences between groups (diagram). CONCLUSION: There are significant differences in cardiac repolarization between AB and MB syndromes. Patients with MB show more prolonged QT-intervals and a higher degree of heterogeneity of ventricular repolarization. Thus, regional midventricular sympathetic denervation may be associated with even higher arrhythmic risk in transient left ventricular dysfunction syndrome.
Circulating miR-338 Cluster activities on osteoblast differentiation: Potential Diagnostic and Therapeutic Targets for Postmenopausal Osteoporosis
Authors: Chujiao Lin, Shuaitong Yu, Runze Jin, Yao Xiao, Minghui Pan, Fei Pei, Xiaojing Zhu, Huarong Huang, Zunyi Zhang, Shuo Chen, Huan Liu, Zhi Chen
Journal: Theranostics (2019)

MicroRNAs (miRNAs) are the most abundant RNA species found in serum, and recently, several miRNAs have been found to be associated with osteoporosis. However, the development of such associated miRNAs into diagnostic and therapeutic targets remains unaddressed, mostly because of a lack of functional validation. Here, we identified circulating miR-338 associated with postmenopausal osteoporosis, and performed functional validation in vivo and in vitro. Methods: We collected the serum from postmenopausal osteoporosis patients (N=15) and female volunteers of the same age but with normal bone density (N=15) and examined the enrichment of miR-338 cluster. We also confirmed such enrichment using mice subjected to ovariectomy at different stages. We employed primary bone marrow stromal cells from mice and the MC-3T3 cell line along with CRISPR, RNA-seq and ChIP-qPCR to validate the biological function of secreted miR-338 cluster on osteoblastic differentiation and their upstream regulators. Moreover, we generated miR-338 knockout mice and OVX mice injected with an inhibitor against miR-338 cluster to confirm its biological function in vivo. Results: We observed a significant enrichment of miR-338 cluster in postmenopausal osteoporosis patients. Such enrichment was also prominent in serum from mice subjected to ovariectomy and was detected much earlier than bone density decreases revealed by micro-CT. We also confirmed the presence of an estrogen-dependent Runx2/Sox4/miR-338 positive feedback loop that modulated osteoblast differentiation, providing a possible explanation for our clinical findings. Moreover, deletion of the miR-338 cluster or direct intravenous injection of an miR-338 cluster inhibitor significantly prevented osteoporosis after ovariectomy. Conclusion: Circulating miR-338 cluster in the serum could serve as a promising diagnostic and therapeutic target for postmenopausal osteoporosis patients.
SP0002 HOT: OSTEOPOROSIS @2019
Authors: Serge Ferrari
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> The goal of osteoporosis therapy is to quickly prevent fragility fractures in subjects at risk and on the longer term to restore bone mass (Bone mineral density, BMD) to levels of appropriate bone strength. Currently approved drugs for treatment of osteoporosis in Europe, namely bisphosphonates, denosumab, and teriparatide all decrease vertebral fracture risk within one year, whereas the benefits on non-vertebral fractures may take nearly two years to appear. <h3>Objectives:</h3> To provide an update of recent trials regarding osteoporosis treatment. <h3>Methods:</h3> Literature review and expert insights into recent analyses of clinical trials. <h3>Results:</h3> New H2H trials, notably with teriparatide compared to risedronate, have shown the superiority of the anabolic therapy in preventing fractures in high risk patients. In GIOP, denosumab increased BMD more than risedronate. More importantly, romosozumab, a monoclonal Ab against sclerostin, was superior to alendronate to reduce fractures in high risk subjects, whereas the sequence of romosozumab and denosumab was superior to placebo followed by denosumab and increased BMD over just two years equivalent to seven years of continuous denosumab. New analyses of long-term denosumab, up to ten years of continuous therapy, have shown continuous BMD gains and further reduction in fracture rates, with T-scores at hip near -1.5 achieving the lowest fracture risk. However several case reports as well as a post-hoc analysis of subjects discontinuing denosumab in the FREEDOM trial have reported an increased risk of multiple vertebral fractures, which may be prevented by a 1-2 yrs consolidation by a bisphosphonate following denosumab therapy (guidelines). <h3>Conclusion:</h3> In summary, while new data and more potent drugs are emerging (romosozumab), fueling the concept that anabolics should be used earlier in the course of therapy in high risk patients, additional long-term data with anti-resorptives indicate that continuous treatment, at least as long as treatment targets (T-scores &gt;-2 and no fractures) are not reached, has a favourable benefits/risk profile. <h3>Disclosure of interests:</h3> None declared