tbuckley/cabot-search huggingface dataset:
Cancer therapy with tumor cell lysate pulsed monocyte-derived dendritic cells in patients with metastastic colon cancer: Improvement by danger signals
Authors: T. Neβelhut, D. Lorenzen, D. Marx, R. Chang, J. Neβelhut, C. Matthes, N. Cillien, W. Stücker, J. Peters
Journal: Journal of Clinical Oncology (2006)

2563 Background: The prognosis of colon cancers with hematogenous spread remains poor at 12–20 months. We report the use of a dendritic cell based immunotherapy to improve patient survival, especially with cell culture conditions mimicking infection. Methods: After isolating monocytes from the blood of 39 patients with metastasized colon cancer, dendritic cells were generated ex vivo in the presence of recombinant cytokines (IL-4; GM-CSF) and autologous serum. The DC loaded with tumor cell lysate were administered to the patients intradermally. Culture conditions were tested for upregulation of costimulatory molecules, downregulation of IL-10 and upregulation of IL-12 secretion by ELISPOT and fluorescence cytometry. Results: DC vaccination induced a clinical response in 9 (23%) patients with a median overall survival after onset of DC-therapy of 12 months (11–44 months for responders and 1–20 months for non-responders) and 23 months after diagnosis of metastases (16–63 months for responders and 1–23 months for non-responders). These data show that a dendritic cell based immunotherapy may prolong the patients overall survival. However, complete remissions are rare. This can be due to weak stimulation of CTL response due to insufficient antigen presentation, lack of costimulatory molecules as well as secretion of IL-10 rather than IL-12 by the DC’s. Here we could show that Toll-like receptors (TLR) ligands like Poly-I:C or lipopeptides as so called danger signals in combination with interferons can induce an upregulation of costimulatory molecules accompanied by inhibition of IL-10 and induction of IL-12 secretion in vitro. By using these culture conditions we induced a clinical complete remission of liver metastases after failure of standard therapy in one patient (overall survival after onset of DC-therapy 13 months, after diagnosis 24 months). Conclusions: According to Matzinger’s hypothesis an effective immune response occurs only by responding to a danger signal associated with infection or stress. Thus, cell culture condition should be used with TLR ligands mimicking a bacterial or viral infection. In general, a dendritic cell based immunotherapy can be successful in advanced stages of colon cancer patients. [Table: see text]
The prognostic role of the WHO classification, urinary 5-hydroxyindoleacetic acid (u5HIAA) and liver function tests (LFTs) in metastatic neuroendocrine carcinomas (NECs) of the gastroenteropancreatic (GEP) tract
Authors: V. Formica, A. R. Norman, D. Cunningham, A. Wotherspoon, B. Sirohi, J. Oates, G. Chong
Journal: Journal of Clinical Oncology (2006)

4092 Background: The aim of this study was to assess the prognostic value of the revised neuroendocrine tumour (NET) WHO classification (2000) and to identify additional prognostic factors. Methods: 119 pts with metastatic NET arising from the GEP tract treated at the RMH were eligible for this retrospective study. All were classified according to WHO guidelines into well-differentiated and poorly-differentiated neuroendocrine carcinomas (WDNEC and PDNEC). Demographic, clinical and biochemical data at diagnosis were recorded as potential prognostic factors. The hazard ratios (HRs) between subgroups of patients were estimated by Cox regression analysis; survival curves were generated by Kaplan-Meier method. Approval for the study was obtained from the local ethics committee. Results: 8% of pts had PDNECs, 92% had WDNECs. Histological differentiation had the most impact on overall survival (OS) (HR = 4.02, 95%CI 1.26–12.82, p = 0.02, using WDNECs as the reference). In a WDNEC-restricted multivariate analysis, significantly abnormal LFTs and elevated u5HIAA were independent prognostic factors for survival (HR = 2.65, 95% CI 1.33–5.30, p = 0.006 and HR = 2.51, 95% CI 1.35–4.63, p = 0.003, respectively). Radiological evidence of liver metastases was not predictive of survival. These variables were used to create a WDNEC-specific prognostic model (low-risk = both normal, intermediate-risk = one abnormal, high-risk = both abnormal) (see table ). Statistically distinct median OS (mOS) were identified for each of the 3 risk groups. High-risk WDNECs had similar poor survival to PDNECs. Conclusion: This analysis supports the prognostic value of the WHO classification for metastatic NETs arising from the GEP tract. Risk stratification using readily available u5HIAA and LFTs may give additional prognostic information for WDNECs, although these observations need to be confirmed in an independent dataset. [Table: see text] No significant financial relationships to disclose.
TELEMEDICINE TO GUIDE AMI MANAGEMENT: INTRODUCING A NEW METRIC FOR EVALUATING EFFICIENCY
Authors: Sameer Mehta, Francisco Fernandez, Carlos Villagran, Sebastian Niklitschek, Jorge Avila, Roberto Botelho, Alejandra Frauenfelder, Mariana Ceschim, Daniel Vieira, Sohail Merchant, Akhil Vaid, Gladys Pinto, Isabella Vallenilla, Genesis Perez del Nogal, Lilly Prieto, Daniela Bou Daher, Maritza Luna, Lorena Pisana, Juhee E. Lee, Jorge Mazzini, Yogaraja Vijayan
Journal: Journal of the American College of Cardiology (2020)
A role for histone H2AX in cell cycle control and apoptosis.
Authors: Jonathan Rios-Doria, Aneliya Velkova, José M. Galán-Caridad, Vesna Dapic, Johana Melendez, Alvaro N A Monteiro
Journal: Cancer Research (2006)

5043  Recent evidence from a wide variety of biological systems has indicated an important regulatory role for post-translation histone modifications in cellular processes such as regulation of gene expression, DNA damage response and recombination. Phosphorylation of histone H2AX at serine 139 is a critical event in the cellular response to DNA damage, yet little is known about the functional implications of this modification. To investigate the role of histone H2AX phosphorylation we ectopically expressed epitope-tagged H2AX or mutants at the phosphorylation site. GFP-tagged wild type H2AX, H2AX Ser139Ala or H2AX Ser139Glu proteins are efficiently expressed localizing exclusively to the interphase nucleus and to condensed chromosomes during mitosis. Moreover, biochemical fractionation indicates that epitope-tagged H2AX proteins are incorporated into nucleosomes. Expression of H2AX Ser139Ala, which disrupts the phosphorylation site, partially abrogated G2/M arrest following ionizing radiation. Conversely, expression of H2AX Ser139Glu, designed as a phosphorylation mimic, induced G2/M arrest in the absence of DNA damage. G2/M arrest induced by H2AX Ser139Glu was independent of the formation of 53BP1-containing foci and ATM activation. In addition, stable cell lines expressing H2AX Ser139Glu or H2AX Ser139Ala had a lower mitotic index than wild-type H2AX. Further analyses revealed that expression of either mutant induced apoptosis and induced higher caspase-3/7 activity compared to expression of wild-type H2AX. Taken together these results demonstrate a role for H2AX Serine 139 phosphorylation in cell cycle regulation and apoptosis.
Tranexamic acid is safe to use following mild-to-moderate traumatic brain injury
Authors: Rob Cook, Johnny Lyon-Maris, Rosie Martin
Journal: BMJ (2020)

The study The CRASH-3 Trial Collaborators . Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial. Lancet 2019;394:1713-23. This trial was funded by NIHR Health Technology Assessment Programme (project number 14/190/01), JP Moulton Charitable Trust, Department of Health and Social Care, Department for International Development, Global Challenges Research Fund, Medical Research Council, and the Wellcome Trust (Joint Global Health Trials scheme). To read the full NIHR Signal, go to: https://discover.dc.nihr.ac.uk/content/signal-000870/tranexamic-acid-following-mild-to-moderate-traumatic-brain-injury-is-safe-and-reduces-deaths
Palliative care in patients with advanced lung cancer in a network of health service research in integrative oncology.
Authors: Friedemann Schad, Jan Axtner, Antje Happe, Matthias Kroez, Burkhard Matthes, Christian Grah, Guenther Spahn, Harald Matthes
Journal: Journal of Clinical Oncology (2013)

e20710 Background: Early palliative care was demonstrated to result in a superior survival and improvement of health related quality of live (HRQL) in patients with advanced lung cancer. Concepts of integrative oncology (IO) offer multimodal therapy strategies aiming to enhance patients’ salutogenic resources in addition to standard care. In the present study we analyzed patients with advanced lung cancer from a clinical registry in Germany. Methods: Data were collected by the Network Oncology, a clinical registry of hospitals and outpatients care specialized in Anthroposophic Medicine and integrative oncology. We analyzed 441 C34 patients of UICC stage IV that had at least one of the following additional therapies: Viscum album, embrocation, therapeutic unction’s, rhythmical massages, lymph drainage, physiotherapy, eurythmy therapy, music or drawing therapy, modeling, speech-, breathing and hyperthermia therapy. We calculated Kaplan-Meier survival based on right censored data and using Greenwoods 95% confidence intervals. Results: 43% of the patients were female and median age was 64 yr (min 32/ max 92). 84% received chemotherapy, 55% radiation and 40% surgery. Most frequent additional therapies were Viscum album (72%), embrocation (43%), therapeutic unction (42%), eurythmy therapy and physiotherapy (both 27%). Patients used combinations up to 9 different additional therapies (median ♀=3, median ♂=2) with significant difference between genders (Fisher’s exact test, &lt; p=0.001). Median length of VA therapy was 6.4 months. Median OS was 1.05yr (95% CI: 0.83 - 1.32), 2 and 3 year survival was 31% and 20%, respectively. Conclusions: Integrative therapy concepts are of growing interest in cancer care. In this observational study patients received conventional and complementary interventions. A relevant number of lung cancer patient use IO when offered in palliative oncology. Median OS seems to be comparable to the palliative care group of Temel et al. 2010 (median OS=0.97yr, 95% CI: 0.53 – 1.41). Health service research in multimodal IO settings needs further evaluation in terms of HRQL measurement and effectiveness.
Beneficial effects of LRP6-CRISPR on prevention of alcohol-related liver injury surpassed fecal microbiota transplant in a rat model
Authors: Linghua Yu, Linlin Wang, Huixing Yi, Xiaojun Wu
Journal: Gut Microbes (2020)

Alcohol intake can modify gut microbiota composition, increase gut permeability, and promote liver fibrogenesis. LRP6 is a signal transmembrane protein and a co-receptor for the canonical Wnt signaling pathway. This study compared the curative effect of LRP6-CRISPR on alcohol-related liver injury with that of traditional fecal microbiota transplant (FMT) and investigated the alteration of the gut microbiome following the treatment. A rat model of alcohol-related liver injury was established and injected with lentiviral vectors expressing LRP6-CRISPR or administered with fecal filtrate from healthy rats, with healthy rat served as the control. Liver tissues of rats were examined by HE staining, Sirius staining, and Oil red O staining, respectively. The expression of LRP6 and fibrosis biomarkers were tested by PCR. The fecal sample of rats was collected and examined by 16S rRNA sequencing. Our data indicated that LRP6-CRISPR was more efficient in the prevention of alcohol-related liver injury than FMT. Microbiome analysis showed that alcohol-related liver injury related to gut microbiota dysbiosis, while treatment with LRP6-CRISPR or FMT increased gut microflora diversity and improved gut symbiosis. Further, bacteria specific to the disease stages were identified. Genera Romboutsia, Escherichia-Shigella, Pseudomonas, Turicibacter, and Helicobacter were prevalent in the intestine of rats with alcohol-related liver injury, while the domination of Lactobacillus was found in rats treated with LRP6-CRISPR or FMT. Besides, Lactobacillus and genera belonging to family Lachnospiraceae, Bacteroidales S24-7 group, and Ruminococcaceae were enriched in healthy rats. LRP6-CRISPR and FMT have beneficial effects on the prevention of alcohol-related liver injury, and correspondently, both treatments altered the disrupted gut microflora to a healthy one.
COVID-19: towards controlling of a pandemic
Authors: Juliet Bedford, Delia Enria, Johan Giesecke, David L Heymann, Chikwe Ihekweazu, Gary Kobinger, H Clifford Lane, Ziad Memish, Myoung-don Oh, Amadou Alpha Sall, Anne Schuchat, Kumnuan Ungchusak, Lothar H Wieler
Journal: The Lancet (2020)

During the past 3 weeks, new major epidemic foci of coronavirus disease 2019 (COVID-19), some without traceable origin, have been identified and are rapidly expanding in Europe, North America, Asia, and the Middle East, with the first confirmed cases being identified in African and Latin American countries. By March 16, 2020, the number of cases of COVID-19 outside China had increased drastically and the number of affected countries, states, or territories reporting infections to WHO was 143.1 On the basis of "alarming levels of spread and severity, and by the alarming levels of inaction", on March 11, 2020, the Director-General of WHO characterised the COVID-19 situation as a pandemic.
APIXABAN VERSUS WARFARIN AND ASPIRIN VERSUS PLACEBO ACCORDING TO RENAL FUNCTION AFTER ACUTE CORONARY SYNDROME OR PCI IN ATRIAL FIBRILLATION: INSIGHTS FROM THE AUGUSTUS TRIAL
Authors: Ziad Hijazi, John H. Alexander, Zhuokai Li, Daniel Wojdyla, Roxana Mehran, Christopher B. Granger, M. Cecilia Bahit, Stephan Windecker, Otavio Berwanger, Sigrun Halvorsen, Peter Sinnaeve, Robert Storey, Renato Lopes
Journal: Journal of the American College of Cardiology (2020)
Non-invasive Reporter Gene Imaging of Cell Therapies, including T Cells and Stem Cells
Authors: Candice Ashmore-Harris, Madeleine Iafrate, Adeel Saleem, Gilbert O. Fruhwirth
Journal: Molecular Therapy (2020)

Cell therapies represent a rapidly emerging class of new therapeutics. They are intended and developed for the treatment of some of the most prevalent human diseases, including cancer, diabetes, and for regenerative medicine. Currently, they are largely developed without precise assessment of their in vivo distribution, efficacy, or survival either clinically or preclinically. However, it would be highly beneficial for both preclinical cell therapy development and subsequent clinical use to assess these parameters in situ to enable enhancements in efficacy, applicability, and safety. Molecular imaging can be exploited to track cells non-invasively on the whole-body level and can enable monitoring for prolonged periods in a manner compatible with rapidly expanding cell types. In this review, we explain how in vivo imaging can aid the development and clinical translation of cell-based therapeutics. We describe the underlying principles governing non-invasive in vivo long-term cell tracking in the preclinical and clinical settings, including available imaging technologies, reporter genes, and imaging agents as well as pitfalls related to experimental design. Our emphasis is on adoptively transferred T cell and stem cell therapies.
Challenges of CAR- and TCR-T cell–based therapy for chronic infections
Authors: Antonio Bertoletti, Anthony Tanoto Tan
Journal: The Journal of Experimental Medicine (2020)

While therapy with T cells engineered with a chimeric antigen receptor (CAR) or a classical T cell receptor (TCR) is revolutionizing cancer treatment, its adoption in infectious diseases has been met with considerable resistance. Can we find its value for the cure of infections?
INSPIRATORY MUSCLE TRAINING IMPROVES SIX-MINUTE WALK DISTANCE IN ADULTS WITH PULMONARY ARTERIAL HYPERTENSION
Authors: Derek Tran, Phillip Munoz, Edmund Lau, Jennifer Alison, Martin Brown, Yizhong Zheng, Patricia Corkery, Keith Wong, Steven Lindstrom, David Celermajer, Glen Davis, Rachael Cordina
Journal: Journal of the American College of Cardiology (2020)
SHORT QT SYNDROME AND SUDDEN CARDIAC DEATH DUE TO A MUTATION IN THE TMEM175 ENDOLYSOSOMAL POTASSIUM CHANNEL
Authors: Juan Jiménez Jáimez, Francisco Bermúdez, Ana Moreno-Manuel, Lilian Gutiérrez Espinosa de los Monteros, María Linarejos Vera-Pedrosa, Miguel Álvarez, Luis Tercedor
Journal: Journal of the American College of Cardiology (2020)
Challenges and opportunities for IBD drug development: from early stage to regulatory approval
Authors: Silvio Danese, Elmer Schabel, Mark Andrew Ainsworth, Laurent Peyrin-Biroulet
Journal: Gut (2020)

Increased understanding of the immunopathology of inflammatory bowel disease (IBD) has resulted in the development of novel therapies such as vedolizumab or ustekinumab, and the investigation of new agents including Janus kinase inhibitors, anti-mucosal vascular addressin cell adhesion molecule-1 agents, anti-interleukin-12/23 monoclonal antibody and sphingosine-1-phosphate receptor-1 selective agonists.1 Over the last years, new approaches to mentoring drug research and testing have been developed. Among these methods, the fast-track drug designation and subsequent approval of safe regimens represent an emerging drug development approach in IBD treatment.2 Since 2001, the European Commission has started a fast-track approval programme for the European Medicines Agency (EMA). The Committee for Human Medicinal Products, established under the EMA, is responsible for such an accelerated review process.2 The requirements and time frames for approval of a drug under the accelerated review process are similar to those used by the United States Food and Drug Administration authorities (FDA). Eligibility for fast-track (in the USA) or accelerated approval (EMA) is based on whether a product will be of major public health interest, particularly from the point of view of therapeutic innovation3 and on endpoints that predict substantial clinical improved outcomes.2

In IBD, this can be difficult to define and the gold standard would probably be complete mucosal or histological healing.2 The cost of IBD care is rising worldwide as IBD incidence and prevalence are rapidly increasing.4 One key reason for the rising cost of IBD treatment is the significant costs of new therapeutic molecules brought into the market, particularly biologics.2 4 Indeed, evidence suggests that the cost of biologic agents now accounts for the main expenditure in treating patients with IBD.5 6 To reduce the cost of IBD drugs, efforts must be made to optimise the drug development process and …
Chemosensitivity and clinical features of <i>EML4</i><i>-ALK-</i>positive patients with advanced non-small cell lung cancer.
Authors: Jangchul Park, Chiaki Kondo, Junichi Shimizu, Yoshitsugu Horio, Kimihide Yoshida, Tetsuya Mitsudomi, Yasushi Yatabe, Toyoaki Hida
Journal: Journal of Clinical Oncology (2012)

e18145 Background: Lung cancers that harbor EML4-ALK can be effectively treated with anaplastic lymphoma kinase (ALK) inhibitors. Recent reports showed that pemetrexed-based therapy might be an effective treatment in patients with ALK-positive NSCLC. However, the efficacy of other regimens is still not known. The purpose of this study is to investigate the clinical characteristics, the efficacy of the cytotoxic chemotherapy in the first and second line setting in EML4-ALK positive NSCLC with advanced stage. Methods: EML4-ALK fusion was screened with RT-PCR and immunohistochemistry. When positive results were obtained with either method, gene rearrangement of ALK was confirmed with fluorescent in-situ hybridization. The clinical efficacy of chemotherapy was evaluated retrospectively. Results: We evaluated 20 EML4-ALK positive patients with advanced stage. Twelve patients were without a history of smoking, and 6 light smokers and 2 smokers. Seventeen (85%) of 20 had stage IV disease. Nine cases were male, and 11 were female. The mean age was 46.3 years (range, 26-79 years). Most of the CT findings at the primary site were masses or nodules, while two cases showed air-space consolidation. In the first line chemotherapy, most of the treatment regimens included carboplatin or cisplatin in combination with one or more therapeutic agents, such as taxans, bevacizumab except one case who was treated only by S-1. In 13 cases which were evaluable, 7/13 (53.8%) had a PR, 4/13 (30.8%) had SD, and 2/13 (15.4%) had PD. The treatment regimens in the second line setting included one therapeutic agent such as docetaxel, pemetrexed, S-1 or an oral ALK inhibitor. Among 10 evaluable cases in the second line setting, 2/10 (20%) had a PR, 5/10 (50%) had SD, and 3/10 (30%) had PD. Two patients who had a PR were all treated by oral ALK inhibitor. Within 7 patients who were treated by cytotoxic agents, none had clinical response. Conclusions: Our study suggests that EML4-ALK positive patients may show relatively favorable response to cytotoxic drug in the first line setting, but low response in the second line setting. These data might be helpful for further clinical trials including EML4-ALK positive patients.
Estrogen receptor β represses breast tumor growth and angiogenesis in vivo
Authors: J. Hartman, K. Lindberg, J. Inzunza, J. Wan, A. Ström, J. Gustafsson
Journal: Journal of Clinical Oncology (2006)

10101 Background: Estrogens are well known stimulators of breast cancer cell growth in vitro as well as in vivo. Two different estrogen receptors exist, namely estrogen receptor (ER) α and β. ERα mediates the proliferative effect of estrogen in breast cancer cells and we have earlier shown that ERβ inhibits cell-cycle progression in vitro. Estrogens are well known stimulators of in vivo breast cancer cell growth as well as angiogenesis, and the effect is mediated through ERα. The function of ERβ in this context is not well understood. Methods: We have used ERα-positive T47D breast cancer cells stably transfected with a Tet/Off regulated ERβ expression vector system. The ERβ-inducible tumor cells are studied in vitro as well as in vivo. Results: By transplanting ERβ-inducible breast cancer cells into SCID-mice, we show that ERβ inhibits tumor growth and reduces the volume of established tumors. Furthermore, we show by immunohistochemistry, that the number of blood microvessels in the tumor periphery is decreased by ERβ expression, counteracting the well-known pro-angiogenic effect of ERα. By Western blot analysis on tumor extracts, we show that the concentration of the important pro-angiogenic growth factors VEGF and bFGF, normally expressed by breast tumor cells, is decreased in the ERβ-expressing tumors compared to the normal tumors. To exclude that the observed anti-angiogenic effect is just a result of reduced tumor growth, we incubated Tet/Off regulated ERβ expressing cells in vitro, during non-hypoxic conditions. We found that the expression of ERβ leads to decreased expression of VEGF and PDGFβ at the mRNA and protein-levels. In transient transfection assays, we found estrogen-ERα mediated up regulation of VEGF, PDGFβ and bFGF-promoter activities in T47D cells, and these activities were all suppressed following co-transfection with an ERβ-expression vector. Conclusions: We conclude that ERβ inhibits growth factor expression at transcriptional level in breast cancer cells; taken together, our data indicates that ERβ inhibits growth and angiogenesis of tumors formed by T47D breast cancer cells. This makes ERβ an interesting therapeutic target in breast cancer and perhaps treatment with the newly designed ERβ-selective ligands might work as a new anti-proliferative and anti-angiogenic therapy. No significant financial relationships to disclose.