tbuckley/cabot-search huggingface dataset:
Upfront triple combination therapy in severe paediatric pulmonary arterial hypertension
Authors: Meindina G. Haarman, Marilyne Lévy, Marcus T.R. Roofthooft, Johannes M. Douwes, Theresia R. Vissia-Kazemier, Isabelle Szezepanski, Rolf M.F. Berger, Damien Bonnet
Journal: European Respiratory Journal (2020)

Treatment strategies in paediatric pulmonary arterial hypertension (PAH) have evolved over the last years, but survival is still poor. Recently, in adults with severe PAH, upfront triple combination therapy (uTCT) from diagnosis has been reported to show significant clinical improvement and excellent long-term outcome. This retrospective, observational study aimed to assess the efficacy of uTCT in paediatric PAH.Children diagnosed with PAH between 2010 and 2019 and started with uTCT were included. World Health Organization Functional Class (WHO-FC), haemodynamics, echocardiography, 6-min walking distance and serum level of N-terminal pro-brain-natriuretic-peptide were assessed at baseline, after 3 and 6 months and at last available follow-up. Events were defined as death, lung transplantation or Potts shunt.21 children (median age 4.8 years (2.5-12.8), 57% females) were included. All children except one were in WHO-FC III or IV (28% and 67%, respectively). After 3 months, one child had died and one child had received a Potts shunt. The remaining 19 children showed clinical and echocardiographic improvement, which persisted at 6 months. Children with idiopathic and heritable PAH showed one-, two- and three-year transplant-free survival estimates of 100%, 94% and 87%, albeit 47% of them receiving a Potts shunt during follow-up.Children with severe PAH, but not pulmonary veno-occlusive disease, improved significantly with uTCT and showed beneficial up to 3-year survival rates, albeit 47% of them receiving a Potts shunt during follow-up. The role of a Potts shunt in conjunction to uTCT in paediatric PAH needs to be further established.
Effect on humoral and cellular immunity and on apoptosis in CIN2, CIN3, and HPV16+ cervical cancer of therapeutic divalent genetic vaccination with CMV replicon system (CRS) delivering HPV16 recombinantly mutated E6 and E7 viral oncogenes targeting p53 and Rb, respectively
Authors: J. Giannios, J. Peristeris, N. Alexandropoulos, T. Kononas, P. Ginopoulos
Journal: Journal of Clinical Oncology (2009)

3062 Background: Prophylactic vaccines have no therapeutic capacity for all the women who are already infected with HPV16 and have developed cervical intraepithelial neoplasia (CIN) or cervical cancer. Approximately 300 million women with CIN and cervical cancer will require therapy in the next decades. Thus, there is a great demand for a therapeutic HPV vaccine. Methods: We developed a cytomegalovirus (CMV) replicon system (CRS) for delivery of the HPV16 recombinantly mutated E6 and E7 genes replacing part of the CMV genome for the HPV genes, which were genetically altered to block binding sites for p53 and Rb.The replicon-vectors infected and co-transfected CIN and cervical cancer cells in animal models derived from HPV16(+) CIN, and cervical Ca cells obtained from patients. The genetic vaccine was administered subcutaneously (SC) with a needless injection system. Results: After vaccination,the viral E6 oncogene did not degrade apoptotic p53, and it blocked activation of telomerase. This induced apoptosis and DNA repair in CIN and cervical cancer cells. Furthermore, the E7 viral oncogene did not degrade the retinoblastoma oncogene (Rb) protein releasing transcription factor E2F. This vaccination led to scheduled cell cycle entry, genetic stability, and mortalization of tumor cells. Humoral and cellular immune responses were exhibited, which led to irreversible D2 apoptotic stage of PCD type I leading to a bystander killing effect of CIN, and cervical cancer cells. BrdU and MTT analysis exhibited inhibition of DNA synthesis and metabolic activity of vaccinated tumor cells compared to controls. Conclusions: This genetic divalent vaccine coding for E6 and E7 mutations designed to prevent p53 and Rb binding sites activated humoral and cellular immune responses leading to apoptosis of CIN and cervical cancer cells. It is up to translational medicine to bring this therapeutic vaccine into the clinic for patients with CIN2, CIN3, and cervical cancer patients. No significant financial relationships to disclose.
Comprehensive elaboration of the cGAS-STING signaling axis in cancer development and immunotherapy
Authors: Juyan Zheng, Junluan Mo, Tao Zhu, Wei Zhuo, Yueneng Yi, Shuo Hu, Jiye Yin, Wei Zhang, Honghao Zhou, Zhaoqian Liu
Journal: Molecular Cancer (2020)

Abstract Cellular recognition of microbial DNA is an evolutionarily conserved mechanism by which the innate immune system detects pathogens. Cyclic GMP-AMP synthase (cGAS) and its downstream effector, stimulator of interferon genes (STING), are involved in mediating fundamental innate antimicrobial immunity by promoting the release of type I interferons (IFNs) and other inflammatory cytokines. Accumulating evidence suggests that the activation of the cGAS-STING axis is critical for antitumor immunity. The downstream cytokines regulated by cGAS-STING, especially type I IFNs, serve as bridges connecting innate immunity with adaptive immunity. Accordingly, a growing number of studies have focused on the synthesis and screening of STING pathway agonists. However, chronic STING activation may lead to a protumor phenotype in certain malignancies. Hence, the cGAS-STING signaling pathway must be orchestrated properly when STING agonists are used alone or in combination. In this review, we discuss the dichotomous roles of the cGAS-STING pathway in tumor development and the latest advances in the use of STING agonists.
A newly discovered role of metabolic enzyme PCK1 as a protein kinase to promote cancer lipogenesis
Authors: Hongfei Jiang, Lei Zhu, Daqian Xu, Zhimin Lu
Journal: Cancer Communications (2020)

Abstract Highly active lipogenesis is essential for rapid tumor growth. Sterol regulatory element‐binding protein (SREBP) is a key transcriptional factor for lipogenesis and activated by reduced sterol and oxysterol levels. However, the mechanism by which cancer cells activate SREBP without altering these sterol/oxysterol levels remains elusive. In one of our recent studies published in Nature entitled “The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for lipogenesis”, we demonstrated that activated AKT‐mediated phosphoenolpyruvate carboxykinase 1 (PCK1) S90 phosphorylation reduces the gluconeogenic activity of PCK1 and triggers its translocation to the endoplasmic reticulum (ER), where PCK1 acts as a protein kinase and uses GTP, rather than ATP, as a phosphate donor to phosphorylate Insig1/2 thereby reducing oxysterol's binding to Insig1/2 and activating SREBP‐mediated lipogenesis for tumor growth. These findings elucidate a coordinated regulation between gluconeogenesis and lipogenesis and uncover a critical role of the protein kinase activity of PCK1 in SREBP‐dependent lipid synthesis.
Efficacy and safety of gastrointestinal bleeding prophylaxis in critically ill patients: an updated systematic review and network meta-analysis of randomized trials
Authors: Ying Wang, Long Ge, Zhikang Ye, Reed A. Siemieniuk, Annika Reintam Blaser, Xin Wang, Anders Perner, Morten H. Møller, Waleed Alhazzani, Deborah Cook, Gordon H. Guyatt
Journal: Intensive Care Medicine (2020)
Comparative genomic and protein signatures and intratumoral treatment responses in patients with metastatic breast cancer (MBC) treated with paclitaxel (PTX) and 2-methoxyestradiol (2ME2)
Authors: C. I. Herold, I. Yang, J. Chi, C. Sidor, L. Parrillo, V. Liotcheva, R. A. Welch, J. Arnott, M. W. Dewhirst, K. L. Blackwell
Journal: Journal of Clinical Oncology (2009)

e22049 Background: Tumors respond to both chemotherapy and radiation through a number of poorly understood survival mechanisms. These potential mechanisms include upregulation of anti-apoptotic and pro-angiogenic pathways, including those regulated by HIF-1α. Sequential MBC biopsies were used to examine 1) the effects of PTX on intratumoral HIF-1α mediated pathways; and 2) the ability of a HIF-1α inhibitor (2ME2) to modulate the tumor's HIF- 1α response to PTX. Methods: Key eligibility included pts with MBC, ECOG 0–2, unlimited prior therapies, and biopsiable tumors. Pts were treated on a 28-day schedule with weekly PTX (90 mg/m 2 D1, D8, D15) and daily oral 2ME2 (1000, 1250,1500 or 2000 mg qid starting D8) and had 3 tumor biopsies: baseline (A); D8 post-PTX/pre-2ME2 (B); D22 post-PTX/post- 2ME2 (C). Serial biopsies were compared for genomic and single protein changes. Results: 20 pts (median age 52 yrs [31- 75]) were treated. 60% had ≥2 prior regimens for MBC, 35% had ≥3. No unexpected grade 3/4 toxicities were seen: neutropenia (n=6), anemia (2), hypophosphatemia (2), PE (1). The clinical benefit rate was 25% (4 PR, 1 SD). There were 13 pairs of tumor biopsies to compare points A/B and 10 to compare B/C. There were no consistent gene expression changes between A and B. Significant differences at C vs. B included changes in hypoxia-responsive genes (including CA9, HIF-2α) and upregulation of pro- angiogenic factors and hemoglobin transcripts. For the B/C comparison, 2 distinct groups emerged: the first (biopsy site liver) showed downregulation of gene expression programs driven by ER and the second (lymph node, breast) showed upregulation of endothelial cell- related genes. Conclusions: Combination therapy with PTX and 2ME2 is a well-tolerated and viable option for delaying disease progression for patients with heavily pretreated MBC. Significant gene expression changes before and after exposure to 2ME2 may reflect changes in tumor microcirculation consistent with the idea of vascular normalization. The potential significance of the differences in gene expression observed in the 2 distinct groups remains to be investigated. Supported by Komen Grant BCTR0504044 (MWD). [Table: see text]
The Chemistry of NO in Cancer: Carcinogenesis and Cancer Cell Survival
Authors: Steven Tannenbaum
Journal: Cancer Research (2008)

LE04  Nitric Oxide (NO) is a free radical that, like oxygen, freely diffuses through biological systems. Its sources are various isoforms of the enzyme Nitric Oxide Synthase (NOS) that use L-arginine as a substrate. The enzymes are ubiquitously distributed throughout most cell types in the body, are both constitutive and inducible, and are regulated by both post-translational modification and localization. The chemistries of NO are at once simple and, at the same time, exceedingly complex. The simplicity is that NO can only carry out 1-electron chemistry, which restricts its initial reactions to atoms and molecules with similar properties, i.e. free radicals and transition metals. The complexity arises from the interactions of the secondary reaction products, which vary according to biological environment.  In the extracellular environment the cells of the innate immune system (macrophages and neutrophils) combine multiple chemistries involving a high output of NO to produce a highly reactive milieu of short-lived molecules, leading to oxidation, nitration, and halogenation of protein and nucleic acids, and potentiating oxidation of unsaturated lipids. This results in cell death, mutagenesis, and carcinogenesis.  In the intracellular environment multiple NOSs function as part of the cell’s regulatory system by modulating canonical signaling pathways, including the caspase pathway, the MAP kinase pathway, and the Akt pathway, through a process known as S-nitrosation. Caspases are shut down directly by S-nitrosation of their active-site cysteines. The other pathways are modulated by inactivation of the phosphatases that help to regulate proteins that are the substrates of kinases. S-nitrosation is an on/off process, so like kinases and phosphatases, NO can participate in maintaining the set-point of the cell. In the case of the cancer cell, the net effect of NO will be to block apoptosis (caspases), enhance survival (Akt), and stimulate growth and migration (MAP kinase). It follows that selective blocking of NOSs can aid in the treatment of some cancers.  This research was supported by National Institutes of Health grant CA26731, by the MIT Center for Environmental Health Sciences with a grant from the National Institute of Environmental Health Sciences (ES002109), and by National Cancer Institute contract N01-CN-43304 with Illinois Institute for Technology.
CRISPR-engineered human brown-like adipocytes prevent diet-induced obesity and ameliorate metabolic syndrome in mice
Authors: Chih-Hao Wang, Morten Lundh, Accalia Fu, Rókus Kriszt, Tian Lian Huang, Matthew D. Lynes, Luiz O. Leiria, Farnaz Shamsi, Justin Darcy, Bennett P. Greenwood, Niven R. Narain, Vladimir Tolstikov, Kyle L. Smith, Brice Emanuelli, Young-Tae Chang, Susan Hagen, Nika N. Danial, Michael A. Kiebish, Yu-Hua Tseng
Journal: Science Translational Medicine (2020)

Human white adipocytes engineered to express UCP1 activate endogenous BAT and protect against diet-induced obesity when transplanted into mice.
Effect of long-term testosterone therapy on molecular regulators of skeletal muscle mass and fibre-type distribution in aging men with subnormal testosterone
Authors: Rikke Kruse, Stine J. Petersson, Louise L. Christensen, Jonas M. Kristensen, Rugivan Sabaratnam, Niels Ørtenblad, Marianne Andersen, Kurt Højlund
Journal: Metabolism (2020)
Potential impact of missing outcome data on treatment effects in systematic reviews: imputation study
Authors: Lara A Kahale, Assem M Khamis, Batoul Diab, Yaping Chang, Luciane Cruz Lopes, Arnav Agarwal, Ling Li, Reem A Mustafa, Serge Koujanian, Reem Waziry, Jason W Busse, Abeer Dakik, Holger J Schünemann, Lotty Hooft, Rob JPM Scholten, Gordon H Guyatt, Elie A Akl
Journal: BMJ (2020)

To assess the risk of bias associated with missing outcome data in systematic reviews.Imputation study.Systematic reviews.100 systematic reviews that included a group level meta-analysis with a statistically significant effect on a patient important dichotomous efficacy outcome.Median percentage change in the relative effect estimate when applying each of the following assumption (four commonly discussed but implausible assumptions (best case scenario, none had the event, all had the event, and worst case scenario) and four plausible assumptions for missing data based on the informative missingness odds ratio (IMOR) approach (IMOR 1.5 (least stringent), IMOR 2, IMOR 3, IMOR 5 (most stringent)); percentage of meta-analyses that crossed the threshold of the null effect for each method; and percentage of meta-analyses that qualitatively changed direction of effect for each method. Sensitivity analyses based on the eight different methods of handling missing data were conducted.100 systematic reviews with 653 randomised controlled trials were included. When applying the implausible but commonly discussed assumptions, the median change in the relative effect estimate varied from 0% to 30.4%. The percentage of meta-analyses crossing the threshold of the null effect varied from 1% (best case scenario) to 60% (worst case scenario), and 26% changed direction with the worst case scenario. When applying the plausible assumptions, the median percentage change in relative effect estimate varied from 1.4% to 7.0%. The percentage of meta-analyses crossing the threshold of the null effect varied from 6% (IMOR 1.5) to 22% (IMOR 5) of meta-analyses, and 2% changed direction with the most stringent (IMOR 5).Even when applying plausible assumptions to the outcomes of participants with definite missing data, the average change in pooled relative effect estimate is substantive, and almost a quarter (22%) of meta-analyses crossed the threshold of the null effect. Systematic review authors should present the potential impact of missing outcome data on their effect estimates and use this to inform their overall GRADE (grading of recommendations assessment, development, and evaluation) ratings of risk of bias and their interpretation of the results.
THU0173 Genetic anticipation in familial rheumatoid arthritis
Authors: EP Sharapova, LI Alexeeva, IA Guseva, SA Finogenova, MY Krylov, EY Samarkina, MA Moshnina, VA Myakotkin
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Rheumatoid arthritis (RA) is à systemic inflammatory disease of connective tissue which is characterised by chronic progressing articular lesion and disturbances in immune system. Aetiology of the disease is still unknown. Nevertheless, the role of genetic factors in its determination is confirmed by multiple family and twins studies. <h3>Objectives</h3> Òî determine if there is evidence for genetic anticipation in RA in multicase RA pedigrees. <h3>Methods</h3> Age at onset and disease severity was compared within 26 parent/offspring pairs with RA. <h3>Results</h3> The age at onset of RA was earlier in the offspring than in parents (26,3 ± 12,5 and 45,65 ± 14,0 correspondingly), and this difference is statistically reliable (ð &lt;0.01). In couples aunts-cousins (N = 6) in mîãå advanced age aunts fall ill (44.Ç ± 15.9 and 25.0 ± 9,4 correspondingly) and the disease onset relating to age is also statistically reliable (ð &lt;0.02). In these multicase RA pedigrees, the offspring had a tendency to more severe disease, despite shorter disease duration and younger age. <h3>Conclusion</h3> These results suggest genetic anticipation occurs in RA, where the beginning of disease manifestation becomes earlier in the following generation.
Challenges and Potential Improvements to Patient Access to Pharmaceuticals
Authors: Mitchell A. Psotka, Mona Fiuzat, Scott D. Solomon, Cynthia Chauhan, G. Michael Felker, Javed Butler, John R. Teerlink, Shashank S. Sinha, Christopher M. O’Connor, Marvin A. Konstam
Journal: Circulation (2020)

Patient access to a drug after US regulatory approval is controlled by complex interactions between governmental and third-party payers, pharmacy benefit managers, distributers, manufacturers, health systems, and pharmacies that together mediate the receipt of goods by patients after prescription by clinicians. Recent medication approvals highlight why and how the distribution of clinically beneficial novel therapies is controlled. Although imposed limitations on availability may be rational considering the fiduciary responsibilities of payers and escalating spending on health care and pharmaceuticals, transparency and communication are lacking, and some utilization management may disproportionately affect vulnerable populations. Analysis of the current health insurance landscape suggests mechanisms by which patient access to appropriate medications can be improved and patient and clinician frustration reduced while acknowledging the financial realities of the pharmaceutical marketplace. We propose creation of a shared, standardized, and transparent process for coverage decisions that minimizes administrative barriers and is defensible on the basis of clinical and cost-effectiveness evidence. These reforms would benefit patients and improve the efficiency of the pharmaceutical system.
Diagnostic accuracy of centralised assays for TB detection and detection of resistance to rifampicin and isoniazid: a systematic review and meta-analysis
Authors: Mikashmi Kohli, Emily MacLean, Madhukar Pai, Samuel G. Schumacher, Claudia M. Denkinger
Journal: European Respiratory Journal (2020)

Various diagnostic companies have developed high throughput molecular assays for tuberculosis (TB) and resistance detection for rifampicin and isoniazid. We performed a systematic review and meta-analyses to assess the diagnostic accuracy of five of these tests for pulmonary specimens. The tests included were Abbott RealTime MTB, Abbott RealTime RIF/INH, FluoroType MTB, FluoroType MTDBR and BD Max MDR-TB assay.A comprehensive search of six databases for relevant citations was performed. Cross-sectional, case-control, cohort studies, and randomised controlled trials of any of the index tests were included. Respiratory specimens (such as sputum, bronchoalveolar lavage, tracheal aspirate, etc) or their culture isolates.A total of 21 included studies contributed 26 datasets. We could only meta-analyse data for three of the five assays identified, as data were limited for the remaining two. For TB detection, the included assays had a sensitivity of 91% or more and the specificity ranged from 97% to 100%. For rifampicin resistance detection, all the included assays had a sensitivity of more than 92%, with a specificity of 99-100%. Sensitivity for isoniazid resistance detection varied from 70 to 91%, with higher specificity of 99-100% across all index tests. Studies that included head-to-head comparisons of these assays with Xpert MTB/RIF for detection of TB and rifampicin resistance suggested comparable diagnostic accuracy.In people with symptoms of pulmonary TB, the centralised molecular assays demonstrate comparable diagnostic accuracy for detection of TB, rifampicin and isoniazid resistance to Xpert MTB/RIF assay, a WHO recommended molecular test.
Reservoir of Fibroblasts Promotes Recovery From Limb Ischemia
Authors: Shu Meng, Jie Lv, Palas K. Chanda, Iris Owusu, Kaifu Chen, John P. Cooke
Journal: Circulation (2020)

The angiogenic response to ischemia restores perfusion so as to preserve tissue. A role for mesenchymal-to-endothelial transition in the angiogenic response is controversial. This study is to determine if resident fibroblasts contribute to angiogenesis.We utilized the murine model of hindlimb ischemia, and in vivo Matrigel plug assay together with lineage tracing studies and single cell RNA-sequencing to examine the transcriptional and functional changes in fibroblasts in response to ischemia.Lineage tracing using Fsp1-Cre: R26R-EYFP mice revealed the emergence within the ischemic hindlimb of a small subset of YFP+ CD144+ CD11b- fibroblasts (E* cells) that expressed endothelial cell (EC) genes. Subcutaneous administration of Matrigel in Fsp1-Cre: R26R-EYFP mice generated a plug that became vascularized within 5 days. Isolation of YFP+ CD11b- cells from the plug revealed a small subset of YFP+ CD144+ CD11b- E* cells which expressed EC genes. Pharmacological or genetic suppression of innate immune signaling reduced vascularity of the Matrigel plug and abrogated the generation of these E* cells. These studies were repeated using human fibroblasts, with fluorescence-activated cell sorting analysis revealing that a small percentage of human fibroblasts that were induced to express EC markers in Matrigel plug assay. Pharmacological suppression or genetic knockout of inflammatory signaling abolished the generation of E* cells, impaired perfusion recovery and increased tissue injury after femoral artery ligation. To further characterize these E* cells, single cell RNA-sequencing studies were performed and revealed 8 discrete clusters of cells expressing characteristic fibroblast genes, of which 2 clusters (C5 and C8) also expressed some EC genes. Ischemia of the hindlimb induced expansion of clusters C5 and C8. The C8 cells did not express CD144, nor did they form networks in Matrigel, but did generate angiogenic cytokines. The C5 fibroblasts most resembled E* cells in their expression of CD144 and their ability to form EC-like networks in Matrigel.Together, these studies indicate the presence of subsets of tissue fibroblasts which seem poised to contribute to the angiogenic response. The expansion of these subsets with ischemia is dependent on activation of innate immune signaling and contributes to recovery of perfusion and preservation of ischemic tissue.