tbuckley/cabot-search huggingface dataset:
Co‐occurrence of <i>TERT</i> promotor mutations with <i>BRAF</i> or <i>NRAS</i> alterations correlates with worse prognosis in melanoma
Authors: Y.‐S. Sheen, C.‐Y. Chu
Journal: British Journal of Dermatology (2020)

Linked Article: Manrique-Silva et al. Br J Dermatol 2021; 184:504–513.
TFE3, a potential therapeutic target for Spinal Cord Injury via augmenting autophagy flux and alleviating ER stress
Authors: Kailiang Zhou, Zhilong Zheng, Yao Li, Wen Han, Jing Zhang, Yuqin Mao, Huanwen Chen, Wanying Zhang, Mi Liu, Ling Xie, Hongyu Zhang, Huazi Xu, Jian Xiao
Journal: Theranostics (2020)

Background and Aim: Increasing evidence suggests that spinal cord injury (SCI)-induced defects in autophagic flux may contribute to an impaired ability for neurological repair following injury. Transcription factor E3 (TFE3) plays a crucial role in oxidative metabolism, lysosomal homeostasis, and autophagy induction. Here, we investigated the role of TFE3 in modulating autophagy following SCI and explored its impact on neurological recovery. Methods: Histological analysis via HE, Nissl and Mason staining, survival rate analysis, and behavioral testing via BMS and footprint analysis were used to determine functional recovery after SCI. Quantitative real-time polymerase chain reaction, Western blotting, immunofluorescence, TUNEL staining, enzyme-linked immunosorbent assays, and immunoprecipitation were applied to examine levels of autophagy flux, ER-stress-induced apoptosis, oxidative stress, and AMPK related signaling pathways. In vitro studies using PC12 cells were performed to discern the relationship between ROS accumulation and autophagy flux blockade. Results: Our results showed that in SCI, defects in autophagy flux contributes to ER stress, leading to neuronal death. Furthermore, SCI enhances the production of reactive oxygen species (ROS) that induce lysosomal dysfunction to impair autophagy flux. We also showed that TFE3 levels are inversely correlated with ROS levels, and increased TFE3 levels can lead to improved outcomes. Finally, we showed that activation of TFE3 after SCI is partly regulated by AMPK-mTOR and AMPK-SKP2-CARM1 signaling pathways. Conclusions: TFE3 is an important regulator in ROS-mediated autophagy dysfunction following SCI, and TFE3 may serve as a promising target for developing treatments for SCI.
AB0006 Hla-drb1 genes distribution in croatian arthritis patients
Authors: D Babić-Naglić, N Laktašić-Žerjavić, B Ćurković, R Žunec, K Potočki
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Rheumatoid arthritis (RA) is chronic inflammatory disease of synovial tissue that leads to destructive joint damage and disability. An genetic association between particular HLA-DRB1 genes and severity of disease course has been documented in various clinical investigations.<sup>1–3</sup> <h3>Objectives</h3> To investigate HLA-DRB1 distribution in patients with non-erosive and erosive joint disease. <h3>Methods</h3> Sixty six patients with nonspecific joint pain and/or arthritis, non-erosive RA and erosive RA were selected. Evaluated parameters were: sex, age, disease duration, tender and swollen joints index (44 joints), functional index (HAQ), ESR, &nbsp;rheumatoid factor, x-ray of hands and feet classified according Larsen score and HLA-DRB1 typing. The presence of one or more susceptible alleles DRB1*0101; *0401; *0404; *0405; *0101 and *1401 was considered as poor prognostic sign. <h3>Results</h3> Non-erosive joint disease (Larsen 0-I) was diagnosed in 37 patients (mean disease duration and range: 30/2–132/months) and 29 patients (55/2–216/months) had erosive changes (Larsen II-V). Susceptible alleles were identified in 26 non-erosive and 21 erosive patients. In the whole group the most frequent genes were DRB1*0101 (30 pts.), *0401 (11 pts.) and *0404 (7 pts.). Seven out of 47 DRB1 positive patients had 2 or more susceptible alleles. There were no statistically significant differences between non-erosive and erosive group in any variable. <h3>Conclusion</h3> DRB1*0101 is the most frequent susceptible allel in Croatian arthritis population. In this study the prevalence of susceptible genes was almost same in non-erosive and erosive joint disease. Our data do not support evidence for more destructive disease course in DRB1 positive patients. <h3>References</h3> Emery P, <i>et al</i>. Genetically determined factors as predictors of radiological change in patients with early symmetrical arthritis. BMJ 1992;305:1387–9 O Dell JR, <i>et al</i>. HLA-DRB1 typing in rheumatoid arthritis: predicting response to specific treatment. Ann Rheum Dis. 1998;57:209–13 Rau R, <i>et al</i>. The effect of HLA-DRB1 genes, rheumatoid factor and treatment on radiographic disease progression in rheumatoid arthritis over 6 years. J Rheumatol. 2000;27:2566–75
Abstract 14571: Decrease in Radiation Dose Using New Imaging Platform for Device Placement
Authors: Lynn Zaremski, Ilir Maraj, Eric Shulman, Faraj Kargoli, Tina Shah, Dmitriy Nevelev, Ephraim Leiderman, Jay Chudow, Jorge Romero, Luigi Di Biase, John Fisher, Kevin Ferrick, Andrew Krumerman
Journal: Circulation (2017)

Introduction: Radiation doses incurred by patients and medical staff have increased, however radiation should be minimized according to the “as low as reasonably achievable” (ALARA) principle. A ne...
The transcription factor BCL-6 controls early development of innate-like T cells
Authors: Marianthi Gioulbasani, Alexandros Galaras, Sofia Grammenoudi, Panagiotis Moulos, Alexander L. Dent, Mikael Sigvardsson, Pantelis Hatzis, Barbara L. Kee, Mihalis Verykokakis
Journal: Nature Immunology (2020)
Intravitreal hydrogels for sustained release of therapeutic proteins
Authors: Blessing C. Ilochonwu, Arto Urtti, Wim E. Hennink, Tina Vermonden
Journal: Journal of Controlled Release (2020)

This review highlights how hydrogel formulations can improve intravitreal protein delivery to the posterior segment of the eye in order to increase therapeutic outcome and patient compliance. Several therapeutic proteins have shown excellent clinical successes for the treatment of various intraocular diseases. However, drug delivery to the posterior segment of the eye faces significant challenges due to multiple physiological barriers preventing drugs from reaching the retina, among which intravitreal protein instability and rapid clearance from the site of injection. Hence, frequent injections are required to maintain therapeutic levels. Moreover, because the world population ages, the number of patients suffering from ocular diseases, such as age-related macular degeneration (AMD) and diabetic retinopathy (DR) is increasing and causing increased health care costs. Therefore, there is a growing need for suitable delivery systems able to tackle the current limitations in retinal protein delivery, which also may reduce costs. Hydrogels have shown to be promising delivery systems capable of sustaining release of therapeutic proteins and thus extending their local presence. Here, an extensive overview of preclinically developed intravitreal hydrogels is provided with attention to the rational design of clinically useful intravitreal systems. The currently used polymers, crosslinking mechanisms, in vitro/in vivo models and advancements are discussed together with the limitations and future perspective of these biomaterials.
Identification of a Tumor Microenvironment-relevant Gene set-based Prognostic Signature and Related Therapy Targets in Gastric Cancer
Authors: Wang-Yu Cai, Zi-Nan Dong, Xiao-Teng Fu, Ling-Yun Lin, Lin Wang, Guo-Dong Ye, Qi-Cong Luo, Yu-Chao Chen
Journal: Theranostics (2020)

Rationale: The prognosis of gastric cancer (GC) patients is poor, and there is limited therapeutic efficacy due to genetic heterogeneity and difficulty in early-stage screening. Here, we developed and validated an individualized gene set-based prognostic signature for gastric cancer (GPSGC) and further explored survival-related regulatory mechanisms as well as therapeutic targets in GC. Methods: By implementing machine learning, a prognostic model was established based on gastric cancer gene expression datasets from 1699 patients from five independent cohorts with reported full clinical annotations. Analysis of the tumor microenvironment, including stromal and immune subcomponents, cell types, panimmune gene sets, and immunomodulatory genes, was carried out in 834 GC patients from three independent cohorts to explore regulatory survival mechanisms and therapeutic targets related to the GPSGC. To prove the stability and reliability of the GPSGC model and therapeutic targets, multiplex fluorescent immunohistochemistry was conducted with tissue microarrays representing 186 GC patients. Based on multivariate Cox analysis, a nomogram that integrated the GPSGC and other clinical risk factors was constructed with two training cohorts and was verified by two validation cohorts. Results: Through machine learning, we obtained an optimal risk assessment model, the GPSGC, which showed higher accuracy in predicting survival than individual prognostic factors. The impact of the GPSGC score on poor survival of GC patients was probably correlated with the remodeling of stromal components in the tumor microenvironment. Specifically, TGFβ and angiogenesis-related gene sets were significantly associated with the GPSGC risk score and poor outcome. Immunomodulatory gene analysis combined with experimental verification further revealed that TGFβ1 and VEGFB may be developed as potential therapeutic targets of GC patients with poor prognosis according to the GPSGC. Furthermore, we developed a nomogram based on the GPSGC and other clinical variables to predict the 3-year and 5-year overall survival for GC patients, which showed improved prognostic accuracy than clinical characteristics only. Conclusion: As a tumor microenvironment-relevant gene set-based prognostic signature, the GPSGC model provides an effective approach to evaluate GC patient survival outcomes and may prolong overall survival by enabling the selection of individualized targeted therapy.
AB0152 The differential diagnostic specificities of purine enzymes activity in rheumatoid arthritis and gout
Authors: AB Zborovsky, VF Martemyanov, MY Stazharov, SA Bedina, EE Mozgovaya
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> The clinical picture of gouty arthritis (GA) and rheumatoid arthritis (RA) can be quite often much alike, and the differential diagnosis of these diseases is rather difficult. The GA and RA patients often have hyperuricemia, which is indicative of purine metabolism breaches in patients with these diseases. <h3>Objectives</h3> To study differential diagnostic specificity of Purine enzymes activity in Rheumatoid arthritis and Gout. <h3>Methods</h3> We observed 71 RA patients. The mean age of the patients ? 43.2 ± 3.6 years. The mean duration of the disease – 11.9 ± 3.6 years. I degree of RA activity was determined in 17 (23.94%), II ? in 44 (61.97%), III ? in 10 (14.09%) observations. 34 Gout patients were examined. The mean age of the patients ? 48.2 ± 2.2 years. The mean duration of the disease 8.8 ± 1.3 years. The intermittent form of Gout was determined in 21 (61.8%), the chronic form ? in 13 (38.2%) observations. Adenosin deaminase (ADA), AMP-desaminase (AMPDA), Xanthine dehydrogenase (XDG), Xanthine oxidase (XO) activities were measured with spectrophotometer, ADA, XDG isoenzymes were examined with method of electrophoresis in agarose gel and obtained enzymograms were evaluated at densitometry. <h3>Results</h3> XDG activity was more high, XO/XDG activities ratio was less in Gout patients in comparison with RA patients (I degree of activity). ADA-2 isoenzymes were more in chronic form of Gout than in RA. We revealed the simultaneous increase of XO, XDG activities in Gout (XO/XDG activities ratio ? 0.6–0.8), but increased XO activity in RA was accompanied by normal or lowered XDG activity (XO/XDG activities ratio ? more 1.0). <h3>Conclusion</h3> XO, XDG activities changes is more essential in differential diagnostics of RA and Gout among studied enzymatic indices.
Long-chain fatty acyl-CoA esters regulate metabolism via allosteric control of AMPK β1 isoforms
Authors: Stephen L. Pinkosky, John W. Scott, Eric M. Desjardins, Brennan K. Smith, Emily A. Day, Rebecca J. Ford, Christopher G. Langendorf, Naomi X. Y. Ling, Tracy L. Nero, Kim Loh, Sandra Galic, Ashfaqul Hoque, William J. Smiles, Kevin R. W. Ngoei, Michael W. Parker, Yan Yan, Karsten Melcher, Bruce E. Kemp, Jonathan S. Oakhill, Gregory R. Steinberg
Journal: Nature Metabolism (2020)
The rise of the souvenir scanners: ultrasonography on the high street
Authors: Sally Howard
Journal: BMJ (2020)

Private scanning outlets are mushrooming, finds Sally Howard , but some pregnant women are dissatisfied with their services, and experts worry they could be causing harm At least 250 private ultrasound clinics have sprung up across UK high streets in recent years. The market leader, Ultrasound Direct, offers a plethora of imaging, including “4D bonding scans” that simulate a moving 3D fetus, a service not offered by the NHS.1 NHS trusts offer two obstetric screenings, at 12 and 20 weeks, to detect multiple pregnancies, assess gestational age, and detect fetal anomalies, typically charging £5 (€5.70; $6.20) for a black and white souvenir print.2 A few trusts offer a third trimester scan. So called souvenir scanning has grown to meet demand from women who want extra reassurance, with costs of up to £250 each time. Some want modalities that the NHS does not routinely offer, such as doppler scanning which audibly simulates the fetal heartbeat. And some find NHS scans rushed or want imaging souvenirs, such as DVDs or keyrings. But The BMJ has learnt of several reports of inaccurate interpretation by souvenir scanners (box 1). Experts say that such scanning can give pregnant women false reassurance, increase anxiety, and lead to unnecessary NHS referrals. Unlike NHS provision, souvenir scanners’ staff are not required to be qualified in obstetric ultrasonography and many businesses have not been inspected. Box 1 ### case studies #### A state of anxiety A woman, who asked not to be named, attended a souvenir scanning outlet at 35 weeks pregnant. She sought reassurance about the position of her second fetus, as … RETURN TO TEXT
Abstract IA03: PARP inhibitor and platinum resistance in ovarian cancer-genome wide CRISPR screens
Authors: Dipanjan Chowdhury
Journal: Clinical Cancer Research (2020)

Abstract High-grade serous ovarian carcinoma (HGSOC) patients with germline mutations in BRCA1/2 exhibit high sensitivity and improved outcome to platinum-based drugs and PARP inhibitors. Three PARP inhibitors (olaparib, rucaparib, niraparib) have recently gained FDA approval for the treatment of HGSOCs. However, de novo and acquired resistance to these agents is common even in the BRCA mutation carriers and pose a significant, unsolved clinical challenge. Here we identify multiple gene complexes involved in PARPi resistance through a loss-of-function CRISPR screen. High-confidence hits include previously identified 53BP1, PARP1, shieldin complex, and ATMIN/DYNLL1 complex. Only for DYNLL1 does low expression correlate with worse outcome in BRCA1-mutant ovarian cancer patients; incidentally, all these patients had platinum-based therapy. In BRCA1-defective HGSOC patients, DNA end resection is greatly compromised and contributes to the loss of HR and PARP inhibitor sensitivity. DNA end resection is a vital process that initiates homologous recombination (HR)-mediated repair of double-stranded DNA breaks and consequently influences genome stability. Loss of DYNLL1 allows DNA end resection and restores HR in BRCA1-mutant cells, thereby inducing resistance to platinum drugs and PARP inhibitors. In primary ovarian carcinomas low BRCA1 expression correlates with increased chromosomal aberrations, and the junction sequences of somatic structural variants indicate the loss of HR. Concurrent decrease in DYNLL1 expression in BRCA1-low ovarian cancers “rescued” this phenotype with reduced genomic alterations and increased homology at putative lesions. From the mechanistic standpoint, we observed that DYNLL1 limits nucleolytic degradation of DNA ends by interacting with the DNA end resection machinery (MRN complex, BLM helicase, and DNA2) in cells. The impact of DYNLL1 on end resection can be recapitulated in vitro; this is dependent on direct interaction with MRE11. Furthermore, DYNLL1 mutants that do not interact with MRE11 phenocopy the PARPi resistance phenotype of DYNLL1/BRCA1-deficient cells. Therefore, we infer that DYNLL1 is an important antiresection factor that significantly influences genomic stability and response to DNA-damaging chemotherapy in ovarian cancer patients. Citation Format: Dipanjan Chowdhury. PARP inhibitor and platinum resistance in ovarian cancer-genome wide CRISPR screens [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr IA03.
A critique of clinical economy: reassessing value and care during covid-19—an essay by Eric Reinhart and Daniel Brauner
Authors: Eric Reinhart, Daniel Brauner
Journal: BMJ (2020)

For decades, American medical practice has been organised around billing codes, with severe consequences for patient care and physician morale. The interruption of routine clinic visits owing to covid-19 presents an opportunity to reconsider the guiding principles of clinical care, write <b>Eric Reinhart</b> and <b>Daniel Brauner</b>
The TLR3 Pathway Including Downstream Interferon Regulating Factors, Regulates Vein Graft Remodeling
Authors: M. de Vries, J.C. Karper, T.C.V. Kraan, E.H. Peters, R.C. de Jong, J.F. Hamming, A.J. Horrevoets, P.H. Quax
Journal: Circulation (2013)
Regional Variation in Use of End-of-Life Care at Hospitals, Intensive Care Units, and Hospices Among Older Adults With Chronic Illness in the US, 2010 to 2016
Authors: Jason H. Maley, Bruce E. Landon, Jennifer P. Stevens
Journal: JAMA Network Open (2020)

This cohort study examines regional patterns in end-of-life health care use among Medicare beneficiaries with chronic diseases treated at US hospitals, intensive care units, and hospice facilities from 2010 to 2016.
Blinatumomab in pediatric patients with relapsed/refractory acute lymphoblastic leukemia: results of the RIALTO trial, an expanded access study
Authors: Franco Locatelli, Gerhard Zugmaier, Noemi Mergen, Peter Bader, Sima Jeha, Paul-Gerhardt Schlegel, Jean-Pierre Bourquin, Rupert Handgretinger, Benoit Brethon, Claudia Rossig, Christiane Chen-Santel
Journal: Blood Cancer Journal (2020)
Abstract 10618: Increased Capture Threshold in Selective His-bundle Pacing Associated With Flecainide Acetate
Authors: Michael Jiang, Jeremiah Wasserlauf, Bradley P Knight, Nishant Verma
Journal: Circulation (2019)

Introduction: Permanent His-bundle pacing (PHBP) is an increasingly common technique to achieve ventricular synchrony during pacing. Effects of antiarrhythmic drugs on PHBP capture thresholds are n...
Temporary Emergency Guidance to STEMI Systems of Care During the COVID-19 Pandemic
Authors: Alice K. Jacobs, Murtuza Ali, Patricia J. Best, Mark Bieniarz, Mauricio G. Cohen, William J. French, Gregg C. Fonarow, Christopher B. Granger, Abhinav Goyal, Timothy D. Henry, Lori Hollowell, Hani Jneid, James G. Jollis, Jason N. Katz, Peter Mason, Venu Menon, Michael Redlener, Jacqueline E. Tamis-Holland, Jessica Zegre-Hemsey
Journal: Circulation (2020)

Subcommittees of the AHA Council on Clinical Cardiology, are responding to the call of concern on ideal ST-segment-elevation myocardial infarction (STEMI) Systems of Care during the coronavirus disease 2019 (COVID-19) pandemic.Emergency interim guidance is being provided, pivoting from the conventional AHA evidence-
A Phase 1 study using autologous antigen presenting cells loaded with BA7072 (APC8024) to treat subjects with metastatic breast cancer that over expresses HER-2/neu
Authors: Lori A. Jones, Michelle E. Melisko, Jami Breen Wollan, Lisa D. Johnson, Jennafer Carlin, Jelle Kylstra, Reiner Laus, John W. Park
Journal: Cancer Research (2004)

1229   APC8024 is an immunotherapy product consisting of autologous antigen presenting cells loaded with a fusion protein (BA7072), which contains GM-CSF and sequences from the intracellular and extracellular portions of HER-2/neu. In this dose-escalation study, 18 subjects with metastatic breast cancer that over expressed HER-2/neu (IHC 3+, or ICH2+ and FISH+) were immunized with three infusions of APC8024, given at biweekly intervals. Subjects were evaluated for safety, immune response and clinical response. All subjects were evaluable for safety and there were no serious treatment-related adverse events. Approximately 50% of the subjects reported mild to moderate pyrexia and rigors after treatment. Antigen specific cellular immune responses were evaluated using T cell proliferation and IFNγ ELISPOT assays. Thirteen of the fourteen subjects evaluable for immune response demonstrated an antigen specific response. The only subject in whom an immune response was not induced had a significant HER-2/neu specific response prior to treatment. The HER-2/neu specificity of the response was confirmed in a subset of subjects by the isolation of HER-2/neu specific T cell clones. Clinically, one partial response in a supraclavicular mass was observed, and seven patients had stable disease (SD) until week 12. Notably, three of these patients showed long-term SD lasting >52 weeks, and all three received retreatment per protocol one year after study entry. Additionally, antigen specific cellular immune responses were induced in two of the three subjects following retreatment. In conclusion, APC8024 was well-tolerated, antigen specific cellular immune responses were induced and potential clinical benefit was observed.
Multicenter Phase I/II Trial of Napabucasin and Pembrolizumab in Patients with Metastatic Colorectal Cancer (EPOC1503/SCOOP Trial)
Authors: Akihito Kawazoe, Yasutoshi Kuboki, Eiji Shinozaki, Hiroki Hara, Tomohiro Nishina, Yoshito Komatsu, Satoshi Yuki, Masashi Wakabayashi, Shogo Nomura, Akihiro Sato, Takeshi Kuwata, Masahito Kawazu, Hiroyuki Mano, Yosuke Togashi, Hiroyoshi Nishikawa, Takayuki Yoshino
Journal: Clinical Cancer Research (2020)

This is a phase I/II trial to assess the efficacy and safety of napabucasin plus pembrolizumab for metastatic colorectal cancer (mCRC).Phase I was conducted to determine the recommended phase 2 dose (RP2D) in a dose escalation design of napabucasin (240 to 480 mg twice daily) with 200 mg pembrolizumab every 3 weeks. Phase II included cohort A (n = 10, microsatellite instability high, MSI-H) and cohort B (n = 40, microsatellite stable, MSS). The primary endpoint was immune-related objective response rate (irORR). PD-L1 combined positive score (CPS), genomic profiles, and the consensus molecular subtypes (CMS) of colorectal cancer were assessed.A total of 55 patients were enrolled in this study. In phase I, no patients experienced dose-limiting toxicities, and napabucasin 480 mg was determined as RP2D. The irORR was 50.0% in cohort A and 10.0% in cohort B. In cohort B, the irORR was 0%, 5.3%, and 42.9% in CPS < 1, 1≤ CPS <10, and CPS ≥ 10, respectively. Patients with objective response tended to have higher tumor mutation burden than those without. Of evaluable 18 patients for CMS classification in cohort B, the irORR was 33.3%, 0%, 33.3%, and 33.3% in CMS1, CMS2, CMS3, and CMS4, respectively. The common grade 3 or higher treatment-related adverse events included fever (10.0%) in cohort A and decreased appetite (7.5%) and diarrhea (5.0%) in cohort B.Napabucasin with pembrolizumab showed antitumor activity with acceptable toxicities for patients with MSS mCRC as well as MSI-H mCRC, although it did not meet the primary end point. The impact of related biomarkers on the efficacy warrants further investigations in the additional cohort.See related commentary by Nusrat, p. 5775.