tbuckley/cabot-search huggingface dataset:
PSF Promotes ER-Positive Breast Cancer Progression via Posttranscriptional Regulation of <i>ESR1</i> and <i>SCFD2</i>
Authors: Yuichi Mitobe, Kaori Iino, Ken-ichi Takayama, Kazuhiro Ikeda, Takashi Suzuki, Kenjiro Aogi, Hidetaka Kawabata, Yutaka Suzuki, Kuniko Horie-Inoue, Satoshi Inoue
Journal: Cancer Research (2020)

Abstract Endocrine therapy is standard treatment for estrogen receptor (ER)-positive breast cancer, yet long-term treatment often causes acquired resistance, which results in recurrence and metastasis. Recent studies have revealed that RNA-binding proteins (RBP) are involved in tumorigenesis. Here, we demonstrate that PSF/SFPQ is an RBP that potentially predicts poor prognosis of patients with ER-positive breast cancer by posttranscriptionally regulating ERα (ESR1) mRNA expression. Strong PSF immunoreactivity correlated with shorter overall survival in patients with ER-positive breast cancer. PSF was predominantly expressed in a model of tamoxifen-resistant breast cancer cells, and depletion of PSF attenuated proliferation of cultured cells and xenografted tumors. PSF expression was significantly associated with estrogen signaling. PSF siRNA downregulated ESR1 mRNA by inhibiting nuclear export of the RNA. Integrative analyses of microarray and RNA immunoprecipitation sequencing also identified SCFD2, TRA2B, and ASPM as targets of PSF. Among the PSF targets, SCFD2 was a poor prognostic indicator of breast cancer and SCFD2 knockdown significantly suppressed breast cancer cell proliferation. Collectively, this study shows that PSF plays a pathophysiologic role in ER-positive breast cancer by posttranscriptionally regulating expression of its target genes such as ESR1 and SCFD2. Overall, PSF and SCFD2 could be potential diagnostic and therapeutic targets for primary and hormone-refractory breast cancers. Significance: This study defines oncogenic roles of RNA-binding protein PSF, which exhibits posttranscriptional regulation in ER-positive breast cancer.
Abstract P3-07-13: Neoadjuvant composite score as a prognostic marker in early and locally advanced triple negative breast cancer
Authors: Biswajit Dubashi, Smita Kayal, Kirankumar Matta, Divya bala Thumaty, Nisha Yadav, D Kadambari, Pampa ch Toi, K Gunaseelan, Prasanth Ganesan
Journal: Cancer Research (2020)

Abstract Aim Triple negative subtype (TNBC) is an aggressive breast cancer with inferior survival. Pathological CR (pCR) is a good surrogate endpoint for survival among patients receiving neoadjuvant chemotherapy (NACT). We attempted to validate the composite score(CPS) (Jaccqueline et al, J Clin Oncol 26:246-252) combining clinical and pathological variables among TNBC patients receiving NACT at our center. Methodology Data of patients with TNBC who underwent NACT between January 2014 to July 2017 was retrospectively analysed. The composite CPS score included cTN stage and y pTN stage, and ranged from 0 to 4. This was calculated using an online software (http://www3.mdanderson.org/app/medcalc/index.cfm?pagename=bcnt). The scores obtained from the calculator was used to develop a risk grouping into low risk (0,1) and High risk (2,3,4). Overall survival (OS)and disease free survival (DFS) were calculated using the Kaplan-Meier method and differences was examined using the log rank test. Results Seventy-eight patients with TNBC [median age: 45 (24-75)] had received NACT (anthracyclines and taxanes). Early and locally advanced breast cancer constituted 17 (21.8 %) and 61 (78.2%) respectively and 22 (28.2 %) achieved pCR. After a median follow up of 28 months (5-62), 3-yr DFS and OS were 59% and 82% respectively for the entire population. The 3-yr DFS in low (n=18) and high risk (n=60) patients was 85.7% and 51.4% respectively (p=0.032). The 3-yr OS in the low and high risk was 93% and 79% respectively(p=0.28, NS). Conclusion Our study supports the use of the composite clinical pathological score (CPS) as a prognostic marker in patients with non-metastatic triple negative breast cancer. The risk stratification developed may help identify patients who may require additional adjuvant therapy. Citation Format: Biswajit Dubashi, Smita Kayal, Kirankumar Matta, Divya bala Thumaty, Nisha Yadav, D Kadambari, Pampa ch Toi, K Gunaseelan, Prasanth Ganesan. Neoadjuvant composite score as a prognostic marker in early and locally advanced triple negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-07-13.
Covid-19: how coronavirus will change the face of general practice forever
Authors: Jacqui Thornton
Journal: BMJ (2020)

<h3>Abstract</h3> Many studies have provided insights into the immune response to COVID-19; however, little is known about the immunological changes and immune signaling occurring during COVID-19 resolution. Individual heterogeneity and variable disease resolution timelines obscure unifying immune characteristics. Here, we collected and profiled &gt;200 longitudinal peripheral blood samples from patients hospitalized with COVID-19, with other respiratory infections, and healthy individuals, using mass cytometry to measure immune cells and signaling states at single cell resolution. COVID-19 patients showed a unique immune composition and an early, coordinated and elevated immune cell signaling profile, which correlated with early hospital discharge. Intra-patient time course analysis tied to clinically relevant events of recovery revealed a conserved set of immunological processes that accompany, and are unique to, disease resolution and discharge. This immunological process, together with additional changes in CD4 regulatory T cells and basophils, accompanies recovery from respiratory failure and is associated with better clinical outcomes at the time of admission. Our work elucidates the biological timeline of immune recovery from COVID-19 and provides insights into the fundamental processes of COVID-19 resolution in hospitalized patients.
Covid-19: Doctors still at “considerable risk” from lack of PPE, BMA warns
Authors: Gareth Iacobucci
Journal: BMJ (2020)

The BMA has warned that doctors are still being placed at “considerable risk” by shortages of personal protective equipment, despite government assurances that enough supplies are being delivered.

On 30 March the association said it was seeking urgent clarity from the government on what risks staff in hospitals and GP surgeries should and should not have to take if they didn’t have adequate PPE. The move follows a warning last week that the shortage of PPE was unacceptable and was putting doctors’ lives at risk.1

The warning was in response to the secretary of state for housing, communities, and local government, Robert Jenrick, saying at the government’s daily briefing on 29 March that “we cannot and should not ask healthcare workers to …
Duration of neonatal oxygen supplementation, erythropoiesis and blood pressure in young adults born preterm
Authors: Adrien Flahault, Camille Girard-Bock, Rafael Oliveira Fernandes, Anik Cloutier, Yves D Pastore, Thuy Mai Luu, Anne Monique Nuyt
Journal: Thorax (2020)

Background Although erythropoiesis is impaired and anaemia frequent in neonates born preterm, haematopoiesis in adults born preterm has not been previously studied. Objective We, thus, aimed to evaluate haemoglobin and erythropoietin levels in young adults born preterm, to identify neonatal events associated with erythropoiesis in adulthood and to examine the relationships of haemoglobin levels with respiratory function and blood pressure. Methods We assessed a cohort of 101 young adults (ages 18–29) born preterm (≤29 weeks of gestation), in comparison to 105 full-term controls. We measured haemoglobin, erythropoietin levels and blood pressure. We also assessed respiratory function using spirometry. Results Compared with controls, tobacco use and sex-adjusted haemoglobin levels were 5.3 (95% CI 2.9 to 7.7) g/L higher in preterm-born individuals, but erythropoietin levels were similar. Duration of oxygen supplementation in the neonatal period was independently associated with higher haemoglobin levels in the preterm group. In young adults born preterm with bronchopulmonary dysplasia, airflow limitation was associated with higher haemoglobin levels. Both systolic (SBP) and diastolic (DBP) blood pressure were increased in individuals born preterm (p=0.042 and p=0.0008, respectively). Higher haemoglobin levels were associated with higher SBP and DBP, independently of term or preterm status. Mediation analysis suggests that haemoglobin increase contributes to 37% and 32% of the effect of preterm birth on SBP and DBP, respectively. Conclusions Haemoglobin levels are higher in young adults born preterm, while erythropoietin levels are similar, especially in case of bronchopulmonary dysplasia and airflow limitation, and haemoglobin increase is associated with elevated blood pressure in this population.
No indication of insulin resistance in idiopathic pulmonary arterial hypertension with preserved physical activity
Authors: Bence M. Nagy, Gabor Kovacs, Adrienn Tornyos, Eva Svehlikova, Vasile Foris, Chandran Nagaraj, Grazyna Kwapiszewska, Thomas R. Pieber, Andrea Olschewski, Horst Olschewski
Journal: European Respiratory Journal (2020)

There is growing interest in metabolic profiling in pulmonary arterial hypertension (PAH) due to current findings suggesting significant metabolic changes causing pulmonary arterial remodelling and linking PAH to insulin resistance [1]. Such findings may have major impact on future diagnostic and therapeutic strategies for PAH. However, most studies have enrolled patients with severe disease whose reduced physical activity may have a profound effect on insulin sensitivity. Insulin resistance might not be a primary cause of severe remodelling of the small pulmonary arteries in idiopathic PAH <http://bit.ly/3c8elot>
The design and development of covalent protein-protein interaction inhibitors for cancer treatment
Authors: Sha-Sha Cheng, Guan-Jun Yang, Wanhe Wang, Chung-Hang Leung, Dik-Lung Ma
Journal: Journal of Hematology & Oncology (2020)

Abstract Protein-protein interactions (PPIs) are central to a variety of biological processes, and their dysfunction is implicated in the pathogenesis of a range of human diseases, including cancer. Hence, the inhibition of PPIs has attracted significant attention in drug discovery. Covalent inhibitors have been reported to achieve high efficiency through forming covalent bonds with cysteine or other nucleophilic residues in the target protein. Evidence suggests that there is a reduced risk for the development of drug resistance against covalent drugs, which is a major challenge in areas such as oncology and infectious diseases. Recent improvements in structural biology and chemical reactivity have enabled the design and development of potent and selective covalent PPI inhibitors. In this review, we will highlight the design and development of therapeutic agents targeting PPIs for cancer therapy.
A randomized proof-of-mechanism trial applying the ‘fast-fail’ approach to evaluating κ-opioid antagonism as a treatment for anhedonia
Authors: Andrew D. Krystal, Diego A. Pizzagalli, Moria Smoski, Sanjay J. Mathew, John Nurnberger, Sarah H. Lisanby, Dan Iosifescu, James W. Murrough, Hongqiu Yang, Richard D. Weiner, Joseph R. Calabrese, Gerard Sanacora, Gretchen Hermes, Richard S. E. Keefe, Allen Song, Wayne Goodman, Steven T. Szabo, Alexis E. Whitton, Keming Gao, William Z. Potter
Journal: Nature Medicine (2020)
Reply to Horita and Takeshi: Thrombomodulin Did Not Benefit Acute Exacerbation of Idiopathic Pulmonary Fibrosis in a Trial
Authors: Yasuhiro Kondoh, Arata Azuma, Jun Tagawa, Sakae Homma
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

The current trial (1) was the only randomized trial.Three observational studies provided data for survival rate difference on Day 90 (3, 5, 6).Because baseline patient characteristics were not significantly different in any item of these three studies, we believe using raw comparison data is allowed.A random-model meta-analysis on the basis of these three reports with 109 patients yielded Day 90 survival rate difference of 26% in favor of the rhTM arm (95% CI, 13-39%; P , 0.001) without heterogeneity (I 2 = 0%; P for heterogeneity = 0.39).Baseline data were different in another observational study with 40 cases (4); however, this study provided adjusted OR for 90-day survival, which made this article eligible for a meta-analysis.Pooled ORs for 90-day survival on the basis of these four studies (3-6) were 3.1 in favor of rhTM-treated patients (95% CI, 1.8-5.3;P , 0.001; I 2 = 0%; P for heterogeneity = 0.54).Most of the control subjects in the non-rhTM arm of these four studies were treated with high-dose corticosteroids with a tapering dose.Some of them were also treated with low-molecular-weight heparin, cyclosporine, immunosuppressants, anticoagulants, antiplatelets, and polymyxin.Two studies adopted 0.06 mg/kg/d rhTM, and the other two adopted 380 U/kg/d rhTM on Days 1-6.In short, there was no clear difference of treatment strategy between the current trial (1) and previous observational studies (3-6).Notably, most of the key authors in the four included articles were named in the author list of the recent article by Kondoh and colleagues (1).We suppose many readers would like to know what introduced this large discrepancy between the current trial (1) and previous observations (3-6).Four additional reports that were excluded from our analysis also revealed favorable outcomes for the rhTM arm; three were excluded because they might include the same patients as an included article (3), and one was excluded because of including nonspecific interstitial pneumonia cases.In any case, we are grateful to Kondoh and colleagues (1) for providing the most up-to-date survival data of AE-IPF cases and alerting us not to use rhTM for AE-IPF.
A randomized phase II study of nivolumab plus ipilimumab versus standard of care in previously untreated and advanced non-clear cell renal cell carcinoma (SUNIFORECAST).
Authors: Marit Ahrens, Bernard Escudier, Ekaterini Boleti, Marc-Oliver Grimm, Marine Gross-Goupil, Philippe Barthelemy, Gwenaelle Gravis, Jens Bedke, Philipp Ivanyi, Andrej Panic, Stefanie Zschaebitz, Sylvie Negrier, Begona Mellado, Anika Biel, Tom Waddell, Pablo Maroto, Margitta Retz, Martin Boegemann, Arndt Hartmann, Lothar Bergmann
Journal: Journal of Clinical Oncology (2020)

TPS5103 Background: Non-clear cell renal cell carcinomas (nccRCC) are a heterogeneous group of tumors accounting for approximately 25% of RCC patients (pts.). Since most clinical trials focus on clear-cell RCC (ccRCC) only, data on treatment strategies for nccRCC are limited. The combination of Nivolumab and Ipilimumab (IO/IO) has recently been approved for treatment in RCC showing a significant improvement in overall response rate (ORR), progression free (PFS), and overall survival (OS) in intermediate and high-risk pts. compared to sunitinib in a phase-III trial. Furthermore retrospective analysis in nccRCC patients have shown promising results for IO/IO as well in these entities. Methods: In this prospective randomized phase-II multicenter European trial adults with advanced or metastatic nccRCC without prior systemic therapy are eligible. Other key inclusion criteria include: available tumor tissue, Karnofsky &gt; 70% and measurable disease per RECIST 1.1. All histological diagnoses are reviewed by a central pathologist. The study plans to randomize ~306 pts. stratified for papillary or non-papillary non-clear cell histology and by the International Metastatic RCC Database Consortium (IMDC) risk score. Pts. will be randomized 1:1 to either i) Nivolumab 3mg/kg intravenously (IV) plus Ipilimumab 1mg/kg IV every 3 weeks for 4 doses followed by Nivolumab fixed dose 240mg IV every 2 weeks or ii) standard of care therapy according to the approved schedule. Treatment will be discontinued in case of unacceptable toxicity or withdrawal of informed consent. Pts may continue treatment beyond progression, if clinical benefit is achieved and treatment is well tolerated. Primary endpoint is the OS rate at 12 months. Secondary endpoints include OS rate at 6 and 18 months, median OS, PFS, ORR and quality of life. The trial is in progress and 122 patients (78 pts with papillary, 37 pts with non-papillary histology) have been enrolled until now. Clinical trial information: NCT03075423 .
Epigenetic Metabolic Reprogramming of Right Ventricular Fibroblasts in Pulmonary Arterial Hypertension
Authors: Lian Tian, Danchen Wu, Asish Dasgupta, Kuang-Hueih Chen, Jeffrey Mewburn, Francois Potus, Patricia D.A. Lima, Zhigang Hong, Yuan-Yuan Zhao, Charles C.T. Hindmarch, Shelby Kutty, Steeve Provencher, Sebastien Bonnet, Gopinath Sutendra, Stephen L. Archer
Journal: Circulation Research (2020)

Rationale: Right ventricular (RV) fibrosis in pulmonary arterial hypertension contributes to RV failure. While RV fibrosis reflects changes in the function of resident RV fibroblasts (RVfib), these cells are understudied. Objective: Examine the role of mitochondrial metabolism of RVfib in RV fibrosis in human and experimental pulmonary arterial hypertension. Methods and Results: Male Sprague-Dawley rats received monocrotaline (MCT; 60 mg/kg) or saline. Drinking water containing no supplement or the PDK (pyruvate dehydrogenase kinase) inhibitor dichloroacetate was started 7 days post-MCT. At week 4, treadmill testing, echocardiography, and right heart catheterization were performed. The effects of PDK activation on mitochondrial dynamics and metabolism, RVfib proliferation, and collagen production were studied in RVfib in cell culture. Epigenetic mechanisms for persistence of the profibrotic RVfib phenotype in culture were evaluated. PDK expression was also studied in the RVfib of patients with decompensated RV failure (n=11) versus control (n=7). MCT rats developed pulmonary arterial hypertension, RV fibrosis, and RV failure. MCT-RVfib (but not left ventricular fibroblasts) displayed excess mitochondrial fission and had increased expression of PDK isoforms 1 and 3 that persisted for &gt;5 passages in culture. PDK-mediated decreases in pyruvate dehydrogenase activity and oxygen consumption rate were reversed by dichloroacetate (in RVfib and in vivo) or siRNA targeting PDK 1 and 3 (in RVfib). These interventions restored mitochondrial superoxide and hydrogen peroxide production and inactivated HIF (hypoxia-inducible factor)-1α, which was pathologically activated in normoxic MCT-RVfib. Redox-mediated HIF-1α inactivation also decreased the expression of TGF-β1 (transforming growth factor-beta-1) and CTGF (connective tissue growth factor), reduced fibroblast proliferation, and decreased collagen production. HIF-1α activation in MCT-RVfib reflected increased DNMT (DNA methyltransferase) 1 expression, which was associated with a decrease in its regulatory microRNA, miR-148b-3p. In MCT rats, dichloroacetate, at therapeutic levels in the RV, reduced phospho-pyruvate dehydrogenase expression, RV fibrosis, and hypertrophy and improved RV function. In patients with pulmonary arterial hypertension and RV failure, RVfib had increased PDK1 expression. Conclusions: MCT-RVfib manifest a DNMT1-HIF-1α-PDK–mediated, chamber-specific, metabolic memory that promotes collagen production and RV fibrosis. This epigenetic mitochondrial-metabolic pathway is a potential antifibrotic therapeutic target.
Abstract P3-08-37: Dynamic and subtype-specific interactions between tumor burden and prognosis in breast cancer
Authors: Hong-Kyu Kim, Sae Byul Lee, Yunhee Choi, Young Wook Ju, Han-Byoel Lee, Wonshik Han, Dong-Young Noh, Jong Won Lee, Hyeong-Gon Moon, Jihye Choi
Journal: Cancer Research (2020)

Abstract Purpose Recent updates of the AJCC staging system in breast cancer incorporated biologic characteristics along with the traditional anatomic tumor burden for outcome prediction. However, potential interactions between the prognostic effect of anatomic factors and the biologic characteristics are not reflected in the new system. In this study, we evaluated the interactions between the prognostic relevance of anatomic tumor burden and the molecular subtypes. Methods From the Korean Breast Cancer Registry Database, we investigated the relationship between the prognostic importance of anatomic tumor burden and molecular subtypes in patients with invasive breast carcinoma who were treated between 1980 and 2014. Tumors were classified into four different molecular subtypes based on the hormonal receptor status and HER2 expression status. (1) HR+/HER2- subtypes; (2) HR+/HER2+ subtypes; (3) HR-/HER2+ subtypes; (4) HR-/HER2- subtypes. Results Breast cancers with different molecular subtypes had unique outcome patterns in relation to anatomic tumor burden. In HR+/HER2+ and HR-/HER2- tumors, the increase in T stages exhibited profound rise in the hazard of death, while the presence of metastatic node was more important in HR+/HER2+ and HR-/HER2+ tumors in 131,178 Stage I to III breast cancer patients. The patterns for increasing risk of deaths along with tumor growth (per centimeter) and metastatic nodes (per one node) were examined in 67,038 patients with tumors 7cm or smaller and less than 8 metastatic nodes. HR+/HER2- and HR-/HER2- tumors showed persistent increase in risk of deaths as tumors grow while the effect was modest in HER2+ tumors. In contrast, the increased number of metastatic nodes was accompanied with persistent rise of risk in HR-/HER2+ tumors while the effect was minimal after 3 or 4 nodes in HR-/HER2- tumors. The interactions between the prognostic significance of anatomic tumor burden and molecular subtypes were statistically significant. Conclusion Our data demonstrates that the prognostic implication of tumor growth and spread, measured by the increase in tumor size and number of metastatic nodes, shows significant association with the molecular subtypes of the breast cancer. Additionally, our data suggest that the association between the prognostic impact and the anatomic tumor burden is rather dynamic that linear within a specific molecular subtype. Citation Format: Hong-Kyu Kim, Sae Byul Lee, Yunhee Choi, Young Wook Ju, Han-Byoel Lee, Wonshik Han, Dong-Young Noh, Jong Won Lee, Hyeong-Gon Moon, Jihye Choi. Dynamic and subtype-specific interactions between tumor burden and prognosis in breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-37.