tbuckley/cabot-search huggingface dataset:
ERK Regulates HIF1α-Mediated Platinum Resistance by Directly Targeting PHD2 in Ovarian Cancer
Authors: Zhuqing Li, Wei Zhou, Yi Zhang, Wei Sun, Mingo M.H. Yung, Jing Sun, Jing Li, Chi-Wei Chen, Zongzhu Li, Yunxiao Meng, Jie Chai, Yuan Zhou, Stephanie S. Liu, Annie N.Y. Cheung, Hextan Y.S. Ngan, David W. Chan, Wei Zheng, Wenge Zhu
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Up to 80% of patients with ovarian cancer develop platinum resistance over time to platinum-based chemotherapy. Increased HIF1α level is an important mechanism governing platinum resistance in platinum-resistant ovarian cancer (PROC). However, the mechanism regulating HIF1α stability in PROC remains largely unknown. Here, we elucidate the mechanism of HIF1α stability regulation in PROC and explore therapeutic approaches to overcome cisplatin resistance in ovarian cancer. Experimental Design: We first used a quantitative high-throughput combinational screen (qHTCS) to identify novel drugs that could resensitize PROC cells to cisplatin. Next, we evaluated the combination efficacy of inhibitors of HIF1α (YC-1), ERK (selumetinib), and TGFβ1 (SB431542) with platinum drugs by in vitro and in vivo experiments. Moreover, a novel TGFβ1/ERK/PHD2-mediated pathway regulating HIF1α stability in PROC was discovered. Results: YC-1 and selumetinib resensitized PROC cells to cisplatin. Next, the prolyl hydroxylase domain-containing protein 2 (PHD2) was shown to be a direct substrate of ERK. Phosphorylation of PHD2 by ERK prevents its binding to HIF1α, thus inhibiting HIF1α hydroxylation and degradation—increasing HIF1α stability. Significantly, ERK/PHD2 signaling in PROC cells is dependent on TGFβ1, promoting platinum resistance by stabilizing HIF1α. Inhibition of TGFβ1 by SB431542, ERK by selumetinib, or HIF1α by YC-1 efficiently overcame platinum resistance both in vitro and in vivo. The results from clinical samples confirm activation of the ERK/PHD2/HIF1α axis in patients with PROC, correlating highly with poor prognoses for patients. Conclusions: HIF1α stabilization is regulated by TGFβ1/ERK/PHD2 axis in PROC. Hence, inhibiting TGFβ1, ERK, or HIF1α is potential strategy for treating patients with PROC.
Abstract 9614: Ca2+-Independent Di-phosphorylation of Myosin Light Chain by Rho-associated Coiled-Coil Protein Kinase (ROCK) in the Subjunctional Regions of Cell-Cell Contact Mediates Thrombin-Induced Barrier Dysfunction in Vascular Endothelial Cells
Authors: Mayumi Hirano, Akiko Hanada, Katsuya Hirano
Journal: Circulation (2011)

A disruption of endothelial barrier function is a predisposing factor for the development of atherosclerosis. The phosphorylation of myosin light chain (MLC) is a key signal of barrier dysfunction....
SYK inhibition with fostamatinib in Waldenström's macroglobulinemia: In vitro cell based assays.
Authors: Vadim Markovtsov, Esteban Masuda
Journal: Journal of Clinical Oncology (2019)

e19047 Background: Waldenström's macroglobulinemia (WM) is characterized by accumulation of IgM secreting neoplastic B cells in the bone marrow (BM). B-cell antigen receptor (BCR) signaling plays a pivotal role in the regulation of integrin-mediated retention of lymphoma cells in the BM. Signaling through the BCR leads to activation of spleen tyrosine kinase (SYK) and downstream kinases which play a role in lymphoma pathobiology. The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib targets BCR-controlled signaling and integrin-mediated adhesion in WM cells, but patients with WM may become refractory to ibrutinib treatment. As SYK signaling is upstream of BTK, we explored the effect of the SYK inhibitor R406 (the active metabolite of fostamatinib) on BCR mediated signaling and cell adhesion in WM. Methods: MWCL-1 cells were treated with R406, CAL101 (PI3 kinase inhibitor) or ibrutinib at concentrations up to 10µM and stimulated with anti-IgM antibodies or PMA. The cells were transferred to plates coated with fibronectin to assess cell adhesion. For the proliferation assays, MWCL-1 cells or primary B cells were pretreated with kinase inhibitors, followed by stimulation of primary B cells with anti-IgM. Results: Anti-IgM or PMA alone stimulated the adhesion of MWCL-1 on fibronectin. The addition of R406 had a comparable effect to ibrutinib on inhibition of IgM mediated cell adhesion (IC50 = 0.32µM), consistent with the effect of both compounds on BCR mediated signaling. Neither compound affected PMA induced cell adhesion, indicating that the effect on IgM mediated cell adhesion was not due to toxicity. Lack of off-target toxicity was further confirmed in the MWCL-1 proliferation assays where the compounds showed less potency than in BCR-mediated assays. Comparable inhibition of adhesion and proliferation was seen with CAL101. Conclusions: Preliminary preclinical studies with R406 show that SYK is involved in BCR mediated signaling and cell adhesion in WM. CAL101 mediated inhibition of adhesion further confirmed the role of SYK, which is upstream of PI3K. R406 was as effective as ibrutinib in blocking WM cell adhesion. Further studies of SYK inhibition with fostamatinib as a potential treatment option for WM are warranted.
Normal Variant 18F-Sodium Fluoride Uptake in the Falx Cerebri Ossification
Authors: Sharjeel Usmani, Fahad Marafi, Fareeda Al Kandari, Najeeb Ahmed
Journal: Clinical Nuclear Medicine (2019)

Abstract Falx cerebri ossification is an incidental finding. Mostly it is easy to diagnose, but can be challenging in few cases, and should be distinguished from calcified meningioma, hematoma, and meningeal infiltration. We report a case of a 46-year-old woman with breast cancer complaining of back pain. 18 F-NaF PET/CT images show focal increase uptake at facet joints of L5/S1 vertebrae and both knees joints, suggesting degenerative disease. There is normal variant 18 F-NaF uptake noted in the ossification at the falx cerebri. Recognition of normal and abnormal extraosseous 18 F-NaF uptake is important for correct interpretation to avoid unnecessary further investigations.
Abstract 362: Early Signs of Life as a Prognostic Factor for Extracorporeal Cardiopulmonary Resuscitation in Refractory Out-of-Hospital Cardiac Arrest
Authors: Guillaume Debaty, Mathilde Nicol, Romain Aubert, Cyriel Clape, Pierre Bouzat, Michel Durand, Gerald Vanzetto, Olivier Chavanon, Alice Hutin, Tahar Chouhied, José Labarère, Lionel Lamhaut
Journal: Circulation (2018)

Introduction: After 20 to 30 minutes of cardiopulmonary resuscitation (CPR) without return of spontaneous circulation (ROSC), cardiac arrest is considered as refractory (RCA). For RCA, extracorporeal CPR (ECPR) is one of the only treatments with a potential benefit on survival. Presence of gasping during CPR has been shown to be strongly associated with a favorable outcome. To our knowledge, signs of life during CPR (such as gasping, movements, pupillary response) has not been studied in the specific context of RCA treated with ECPR. Hypothesis: We assessed the relationship between survival with favorable neurologic outcomes and presence of early signs of life during or before CPR in RCA treated with ECPR. Methods: We carried out a multicenter observational study of patients with out-of-hospital RCA treated with ECPR in 3 cities in France. Primary outcome was favorable neurologic outcome at 30 days defined as CPC score ≤ 2. Signs of life were defined as gasping or recovery of normal breathing, any pupillary response or any movements during CPR. Patient selection for ECPR was decided according to french guidelines criteria such as initial rhythm, no-flow duration, expected transport time and EtCO2 &gt; 10 mmHg. A logistic regression analysis was performed. P -values &lt; 0.05 were considered statistically significant. Results: Overall, 437 patients treated with ECPR were included with 71 (16%) patients with CPC ≤ 2 at 30 days. Signs of life were observed in 261 (59%) patients, with 136 (31%) patients presenting gasping or respiratory movement, 155 (35%) a pupillary response, and 49 (11%) movements during CPR. Overall 63/261 (24.1%) patients with signs life survived with favorable neurologic outcome vs. 8/176 (4.5%) without signs of life, p&lt;0.0001. In multivariate analysis, factors associated with favorable outcome were: signs of life during CPR (OR 11.0, 95%CI 3.7-32.5; p&lt;0.001), first recorded rhythm VF/VT (OR 3.4, 95%CI 1.3-8.9; P=0.011), low-flow duration per min (OR 0.99, 95%CI 0.98-1.00; p=0.032). Conclusions: These results highlight the importance of signs of life before or during CPR on neurological outcomes for RCA treated with ECPR. These results could help select patients with good chance of survival in whom we should not give up resuscitation efforts too soon.
A call for mapping the development of the microbiota-gut-brain axis during human infancy
Authors: Caroline Malory Kelsey, Tobias Grossmann
Journal: Behavioral and Brain Sciences (2019)

Abstract We argue for the importance of looking at the microbiota-gut-brain axis from a human developmental perspective. For this purpose, we first briefly highlight emerging research with infants attesting that the microbiome plays a role in early brain and cognitive development. We then discuss the use of developmentally informed humanized mouse models and implications of microbiome research that go beyond probiotic administration.
New mechanistic insights into possible radiobiologic and pathophysiologic explanations for unexpectedly impressive outcomes data observed for hormone-refractary metastatic prostate cancer patients treated with radium 223.
Authors: Roger M. Macklis, A. Oliver Sartor
Journal: Journal of Clinical Oncology (2012)

10623 Background: The ALSYMPCA Trial of 223Ra (“Alpharadin”) for men with metastatic castrate-resistant prostate cancer was a Phase III randomized trial comparing 223 Ra plus SOC vs best SOC. This trial was stopped early after 922 patients enrolled at over 100 centers achieved primary (overall survival) and all secondary endpoints including median survived (14 vs 11.2 m) time to first SRE (13.6 m vs 8.4 m) and time to PSA progression.These unexpectedly positive results prompted us to review some of the unique aspects of alpha-particle radiobiology and ultra-short range molecular targeting capabilities. Methods: Literature analysis. Results: The highly energetic alpha particles such as those released during decay of 223 Ra (T 1/2 = 11.4 mins) display unique radiobiologic and dosimetric aspects. The nuclear dose required in vitro for approximately 90% target cell kill is less than 1 Gy and electron micrographs shortly after exposure confirm bizarre blebbing and condensation of chromosomal material characteristic of apoptosis. Bovine aortic endothelial cells exposed to alpha particle radiation indicate that the radiobiologic effects depend heavily on cell culture condition with nonuniform DNA strand break damage observed in isolated detached cells. The subcellular alpha particle path length appears to allow specific target cell populations to be killed within bony stroma without excessive damage to nearby sensitive hematopoietic cells. 223 Ra treatment in rodent models showed that this family of Ca ++ analogs delivers extremely high doses to stromal elements such as bone-resorbing osteoclasts and this selectivity may aid in decreasing SREs. Conclusions: We highlight the fact that some basic radiobiologic and cell compartment-specific stromal localization principles known to be effective in alpha particle radiopharmaceutical therapy may contribute to the very positive clinical outcomes observed while allowing subcellular damage accumulation to target cell groups.
Trastuzumab (T-mab) in combination with docetaxel/cisplatin/S-1 (DCS) for patients with HER2-positive metastatic gastric cancer: Feasibility and preliminary efficacy.
Authors: Yasushi Sato, Tetsuji Takayama, Hiroyuki Ohnuma, Masahiro Hirakawa, Takahiro Osuga, Hiroshi Miyamoto, Tamotsu Sagawa, Yasuhiro Sato, Yasuo Takahashi, Shinich Katsuki, Tokunori Okuda, Kohichi Takada, Tsuyoshi Hayashi, Tsutomu Sato, Koji Miyanishi, Rishu Takimoto, Masayoshi Kobune, Takayuki Nobuoka, Koichi Hirata, Junji Kato
Journal: Journal of Clinical Oncology (2014)

124 Background: Recently the efficacy of trastuzumab (T-mab) for HER2-positive gastric cancer has been reported. We have developed a triplet-drug combination regimen consisting of docetaxel, CDDP, and S-1 (DCS) and reported that the regimen provides very high response rates (BJC 2007; CCP 2009 and 2013). To increase the efficacy of DCS in patients (pts) with HER2-positive unresectable gastric cancer, we carried out a feasibility study for the DCS-T-mab (DCS-T) regimen. Methods: Eligibility criteria included the following: age between 20 and 80 years; unresectable HER2-positive metastatic gastric cancer; normal cardiac function. Pts received oral S-1 (40 mg/m 2 b.i.d.) on days 1-14, intravenous cisplatin (60 mg/m 2 ), docetaxel (50 mg/m 2 ) and T-mab (8 mg/kg in the first cycle and 6 mg/kg in the second cycle and thereafter) on day 8 every 3 weeks. Results: This study included 16 pts: median age, 60 years (34 – 76 years), 11 males and 5 females. PS 0/1/2, 10/4/2; differentiated/undifferentiated-type histology, 11/5; U/M/L, 7/8/1; HER2 3+, 13; HER2 2+/FISH+, 3; T3/T4a/T4b, 11/4/1; N0/N1/N2/N3, 2/0/4/10; and distant lymph nodes/liver/peritoneum/lungs/bone/ovaries, 11/7/4/2/1/1. The completion rate until the third cycle was 100%. According to the RECIST criteria, the objective response rate was 93.3%, and the median cycle to response was 1 (1–3 cycles). Adverse events of grade 3 or greater severity were: leukopenia/neutropenia, 68.8/81.3%; FN, 12.5%; anorexia, 25%; and diarrhea, 25%. All of these side effects were well controlled. Non-curative factors disappeared in 7 of 16 cases and R0 resection was carried out in 6 cases (37.5%) including 2 pts with liver metastases. A pathological response was found in 83 % of 6 resected cases. At a median follow-up of 9.8 months (2.3 – 23 months), median PFS was 12.8 months and median OS was not yet reached. Conclusions: T-mab in combination with DCS is a feasible regimen in pts with unresectable HER2-positive gastric cancer. The observed response rate is very promising and warrants further investigation. Clinical trial information: UMIN000005603.
Clinical negligence: NHS paid out £2.4bn last year
Authors: Gareth Iacobucci
Journal: BMJ (2019)

Medical defence experts have urged the UK government to hasten reform of the legal process for resolving clinical negligence claims after the latest figures showed that the cost to the NHS in England rose again last year.

Figures published in the annual report of NHS Resolution (formerly the NHS Litigation Authority) show that the NHS paid out £2.4bn (€2.7bn; $3bn) on …
The first year of treatment predicts the prognosis of asthma over 25 y—A prospective study
Authors: Ritva Kauppinen, Vesa Vilkka, Harri Sintonen, Jouni Hedman
Journal: Allergy (2019)

Abstract Background An investigator‐driven, real‐life follow‐up study of adult‐onset steroid‐naïve, newly diagnosed asthma (162 patients) to investigate the treatment results over the 25‐year course of the disease and whether the first treatment year's forced expiratory volume in one second (FEV 1 ) predicts the long‐term prognosis. Methods Eighty‐three per cent of the 133 living patients participated in the 25‐year examinations. At this visit, basic asthma examinations including lung function, as well as questionnaires for health‐related quality of life (HRQoL), GINA and the Asthma Control Test, were used for evaluation. The use of medication and remission was verified. Results There was no statistically significant change in mean FEV 1 % predicted (FEV 1 %) from baseline to the 25‐year control. The changes in FEV 1 % during the first year predicted the results at the end of follow‐up. Normal FEV 1 % at the end of the first year predicted normal FEV 1 , and below‐normal FEV 1 % at 1 year predicted below‐normal FEV 1 % at 25 years. Twenty‐nine patients (26.4%) had discontinued their medication, and six (5.5%) used ICS periodically. Clinical remission was reached by 16.4% of the patients, and 7.6% reached functional remission. The general HRQoL remained unchanged. Conclusion In adult‐onset asthma, the level of FEV 1 reached during the first treatment year seems to predict the later lung function level. One quarter of the patients discontinued the asthma treatment, but their HRQoL was better than that of those continuing to use ICS. Clinical remission was reached by 16% of the patients, which is in concordance with other studies.
Identifying obstacles to optimal integration of cancer immunotherapies in the community setting.
Authors: Latha Shivakumar, Christine B. Weldon, Lorna Lucas, Tara Perloff
Journal: Journal of Clinical Oncology (2019)

87 Background: The rapidly expanding indications for cancer immunotherapies pose a significant challenge to community clinicians to integrate this new class of agents into practice. Community cancer centers need guidance around the practical issues that must be addressed to implement immunotherapy safely and effectively to patients in their own communities. The Association of Community Cancer Centers (ACCC) initiated a quality improvement (QI) research study to assess the impact of comprehensive educational interventions targeting the multidisciplinary cancer care (MDCC) team on evidence-based integration of immunotherapies in the community setting. Methods: The QI study collected baseline data from two community cancer centers to identify barriers to optimal implementation of immunotherapies at each institution for the following metrics: co-morbidities in patients, immune-related adverse events (irAEs), laboratory tests, ER visits and hospitalizations, patient education materials, and immunotherapeutic adherence. Retrospective data was collected for 100 patients initiating immunotherapy between Dec 2017-April 2018. Results: Analysis of the data revealed that only 61% of the patients fully completed the immunotherapy treatment as planned. Eighty-one percent of patients were found to have 4 or more irAEs. On average patients were each diagnosed with more than 2 co-morbidities, including cardiac disease, diabetes, dyslipidemia, hypothyroidism, hypertension, and obesity. Using Fisher’s exact test to calculate two-tailed P values, we attempted to investigate a correlation between the number of co-morbidities to the lack of treatment adherence. We found a trend towards statistical significance between lack of treatment adherence and patients with two or more co-morbidities ( P value = 0.1256). Conclusions: Timely management of irAEs is crucial for the adherence to the immunotherapy regimen. The baseline data collected in our QI study revealed a trend towards the impact of the presence of two or more co-morbidities on treatment adherence. However, we did not find a statistically significant correlation between treatment adherence and the number of irAEs recorded in patients.
Genome-wide association study of peripheral artery disease in the Million Veteran Program
Authors: Derek Klarin, Julie Lynch, Krishna Aragam, Mark Chaffin, Themistocles L. Assimes, Jie Huang, Kyung Min Lee, Qing Shao, Jennifer E. Huffman, Pradeep Natarajan, Shipra Arya, Aeron Small, Yan V. Sun, Marijana Vujkovic, Matthew S. Freiberg, Lu Wang, Jinbo Chen, Danish Saleheen, Jennifer S. Lee, Donald R. Miller, Peter Reaven, Patrick R. Alba, Olga V. Patterson, Scott L. DuVall, William E. Boden, Joshua A. Beckman, J. Michael Gaziano, John Concato, Daniel J. Rader, Kelly Cho, Kyong-Mi Chang, Peter W. F. Wilson, Christopher J. O’Donnell, Sekar Kathiresan, Philip S. Tsao, Scott M. Damrauer
Journal: Nature Medicine (2019)
The Clinical Value of Proposed Risk Stratification Tools in Pediatric Pulmonary Arterial Hypertension
Authors: Meindina G. Haarman, Johannes M. Douwes, Mark-Jan Ploegstra, Marcus T. R. Roofthooft, Theresia R. Vissia-Kazemier, Hans L. Hillege, Rolf M. F. Berger
Journal: American Journal of Respiratory and Critical Care Medicine (2019)
Cell type-specific epigenetic links to schizophrenia risk in the brain
Authors: Isabel Mendizabal, Stefano Berto, Noriyoshi Usui, Kazuya Toriumi, Paramita Chatterjee, Connor Douglas, Iksoo Huh, Hyeonsoo Jeong, Thomas Layman, Carol A. Tamminga, Todd M. Preuss, Genevieve Konopka, Soojin V. Yi
Journal: Genome biology (2019)

The importance of cell type-specific epigenetic variation of non-coding regions in neuropsychiatric disorders is increasingly appreciated, yet data from disease brains are conspicuously lacking. We generate cell type-specific whole-genome methylomes (N = 95) and transcriptomes (N = 89) from neurons and oligodendrocytes obtained from brain tissue of patients with schizophrenia and matched controls.The methylomes of the two cell types are highly distinct, with the majority of differential DNA methylation occurring in non-coding regions. DNA methylation differences between cases and controls are subtle compared to cell type differences, yet robust against permuted data and validated in targeted deep-sequencing analyses. Differential DNA methylation between control and schizophrenia tends to occur in cell type differentially methylated sites, highlighting the significance of cell type-specific epigenetic dysregulation in a complex neuropsychiatric disorder.Our results provide novel and comprehensive methylome and transcriptome data from distinct cell populations within patient-derived brain tissues. This data clearly demonstrate that cell type epigenetic-differentiated sites are preferentially targeted by disease-associated epigenetic dysregulation. We further show reduced cell type epigenetic distinction in schizophrenia.
Generation of expandable human pluripotent stem cell-derived hepatocyte-like liver organoids
Authors: Seon Ju Mun, Jae-Sung Ryu, Mi-Ok Lee, Ye Seul Son, Soo Jin Oh, Hyun-Soo Cho, Mi-Young Son, Dae-Soo Kim, Su Jung Kim, Hyun Ju Yoo, Ho-Joon Lee, Janghwan Kim, Cho-Rok Jung, Kyung-Sook Chung, Myung Jin Son
Journal: Journal of Hepatology (2019)