tbuckley/cabot-search huggingface dataset:
Effect of brazilin on apoptosis and suppression of histone deacetylase in multiple myeloma U266 cells.
Authors: Bonglee Kim, Sung Hoon Kim
Journal: Journal of Clinical Oncology (2012)

e13514 Background: Brazilin [7, 11b-dihydrobenz(b)indeno[1,2-d]pyran-3, 6a, 9, 10(6H)-tetrol] isolated from Caesalpinia sappan has been showed various biological activities such as anti-inflammationy, anti-bacteria and anti-platelet aggregation. However, there is no report on its anti-cancer activity. Methods: In the present study, the anti-cancer mechanism of brazilin was investigated on apoptosis and cell cycle arrest in human multiple myeloma U266 cells. Results: Brazilin significantly increased sub-G1 population and TUNEL-positive cells undergoing apoptosis. Also, brazilin activated caspase-3 and regulated the expression of Bcl-2 family proteins including Bax, Bcl-x L and Bcl-2, via mitochondria-dependent pathway. Futhermore, cell cycle analysis revealed that brazilin induced G2/M arrest of cell cycle along with apoptosis induction in U266 cells. Consistently, brazilin elevated the expression of cyclin-dependent kinase (CDK) inhibitor proteins p21 and p27 and activated G2 checkpoint-related proteins such as Chk1, Chk2 and γ-H2Ax. Of note, brazilin significantly inhibited the activity of histone deacetylases (HDACs), transcription factors involved in the regulation of apoptosis and cell cycle arrest and the expression of HDAC-1 and -2 at both protein and mRNA levels. Notably, brazilin significantly potentiated the cytotoxic effect of chemotherapeutic agents such as bortezomib or doxorubicin in U266 cells. Conclusions: Taken together, our findings suggest that brazilin has a chemotherapeutic potential, via HDAC-mediated apoptosis and G2/M arrest for multiple myeloma treatment.
GEMINI: a variational Bayesian approach to identify genetic interactions from combinatorial CRISPR screens
Authors: Mahdi Zamanighomi, Sidharth S. Jain, Takahiro Ito, Debjani Pal, Timothy P. Daley, William R. Sellers
Journal: Genome biology (2019)

Systems for CRISPR-based combinatorial perturbation of two or more genes are emerging as powerful tools for uncovering genetic interactions. However, systematic identification of these relationships is complicated by sample, reagent, and biological variability. We develop a variational Bayes approach (GEMINI) that jointly analyzes all samples and reagents to identify genetic interactions in pairwise knockout screens. The improved accuracy and scalability of GEMINI enables the systematic analysis of combinatorial CRISPR knockout screens, regardless of design and dimension. GEMINI is available as an open source R package on GitHub at https://github.com/sellerslab/gemini .
Combining integrated systems-biology approaches with intervention-based experimental design provides a higher-resolution path forward for microbiome research
Authors: J. Alfredo Blakeley-Ruiz, Carlee S. McClintock, Ralph Lydic, Helen A. Baghdoyan, James J. Choo, Robert L. Hettich
Journal: Behavioral and Brain Sciences (2019)

Abstract The Hooks et al. review of microbiota-gut-brain (MGB) literature provides a constructive criticism of the general approaches encompassing MGB research. This commentary extends their review by: (a) highlighting capabilities of advanced systems-biology “-omics” techniques for microbiome research and (b) recommending that combining these high-resolution techniques with intervention-based experimental design may be the path forward for future MGB research.
Exploratory analysis based on tumor location of REACHIN, a randomized, double-blinded, placebo-controlled phase 2 trial of regorafenib after failure of gemcitabine and platinum-based chemotherapy for advanced/metastatic biliary tract tumors
Authors: A. Demols, I. Borbath, M. Van den Eynde, G. Houbiers, M. Peeters, R. Marechal, T. Delaunoit, J. Goeminne, S. Laurent, S. Holbrechts, M. Paesmans, J. Van Laethem
Journal: Annals of Oncology (2019)
The role of Rac proteins in glioblastoma stem cells.
Authors: Yun-Ju Lai, Jei-Hwa Yu, Braden C McFarland, Etty N Benveniste
Journal: Journal of Clinical Oncology (2013)

e13011 Background: Glioblastoma is the grade 4 astrocytoma which is notorious for its highly invasive phenotype, very low survival rate and generally poor responses to conventional therapies. Glioblastoma stem-like cells (GSC), which are usually more resistant to therapeutic treatment, may account for the poor prognosis of this disease. Rac (Ras-related C3 botulinum toxin substrate) is a subfamily of Rho small GTPase which function is regulation of actin cytoskeleton rearrangement. While Rac1 is expressed ubiquitous in different tissues and cells, Rac2 is highly expressed in the mesenchymal subtype of glioblastoma according to the TCGA (the Cancer Genome Atlas) database, and Rac3 is mainly expressed in the brain. Methods: We used Rac proteins overexpressing-glioblastoma cellines derived GSC and Rac proteins specific siRNA harboring-GSC to perform colony formation assay and migration assay. Results: Here we report that Rac proteins overexpressing glioblastoma stem-like cells derived from glioblastoma cell lines have higher proliferation rate and stronger responses to LPA-induced cell migration. Knocking-down their expression by specific siRNA reduces the proliferation and migration of these cells. Instead of Rac1, Rac2 and Rac3 are more effective on promoting proliferation and migration of glioblastoma stem-like cells. Moreover, Rac proteins promote glioblastoma progression is associated with activation of JAK-STAT and ERK pathway. Conclusions: Although Rac1 is the most studied one in the Rac family, and has also been implicated in the progression of different cancers, however, it is homogeneously expressed in all different tissues, and plays important roles in normal cellular functions involving cell movement, such as wound healing, make it not a good candidate for specific drug targeting. According to our results, Rac2 or Rac3 serve as a better potential therapeutic targets for glioblastoma treatment.
Classification of Culprit Ruptured Plaque Morphologies in Patients With STEMI
Authors: Chao Wang, Sining Hu, Na Feng, Ji Li, Yini Wang, Hui Dong, Rong Sun, Huai Yu, Lulu Li, Yuhan Qin, Xue Feng, Zhaoyue Li, Abigail Afolabi, Ikramullah Syed, Shaosong Zhang, Giulio Guagliumi, Haibo Jia, Bo Yu
Journal: JACC. Cardiovascular imaging (2019)
2018 update of the EULAR recommendations for the role of the nurse in the management of chronic inflammatory arthritis
Authors: Bianca Bech, Jette Primdahl, Astrid van Tubergen, Marieke Voshaar, Heidi A Zangi, Lurdes Barbosa, Carina Boström, Boryana Boteva, Francesco Carubbi, Françoise Fayet, Ricardo J O Ferreira, Kirsten Hoeper, Agnes Kocher, Marja Leena Kukkurainen, Vivienne Lion, Patricia Minnock, Antonella Moretti, Mwidimi Ndosi, Milena Pavic Nikolic, Michael Schirmer, Hana Smucrova, Jenny de la Torre-Aboki, Jennifer Waite-Jones, Yvonne van Eijk-Hustings
Journal: Annals of the Rheumatic Diseases (2019)

To update the European League Against Rheumatism (EULAR) recommendations for the role of the nurse in the management of chronic inflammatory arthritis (CIA) using the most up to date evidence. The EULAR standardised operating procedures were followed. A task force of rheumatologists, health professionals and patients, representing 17 European countries updated the recommendations, based on a systematic literature review and expert consensus. Higher level of evidence and new insights into nursing care for patients with CIA were added to the recommendation. Level of agreement was obtained by email voting. The search identified 2609 records, of which 51 (41 papers, 10 abstracts), mostly on rheumatoid arthritis, were included. Based on consensus, the task force formulated three overarching principles and eight recommendations. One recommendation remained unchanged, six were reworded, two were merged and one was reformulated as an overarching principle. Two additional overarching principles were formulated. The overarching principles emphasise the nurse's role as part of a healthcare team, describe the importance of providing evidence-based care and endorse shared decision-making in the nursing consultation with the patient. The recommendations cover the contribution of rheumatology nursing in needs-based patient education, satisfaction with care, timely access to care, disease management, efficiency of care, psychosocial support and the promotion of self-management. The level of agreement among task force members was high (mean 9.7, range 9.6-10.0). The updated recommendations encompass three overarching principles and eight evidence-based and expert opinion-based recommendations for the role of the nurse in the management of CIA.
Multisystem immune-related adverse events from anti-PD-1/PD-L1 in patients with lung cancer: Incidence, clinical patterns, management, and outcomes.
Authors: Bairavi Shankar, Jiajia Zhang, Durrant Barasa, Patrick M. Forde, Josephine Louella Feliciano, Kristen Marrone, Ronan Joseph Kelly, David S. Ettinger, Christine L. Hann, Julie R. Brahmer, Jarushka Naidoo
Journal: Journal of Clinical Oncology (2019)

84 Background: Anti-PD-1/PD-L1 immune checkpoint inhibitors (ICIs) for cancer may cause immune-related adverse events (irAEs). Large clinical trials and meta-analyses have identified the spectrum of single organ-specific irAEs that may occur with these agents. However, patients treated with these agents may develop irAEs involving multiple organ systems. The prevalence and clinical patterns of multi-system irAEs and their management have yet to be elucidated. Methods: Patients with lung cancer treated with either PD-1/PD-L1 monotherapy or PD-1/PD-L1-based combinations at Johns Hopkins Hospital were identified. Clinical, radiologic and pathologic data were stored in an IRB-approved database. irAEs were identified through retrospective chart review and confirmed by a multidisciplinary team. Multi-system irAEs were defined as irAEs in +1 organ system. Patients with multi-system irAEs, their clinical patterns, management and outcomes were identified. Results: 319 patients were identified (NSCLC: 299, 93.7%; SCLC: 20, 6.3%) and received treatment with either PD-1/PD-L1 monotherapy (197, 61.8%) or combinations (122, 38.2%: + chemotherapy = 42; +immunotherapy = 41; +other = 39). Of these patients, 77 (24.1%) developed 1 irAE, and 16 (5%) developed multi-system irAEs (2 irAEs: 14; 3 irAEs: 2). The most common irAEs were pneumonitis (42, 13.2%), dermatitis (11, 3.4%), and hypothyroidism (9, 2.8%). The most common multi-system irAEs was pneumonitis/dermatitis (3, 3.9%). Patients who developed dermatitis, colitis, or hypothyroidism were most likely to develop multi-system irAEs (all p &lt; 0.05). Management and outcome data for individual and multi-system irAEs will be presented. Conclusions: Patients treated with ICIs may develop multi-system irAEs. In the first report of this clinical entity, we identified that 5% of lung cancer patients treated with PD-1/PD-L1 developed multi-system irAEs, and that those who developed dermatitis, colitis, or hypothyroidism were most likely to develop multi-system events. These data have important implications for interdisciplinary patient management in the era of cancer immunotherapy.
Detection of doxorubicin cardiotoxicity in patients with breast cancer by 99mTc-MIBI myocardial perfusion tomography
Authors: F. Morales-Vasquez, S. García, H. Lopez-Basave, R. Altamirano-Ley
Journal: Journal of Clinical Oncology (2006)

10775 Background: Cardiotoxicity is a well-known side effect of several cytotoxic drugs especially of the anthracyclines and can lead to long term morbidity. Endomyocardial biopsy is the only specific test for early diagnosis of anthracycline-induce toxicity. Efforts are continuing on finding a more sensitive and reliable predictor of eventual clinic cardiac dysfunction. Therefore, it is crucial that careful monitoring to identify those patients patients who are at risk of developing unpredectible and some times-irreversible dysfunction. Serial measurement of left ventricular ejection fraction by radionuclide angiography remains a useful and widely adopted modality in monitoring patients that are receiving doxorubicin. Objective: To investigate the value of 99mTc-MIBI myocardial perfusion tomography to detect myocardial damage in patients with breast cancer under chemotherapy. Methods: Thirty patients were examined from May to December 2000 by electrocardiogram (ECG), nuclear angiography for detecting left ventricular ejection fraction (LVEF) and 99mTc-MIBI myocardial perfusion was performed before chemotherapy and after chemotherapy. Results: Fifteen patients were treated by continuos infusion over 24 hr, nine patients over 48 hr and 6 patients were treated by bolus. The patients presented with a decrease of &gt; or = 9% in absolute ejection fraction at 200–320 mg/m 2 with 99mTc-MIBI and 5% with nuclear angiography. Gated myocardial perfusion scintigraphy results were abnormal in four patients (12.9%). All patients were treated by continuos infusion and the radiotherapy was absent. Other factors were investigated: hypertension, diabetes, smoker and obesity. Conclusions: 99 mTc-MIBI studies are helpful in the assessment of doxorubicin cardiotocixity. Anthracyclines induced myocite injury symptomatic or asymptomatic; uptake at intermediate cumulative doses identifies patients at risk of cardiotoxicity before ejection fraction deteriorates. The 99-mTc-MI BI imaging may be a sensitive method for non invasive visualization of myocardial cell damage and useful in the early diagnosis of specific heart muscle disease. Doxorubicin cause silent myocardial ischemia. No significant financial relationships to disclose.
Factors associated with severity of immune checkpoint inhibitor gastroenterocolitis requiring hospitalization in melanoma patients.
Authors: Michael Sang Hughes, Hui Zheng, Leyre Zubiri, Michael Dougan, Ian Matthew Allen, Gabriel Molina, Melissa Lumish, Megan Mooradian, Kerry Lynn Reynolds
Journal: Journal of Clinical Oncology (2019)

81 Background: Immune checkpoint inhibitors (ICIs) have resulted in a subset of patients experiencing durable responses in solid and liquid malignancies. ICIs can be associated with adverse events, including gastroenterocolitis (GEC), that require immunosuppression and even hospitalization. Currently, no data determine the severity of patients hospitalized for ICI-related GEC. Our primary objective was to identify candidate surrogate endpoints that may predict the severity of ICI-related GEC; our secondary objective was to identify predictors of glucocorticoid (GC) response. Methods: In a retrospective cohort study, we identified melanoma patients who developed ICI-related GEC requiring hospitalization at Massachusetts General Hospital between 6/1/11 and 12/31/17. We extracted clinical, laboratory, radiographic, and pathological data; linear regression was used to estimate trends. Additional subgroup analyses were performed. Results: 69/1842 (3.7%) melanoma patients treated with ICI developed GEC requiring hospitalization (total 98 admissions). Mean age was 64 +/- 13; 42 (61%) were male. Readmission rate was 21/69 (30.4%); 6/21 (28.6%) required multiple readmissions. 90/98 (92%) were confirmed by histopathologic examination. 26/69 (37.7%) responded to GCs; 43/69 (62.3%) required second-line immunosuppression (e.g. TNFi) and/or operative intervention. ECOG PS (at initial ICI administration) was associated with response of GEC to GCs (p = 0.04). Lymphocyte count (p = 0.03), % lymphocyte count (p = 0.02), and LDH (p = 0.004) on admission were independently associated with GEC requiring second-line immunosuppression. Conclusions: Admissions for ICI-related GEC are infrequent, but they are associated with a high readmission rate and the need for second-line immunosuppression. We show that high ECOG PS at time of ICI administration may be a predictor of GC response in ICI-related GEC requiring hospitalization. We also propose that low % lymphocyte count and high LDH may serve as clinical biomarkers of severity in ICI-related GEC requiring hospitalization. Our findings suggest the need for further research and validation of these proposed biomarkers.
Abstract 11775: Initial US Experience With a Technician Supported Remote Interrogation System for Cardiac Implantable Electronic Devices in the Emergency Department and Perioperative Areas
Authors: Imdad Ahmed, Amisha Patel, Timothy Balgaard, Lynda E Rosenfeld
Journal: Circulation (2015)

Introduction: Patients (Pts) with cardiac implantable electronic devices (CIED)s often require device interrogation and interpretation in the Emergency Department (ED) or perioperative areas (OR) where personnel and equipment to perform this procedure are often not available. CareLink Express (CLE) (Medtronic, Inc.) is a new technician supported real time remote interrogation system designed to facilitate this process. Objective: The aim of this retrospective study was to assess the efficiency of CLE compared to traditional device management (TDM) and examine its findings. Methods: Data from the Medtronic deidentified database were used to assess CLE use and performance in the ED and OR from 01/2012 - 10/2014. All 7044 CLE transmissions from 136 US sites originating in the ED or OR, were compared to 217 TDM requests in 5 geographically diverse US sites where, prior to CLE, CIED interrogations and interpretations were performed by calling an industry representative to the ED or OR. Results: Compared to TDM, CLE resulted in a 78% reduction in the time to device interrogation and interpretation: (100±140 min to 22+14 min, P&lt;0.0001). It improved response time and consistency in both the ED: 82+103 min to 23+18 min P&lt;0.01, and OR: 127+181 min to 16.5+9.5 min P&lt;0.0001. Overall, actionable events (arrhythmia, device/lead abnormalities) (AE) were found infrequently (ED AE: 9.9%; OR: 4.1%). AE were found in only 13.6% of Pts with a perceived shock and 6.5% of those presenting with syncope. AE were much more common in Pts with suspected abnormal device function (30.4%) or audible alerts (52.6%). Pts not enrolled in a remote monitoring system were almost 3 times more likely to have an AE identified than those enrolled in such a program (23.9% vs 8.2%, p&lt;0.0001) and the presence of an older CIED system was associated with an increased likelihood of finding an AE with CLE use (7.4% in year 1 vs 31% after 10 years). Conclusions: The large number of Pts with CIEDs, and the opportunity to quickly and predictably identify the minority with high risk/life-threatening AE from the low risk majority, strongly support CLE as an attractive tool to save time, and improve resource utilization, especially in sites such as the ED and OR which are expensive and place a high priority on efficiency.
Immune pneumonitis-related treatment discontinuations and outcomes in metastatic non-small cell lung cancer treated with nivolumab: A pooled analysis from a multi-institutional international collaboration.
Authors: Abdul Rafeh Naqash, Dwight Hall Owen, Biagio Ricciuti, Yukihiro Toi, Rita Chiari, Nitika Sharma, Sandip H. Patel, Shunichi Sugawara, Cynthia R. Cherry, Jarred Thomas Burkart, Andrea De Giglio, Jun Sugisaka, Mark Bowling, Gregory Alan Otterson, Paul R. Walker
Journal: Journal of Clinical Oncology (2019)

118 Background: Immune-related adverse events (irAEs) due to immune-checkpoint inhibitors (ICI) can lead to significant morbidity. Immune pneumonitis (IP) constitutes one of the common irAEs in non-small cell lung cancer (NSCLC) with a reported incidence of 3-5%. However outside of clinical trials there is a paucity of data regarding incidence/outcomes of IP in nivolumab (N) treated metastatic-NSCLC (m-NSCLC). Methods: We retrospectively pooled data of 381 m-NSCLC patients (pts) from four cohorts treated with N within different treatment time periods: East Carolina University, USA: 4/2015- 2/2018; Ohio State University, USA: 6/2013-6/2016; University of Perugia, Italy: 10/2013-9/2017, and Sendai Kousei Hospital, Japan: 1/2016-1/2018. IP identification was based on clinical diagnosis of treating team. Grade (G) was based on Common Terminology Criteria for Adverse Events (CTCAE v 4.03). Time to immune pneumonitis (TTIP) was the time from starting N to diagnosis of IP. Results: The rate of IP was 13.1% (n=50) with 68% of IP presenting as the index irAE. Median TTIP was 9.75 weeks (range: 0.25-73.7) with G1 (24.0%), G2 (36.0%), G3 (36.0%), G4 (4.0%). 57.9% of IP ≥G2 had TTIP ≤ 3 months (m). For all-G (IP), 22.0% pts had stopped N before IP either due to non-IP irAEs or progression. Excluding these, treatment discontinuations (d/c) attributed to IP ≥ G2 were 66.6%. IP ≥G2 had higher treatment d/c when TTIP was ≤ 3m vs. &gt; 3m (51.8% vs. 14.8%; P=0.09). Median overall survival (OS) by log rank test for pts with any grade IP vs. no IP was not statistically significant (13.7 vs. 7.5m; P =0.14). IP ≥G2 occurring at &gt; 3m had longer median OS vs. IP ≥G2 occurring in ≤3m (16.7 vs. 3.6m, P=0.008), which was not significant at a 3m landmark analysis when accounting for time on N (P= 0.31). Conclusions: Our real-world multi-institutional data shows a higher incidence of IP in m-NSCLC. We also see a trend for frequent ICI d/c in IP ≥ G2 occurring within 3 months that may ultimately influence OS per our landmark analysis. Thus aggressive and early symptom management specifically directed at allowing reinitiation of ICI after IP needs to be considered.
The inhibition of p21 on irradiation-induced apoptosis in EL-4 cells.
Authors: Feng-qin Yan, Jian-qiu Wang, Shi-bo Fu, Fang-zheng Wang, Zhen-fu Fu, Gui-zhi Ju
Journal: Journal of Clinical Oncology (2012)

e13558 Background: To elucidate the effect of p21 on ionizing radiation-induced apoptosis in EL-4 cells. Methods: In EL-4 cells, RT-PCR, immunocytochemistry and flow cytometry (FCM) were used to analyze the changes in the expression of p21 with time and doses caused by ionizing radiation; RNAi was used to silence the expression of p21 in EL-4 cells; FCM was applied to analyze the distribution of cell cycle,the number of the chromosome and the apoptosis in wild or p21-silencing EL-4 cells exposed to X-rays. Results: In EL-4 cells, p21 protein level was markedly increased at 8 ~ 72 h after exposure in 4.0 Gy of X-ray in vitro (p&lt;0.01), as well as exposed in 1.0 ~ 4.0 Gy of X-ray at 24 h in vitro (p&lt;0.05). Results of time-course experiments showed that, in EL-4 cells exposed to 4.0 Gy X-rays, the percentage in G0/G1 phase increased while that in S phase decreased, significantly different with the sham-irradiated groups (p&lt;0.05), during 8-48h after exposure; the percentage of diploid cells increased significantly during 8-48 h (p&lt;0.01), and the percentage of tetraploid and octoploid cells decreased significantly at 2 h and 8 h (p&lt;0.05); the percentage of apoptosis during 2-72 h increased significantly (p&lt;0.05-p&lt;0.01). Compared with wild EL-4 cells, in p21-silencing EL-4 cells, the distribution of cell cycle had no apparent difference; the percentage of diploid cells decreased significantly and the percentage of octoploid cells increased significantly (p&lt;0.01); the percentage of apoptosis increased significantly (p&lt;0.05). Conclusions: p21 inhibited the apoptosis induced by ionizing radiation in EL-4 cells.
GP academic is suspended for six months after misleading employers about outside work
Authors: Clare Dyer
Journal: BMJ (2019)

A professor of general practice who misled his employers at Warwick Medical School about his outside work and earnings has been suspended from the UK medical register for six months.

When Robert Walton took up his post at Warwick in May 2017 he was already working privately for up to two days a week for Summertown Health Centre in Oxford and one day a week at Queen Mary University of London.

Before taking up his post he was told by the dean of Warwick Medical School that he would need to complete an application if he were to undertake outside work.

In an email Walton asked the dean whether it would be possible for him to keep his earnings …