tbuckley/cabot-search huggingface dataset:
A Novel α-Calcitonin Gene-Related Peptide Analogue Protects Against End-Organ Damage in Experimental Hypertension, Cardiac Hypertrophy, and Heart Failure
Authors: Aisah A. Aubdool, Pratish Thakore, Fulye Argunhan, Sarah-Jane Smillie, Moritz Schnelle, Salil Srivastava, Khadija M. Alawi, Elena Wilde, Jennifer Mitchell, Keith Farrell-Dillon, Daniel A. Richards, Giuseppe Maltese, Richard C. Siow, Manasi Nandi, James E. Clark, Ajay M. Shah, Anette Sams, Susan D. Brain
Journal: Circulation (2017)

Research into the therapeutic potential of α-calcitonin gene-related peptide (α-CGRP) has been limited because of its peptide nature and short half-life. Here, we evaluate whether a novel potent and long-lasting (t½ ≥7 hours) acylated α-CGRP analogue (αAnalogue) could alleviate and reverse cardiovascular disease in 2 distinct murine models of hypertension and heart failure in vivo.The ability of the αAnalogue to act selectively via the CGRP pathway was shown in skin by using a CGRP receptor antagonist. The effect of the αAnalogue on angiotensin II-induced hypertension was investigated over 14 days. Blood pressure was measured by radiotelemetry. The ability of the αAnalogue to modulate heart failure was studied in an abdominal aortic constriction model of murine cardiac hypertrophy and heart failure over 5 weeks. Extensive ex vivo analysis was performed via RNA analysis, Western blot, and histology.The angiotensin II-induced hypertension was attenuated by cotreatment with the αAnalogue (50 nmol·kg-1·d-1, SC, at a dose selected for lack of long-term hypotensive effects at baseline). The αAnalogue protected against vascular, renal, and cardiac dysfunction, characterized by reduced hypertrophy and biomarkers of fibrosis, remodeling, inflammation, and oxidative stress. In a separate study, the αAnalogue reversed angiotensin II-induced hypertension and associated vascular and cardiac damage. The αAnalogue was effective over 5 weeks in a murine model of cardiac hypertrophy and heart failure. It preserved heart function, assessed by echocardiography, while protecting against adverse cardiac remodeling and apoptosis. Moreover, treatment with the αAnalogue was well tolerated with neither signs of desensitization nor behavioral changes.These findings, in 2 distinct models, provide the first evidence for the therapeutic potential of a stabilized αAnalogue, by mediating (1) antihypertensive effects, (2) attenuating cardiac remodeling, and (3) increasing angiogenesis and cell survival to protect against and limit damage associated with the progression of cardiovascular diseases. This indicates the therapeutic potential of the CGRP pathway and the possibility that this injectable CGRP analogue may be effective in cardiac disease.
P17.18 Fractionated Stereotactic Radiosurgery (FSRS) in Metastatic Brain Tumors
Authors: G. Yee, M. Kim, E. Kim, C. Yoo, W. Kim
Journal: Neuro-Oncology (2017)

Objective: To evaluate the efficacy of fractionated stereotactic radiosurgery (FSRS) to large or eloquent area cerebral metastases. Methods: A retrospective analysis of 16 patients who had received FSRS (less than 3 fractions) for cerebral metastases from Mar. 2013 to Mar. 2016 was performed. All tumors were treated with the frameless LINAC-based, Novalis -Tx system. Patients who underwent single session of SRS to the tumors were excluded. All patients were treated with 3 fractions. The mean planning target volume was 20.68 cm3 (6.9 - 53.9 cm3). The mean dose was 10 Gy per day at 90% isodose line with 3 fractions for three consecutive days. Results: Primary origin was lung, G-I tract and breast in order. Four patients were dead during follow up period. The mean survival time was 14.8 months and local tumor control rate was 87.5%. Radiation necrosis was developed in 1 patient. Conclusions: Limited number of patients and short follow up period is not enough to conclude the efficacy of fractionated stereotactic radiosurgery (FSRS). However, FSRS might be a good treatment modality for the patients had large or eloquent area cerebral metastases.
Infusion-Compatible Antibiotic Formulations for Rapid Administration to Improve Outcomes in Cancer Outpatients With Severe Sepsis and Septic Shock: The Sepsis STAT Pack
Authors: Jason D. Goldman, Amelia Gallaher, Rupali Jain, Zach Stednick, Manoj Menon, Michael J. Boeckh, Paul S. Pottinger, Stephen M. Schwartz, Corey Casper
Journal: Journal of the National Comprehensive Cancer Network (2017)

Background: Patients with cancer are at high risk for severe sepsis and septic shock (SS/SSh), and a delay in receiving effective antibiotics is strongly associated with mortality. Delays are due to logistics of clinic flow and drug delivery. In an era of increasing antimicrobial resistance, combination therapy may be superior to monotherapy for patients with SS/SSh. Patients and Methods: At the Seattle Cancer Care Alliance, we implemented the Sepsis STAT Pack (SSP) program to simplify timely and effective provision of empiric antibiotics and other resuscitative care to outpatients with cancer with suspected SS/SSh before hospitalization. Over a 49-month period from January 1, 2008, through January 31, 2012, a total of 162 outpatients with cancer received the intervention. A retrospective cohort study was conducted to determine outcomes, including mortality and adverse events associated with the use of a novel care bundle designed for compatibility of broad-spectrum antibiotics and other supportive care administered concurrently via rapid infusion at fixed doses. Results: Of 162 sequential patients with cancer and suspected SS/SSh who received the SSP, 71 (44%) were diagnosed with SS/SSh. Median age was 53 years and 65% were men; 141 (87%) had hematologic malignancies, 77 (48%) were transplant recipients, and 80 (49%) were neutropenic. Median time to completion of antibiotics was 111 minutes (interquartile range, 60–178 minutes). A total of 71 patients (44%) had bacteremia and 17% of 93 isolates were multidrug-resistant. Possibly related nephrotoxicity occurred in 7 patients, and 30-day mortality occured in 6 of 160 patients (4%), including 3 of 71 (4%) with SS/SSh. Risk of developing SSh or death within 30 days increased 18% (95% CI, 4%–34%) for each hour delay to completion of antibiotics (P=.01). Conclusions: Rapidly administered combination antibiotics and supportive care delivered emergently to ambulatory patients with cancer with suspected SS/SSh was well-tolerated and associated with excellent short-term survival.
P08.17 Mitotic checkpoint inhibition augments Tumor-Treating-Field (TTField) effects on glioblastoma cells
Authors: A. F. Kessler
Journal: Neuro-Oncology (2017)

Introduction: Treatment of glioblastoma (GBM) patients with Tumor Treating Fields (TTFields) in addition to standard therapy showed significant increase in progression free and overall survival (EF-14 trial). TTFields are alternating electric fields with low intensity (1-3V/cm) and intermediate frequency (100-400kHz) that disrupt cell division through the inhibition of spindle fiber formation. The chemotherapeutic agent Vincristine also inhibits spindle fiber formation but in contrast to TTFields, Vincristine therapy is associated with severe side effects. The spindle assembly checkpoint (SAC) diminishes the therapeutic effects of spindle damaging agents by monitoring the correct segregation of sister chromatids. An Inhibition of Monopolar spindle 1 (MPS1), the key regulator of SAC, when combined with Vincristine shows a synergistic effect on GBM growth in mice. Therefore, we hypothesized that MPS1 inhibition could increase the efficacy of TTFields. Materials and Methods: Utilising the Novocure inovitro™ laboratory research system, 30,000 human GBM U87 cells were treated with TTFields (200kHz) alone or with 4µM of the MPS1 inhibitor MPS1-IN-3 (IN3) either alone or in combination with TTFields. Cell numbers and apoptosis (Annexin V staining) were evaluated after 24h, 48h and 72h of treatment. Cell numbers were also evaluated at 24h and 72h after end of treatment (eot). Results: Treatment with TTFields plus IN3 resulted in an earlier response. After 72h, the cell number decreased by 77.5% compared to TTFields alone (p = 0.0201) and by 50% compared to MPS1-inhibition with IN3 (p = 0.0344). While the cells treated with TTFields alone decreased for another 24h after eot and then started to recover, the combination of TTFields and IN3 resulted in a decrease of cell numbers by an additional 92% at 72h after eot of TTFields (p = 0.0086). All cells recovered in instances when IN3 treatment ended after 72h. The combination treatment of TTFields plus IN3 induced an early stage of apoptosis in 44% of the cells, compared to 14% with TTFields alone (p = 0.0002) and 4% with IN3 alone (p < 0.0001). Conclusions: TTFields are an approved new treatment modality for GBM. A combination of physical damage of the spindle apparatus by TTFields and chemical inhibition of the SAC led to earlier and prolonged effects, which significantly augment TTFields efficacy. This work was supported by the Familie Mehdorn Stiftung.
Should doctors engage with counterterrorism?
Authors: Fiona Godlee
Journal: BMJ (2017)

Terrorists’ tactics have changed, and security services have had to change theirs in response. We are seeing fewer highly trained extremists carrying out carefully planned attacks and more lone actions by vulnerable people incited by internet propaganda. Last month’s attacks on Westminster Bridge and in Paris bear this out. But does this mean that doctors should change how they behave?

The government’s Prevent strategy puts a duty of care on NHS trusts to report people they think are at risk of committing terrorist acts. Actual rates of referrals are low, according to information obtained by The BMJ , but concerns about the effect of …
P08.04 “The development tumor model” used to biologically and spatiotemporally follow and understand glioblastoma evolution in the whole brain and to test and monitor new therapies
Authors: E. Brognaro
Journal: Neuro-Oncology (2017)

To date, “The development tumor model” (TDTM) is the only preclinical animal model which can replicate the entire glioblastoma natural history both in the bulk and in the microinfiltrated brain parenchyma. Furthermore, the model is perfectly suited to testing new therapies and continuously monitor subclonal emerging populations after treatment in order to identify molecular predictors of response to innovative therapies. TDTM is a xenogeneic orthotopic transplantation model using glioblastoma-derived cell lines from the pre-hypoxic phase of the founding clone (or of the more ancestral one, inferred after reconstruction of the phylogenetic tree) cultivated in a neurobasal serum-free medium as transplanted material. The model posits the transplantation of the same number of cells into several genetically identical immunocompromised rodents (an inbred strain of mice or rats) at the same time (time zero). Thus, the model creates a pool of twin immunodeficient transplant animals examined under the same conditions. By sacrificing one animal a week (or choosing any time interval as needed) and obtaining multiple biopsies (from the bulk, ipsilateral hemisphere, corpus callosum, contralateral hemisphere) and stainings on sections during the progression of the xenograft, we can biologically and spatiotemporally (i.e geographically and longitudinally) reproduce and monitor both the entire evolution in the bulk (appreciating the evolving variegated clonal architecture and increasingly more complex intratumor heterogeneity) and detect all the steps, from the beginning to the end of the natural history, of brain parenchyma microinfiltration. The model, continuosly monitoring the progression of the brain parenchyma microinfiltration over the development of the glioblastoma xenograft, will enable us to sperimentally demonstrate the hypothesis (that many radiological, clinical, surgical clues and the genetic analysis of distant recurrences indicate) that the entire brain parenchyma microinfiltration happens in very early stages of glioblastoma development or likely even before the growth of the primary tumor bulk by the CSCs of the founding clone. Indeed, TDTM can enable us to identify the CSCs in the brain parenchyma shedding light on the perivascular parenchymal niche where founder CSCs have exited the cell-cycle and settle quiescent in G0 state until activation. Furthermore and fundamentally, TDTM is perfectly suitable to test novel therapies. By delivering to all rodents at the same time the identical dose and modality of therapeutic treatments over xenograft progression, the model can allow us to follow the dynamics, response and emergence of subclones both in the bulk and in the microinfiltrated brain parenchyma that occur during and after innovative therapies such as chemotherapy, radiotherapy, immunotherapy or others.
Investigation of disseminated intravascular coagulation in 118 patients with meningococcal disease
Authors: Ludek Roznovsky, Vera Struncova, Vacla Dostal, Stanislav Plisek, Ivo Burget, Z. Herodes, Pavel Chalupa, Pavel Dlouhy, Jiri Svejda, Pavla Kriz
Journal: Clinical Microbiology and Infection (2001)
Diagnostic work-up and specific causes of acute kidney injury
Authors: Michael Darmon, Marlies Ostermann, Jorge Cerda, Meletios A. Dimopoulos, Lui Forni, Eric Hoste, Matthieu Legrand, Nicolas Lerolle, Eric Rondeau, Antoine Schneider, Bertrand Souweine, Miet Schetz
Journal: Intensive Care Medicine (2017)
Abstract 346: Genome-wide Bisulfite Sequencing After Isoproterenol Identifies DNA Methylation Modules Influencing Heart Failure Susceptibility
Authors: Haodong Chen, Luz D Orozco, Liudmilla Rubbi, Jessica Wang, Christoph D Rau, Douglas Chapski, Shuxun Ren, Yibin Wang, Matteo Pellegrini, Aldons J Lusis, Thomas M Vondriska
Journal: Circulation Research (2013)

DNA methylation is an epigenetic mechanism that controls gene expression. Recent studies of human samples linked dysregulation of DNA methylation to cardiovascular diseases. However, whether DNA methylation is mechanistically involved in disease pathogenesis is unknown. To determine how DNA methylation participates in the development of heart failure, we measured the DNA methylome in healthy and hypertrophic mouse hearts (and in isolated cardiac myocytes in parallel experiments) using reduced representational bisulfite sequencing. Isoproterenol (ISO) minipumps were implanted in two mouse strains with opposite phenotypes: BUB/BnJ, which is resistant to ISO-induced hypertrophy/failure, and BALB/cJ, which is susceptible. DNA and mRNA were isolated from hearts and myocytes and analyzed by bisulfite sequencing and microarrays, respectively. The results reveal three levels of information about the methylome: basal differences between the resistant and susceptible strains, loci affected in a disease-associated manner, and strain-specific changes in methylation following ISO treatment_which serve as novel targets to understand the genetic basis of differential incidence of heart failure. We observed 1,122 loci undergoing a &gt;20% change in methylation after ISO in either strain (p&lt;0.05). Our data also showed significant ISO-induced methylation differences in genes related to myofibril assembly (GO:0031032, p=6e-7) and increased heart weight (MP:0002833, p=2e-6). We selected the top 15,000 promoter-associated CpGs with high variation among samples and carried out an unbiased weighted correlation network analysis (WGCNA) of these methylation data. We identified a module of promoter-associated CpGs whose demethylation is highly correlated with ISO treatment in both strains (75 CpGs, Pearson correlation=0.898, p=0.001). We also identified modules with strain-specific responses to ISO treatment. Interestingly, we found a module of 109 CpGs whose methylation is increased in BALB/cJ strain after ISO treatment, but decreased in BUB/BnJ strain. Our data demonstrate global changes in DNA methylation in the adult heart during the development of disease and reveal networks of modified loci that influence heart failure susceptibility.
Sixty seconds on . . . a cure for dementia
Authors: Anne Gulland
Journal: BMJ (2017)

Sorry, I just wanted to get your attention. In a study published in Brain researchers have announced that two drugs that have been found to prevent brain cell death in mice with neurodegenerative disease are safe to test in humans.1

In 2013 a Medical Research Council team at the University of Leicester identified a major pathway that leads to brain cell death in mice.2 Misfolded (or faulty) proteins …
Apatinib Inhibits Proliferation and Induces Apoptosis of Acute Myeloid Leukemia Stem/Progenitor like Cell Line(kg1α cells) By Inhibition PI3K/AKT Signal Pathway
Authors: Bing Xu, Zhi-feng Li, Man-man Deng, Jie Zha, Yong Zhou, Zhi-hong Fang
Journal: Blood (2016)
P12.16 The immunohistochemical analysis of Leptin and its receptor in meningiomas
Authors: G. Bhavani, D. Gochhait
Journal: Neuro-Oncology (2017)

Background: Meningiomas account for 30% of all intracranial tumours with marked female preponderance. These tumours arise in meningothelial cells and radiologically characterised by dural tail. Most of the meningiomas are categorised under grade 1 (benign). WHO grades II and III and are associated with higher risk of recurrence and shorter survival times. Brain invasion alone suffice for atypical meningiomas. With increase in tumour grade, additional progression- associated molecular aberrations can be found; however most relevant genes are yet to be identified. New evidence suggests that leptin can be involved in progression of brain tumors. Leptin is found to be a potent angiogenic factor by upregulation of vascular endothelial growth factor (VEGF) and plays a role in migration and invasion. Leptin functions via the JAK-STAT signalling pathway and functions in tandem with its receptor, Ob-R. In this regard the potential role of leptin and its receptor in carcinogenesis of meningiomas was analysed. Methods: The tissue samples of 70 cases of meningiomas were collected after the excision of tumor with informed consent. The immunohistochemical (IHC) analysis were carried out to assess the expression of leptin and its receptor. Results: The present study demonstrates that the leptin and its receptor is expressed in these cases and could play a role in tumor progression. Of the total 70 cases, 60 cases were grade 1 (86%), 7 cases were grade 2 (10%) and 3 cases were grade 3(4%). On IHC conducted for the above mentioned markers, the positive expression of these proteins were measured quantitatively and correlated with degree of malignancy which was also statistically significant (p<0.05) with the grade of tumor. Conclusion: The expression of leptin and its receptor has never been studied in meningiomas amongst the Asian population. Rudimentarily, this supplements in understanding the involvement of these proteins in the molecular pathway that may play a role in progression of meningiomas. Therefore, evidence of leptin expression in meningiomas can form a basis for targeted therapy.
Implementation of NCCN palliative care guidelines by member institutions.
Authors: Diane G. Portman, Alexandra Albizu-Rivera, Sarah Thirlwell, Shirley N. Codada, Kristine A. Donovan
Journal: Journal of Clinical Oncology (2014)

15 Background: To promote access to quality, evidence-based palliative care (PC) and help cancer patients experience the best quality of life possible throughout the illness trajectory, the National Comprehensive Cancer Network (NCCN) has developed PC guidelines to guide symptom screening, assessment, PC interventions, and reassessment by the oncology team. We sought to evaluate use of the guidelines among NCCN member institutions. Methods: In April and May 2014 an invitation and reminders to participate in an online survey were sent electronically to NCCN PC guidelines panel members. If a panel member did not reply, individuals involved in the provision of PC at the same institution were approached. Results: Responses were received from 21 (84%) of the 25 member institutions. All of the institutions report having an interdisciplinary team with PC expertise. Among respondents, 38% have an accredited/certified PC program and 52% have an institutional PC quality improvement program in place. Fifty-two percent submit data to the National Palliative Care Registry. Forty-three percent have guidelines or triggers in place for the use of PC services. Only 10% actively employ the NCCN guidelines to screen for PC needs or make PC referrals; the guidelines are more often used to guide patient assessment (38%) and clinical practice (43%). When asked to endorse other PC referral criteria, 76% indicated the discretion of the oncology provider(s) and 29% the National Consensus Project for Quality Palliative Care. Sixty-two percent agree providers concur on the elements of PC and 29% agree as to who should receive PC. Only 19% agree early integration of PC should occur for all oncology patients and 43% agree PC referrals occur in a timely and efficient manner. The most frequently cited barriers to the provision of quality PC are: attitudes toward PC (71%), insufficient staffing (61%) and limited financial resources (57%). Conclusions: Implementation of the guidelines at NCCN member institutions is incomplete. There appears to be a lack of consensus about when and for whom PC should be provided. Future research should be designed to enhance understanding of the barriers to care and improve implementation of the guidelines.
Short lung transplant donor telomere length is associated with decreased CLAD-free survival
Authors: Hilary E Faust, Jeffrey A Golden, Raja Rajalingam, Angelia S Wang, Gary Green, Steven R Hays, Jasleen Kukreja, Jonathan P Singer, Paul J Wolters, John R Greenland
Journal: Thorax (2017)

Telomere length (TL) decreases with cellular ageing and biological stressors. As advanced donor and recipient ages are risk factors for chronic lung allograft dysfunction (CLAD), we hypothesised that decreased age-adjusted donor TL would predict earlier onset of CLAD. Shorter donor TL was associated with increased risk of CLAD or death (HR 1.26 per 1 kb TL decrease, 95% CI 1.03 to 1.54), particularly for young donors. Recipient TL was associated with cytopenias but not CLAD. Shorter TL was also seen in airway epithelium for subjects progressing to CLAD (p=0.02). Allograft TL may contribute to CLAD pathogenesis and facilitate risk stratification.