tbuckley/cabot-search huggingface dataset:
Imatinib dose hike in suboptimal response and failure in CML CP: Results from a developing nation.
Authors: Muralidhar Gullipalli, Vijay Gandhi Linga, Rajesh Kota, Krishnamani Kalpathi, Rahul Narayan Maddi, Vamshi Krishna Reddy Goteke, Ravi Sankar Arigela, Srividya Nasaka, Ranga Raman Ganta, Sadashivudu Gundeti, Raghunadharao Digumarti
Journal: Journal of Clinical Oncology (2013)

e18003 Background: As perEuropean Leukemia Net (ELN) guidelines Imatinib 400mg/day is the standard of care in CML-CP. Options for patients with suboptimal response and failure are dose hike or change to second line TKIs. In resource poor countries where second line TKIs are expensive, dose hike of Imatinib may be an alternative. Methods: We retrospectively analyzed all CML - CP patients requiring dose hike at our centre from 2003-2009. Mutational analysis could not be performed. The trigger for dose hike to 600mg was suboptimal response or failure as per ELN 2010 guidelines. Event free survival (EFS), transformation free survival (TFS), and overall survival (OS) were analysed. EFS was defined as time from dose escalation to transformation to BC/AP or lost to follow up or death due to any cause. OS was defined as time from dose escalation to death. TFS was defined as progression to BC/AP from dose hike. Cytogenetic response was evaluated. Statistical analysis is done using Graphpad Prism. Results: There were 76 patients with a median age of 35 years (range, 13-68) and M: F ratio of 1.8:1.Trigger for dose hike was failure in 56 patients (73%) and suboptimal response in 27%. In failure group, after dose hike, complete cytogenetic response (CCR) was achieved in 41/56 (73%), partial (PCR) 4/56(7%), minor 5/56(9%), nil cytogenetic response in 6/56(10%). In suboptimal group CCR were seen in15/20(75%). Five year EFS, TFS and OS in both the groups together were 64.3%, 91.9%, and 94.7% respectively. The five year EFS, TFS and OS in failure group were 63.4%, 93.3% and 95.1% respectively. Five year EFS, TFS and OS in suboptimal group were 62.8%, 88.5% and 94.4% respectively. There was no significant difference between suboptimal and failure groups (p values for EFS-0.8414, TFS- 0.446,OS-0.7368). 75% patients experienced manageble toxicities. Conclusions: Dose hike to 600mg is still one of the viable options in CML CP patients with suboptimal response or failure in resource limited countries with an acceptable toxicity profile.
Abstract 021: Extended Proliferation Capacity of Cardiomyocytes is Insufficient to Complete Cardiac Regeneration in Mice with a Mutation of Cardiac Myosin Binding Protein C
Authors: Gregory M Fomovsky, Joseph B Gannon, Kimberly K Schaefer, Jianming Jiang, Hiroko Wakimoto, Hesham A Sadek, Jonathan G Seidman, Christine E Seidman, Richard T Lee
Journal: Circulation Research (2013)

Introduction: Adult mammalian cardiac regeneration rate is inadequate to compensate for the loss of myocardium following injury. One-day old (P1) mice fully regenerate myocardium after ventricular apex resection by division of cardiomyocytes (CMs). This regeneration ability is lost by P7. While CMs of a P1 mouse are mostly mononuclear, CMs withdraw from cell cycle and become mostly binuclear in the first post-natal week. CMs in mice with a mutation of a sarcomeric cardiac myosin-binding protein C (MyBP-C t/t ) have an extended proliferating capacity. In MyBP-C t/t mice, there are more CMs per ventricle and a significant number of CMs remain mononuclear compared to WT. Hypothesis: The loss of regeneration potential during the first post-natal week in WT mice is a result of rigid sarcomeric structure of maturing CMs, and a mutation of sarcomeric MyBP-C would extend the regenerative capacity of CMs beyond P1. Methods: We performed apical resections on P10 MyBP-C t/t and WT mice with sham-operated controls (n=61 of 118 survived surgery). For the resection surgery, neonates were anesthetized on ice, causing transient sedation, apnea and asystole. We assessed cardiac regeneration over two weeks by measuring cell cycle activity: Ki67 and pH3 expressions, and BrdU incorporation. Results: All cell cycle activity markers in MyBP-C t/t CMs were significantly higher than in WT. At 7 days-post resection (dpr) the number of BrdU-positive CM nuclei per 40X field was (mean±SD): 1.8±1.2 in MyBP-C t/t resections (n=4), 0.7±0.3 in MyBP-C t/t shams (n=5), 0.3±0.3 in WT resections (n=3), and 0.2±0.2 in WT shams (n=3). However, an increase in cell cycle activity in MyBP-C t/t resected hearts was not significant compared to MyBP-C t/t sham controls. Interestingly, using VonKossa silver staining, we observed pronounced dystrophic calcifications due to CM necrosis in MyBP-C t/t resected hearts only. The calcifications filled the resected area and were positive for cardiac troponin and proliferation markers as early as 3dpr, suggesting that proliferating CMs underwent necrosis and aborted regeneration. Conclusion: An extended proliferation capacity of MyBP-C t/t CMs beyond the first post-natal week is insufficient for complete cardiac regeneration following apical resection.
Differential glycosylation and splicing generates novel CD164 isoforms: A mechanism to control the functions of CD164 as an adhesion molecule and a potent negative regulator of hematopoiesis.
Authors: S M Watt, J Chan, J Lee-Prudhoe, R Doyonnas, M Tavian, I Rappold, Bruno Peault, A C W Zannettino, P J Simmons, H J Buehring
Journal: Blood (1998)
Cardiopulmonary Resuscitation in Adults and Children With Mechanical Circulatory Support: A Scientific Statement From the American Heart Association
Authors: Mary Ann Peberdy, Jason A. Gluck, Joseph P. Ornato, Christian A. Bermudez, Russell E. Griffin, Vigneshwar Kasirajan, Richard E. Kerber, Eldrin F. Lewis, Mark S. Link, Corinne Miller, Jeffrey J. Teuteberg, Ravi Thiagarajan, Robert M. Weiss, Brian O’Neil
Journal: Circulation (2017)

Cardiac arrest in patients on mechanical support is a new phenomenon brought about by the increased use of this therapy in patients with end-stage heart failure. This American Heart Association scientific statement highlights the recognition and treatment of cardiovascular collapse or cardiopulmonary arrest in an adult or pediatric patient who has a ventricular assist device or total artificial heart. Specific, expert consensus recommendations are provided for the role of external chest compressions in such patients.
A retrospective review of baseline balance scores in college athletes
Authors: Elizabeth Delasobera, Mallory Shasteen, Keon Parsa, Justin Wierenga
Journal: British Journal of Sports Medicine (2017)

Objective This study examines differences in baseline balance scores in order to establish normative data in college athletes, and also determine the potential effect of gender, sport, and concussion history on baseline performance. Design Retrospective review Setting Pre-participation evaluations of athletes at an American university. Participants 961 varsity athletes, ages 17 to 21, both male and female from 2011 to 2015. Independent Variables Gender, sport, and history of prior concussions. Dependent Variable Baseline Balance Error Scoring System (BESS) scores. Main Results The baseline BESS score for all athletes averaged 16.13 (range 2 to 40). Baseline BESS scores were significantly different in males (15.78) compared to females (16.84), with a difference of 1.056 (95% CI 0.233 to 1.890, P=0.013). Baseline scores averaged 17.40 in athletes with history of concussion compared to 16.45 in athletes with no prior concussion (CI 0.866 to 2.780, P=0.301). When comparing scores by sport, there were no significant differences in baseline scores between females who played field hockey, softball, volleyball, basketball, lacrosse, or soccer. There were no significant differences in baseline scores between males who played baseball, football, basketball, lacrosse, or soccer. Conclusions When balance testing is used to assess an athlete after concussion injury, normative balance scores may be used in the absence of baseline scores. History of concussion and type of sport do not play a significant role in baseline balance assessment, however gender may alter the normative baseline data slightly Competing interests None.
Comparing performance on baseline computerized neurocognitive and balance
Authors: Michelle L Weber, Julianne D Schmidt, Nicole L Hoffman
Journal: British Journal of Sports Medicine (2017)

Objective To compare head impact severity between high and low performers on baseline neurocognitive and balance assessments in collegiate American football athletes. Design Prospective cohort. Setting On-field/Concussion Research Laboratory. Participants Thirty collegiate American football players (height: 187.0 cm, 95% CI: 184.6, 189.4; mass: 105.4 kg, 95% CI: 99.3, 111.6; age: 21.0 years, 95% CI: 20.5, 21.5). Interventions Participants completed a baseline neurocognitive assessment (Immediate Post-Concussion Assessment and Cognitive Test) and balance exam (Sensory Organization Test). Participants wore accelerometers (Head Impact Telemetry System) to capture measures of severity for 13,537 head impacts. Outcome measures Groups were divided into higher and lower performance groups using a median split for independent variables including composite neurocognitive (verbal memory, visual memory, processing speed, reaction time and impulse control) and balance performance. Random intercepts general linear models were used to compare linear acceleration (g), rotational acceleration (rad/s2), and Head Impact Technology severity profile (HITsp-unitless) between higher and lower performing groups (α=0.05). Position group was included in all models. Main results Athletes with slower reaction time had a trend towards higher linear acceleration (higher 26.4, 95% CI: 24.6, 28.3; lower 24.6, 95% CI: 23.7, 25.7; p =0.080) and significantly higher rotational acceleration (higher 1020.2, 95% CI: 990.1, 1051.2; lower 946.6, 95% CI: 910.0, 984.8; p =0.003). Conclusions Athletes with slower reaction time may be slower to prepare for collisions, resulting in higher magnitude head impacts. Clinicians should recognize athletes with slower reaction time on baseline neurocognitive assessments and understand the on-field implications. Research is needed to further identify a reaction time threshold between high and low performers, and risk of sustaining higher magnitude head impacts. Competing interests None.
HGG-15. MAPK PATHWAY ACTIVATION IN K27M MUTATED GLIOMAS – ASSOCIATION WITH CLINICAL PARAMETERS AND SURVIVAL
Authors: Julia E. Neumann, Markus Glatzel, Armin Giese, Jochen Herms, Ulrich Schüller
Journal: Neuro-Oncology (2017)

K27M midline gliomas are defined by point mutations within the chromatin modifiers H3 and are represented as a new separate entity in the new version of the WHO classification for tumors of the central nervous system. These tumors arise in midline structures of the brain, the brain stem and the spinal cord. They occur in children and young adults and are usually associated with a bad clinical outcome. We and others previously reported Mitogen-activated protein kinase (MAPK) pathway activation via BRAF or FGFR1 hotspot mutations in single cases of K27M gliomas. In contrast to K27M mutations, MAPK activation is strongly associated with pediatric low-grade astrocytomas, that show a favorable survival. In the context of K27M glioma, the clinical significance of co-occuring BRAF or FGFR1 mutations remains unclear. We screened a cohort of patients with K27M mutated gliomas for BRAF or FGFR1 mutations. So far, we detected three cases with FGFR1 mutations (K656E and N546K) and two cases with BRAF V600E mutations. These cases showed a favorable survival in comparison to other K27M cases in our series and in comparison to previously reported patient cohorts of K27M glioma. Our results shed light on the frequency and clinical impact of MAPK pathway activation in K27M mutated gliomas with implications for targeted therapies and prognosis of patients.
Control of amino acid transport coordinates metabolic reprogramming in T-cell malignancy
Authors: K M Grzes, M Swamy, J L Hukelmann, E Emslie, L V Sinclair, D A Cantrell
Journal: Leukemia (2017)

This study explores the regulation and importance of System L amino acid transport in a murine model of T-cell acute lymphoblastic leukemia (T-ALL) caused by deletion of phosphatase and tensin homolog deleted on chromosome 10 (PTEN). There has been a strong focus on glucose transport in leukemias but the present data show that primary T-ALL cells have increased transport of multiple nutrients. Specifically, increased leucine transport in T-ALL fuels mammalian target of rapamycin complex 1 (mTORC1) activity which then sustains expression of hypoxia inducible factor-1α (HIF1α) and c-Myc; drivers of glucose metabolism in T cells. A key finding is that PTEN deletion and phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3) accumulation is insufficient to initiate leucine uptake, mTORC1 activity, HIF1α or c-Myc expression in T cells and hence cannot drive T-ALL metabolic reprogramming. Instead, a key regulator for leucine transport in T-ALL is identified as NOTCH. Mass spectrometry based proteomics identifies SLC7A5 as the predominant amino acid transporter in primary PTEN−/− T-ALL cells. Importantly, expression of SLC7A5 is critical for the malignant transformation induced by PTEN deletion. These data reveal the importance of regulated amino acid transport for T-cell malignancies, highlighting how a single amino acid transporter can have a key role.
Deaths from Alzheimer’s Disease — United States, 1999–2014
Authors: Christopher A. Taylor, Sujay F. Greenlund, Lisa C. McGuire, Hua Lu, Janet B. Croft
Journal: MMWR Morbidity and Mortality Weekly Report (2017)

Alzheimer's disease (Alzheimer's), an ultimately fatal form of dementia, is the sixth leading cause of death in the United States, accounting for 3.6% of all deaths in 2014 (1,2). Alzheimer's deaths can be an indicator of paid and unpaid caregiver burden because nearly everyone in the final stages of Alzheimer's needs constant care, regardless of the setting, as the result of functional and cognitive declines (2). To examine deaths with Alzheimer's as the underlying cause, state-level and county-level death certificate data from the National Vital Statistics System for the period 1999-2014 were analyzed. A total of 93,541 Alzheimer's deaths occurred in the United States in 2014 at an age-adjusted (to the 2000 standard population) rate of 25.4 deaths per 100,000 population, a 54.5% increase compared with the 1999 rate of 16.5 deaths per 100,000. Most deaths occurred in a nursing home or long-term care facility. The percentage of Alzheimer's decedents who died in a medical facility (e.g., hospital) declined from 14.7% in 1999 to 6.6% in 2014, whereas the percentage who died at home increased from 13.9% in 1999 to 24.9% in 2014. Significant increases in Alzheimer's deaths coupled with an increase in the number of persons with Alzheimer's dying at home have likely added to the burden on family members or other unpaid caregivers. Caregivers might benefit from interventions such as education, respite care, and case management that can lessen the potential burden of caregiving and can improve the care received by persons with Alzheimer's.
Recovery of ethanol-induced <i>Akkermansia muciniphila</i> depletion ameliorates alcoholic liver disease
Authors: Christoph Grander, Timon E Adolph, Verena Wieser, Patrick Lowe, Laura Wrzosek, Benedek Gyongyosi, Doyle V Ward, Felix Grabherr, Romana R Gerner, Alexandra Pfister, Barbara Enrich, Dragos Ciocan, Sophie Macheiner, Lisa Mayr, Matthias Drach, Patrizia Moser, Alexander R Moschen, Gabriel Perlemuter, Gyongyi Szabo, Anne Marie Cassard, Herbert Tilg
Journal: Gut (2017)

Objective Alcoholic liver disease (ALD) is a global health problem with limited therapeutic options. Intestinal barrier integrity and the microbiota modulate susceptibility to ALD. Akkermansia muciniphila , a Gram-negative intestinal commensal, promotes barrier function partly by enhancing mucus production. The aim of this study was to investigate microbial alterations in ALD and to define the impact of A. muciniphila administration on the course of ALD. Design The intestinal microbiota was analysed in an unbiased approach by 16S ribosomal DNA (rDNA) sequencing in a Lieber-DeCarli ALD mouse model, and faecal A. muciniphila abundance was determined in a cohort of patients with alcoholic steatohepatitis (ASH). The impact of A. muciniphila on the development of experimental acute and chronic ALD was determined in a preventive and therapeutic setting, and intestinal barrier integrity was analysed. Results Patients with ASH exhibited a decreased abundance of faecal A. muciniphila when compared with healthy controls that indirectly correlated with hepatic disease severity. Ethanol feeding of wild-type mice resulted in a prominent decline in A. muciniphila abundance. Ethanol-induced intestinal A. muciniphila depletion could be restored by oral A. muciniphila supplementation. Furthermore, A. muciniphila administration when performed in a preventive setting decreased hepatic injury, steatosis and neutrophil infiltration. A. muciniphila also protected against ethanol-induced gut leakiness, enhanced mucus thickness and tight-junction expression. In already established ALD, A. muciniphila used therapeutically ameliorated hepatic injury and neutrophil infiltration. Conclusion Ethanol exposure diminishes intestinal A. muciniphila abundance in both mice and humans and can be recovered in experimental ALD by oral supplementation. A. muciniphila promotes intestinal barrier integrity and ameliorates experimental ALD. Our data suggest that patients with ALD might benefit from A. muciniphila supplementation.
Overall survival analysis of the FOXFIRE prospective randomized studies of first-line selective internal radiotherapy (SIRT) in patients with liver metastases from colorectal cancer.
Authors: Ricky A. Sharma, Harpreet Singh Wasan, Guy A. Van Hazel, Volker Heinemann, Navesh K. Sharma, Julien Taieb, Jens Ricke, Jamie Mills, Nicholas Paul Tait, Philip Boardman, Marc Peeters, Michael P. N. Findlay, Pradeep Singh Virdee, Joanna Moschandreas, Val Gebski, Sharon Love, Alastair Gray, Peter Gibbs
Journal: Journal of Clinical Oncology (2017)

3507 Background: The FOXFIRE, SIRFLOX and FOXFIRE-Global (FF-SF-FFG) randomized studies evaluated the efficacy of combining first-line chemotherapy for metastatic colorectal cancer (mCRC) with selective internal radiotherapy (SIRT) using yttrium-90 resin microspheres in patients with liver metastases. The studies were designed for prospective, combined analysis of overall survival (OS). Methods: FF-SF-FFG randomized (1:1) chemotherapy-naïve mCRC patients (performance status 0/1) with liver metastases not suitable for curative resection/ablation. Arm A was oxaliplatin-based chemotherapy (mFOLFOX6/ OxMdG) ± investigator-chosen biologically targeted agent. Arm B was the same systemic therapy (oxaliplatin dose modification) + single treatment SIRT with cycle 1/2 of chemotherapy. Primary tumor in situ and/or limited extra-hepatic metastases were permitted. Minimum sample size was 1075 patients (HR 0.8, 80% power, two-sided 5% significance). Secondary outcomes included PFS, liver-specific PFS and response rate. Apart from safety, outcomes were analysed on intention-to-treat population using meta-analytic methods of pooled individual patient data. Results: Between 2006 and 2014, 1103 patients were randomized in 14 countries. Median age was 63 years (range 23-89); median follow-up 43.3 months. There were 844 deaths. There was no difference in OS (HR 1.04; 95% CI 0.90-1.19, p= 0.609) or PFS (HR 0.90, CI 0.79-1.02, p= 0.108) between Arms. Objective response rate ( p= 0.001) and liver-specific progression (HR 0.51, CI 0.43-0.62, p&lt; 0.001) were significantly more favorable in Arm B. Patients in Arm B had higher risk of non-liver progression as first event (HR 1.98, CI 1.53-2.58, p&lt; 0.001). Grade 3-5 adverse events were more common in Arm B (74.0%) than A (66.5%), p= 0.009. In health status questionnaires, EQ-5D utility scores were not significantly different between Arms at 6, 12 or 24 months. Conclusion: Despite higher response rates and improved liver-specific PFS, the addition of SIRT to first-line oxaliplatin-fluorouracil chemotherapy for patients with liver-only and liver-dominant mCRC did not improve OS or PFS. Clinical trial information: 83867919.
Anticoagulation and Survival in Pulmonary Arterial Hypertension
Authors: Karen M. Olsson, Marion Delcroix, H. Ardeschir Ghofrani, Henning Tiede, Doerte Huscher, Rudolf Speich, Ekkehard Grünig, Gerd Staehler, Stephan Rosenkranz, Michael Halank, Matthias Held, Tobias J. Lange, Juergen Behr, Hans Klose, Martin Claussen, Ralf Ewert, Christian F. Opitz, C. Dario Vizza, Laura Scelsi, Anton Vonk-Noordegraaf, Harald Kaemmerer, J. Simon R. Gibbs, Gerry Coghlan, Joanna Pepke-Zaba, Uwe Schulz, Matthias Gorenflo, David Pittrow, Marius M. Hoeper
Journal: Circulation (2013)

Background— For almost 30 years, anticoagulation has been recommended for patients with idiopathic pulmonary arterial hypertension (IPAH). Supporting evidence, however, is limited, and it is unclear whether this recommendation is still justified in the modern management era and whether it should be extended to patients with other forms of pulmonary arterial hypertension (PAH). Methods and Results— We analyzed data from Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA), an ongoing European pulmonary hypertension registry. Survival rates of patients with IPAH and other forms of PAH were compared by the use of anticoagulation. The sample consisted of 1283 consecutively enrolled patients with newly diagnosed PAH. Anticoagulation was used in 66% of 800 patients with IPAH and in 43% of 483 patients with other forms of PAH. In patients with IPAH, there was a significantly better 3-year survival ( P =0.006) in patients on anticoagulation compared with patients who never received anticoagulation, albeit the patients in the anticoagulation group had more severe disease at baseline. The survival difference at 3 years remained statistically significant ( P =0.017) in a matched-pair analysis of n=336 IPAH patients. The beneficial effect of anticoagulation on survival of IPAH patients was confirmed by Cox multivariable regression analysis (hazard ratio, 0.79; 95% confidence interval, 0.66–0.94). In contrast, the use of anticoagulants was not associated with a survival benefit in patients with other forms of PAH. Conclusions— The present data suggest that the use of anticoagulation is associated with a survival benefit in patients with IPAH, supporting current treatment recommendations. The evidence remains inconclusive for other forms of PAH. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01347216.