tbuckley/cabot-search huggingface dataset:
Abstract 92: The Protective Effect of β3-Adrenergic Signaling Occurs via Differential Phosphorylation of nNOS in Cardiac Myocytes
Authors: Vabren L Watts, Fernando M Sepulveda, Oscar H Cingolani, Xiaolin Niu, Karen L Miller, Rosa Kim, Konrad Vandegaer, Lili A Barouch
Journal: Circulation Research (2012)

Objective: The aim of this study is to identify the mechanisms involved in β3-adrenoreceptor (β3-AR)-dependent cardiac protection via nNOS signaling in cardiomyocytes in the setting of hypertrophy. Background: β3-AR and its downstream signaling pathways are recognized as novel modulators of heart function. Unlike β1- and β2-ARs, β3-ARs are stimulated at high catecholamine concentrations and induce negative inotropic effects, it serves as a “brake” to protect the heart from catecholamine overstimulation. We previously showed that β3-agonism restored left ventricular function, generated nitric oxide, and suppressed reactive oxygen species in mouse myocardium after pressure overload. Interestingly, cardioprotection was lost after acute nNOS inhibition and in nNOS -/- animals. Methods: Neonatal rat ventricular cardiomyocytes (NRVMs) were isolated from 2-4 day old Sprague-Dawley pups. Cells were treated with hypertrophic agents (angiotensin II, endothelin-1, and norepinephrine), the specific β3-AR agonist (BRL-37433),and phosphometic Sindbis viruses for nNOS. Results: Forty-eight hours of ET-1 (100nM) or 72 hours of NE (100μ M) treatment increased cell size and β3-AR mRNA expression vs. untreated cells. In hypertrophied cardiomyocytes, BRL (75nM) reduced cell size and induced NOS activity, nNOS phosphorylation at stimulatory site Ser1412, dephosphorylation of deactivation site Ser847, and ROS suppression. BRL-dependent NOS activity and ROS suppression were both attenuated by the nNOS inhibitor L-VNIO. NOS activity was also attenuated by phosphomemetic mutants Ser1412A (constitutively dephosphorylated) and Ser847D (constitutively phosphorylated). In addition, G i/o and Akt inhibition suppressed BRL-induced nNOS-Ser1412 phosphorylation and NOS activity. Conclusion: Our data suggest that BRL regulates β3-specific myocardial NOS activity via alterations in nNOS phosphorylation in isolated hypertrophied myocytes and failing hearts of murine animals. This is the first study to demonstrate a role for nNOS phosphorylation as a key factor in cardiac myocyte and β3-AR signaling. These results contribute significantly to our understanding of the cardiac protection.
High-content DNA damage assay: Simultaneous measurement of H2AX phosphorylation, ATM activation, and DNA content
Authors: Elena Holden, Ed Luther, Andy Keys, Alex Smoligovets, Zbigniew Darzynkiewicz
Journal: Clinical Cancer Research (2007)

A17  The ability to reliably and quantitatively detect DNA damage is critical to cancer research. Multi-parameter cytometric measurements of the levels of γH2AX and activated ATM expression allow estimation of the extent of DNA damage caused by multiple factors such as ionizing radiation, carcinogenic agents, anti-cancer drugs and correlation of this damage with the cell cycle phase. Using laser scanning cytometry (LSC) technology we measured globally per nucleus and by enumeration of immunofluorescence (IF) foci γH2AX expression and ATM activation (ATM-Ser1981 phosphorylation; pATM).  In dual-label γH2AX/DNA and pATM/DNA content studies, we validated quantification of the number of foci representing individual double strand breaks (DSBs) per nucleus in relation to the cell cycle phase. At low levels of DSBs, both pH2AX and pATM presented as distinct foci, reporting the number of DSBs per nucleus. At higher levels, when foci were too dense for individual enumeration, the overall immunofluorescence integrated over the nucleus was successfully applied as a measure of the pH2AX activation. After establishing background (constitutive) levels of DNA damage in cell lines, we administered treatment with topoisomerase inhibitor camptothecin (CPT), which showed that cells in S-phase were all saturated with γH2AX, while individual foci could be enumerated in cells in G1 and G2. We also demonstrated that the number of foci was reduced after treatment with 2-deoxy-D-glucose, implicating metabolically generated oxidants as the cause of the DSBs. Dual-label pATM/DNA content studies showed similar results, with pATM aggregating in foci within nuclei in response to oxidative stress.  Finally, we established a high-content DNA damage assay comprising simultaneous measurement of pH2AX, pATM (expression levels and individual foci counts for both) and DNA content. This novel multi-parameter biomarker assay allows simultaneous assessment of ATM activation, H2AX phosphorylation and correlation with the cell cycle phase. It is particularly well suited for detection of low levels of DNA damage, such as occurring constitutively. Our results suggest that activated ATM foci are fewer and more diffuse than those of γH2AX. However, since ATM activation is upstream of H2AX phosphorylation in the DNA DSB repair pathway, it could serve as a useful early marker for these lesions. We will present the results of several screens for compounds that induce or inhibit DNA damage, as well as an assessment of DNA protective properties of “antioxidants” available in general health stores.
Everolimus with paclitaxel and carboplatin as first-line treatment for metastatic large-cell neuroendocrine lung carcinoma: a multicenter phase II trial
Authors: P. Christopoulos, W. Engel-Riedel, C. Grohé, C. Kropf-Sanchen, J. von Pawel, S. Gütz, J. Kollmeier, W. Eberhardt, D. Ukena, V. Baum, I. Nimmrich, C. Sieder, P.A. Schnabel, M. Serke, M. Thomas
Journal: Annals of Oncology (2017)

Large-cell neuroendocrine carcinoma of the lung (LCNEC) is a rare disease with poor prognosis and limited treatment options. Neuroendocrine tumors frequently show overactivation of the mTOR pathway. Based on the good activity of the mTOR inhibitor everolimus in different types of neuroendocrine tumors and the results of a previous phase I trial, we evaluated the efficacy and safety of everolimus in combination with carboplatin and paclitaxel as upfront treatment for patients with advanced LCNEC.In this prospective, multicenter phase II trial chemotherapy-naive patients with stage IV LCNEC received 5 mg everolimus daily combined with paclitaxel 175 mg/m2 and carboplatin AUC 5 every 3 weeks for a maximum of four cycles followed by maintenance everolimus 5 mg daily until progression. Efficacy parameters were determined based on central radiologic assessment.Forty-nine patients with a mean age of 62 ±9 years and a predominance of male (71%) smokers (98%) were enrolled in 10 German centers. The overall response rate was 45% (95% confidence interval [CI] 31%-60%), the disease control rate 74% (CI 59%-85%), the median progression-free survival 4.4 (CI 3.2-6) months and the median overall survival 9.9 (CI 6.9-11.7) months. The progression-free survival rate at 3 months (primary end point) was 76% (CI 64%-88%) according to Kaplan-Meier. Grade-3/4 toxicities occurred in 51% of patients and mainly consisted of general physical health deterioration (8%), cytopenias (24%), infections (10%) and gastrointestinal problems (8%). Typical everolimus-related adverse events, like stomatitis, rash and ocular problems occurred only in a minority of patients (<15%) and were exclusively of grade 1-2.Everolimus in combination with carboplatin and paclitaxel is an effective and well-tolerated first-line treatment for patients with metastatic LCNEC.EudraCT number 2010-022273-34, NCT01317615.
TMOD-07. NTRK3 GENE FUSIONS DRIVE TUMORIGENESIS IN NOVEL MODELS OF PEDIATRIC HIGH GRADE GLIOMA
Authors: Laura Hover, Alexander Diaz, Brent Orr, Suzanne Baker
Journal: Neuro-Oncology (2017)

A greater understanding of the unique drivers of pediatric high-grade gliomas (pHGG) is needed as the two-year survival rate is only 10–30%. We recently discovered the presence of structural variants in 47% of pHGG. Recurrent fusions were found involving neurotrophin receptors (NTRK) in 7% of all pHGG and 40% of non-brainstem HGG in infants. One chimeric gene we identified encoded the ETS transcription factor, ETV6, fused to the kinase domain of NTRK3 causing ligand-independent kinase activity. ETV6-NTRK3 has been identified in other neoplasms including congenital-infantile fibrosarcoma and AML. To examine the role of ETV6-NTRK3 in glioma formation in vivo, we developed an implantation model. Cortical astrocytes with conditional loss of p53 in neural stem cells were harvested from mice at P2, transduced with a vector expressing ETV6-NTRK3, and were implanted into the cortex of adult mice. Even with a transduction efficiency of only 1.5–2%, all mice implanted with transduced astrocytes developed HGG with a median survival of 36 days. Next, to study ETV6-NTRK3 in the development of pediatric gliomas, we generated a spontaneous tumor model in which mice expressed a conditional knock-in ETV6-NTRK3 allele and conditional loss of p53 in primitive neural stem cells. Mice expressing ETV6-NTRK3 and null p53 showed rapid development and complete penetrance of high-grade glioma with a median survival of 18 days. Evidence of HGG development was readily detectable by P5, accurately recapitulating onset of pediatric gliomagenesis. Analysis showed ETV6-NTRK3 primary astrocytes had increased proliferation compared to control astrocytes and HGGs driven by ETV6-NTRK3 showed a high proliferative index, MAPK, PI3K and PLCγ activity. In vitro and in vivo models were employed to identify oncogenic targets downstream of NTRK fusions and for preclinical testing of TRK selective inhibitors.
PK/PD relationships: Following the target of bortezomib (Velcade)
Authors: Julian Adams
Journal: Clinical Cancer Research (2008)

CN02-01   An important hallmark of the cancer cell is that it possesses multiple genetic lesions which are accumulated throughout transformation to the malignant phenotype. As a result, there are multiple proteins being produced with either loss of function, or gain of function mutations. This places an extraordinary burden on the cancer cell to “maintain” the semblance of orderly formation and turnover of proteins in the cell. These excess proteins are either “chaperoned” for useful function for the cell, via the Hsp90 complex or degraded by the universal proteolytic machinery, through the ubiquitin-proteasome pathway. VELCADE, an inhibitor of the proteasome, was recently approved by the FDA, and the European authorities, which highlights the critical role for maintaining protein balance in the cell. We will discuss the discovery and development of VELCADE. The unique observation that the transcription factor NF-kB is regulated through proteasomal degradation eventually led to the recognition of the need to treat multiple myeloma patients, where NF-kB and its gene products are critical to the survival of this, and many other, tumor types. As well, we will introduce other inhibitors in the protein homeostatic maintenance program of the cancer cell. We at Infinity Pharmaceuticals, Inc. are now pursuing inhibitors of the Hsp90 complex, which also regulates many survival functions in cancer cells, related to disrupting the cancer cell’s ability to manage the excess flux of mutant proteins.
Feasibility of exercise for adolescents with persisting symptoms following a sport-related concussion: a randomized controlled trial
Authors: Catherine Chan, Noah Silverberg, Jacqueline Purtzki, Kathy Wong, Grant Iverson, Isabelle Gagnon
Journal: British Journal of Sports Medicine (2017)

Objective To describe the feasibility and safety of a randomised controlled trial (RCT) comparing active rehabilitation (AR) to treatment as usual (TAU) in adolescents with persistent symptoms following a sport-related concussion. Design Partially blinded, pilot RCT. Setting Outpatient Rehabilitation Hospital. Participants 13 adolescents enrolled and completed the study (10 girls, 3 boys). All were between the ages of 12–18 and were symptomatic for greater than 4 weeks. Participants were excluded if they had more than 1 concussion in the last year, any active mental health disorder, or if their concussion occurred more than 1 year from enrolment. Intervention Participants were randomly allocated to TAU (occupational therapy and school recommendations) or AR. AR included aerobic exercise, positive visualisation techniques, and sport-specific exercises. AR sessions were supervised by a physiotherapist, and a blinded assessor monitored all participants weekly. Outcome measures Investigators monitored symptoms using the Post-Concussion Symptom Inventory. Secondary outcome measures included activity level, balance, mood, fatigue, and return to school. Main results 125 individuals were screened over a 1.25 year period. Of the 22% of individuals deemed eligible, 15 declined to participate. Most commonly, individuals were excluded due to being unreachable, uninterested, or having more than one concussion. No drop outs occurred. An external committee reviewed two adverse events in TAU and 1 adverse event in the AR group. All adverse events were unrelated to the intervention and study procedures. Conclusions Based on this small pilot study, exercise appeared safe in this sample of youth with persistent symptoms. Competing interests None.
Joint modeling of longitudinal health-related quality of life (HRQoL) data and survival.
Authors: Divine Ewane Ediebah, Francisca Galindo-Garre, Bernard M.J. Uitdehaag, Jolie Ringash, Jaap C. Reijneveld, Linda Dirven, Efstathios Zikos, Corneel Coens, Martin J. Van Den Bent, Andrew Bottomley, Martin J.B. Taphoorn
Journal: Journal of Clinical Oncology (2014)

2034 Background: In cancer clinical trials, several outcome measures may co-vary. Both treatment itself and treatment-related impairment of health-related quality of life (HRQoL) may affect survival. When these effects are analyzed separately, bias may arise. Therefore, our aim is to investigate the combined effect of treatment and longitudinally measured HRQoL on survival. Methods: We analyzed data from an EORTC randomized clinical trial (RCT) of 288 patients with anaplastic oligodendrogliomas who received radiotherapy (RT) alone or RT plus procarbazine, lomustine and vincristine (PCV) chemotherapy. HRQoL was assessed with the EORTC QLQ-C30 and Brain Cancer Module, at baseline, at the end of RT, and then every 3 to 6 months until progression. The appetite loss (AP) scale was pre-selected as the primary HRQoL endpoint, because this scale was previously found to be significantly different between the two treatment arms. Joint modeling was used to assess the combined effect of treatment and treatment-related AP on survival. The hazard ratios (HRs) for treatment effect were calculated using three different modeling strategies: Cox model with treatment only (model 1 [M1]), Cox model with treatment and time-dependent AP score (model 2 [M2]) and the joint model (model 3 [M3]). Results: In general, treatment with RT plus PCV chemotherapy resulted in decreased risk of death compared to RT alone. Estimated HR for treatment was 0.76 (95% CI 0.58–1.00) for M1, 0.72 (0.55–0.96) for M2 and 0.69 (0.52–0.92) for M3. This corresponds to a lower risk of death of 24% in M1, 28% in M2 and 31% in M3, for patients treated with RT plus PCV chemotherapy. Treatment-related AP resulted in increased risk of death, with estimated HR of 1.06 (1.01–1.12) for M2 and 1.13 (1.03–1.23) for M3. This translates to a 13% increased risk of death in M3 as compared to 6% increased risk of death in M2 for every 10-points increase of AP. Conclusions: Our findings suggest that part of the survival benefit of treatment with RT plus PCV chemotherapy can be masked by the negative effect that this treatment has on patients’ HRQoL. In our study, up to 7% of the theoretical treatment efficacy was lost through increased AP affecting survival. Clinical trial information: NCT00002840.
GLADIATOR: a global approach for elucidating disease modules
Authors: Yael Silberberg, Martin Kupiec, Roded Sharan
Journal: Genome Medicine (2017)

Understanding the genetic basis of disease is an important challenge in biology and medicine. The observation that disease-related proteins often interact with one another has motivated numerous network-based approaches for deciphering disease mechanisms. In particular, protein-protein interaction networks were successfully used to illuminate disease modules, i.e., interacting proteins working in concert to drive a disease. The identification of these modules can further our understanding of disease mechanisms. We devised a global method for the prediction of multiple disease modules simultaneously named GLADIATOR (GLobal Approach for DIsease AssociaTed mOdule Reconstruction). GLADIATOR relies on a gold-standard disease phenotypic similarity to obtain a pan-disease view of the underlying modules. To traverse the search space of potential disease modules, we applied a simulated annealing algorithm aimed at maximizing the correlation between module similarity and the gold-standard phenotypic similarity. Importantly, this optimization is employed over hundreds of diseases simultaneously. GLADIATOR's predicted modules highly agree with current knowledge about disease-related proteins. Furthermore, the modules exhibit high coherence with respect to functional annotations and are highly enriched with known curated pathways, outperforming previous methods. Examination of the predicted proteins shared by similar diseases demonstrates the diverse role of these proteins in mediating related processes across similar diseases. Last, we provide a detailed analysis of the suggested molecular mechanism predicted by GLADIATOR for hyperinsulinism, suggesting novel proteins involved in its pathology. GLADIATOR predicts disease modules by integrating knowledge of disease-related proteins and phenotypes across multiple diseases. The predicted modules are functionally coherent and are more in line with current biological knowledge compared to modules obtained using previous disease-centric methods. The source code for GLADIATOR can be downloaded from http://www.cs.tau.ac.il/~roded/GLADIATOR.zip .
Preliminary Results of a Phase 1b Dose Escalation and Dose Expansion Study of GS-4059 in Combination with Idelalisib in Subjects with B-Cell Malignancies
Authors: Gilles A. Salles, Franck Morschhauser, Bruce Cheson, Simon A. Rule, Christopher Fegan, Cartron Guillaume, Cara Nelson, Yingsi Yang, Siddhartha Mitra, Alexander Starodub, Martin J.S. Dyer
Journal: Blood (2016)
Clinical and economic evaluation of trastuzumab for metastatic breast cancer in Brazil: A public health system perspective.
Authors: Andre Deeke Sasse, Adriana Camargo Carvalho
Journal: Journal of Clinical Oncology (2014)

e17525 Background: Trastuzumab is a recombinant humanized monoclonal antibody that selectively targets the extra-cellular domain of the HER2 receptor, and has significantly improved outcomes for women with both early and metastatic HER2-positive breast cancer. In 2013, Brazilian National Sanitary Vigilance Agency (ANVISA) approved trastuzumab only for adjuvant treatment in patients with early breast cancer. The objective of this assessment is to critically review the efficacy of the combination of trastuzumab to first-line chemotherapy in patients with HER-positive metastatic breast cancer, and evaluate the cost-effectiveness and budgetary impact in Brazil, using a Public Health System perspective. Methods: A systematic review was conducted, with meta-analysis of all randomized clinical trials (RCTs) that evaluated chemotherapy with or without trastuzumab in patients with advanced breast cancer. Incremental cost per life-year (LY) gained with the combination treatment was evaluated using a Markov modeling approach, and real-world cost data. Costs and outcomes were discounted at 5% annually, for a life-time horizon. Budgetary impact was estimated using epidemiologic and economic data from the Brazilian Public Health System. Results: We included results reported from four RCTs, with a total of 864 patients included in the meta-analyses. Compared to chemotherapy alone, the addition of trastuzumab to chemotherapy enhanced both Overall Survival (HR 0.81, CI95% 0.66-0.99, P 0.04) and Progression-Free Survival (HR 0.51, CI95% 0.43-0.61, P <0,001). Trastuzumab combined to chemotherapy, versus chemotherapy alone, resulted in a gain of 0.44 LY, with an incremental cost of $17,500 per patient. Thus, the cost per LY gained was $39,750. The net budgetary impact was estimated to be $26,530,680 in the first year of incorporation. Conclusions: The addition of trastuzumab to chemotherapy in patients with advanced breast cancer prolongs OS and PFS. Due to its high unit price, this strategy has a cost-effectiveness ratio slightly above the threshold usually recommended for incorporation, and has a high net budgetary impact.
Novel unroofing approach for incipient suprapapillary stone perforation causing papillary invagination (“the crescent sign”)
Authors: Vincent Zimmer, Frank Lammert
Journal: Endoscopy (2017)

This is the case of an 89-year-old man undergoing emergency endoscopic retrograde cholangiography (ERC) for acute cholangitis. However, no en face view of the papilla was obtained after duodenoscope advancement but instead an edematous bulky mass surrounded by a semilunar slit was visible. [Fig. 1 a, b] depicts the level of the papilla in the short and long axes, providing crescent-like clues to the diagnosis (“the crescent sign”). “High grade” edema with “papillary invagination” was confirmed by papillotome traction after probing the slit ([Fig. 1 c]). Further palpation revealed an incipient suprapapillary stone perforation ([Fig. 1 d]).
Presenting symptoms and recovery time among youth athletes with and without a history of concussion
Authors: Kelly Russell, Cameron Krisko, Michael Ellis
Journal: British Journal of Sports Medicine (2017)

Objective Determine if youth athletes with a history of concussion had more symptoms, higher symptom score, longer recovery, or were more likely to be diagnosed with Post-Concussion Syndrome (PCS) than those with no history of concussion. Design Retrospective chart review. Setting Paediatric, multi-disciplinary concussion. Participants 306 youth (mean 14.0 years, SD 2.3; 65.5% male) with an acute sport-related concussion. Intervention (or assessment of risk factors) Self-reported concussion history. Outcome measures Recovery days were days between concussion and medical clearance by the neurosurgeon. Medical clearance occurred after tolerating full-time school, completing return-to-play protocol, and absence of vestibulo-ocular dysfunction. Initial symptoms were reported on the Post Concussion Symptom Severity score (PCSS); symptom severity was the total PCSS score. The neurosurgeon diagnosed Post-Concussion Syndrome (PCS) using ICD-10 criteria of symptoms for at least 30 days. Main results Median number of initial symptoms was 5.5 (IQR: 1–10) for youth with no concussion history and 7.0 (IQR: 2–14) with a concussion history (p=0.04). Initial median PCSS score was 9 (IQR: 1–22) for youth with no concussion history and 13 (IQR: 3–34) with a concussion history (p=0.03). Median recovery days was 22 (IQR: 15–43) for those with no concussion history compared to 23 (IQR: 16–39) with a concussion history (p=0.41). There was no significant difference in subsequently being diagnosed with PCS (no concussion history: 40.1%, ?concussion history: 41.7%, p=0.73). Conclusions Despite a significantly higher initial symptom burden among those with a concussion history, there was no increased risk of protracted recovery or subsequent diagnosis of PCS. Competing interests None.