tbuckley/cabot-search huggingface dataset:
Evaluation of the novel Bruton′s tyrosine kinase (BTK) inhibitor GDC-0853 in chronic lymphocytic leukemia (CLL) with wild type or C481S mutated BTK.
Authors: Sean David Reiff, Daphne Guinn, Rose Mantel, Lisa Smith, Carolyn Cheney, Amy J. Johnson, John C. Byrd, Jennifer Ann Woyach
Journal: Journal of Clinical Oncology (2016)

7530 Background: BTK is an attractive target in CLL. Ibrutinib (IB), a first in class irreversible BTK inhibitor (BTKi), abrogates important survival signals in CLL by proximally blocking multiple pathways. Despite IB’s ability to produce remissions in patients, resistance can occur via mutation at its BTK binding site. IB also inhibits ITK, limiting antibody dependent cytotoxicity (ADCC) and the efficacy of antibody therapy. Here we demonstrate the potential utility of a novel BTKi, GDC-0853, which does not rely upon the C481 site of BTK and lacks ITK inhibition. Methods: In vitro studies used freshly purified B cells from primary CLL samples treated with BTKi at a concentration of 1µM. Signaling was investigated by immunoblot while viability, CD86 expression, and migration were measured by flow cytometry. Natural killer (NK) cell ADCC was measured by chromium release. Results: GDC-0853 reduced the activation of BTK and its downstream targets PLCg2, AKT, and ERK following αIgM stimulation (79%, 44%, 60%, and 86% respectively; p ≤ 0.05). GDC-0853 modestly decreased CLL viability and abrogated the protective effect of stromal co-culture (10% viability decrease p = 0.012). Increases in CD86 expression induced by CpG were decreased 40% following treatment with GDC-0853 (p = 0.001). We also found that GDC-0853 diminished CXCL12 induced chemotaxis by 51% (p = 0.028). Unlike IB, GDC-0853 inhibited signaling of both WT and C481S mutated BTK in transfected HEK293T cell lines. Also unlike IB, GDC-0853 preserved NK cell ADCC with clinical αCD20 antibodies. While IB significantly decreased ADCC with rituximab, ofatumumab, and obinutuzumab, there was no change in NK cell mediated ADCC following treatment with GDC-0853. Conclusions: GDC-0853 represents an exciting development in BTK targeted therapy. Agents like this which bind outside BTK C481 may circumvent resistance to IB. Additionally, GDC-0853 may also enable effective combinations with antibody therapies, potentially prolonging remissions. Given these compelling data we believe further clinical exploration of GDC-0853 as monotherapy and in combination with αCD20 antibody therapies is justified.
Abstract 63: Missense Mutation Lys18Asn in Dystrophin that Triggers X-Linked Cardiomyopathy Affects Protein Structure, Decreases Protein Stability and Increases Protein Unfolding
Authors: Krishna Mallela, Surinder Singh, Geoffrey Armstrong
Journal: Circulation Research (2012)

A genetic mutation in dystrophin that replaces lysine at amino acid position 18 by an asparagine (K18N) results in X-linked cardiomyopathy (XCM), however, the underlying molecular mechanisms are not known. Such knowledge might help in developing effective therapies to treat XCM. The first step in understanding disease-triggering mechanisms is to probe how mutation affects protein structure and function. The K18N mutation occurs in the N-terminal actin binding domain (N-ABD) of dystrophin. Here, we examined the effect of K18N on the structure, stability, and function of N-ABD. Fig. 1A shows the 15 N- 1 H HSQC NMR spectrum before and after the mutation. Each crosspeak in the spectrum represents the structure around an amino acid. Mutation affects the position of nearly all the crosspeaks. These changes are not just located at the mutation site, but were observed in regions far away from the mutation site and also in the three actin binding regions with which N-ABD interacts with actin. In addition, the mutation makes the protein more dynamic. These structural changes result in decreased actin binding function of N-ABD. Also, the K18N mutation decreases the stability by ΔΔG = 5.3 kcal/mol (Fig. 1B) and increases the rate of unfolding by 3.2 times (Fig. 1C), which exponentially increase the relative population of unfolded state that is more prone to proteolysis and hence will result in decreased levels of the functional protein. These results indicate that the physical mechanism by which the K18N mutation triggers the disease might be by affecting protein structure leading to decreased actin binding and by decreasing the net protein levels leading to decreased net function.
Sleep deprivation predisposes allergic mice to neutrophilic lung inflammation
Authors: Jethe O.F. Nunes, Juliana de Souza Apostolico, David A.G. Andrade, Francieli S. Ruiz, Edgar R. Fernandes, Monica L. Andersen, Alexandre C. Keller, Daniela S. Rosa
Journal: Journal of Allergy and Clinical Immunology (2017)
Mutation analysis of mucosal and cutaneous melanomas during progression.
Authors: Giuseppe Palmieri, Maria Colombino, Milena Casula, Amelia Lissia, Gerardo Botti, Giosuè Scognamiglio, Corrado Caraco, Paolo Antonio Ascierto, Filippo Fraggetta, Panagiotis Paliogiannis, Antonella Manca, MariaCristina Sini, Valentina Doneddu, Antonio Cossu
Journal: Journal of Clinical Oncology (2017)

e21047 Background: The prevalence of mutations in driver genes during progression in cutaneous and mucosal melanomas remains inconclusive. We investigated the prevalence and distribution of mutations in main candidate genes involved in melanomagenesis among different melanoma tissues using a next-generation sequencing (NGS) approach. Methods: Forty-eight tumor samples from 36 patients with mucosal melanoma (MM) and fifty-two tumor samples from 34 patients with cutaneous melanoma (CM) were collected, after obtaining patients’ written informed consent for tissue sampling. Genomic DNA was isolated from macrodissected tumor tissues containing at least 80% neoplastic cells and analyzed for mutations in 25 most common melanoma-associated oncogenes and tumor suppressor genes, using the IMI Diagnostic Melanoma Panel on the Ion Torrent platform (Life Technologies, USA). Results: A total of 100 tumor tissues from 70 melanoma patients were analyzed. BRAF mutations were detected in 21/34 (62%) CM patients and 13/36 (36%) mm patients. The second most prevalent mutations were found in K-/N-RAS (6/34; 18%) and cKIT (6/36; 17%) genes among CM and mm patients, respectively. No concomitant mutations of BRAF, RAS, and cKIT genes were detected. Among others, mutations were more frequently found in CCND1 (20%), ARID2 (16%), and NF1(12%) genes, considering the entire series of patients. Vast majority of patients who had paired samples of primary and secondary melanomas showed consistent mutation patterns between primary tumors and metastatic lesions. Similar frequencies of mutations in driver genes were seen across metastatic sites. Conclusions: In the era of targeted therapies, assessment of the spectrum and distribution of mutations in main molecular targets among patients with melanoma is needed. Our findings about the prevalence of mutations in driver genes in paired tumor lesions from patients with cutaneous and mucosal melanoma may be useful in the management of such diseases. The Italian Melanoma Intergroup (IMI) includes the following additional members who participated as investigators in this study: Mario Mandalà, Paola Queirolo, Ignazio Stanganelli, Vanna Chiarion Sileni, Pietro Quaglino, Anna Maria Di Giacomo.
Refinement of the Affordable Care Act: A Progressive Perspective
Authors: Olveen Carrasquillo, Michael Mueller
Journal: Annual Review of Medicine (2017)

The Affordable Care Act (ACA) was the most significant expansion of health coverage since Medicare and Medicaid were enacted. The law resulted in approximately 13–20 million uninsured persons gaining coverage. Despite these gains, the ACA has numerous shortcomings. For progressives, the ACA was a unique opportunity to provide access to high-quality, comprehensive, equitable health coverage to all persons living in the United States. Using this perspective as our framework, in this review we highlight some of the limitations of the ACA and potential areas for refinement. We conclude that the ACA fell far short of the goal of achieving universal coverage and that the coverage made available through the ACA was not equitable. In addition, the ACA expanded coverage by building onto a highly fragmented, inefficient, and costly health system. Thus, it did little to control health costs. A more fiscally prudent approach would have been built upon more successful existing programs, such as a Medicare for All.
Tailored endpoints: A proposal for design of future clinical trials in metastatic breast cancer (MBC).
Authors: Caterina Fontanella, Marta Bonotto, Pamela Driol, Francesca Valent, Lorenzo Gerratana, Stefania Russo, Claudia Andreetta, Alessandro Minisini, Mauro Mansutti, Roberta Sottile, Gianpiero Fasola, Fabio Puglisi
Journal: Journal of Clinical Oncology (2012)

e13058 Background: Widespread access to active agents against MBC has produced significant improvements in survival, even though few phase III trials are powered to detect overall survival (OS) effects. However, regulatory agencies hold OS as gold standard for approval of new drugs. OS can be portioned into the sum of progression-free survival (PFS) and survival post-progression (SPP). Recent data suggest that OS is a reasonable primary endpoint only when median SPP is short. On the other hand, patients enrolled in first-line trials could have a long life-expectancy. Aim of this study was to evaluate PFS, OS and SPP in a consecutive series of patients with MBC in order to obtain information as a basis for design of future clinical trials. Methods: Four hundred patients with MBC diagnosed from January 2004 to February 2011 at University Hospital of Udine, Italy, were included in the study. We examined the role of potential of disease and patients’ characteristics in influencing the different measures of outcome. Results: Median OS was 33.71 months (mo), in line with the best literature. Median PFS at first-line (PFS1) was 9.33 mo, with linear decrease at second (5.06), third (3.58), and fourth (3.19) line, respectively. Median SPP after first-line (SPP1) was 18.69 mo. Interestingly, differences in outcome were noticed according to immunophenotype. The best prognosis was observed in luminal A disease (OS= 46.72 mo, PFS1= 15.61 mo, SPP1= 25.43 mo). In luminal B disease, median OS was 27.66 mo, PFS1 8.94 mo, and SPP1 13.21 mo, respectively. In patients with HER2-positive disease, mainly treated with anti-HER2 therapy, outcome approached that of luminal A disease (OS= 41.10 mo, PFS= 9.89 mo, SPP1 18.69 mo). Patients with triple negative disease (TNBC) experienced the worst prognosis (OS= 8.54 mo, PFS1= 4.04 mo, SPP1= 2.83 mo). Conclusions: The study demonstrated different results in the measures of outcome according to the line of treatment and specific disease characteristics. As a consequence, endpoints of clinical trials should be tailored taking into consideration prognostic/predictive factors as well as the line of treatment.
Multicenter Analysis of Clinical Characteristics and Long-Term Outcomes of Transjugular Intrahepatic Portosystemic Shunt Procedure for MPN-Associated Portal Hypertension
Authors: Christopher R Reilly, Daria V. Babushok, Karlyn Martin, Jerry L. Spivak, Michael Streiff, Brady Stein, Alison R Moliterno, Elizabeth O. Hexner
Journal: Blood (2016)
Predictive validity of NeoAdjuvant Rectal (NAR) Score and pathologic complete response (ypCR) for overall survival (OS) as surrogate endpoints in rectal cancer clinical trial.
Authors: Greg Yothers, Thomas J. George, Carmen Joseph Allegra, Jean-Francois Bosset, Krzysztof Bujko, Laurence Collette, Michael J. O'Connell, Jerome Doyen, Carlos Fernandez-Martos, Jean Francois Seitz, Norman Wolmark
Journal: Journal of Clinical Oncology (2016)

3533 Background: ypCR (absence of primary tumor and nodal metastases) and more recently NAR score (weighted combination of ypN and downstaging of T) have been used as primary endpoints in neoadjuvant clinical trials for rectal cancer. Unlike OS, both surrogate endpoints are available shortly after surgery. While both have demonstrated patient-level association with OS, neither has been tested for trial-level association. Methods: Mean difference in NAR score and log odds ratios (ORs) for ypCR were tested for linear association with log hazard ratios (HRs) for OS. Treatment (trt) comparisons were weighted by the inverse of the SE of the log HR for OS, giving precise estimates more weight. Steiger's Z test was used to compare predictive validity. NAR = ((5 ypN – 3 (cT – ypT) + 12)^2) / 9.61. Results: Data from 6 randomized trt comparisons from 5 international clinical trials of contemporary neoadjuvant therapy for rectal cancer were analyzed in this meta-analysis including 4705 patients and 931 deaths overall (Table). For all 6 comparisons, point estimates for both NAR and ypCR were concordant with OS (same direction of trt effect). NAR (R-squared = 0.1292) had numerically greater predictive validity for OS than did ypCR (R-squared = 0.0169), (p = 0.38). Conclusions: NAR has nominally greater predictive validity for OS than does ypCR. Efforts to identify or improve short term surrogate endpoints for OS should continue. Support: CA-180868, -189867, -180822; Sanofi; Roche. Trial Control Experimental Patients (Deaths) OS HR (95%CI) NAR Mean Dif (95%CI) ypCR OR (95%CI) NSABP R-04 5-FU Capecitabine 1481 (248) 0.83 (0.65, 1.07) -1.13 (-2.59, 0.34) 1.20 (0.93, 1.54) NSABP R-04 No Oxaliplatin Oxaliplatin 1215 (193) 0.92 (0.69, 1.22) -0.33 (-1.94, 1.29) 1.15 (0.87, 1.53) FFCD 9203 RT ChemoRT 687 (125) 0.98 (0.76, 1.28) -1.57 (-3.64, 0.49) 3.77 (1.84, 7.73) GCR3 ChemoRT Chemo à ChemoRT 95 (24) 1.46 (0.64, 3.33) 4.16 (-0.79, 9.12) 0.94 (0.31, 2.86) Polish Std RT Short Course RT 286 (85) 1.02 (0.67, 1.57) 7.39 (3.86, 10.92) 0.04 (0.01, 0.31) EORTC 22921 RT ChemoRT 941 (256) 0.98 (0.82, 1.18) -4.80 (-6.53, -3.07) 3.00 (1.79, 5.03) RT = Radiotherapy; Chemo = Chemotherapy; Std = Standard
Influence of Cytarabine Metabolic Pathway Polymorphisms in Acute Myeloid Leukemia Induction Treatment
Authors: Juan Eduardo Megías-Vericat, Montesinos Pau, María José Herrero, Federico Moscardó, Virginia Bosó, David Martínez-Cuadrón, Luis Rojas, Rebeca Rodríguez-Veiga, David Hervás, Blanca Boluda, Luis Sendra, Jaime Sanz, Antonio Miguel, Jose Cervera, José Luis Poveda, Salvador F Aliño, Miguel Ángel Sanz
Journal: Blood (2016)
Abstract 89: The Ventriculo-Ventricular Coupling Index: A Novel Approach to Assessing Biventricular Function
Authors: Navin K Kapur, Mark J Aronovitz, Robert Blanton, Emily Mackey, Vikram Paruchuri, Xiaoying Qiao, Gerard H Daly, David A Kass, Richard H Karas
Journal: Circulation Research (2012)

Bi-ventricular (Bi-V) function in primary pulmonary hypertension (PPH) or PH secondary to left heart failure (SPH) remains difficult to characterize. As a measure of ventricular efficiency, ventriculo-arterial coupling (VAC) is calculated as the ratio of effective arterial elastance (Ea) to end-systolic elastance (Ees). No measure currently assesses ventriculo-ventricular coupling (VVC). Therefore, we developed a novel catheter-based approach to quantify Bi-V function using pressure-volume loop (PVL) analysis and hypothesized that Bi-V VAC ratios, defined as the VVC index (VVCI), may discriminate PPH and SPH. Methods: Adult male mice (n=6/group) underwent constriction of the pulmonary artery (PAC) or thoracic aorta (TAC) to model PPH and SPH respectively. Sham-operated animals underwent a left thoracotomy. Closed chest simultaneous Bi-V catheterization was performed after 7 days in PPH and 10 weeks in SPH. Conductance catheters were used for right and left ventricular PVL analysis via the right external jugular vein and right common carotid artery under steady-state conditions and with variable preload. Results: Steady-state Bi-V PVL and changes in VAC ratios and the VVCI are shown below. In sham mice VAC ratios and the VVCI reflect optimal ventricular efficiency. In PPH, the VVCI is significantly increased, while in SPH, the VVCI is significantly decreased compared to controls. Conclusion: These results identify a novel method to quantify Bi-V function in mice and further show that the VVCI can distinguish PPH and SPH. These findings have important implications for examining cardiac function in preclinical and clinical studies of left- and right-sided heart failure.
A first-in-human (FIH) dose-escalation study of the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of intravenous BAL101553, a novel microtubule inhibitor, in adult patients with advanced solid tumors.
Authors: Alan Hilary Calvert, Michael Gonzalez, Sushila Ganguli, Matthew Ng, Sarah Benafif, Marta Capelan, Robert Goldstein, Krunal Shah, Claire Jarvis, Michael Flynn, Martin Forster, Stephanie Anderson, Anne Schmitt-Hoffman, Heidi Lane, Marc Engelhardt, Alison L. Hannah, Alexandar Tzankov, Felix Bachmann, L Rhoda Molife, Rebecca Kristeleit
Journal: Journal of Clinical Oncology (2013)

2566 Background: BAL101553, a pro-drug of the small molecule BAL27862, is a novel microtubule targeting agent (MTA) with cytotoxic and vascular disrupting properties. Pre-clinical data showed anti-proliferative activity in several in vitro and xenograft tumour models, including tumours refractory to conventional MTAs through diverse resistance mechanisms. Primary objectives of this FIH study were determination of the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). Secondary objectives included the evaluation of PK, PD and anti-tumour activity. Methods: An accelerated titration dose-escalation design was used. Eligible patients (pts) with advanced solid tumours, who had failed standard therapy, received BAL101553 as a 2-h intravenous infusion on days 1, 8 and 15 of a 28-day cycle. Adverse events (AEs) were assessed according to CTCAEv4. Disease response was assessed by RECIST 1.1 every 2 cycles. Results: 16 pts (7 male; median age 52 years; range 29-80) with solid tumours were treated at 4 dose levels (15, 30, 45 and 60 mg/m 2 ). DLTs were observed at 60 mg/m 2 and included rapidly reversible grade (G) 3 hypertension (HTN) and G3 reduced mobility/ dizziness. DLT criteria for HTN were subsequently modified. Frequent drug-related AEs were injection site reactions, nausea, vomiting (all G1-2), and G2-3 HTN (transient during the infusion; responding to nifedipine). One pt experienced G2 peripheral neuropathy at 60 mg/m 2 . PK analyses indicated conversion of BAL101553 to the active BAL27862, dose proportional exposure for both compounds and a half-life of BAL27862 in a range of 11 to 27 h. Preliminary tumour PD data comparing pre/post biopsies showed loss of CD34+ capillaries and focally decreased proliferation. A confirmed partial response was demonstrated in 1 pt with ampullary (pancreaticobiliary) cancer maintained on treatment for &gt;16 cycles with intra-pt dose escalation. 2 pts (laryngeal and rectal cancer) demonstrated stable disease &gt;16 weeks. Conclusions: BAL101553 is well tolerated up to 60 mg/m 2 with evidence of anti-tumour activity. Dose escalation continues to determine the MTD. Clinical trial information: NCT01397929.
PD-1, PD-L1, and B7-H3 expression in Human Immunodeficiency Virus (HIV) infected patients with aerodigestive (AD) cancers (CA).
Authors: Katherine Ann Scilla, Jonathon Heath, Olga B. Ioffe, Ashley L Cellini, Martin J. Edelman, Dan Paul Zandberg, David Riedel, Josephine Louella Feliciano
Journal: Journal of Clinical Oncology (2016)

11607 Background: Co-signaling molecules PD-L1, B7-H3, and PD-1 play a key role in CA immunology. Their expression has not been characterized for AD tumors in patients with HIV. Methods: We reviewed 30 cases of archived tissue from HIV-infected patients with head and neck (H&N) (n = 17) and lung (n = 13) CA from 2001-2011. Baseline demographics, CD4 count, HIV RNA viral load (VL) and antiretroviral therapy (ART) at diagnosis were collected. Immunostained tumor sections were analyzed for percent of tumor cells expressing PD-L1 and B7-H3 (Abcam), and percent of tumor infiltrating lymphocytes (TIL) expressing PD-1 (Abcam). Positive expression was defined as staining > 5% of tumor cells. Correlation between CD4 or VL with biomarkers was performed using Spearman’s rank correlation, Rs. Results: Of H&N CA, 9 (52.9%) were positive for PD-L1 (mean % expression 14.7, 95%CI 3.9-25.5), 16 (94.1%) were positive for B7-H3 (mean % expression 49.4, 95%CI 35.4-63.4), and 14 (82.4%) had TIL that were positive for PD-1 (mean % expression 44.7, 95%CI 29.1-60.3). In lung CA, 3 (23.1%) were positive for PD-L1 (mean % expression 20, 95%CI -0.7-40.7), 12 (92.3%) were positive for B7-H3 (mean % expression 66.2, 95%CI 48.2-84.2), and 9 (69.2%) had TIL that were positive for PD-1 (mean % expression 25.4, 95%CI 9.6-41.2). All 3 lung tumors that stained positive for PD-L1 had high levels of PD-L1 expression (80-90%). In lung CA, CD4 count positively correlated with %PD-L1 (Rs = 0.61, p = 0.05). In H&N CA, VL positively correlated with %PD-1 expression in TIL (Rs = 0.73, p = 0.003). Conclusions: AD tumors in patients with HIV express PD-L1 and B7-H3, and have TIL that express PD-1. Our data suggests that patients with AD CA and HIV have similar rates of biomarker expression compared to published rates in non-HIV patients. Our findings support inclusion of these patients in future immunotherapy trials. Patient Characteristics at Diagnosis H&N CA [n = 17] Lung CA [n = 13] Mean Age (years) 49.3 50.5 Male Sex 11 (64.7%) 8 (61.5%) Black Race 15 (88.2%) 13 (100.0%) Mean CD4 count (range) 254 (6-620) [n = 15] 307 (37-617) [n = 11] Mean HIV VL (range) 61,708 (0-468,382) [n = 14] 29,400 (0-100,000) [n = 11] On ART 9 (60.0%) [n = 15] 5 (38.5%) [n = 13]
PTU-029 Bowel cancer screening and the use of aspirin and non-steroidal anti-inflammatory drugs (nsaids) – prospective population based analysis
Authors: AS Taha, RH Diament, C McCloskey, T Craigen, A Simpson, A Carrigan, L Freeburn, WJ Angerson
Journal: Gut (2017)

Introduction  Despite being the third most common cancer, after those of the lung and breast, treatment of bowel cancer may have more than 90% success rate if it is detected early. This has prompted many health authorities to invest in bowel screening programmes.  AIMS  Given the wide use of aspirin and NSAIDs and their potential effects on gut mucosa, we aimed to compare the bowel-screening colonoscopic findings in users vs. non-users of these agents.  Method  
In our area – with a population of 370590 – subjects aged 50–74 years were invited to participate in bowel screening. They were provided with guaiac peroxidise faecal occult blood test (gFOBT) kits in order to collect 2 faecal samples from each of 3 bowel movements. The analytical cut-off for the kit was 0.6 mgHb/gm faeces. Patients with positive gFOBT were interviewed and, if agreeable, underwent colonoscopy in one of two endoscopy centres serving our region. The Mann-Whitney test, Fisher’s exact test and odds ratios (95% CIs) were used as appropriate.
  Results  Between January and August 2016, 49 176 subjects aged 50–74 years were sent gFOBT kits, of whom 26 926 completed and returned these kits (54.8% uptake); 598 had positive results (2.2% positivity rate), and these were invited to attend for colonoscopy. The results of 335 patients attending our centre are presented in Tables 1 and 2 below.  Conclusion  (1) Bowel cancer screening in our population, using gFOBT, was associated with 54.8% uptake and 2.2% positivity for faecal occult blood. (2) At colonoscopy, the use of aspirin or NSAIDs was associated with fewer patients with big polyps; the polyps were also significantly smaller in size in users of these drugs. Allowing for possible confounding factors, these results might be relevant to bowel screening programmes and to bowel cancer chemoprevention.  Disclosure of Interest  None Declared