tbuckley/cabot-search huggingface dataset:
Antibody-mediated rejection across solid organ transplants: manifestations, mechanisms, and therapies
Authors: Nicole M. Valenzuela, Elaine F. Reed
Journal: Journal of Clinical Investigation (2017)

Solid organ transplantation is a curative therapy for hundreds of thousands of patients with end-stage organ failure. However, long-term outcomes have not improved, and nearly half of transplant recipients will lose their allografts by 10 years after transplant. One of the major challenges facing clinical transplantation is antibody-mediated rejection (AMR) caused by anti-donor HLA antibodies. AMR is highly associated with graft loss, but unfortunately there are few efficacious therapies to prevent and reverse AMR. This Review describes the clinical and histological manifestations of AMR, and discusses the immunopathological mechanisms contributing to antibody-mediated allograft injury as well as current and emerging therapies.
Increased Cardiovascular Risk Associated With E-Cigarette Use
Authors: Fabian Sanchis-Gomar, Giuseppe Lippi, Carme Perez-Quilis
Journal: JAMA Cardiology (2017)

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Family history of breast cancer in non-<i>BRCA</i> male breast cancer: A case-control study.
Authors: Gregory Sampang Calip, Katherine Rebecca Exten, Garth H Rauscher, Krystal Brown, Ryan Bernhisel, John Kidd, Jennifer Saam, Johnathan Lancaster, Kent Hoskins
Journal: Journal of Clinical Oncology (2017)

e13032 Background: Approximately 85% of male breast cancer (MBC) patients test negative for a BRCA mutation, and the role of genetic predisposition is unclear. Cancer risk counseling for unaffected relatives of BRCA-negative MBC patients relies on accurate cancer risk estimates, but there is limited data on the risk of breast cancer (BC) for relatives of these men. We characterized the association between MBC and family history of BC in patients who test negative for BRCA mutations in order to facilitate cancer risk counseling and to explore the possibility of unidentified MBC susceptibility alleles. Methods: We performed a case-control study of patients who had full length sequencing and large-rearrangement analysis for germline mutations in BRCA1/2 or the mismatch repair (MMR) genes at a commercial laboratory from 2006-2012. Cases were MBC patients who tested negative for a BRCA1/2 mutation (n = 3,647); controls were male colon cancer patients who tested negative for mutations in MMR genes (n = 4,269). Information on family history of BC was ascertained from test request forms completed by the ordering healthcare provider at the time of testing. Unconditional multivariable logistic regression models estimated odds ratios (OR) and 95% confidence intervals (CI) for associations between family history of BC in first- (FDR) and second-degree relatives (SDR) and MBC with adjustment for potential confounders (age, ethnicity, year of testing). Results: Compared to controls, MBC cases had higher odds of BC in a FDR or SDR (OR = 4.7; 95% CI 4.1, 5.3). Associations were strongest for family history of BC in 1 female FDR (OR = 3.9; 95% CI: 3.3, 4.6), ≥2 female FDR (OR = 7.5; 95% CI 5.0, 11.4), BC in a FDR &lt; 45 years old (for cases diagnosed &lt; 45, OR = 6.9; 95% CI 3.9, 12.4), a male FDR or SDR with BC (OR = 17.9; 95% CI 7.6, 42.1), and both a male and female FDR or SDR with BC (OR = 15.7; 95%CI 4.4, 55.3). Conclusions: MBC patients who test negative for a BRCA mutation have significantly higher odds of reporting family members affected by breast cancer, particularly with affected FDR &lt; 45 years old, multiple affected relatives, and male relatives with BC. This data can guide risk counseling in MBC families, and suggests the existence of unidentified MBC susceptibility alleles.
Left Main Coronary Artery Compression in Patients With Pulmonary Arterial Hypertension and Angina
Authors: Nazzareno Galiè, Francesco Saia, Massimiliano Palazzini, Alessandra Manes, Vincenzo Russo, Maria Letizia Bacchi Reggiani, Gianni Dall'Ara, Enrico Monti, Fabio Dardi, Alessandra Albini, Andrea Rinaldi, Enrico Gotti, Nevio Taglieri, Cinzia Marrozzini, Luigi Lovato, Maurizio Zompatori, Antonio Marzocchi
Journal: Journal of the American College of Cardiology (2017)
Age and Gemtuzumab Ozogamicin Influence the Prognostic Impact of TET2 Expression and Splicing in Intensively Treated Patients with Acute Myeloid Leukemia
Authors: Antony Ceraulo, Aminetou Mint-Mohamed, Delphine Maucort-Boulch, Helene Lapillone, Guy Leverger, Etienne Paubelle, Xavier Thomas, Olivier Nibourel, Claude Preudhomme, Sylvie Castaigne, Hervé Dombret, Lea Herpe, Christine Ragu, Yves Bertrand, Franck Mortreux, Eric Wattel
Journal: Blood (2016)
Phosphorylation of CtIP by ATM regulates its own expression and activates both G1/S and G2/M checkpoints
Authors: Changxian Shen, Hong Guo, Padma Thimmaiah, Carol S. Newlon, Mary-Ann Bjornsti
Journal: Cancer Research (2005)

2578  CtIP was initially identified as a protein interacting with CtBP, Rb family proteins and BRCA1, all of which are involved in transcriptional regulation of gene expression. Together with CtBP, CtIP can repress BRCA1-dependent trans-activation of p21 promoter; Rb was also previously shown to regulate p21 expression. Upon ionizing radiation (IR), CtIP was phosphorylated at serine664 and serine745 by ATM. However, the consequence of this phosphorylation remains unclear. To address this question, we generated both stable and tetracycline-inducible clones expressing CtIP(S664/745A) dominant-negative mutant protein to elucidate the biological function of phosphorylation of CtIP by ATM. Cells expressing GFP-CtIP(S664/745A) were hypersensitive to IR based on colony formation assay and have partial defects on both IR-induced G1/S and G2/M checkpoints, as indicated by BrdU incorporation and mitotic index analysis. Since p21 is an important cell cycle regulator for both G1 /S and G2/M checkpoints, induction of p21 was compromised in these cells expressing GFP-CtIP(S664/745A). Therefore CtIP may regulates checkpoint through regulating p21 expression. In addition, in cells expressing GFP-CtIP(S664/745A), the endogenous CtIP protein level decreases. Northern Blot and RT-PCR indicates this regulation is at RNA level. CtIP promoter activity is repressed in cells expressing GFP-CtIP(S664/745A), and CHIP assay indicates CtIP binds to its own promoter at E2F sites. Further analysis of CtIP promoter activity in a pair of wild-type and mutant Rb cell lines (SaoS-2 and SR5) indicates this regulation is dependent on Rb. Surprisingly, knocking down CtIP did not release this repression, on the other hand, the repression is even enhanced. We hypothesize that CtIP serves as a molecular module to remove the repression by Rb and thus influence cell cycle progression and checkpoint activation.
Phase II study on radiofrequency ablation in stage 0 and I breast cancer without extensive intraductal components.
Authors: Shigeru Imoto, Shinji Nagamine, Toshikazu Ito, Hitoshi Tsuda, Mitsuhiro Tozaki, Satoshi Morita, Takayuki Ueno
Journal: Journal of Clinical Oncology (2017)

e12094 Background: We reported about a multi-center registration study on radiofrequency ablation (RFA) in early breast cancer (BC) (ASCO2012 #1119). Although various devices and ablation procedure were used, 5-year’s recurrence-free survival was 96% in 425 cases of T1BC treated with RFA alone. To validate complete pathological ablation in BC, we started a non-randomized phase II study in 2013 (UMIN000013836). Methods: Unilateral BC patients with stage 0 (TisN0M0) or I (T1N0M0 or T1N1miM0) were eligible. Tumor diameter of 2cm or less should be diagnosed by ultrasound and MR mammography. RFA was performed by Cool-tip RF ablation system (Covidien, USA). One month later, ablated tissue was collected by core needle biopsy or vacuum-assisted breast biopsy. Cell viability was determined by central review of independent pathologists using tumor specimens stained with hematoxylin–eosin and nicotinamide adenine dinucleotide (NADH) diaphorase. In case of complete ablation, breast irradiation and adjuvant therapy was planned. In case of incomplete ablation, partial mastectomy was recommended. The primary endpoint is complete ablation rate. The secondary endpoints are breast deformity after RFA, relapse-free survival and overall survival for 10 years. Two-step design consisting of 9 cases at 1st step and 20 cases at 2nd step was used for statistical evaluation. We expected complete ablation rate of 95% and 29 cases were needed to reject the null hypothesis that complete ablation rate would be less than 80% at lower threshold. Thus, 32 cases were required. Results: Thirty-six patients were enrolled between February 2013 and May 2016. The mean tumor size was 1.3 cm measured by MR mammography. Two patients were ineligible because of macrometastasis in a sentinel node. Of 34 eligible patients, one patient had viable cancer cells with NADH diaphorase staining in ablated specimens. Finally, complete ablation rate was 97%. As of January 2017, one patient, who refused adjuvant therapy and breast irradiation, had in-breast tumor recurrence adjacent to previously ablated lesion. Conclusions: Long-term follow-up should be needed, but RFA in early BC is a promising strategy instead of breast-conserving surgery. Clinical trial information: UMIN000013836.
Targeted ablation of IKK2 improves skeletal muscle strength, maintains mass, and promotes regeneration
Authors: Foteini Mourkioti, Paschalis Kratsios, Tom Luedde, Yao-Hua Song, Patrick Delafontaine, Raffaella Adami, Valeria Parente, Roberto Bottinelli, Manolis Pasparakis, Nadia Rosenthal
Journal: Journal of Clinical Investigation (2007)
Characteristics of advanced non-small cell lung cancer (aNSCLC) patients (pts) receiving molecular diagnostic (MD) testing in U.S. routine clinical practice.
Authors: Lisa I Wang, Ashwini Shewade, Peter Lambert, Brandon Arnieri, William Capra, Mohsen Khorshid, Tariq I Mughal, Laurie M. Gay, Damian R. Page, Stefan Foser
Journal: Journal of Clinical Oncology (2017)

e20627 Background: Hybrid capture (HC)-based next generation sequencing (NGS) combined with extensive molecular interpretation, such as Foundation Medicine (FMI) testing, is increasingly important for a comprehensive molecular diagnosis in the routine clinical management of lung cancer (LC) pts. FMI and other NGS platforms (including HC alone) support optimal treatment (trt) decisions by assessing multiple genetic alterations that drive LC progression. Our aim was to characterize aNSCLC pts receiving FMI or other types of MD tests using a real world oncology electronic health record (EHR) database. Methods: Flatiron aggregates pt-level EHR from a large network of cancer clinics in the US. Inclusion criteria were aNSCLC diagnosis and ≥2 clinic visits within the Flatiron network on or after January 1, 2011. Presence of MD testing was based on 5 LC biomarkers ( EGFR, ALK, KRAS, ROS1, PD-L1). Demographic and tumor characteristics at the time of aNSCLC diagnosis and trts received were summarized across 3 mutually exclusive testing groups (grps): FMI, other NGS and non-NGS. Results: As of Sept 30, 2016, the aNSCLC cohort included 30,489 pts across 4 groups: FMI (1,019 pts); other NGS (1,327 pts); non-NGS (15,205); no tests (12,938). As expected, the number of pts with FMI or NGS testing has increased in recent years. Pts in the FMI grp tended to be younger (66 vs. 68-69 years), non-smokers (25% vs. 17-19%) and have squamous cell histology (13% vs. 8-10%) compared to other MD test grps. 30% of FMI pts received testing prior to initiating first trt, compared with 38% of other NGS and 53% of non-NGS pts. For 565 pts (of 1,019) with available data on first trt after FMI testing, 24% (136 pts) initiated a NCCN recommended targeted trt for LC. In the FMI grp, 528 pts (52%) received at least one other MD test: EGFR (89%), ALK (83%), ROS1 (39%), KRAS (31%), PD-L1 (18%) and test types were 67% FISH, 55% PCR, 17% other NGS and 15% IHC. Conclusions: Differences in age, smoking and histology exist between pts receiving FMI vs. other MD tests. This analysis of a large real world pt cohort tested with FMI further supports the value of broad genomic profiling to identify rare driver mutations and ensure optimal trt.
MicroRNA-133 Modulates the β <sub>1</sub> -Adrenergic Receptor Transduction Cascade
Authors: Alessandra Castaldi, Tania Zaglia, Vittoria Di Mauro, Pierluigi Carullo, Giacomo Viggiani, Giulia Borile, Barbara Di Stefano, Gabriele Giacomo Schiattarella, Maria Giovanna Gualazzi, Leonardo Elia, Giuliano Giuseppe Stirparo, Maria Luisa Colorito, Gianluigi Pironti, Paolo Kunderfranco, Giovanni Esposito, Marie-Louise Bang, Marco Mongillo, Gianluigi Condorelli, Daniele Catalucci
Journal: Circulation Research (2014)

Rationale : The sympathetic nervous system plays a fundamental role in the regulation of myocardial function. During chronic pressure overload, overactivation of the sympathetic nervous system induces the release of catecholamines, which activate β-adrenergic receptors in cardiomyocytes and lead to increased heart rate and cardiac contractility. However, chronic stimulation of β-adrenergic receptors leads to impaired cardiac function, and β-blockers are widely used as therapeutic agents for the treatment of cardiac disease. MicroRNA-133 (miR-133) is highly expressed in the myocardium and is involved in controlling cardiac function through regulation of messenger RNA translation/stability. Objective : To determine whether miR-133 affects β-adrenergic receptor signaling during progression to heart failure. Methods and Results : Based on bioinformatic analysis, β 1 -adrenergic receptor (β 1 AR) and other components of the β 1 AR signal transduction cascade, including adenylate cyclase VI and the catalytic subunit of the cAMP-dependent protein kinase A, were predicted as direct targets of miR-133 and subsequently validated by experimental studies. Consistently, cAMP accumulation and activation of downstream targets were repressed by miR-133 overexpression in both neonatal and adult cardiomyocytes following selective β 1 AR stimulation. Furthermore, gain-of-function and loss-of-function studies of miR-133 revealed its role in counteracting the deleterious apoptotic effects caused by chronic β 1 AR stimulation. This was confirmed in vivo using a novel cardiac-specific TetON-miR-133 inducible transgenic mouse model. When subjected to transaortic constriction, TetON-miR-133 inducible transgenic mice maintained cardiac performance and showed attenuated apoptosis and reduced fibrosis compared with control mice. Conclusions : miR-133 controls multiple components of the β 1 AR transduction cascade and is cardioprotective during heart failure.
Estimating the effects of patient-reported outcome (PRO) diarrhea and pain measures on PRO fatigue: Data analysis from a phase II study of abemaciclib monotherapy, a CDK4 and CDK6 inhibitor, in patients with HR+/HER2- breast cancer after chemotherapy for metastatic disease—MONARCH 1.
Authors: Mark Boye, Katherine Houghton, Donald E Stull, Claire Ainsworth, Gregory L Price
Journal: Journal of Clinical Oncology (2017)

1060 Background: Investigators reporting treatment-emergent adverse events (TEAEs) in the 3 rd line or greater abemaciclib MONARCH1 Phase 2 study observed Grade 1-3 diarrhea, fatigue, and abdominal pain in 90, 65, and 39% of the patients (n = 132). Unknown is the extent that diarrhea and overall pain add to fatigue in this setting. Using patient-reported outcome (PRO) measures, we conducted cross-sectional and longitudinal multivariate analyses to estimate these effects. Methods: Data came from a single-arm, open-label study of previously-treated patients with mBC. Throughout the study, the Brief Pain Inventory and the EORTC QLQ-C30 v3 were co-administered. All constructs and items from these two questionnaires –except EORTC Items 25 and 28 (memory and financial difficulties) - were used to estimate the Structural Equation Model (SEM) and the direct and indirect effects of pain and diarrhea on fatigue. Extended pattern mixture modeling (ePMM) – a latent variable modeling method that allows the explicit analysis of missing data and identifies subgroups with differential changes over time – was used to explore these relationships from screening through cycle 8. Results: SEM results showed that at cycle 2 of treatment, pain was a significant predictor of fatigue (b = 0.68; P &lt; 0.001; CI 0.48 – 0.90); diarrhea was not a significant predictor of fatigue (b = 0.06; P = 0.12; CI -0.04 – 0.17). ePMM results across eight 30-day cycles found three fatigue subgroups: no change, improvement, worsening then improvement. Belonging to a similar pain subgroup predicted belonging to the corresponding fatigue subgroup (ref class was no change; improving b = 5.03, P = 0.004; worsening b = 22.01, P &lt; 0.001); the same was not true for diarrhea and fatigue (ref class was no change; improving b = 0.213, P = 0.75; worsening b = 0.04, P = 0.97). Conclusions: These results suggest that for patients undergoing 3 rd line or greater mBC treatment, pain is a significant predictor of fatigue early and over the course of the trial. However, diarrhea is not a significant predictor of fatigue. Clinical trial information: NCT02102490.
Identification of serum biomarkers for lung cancer using multiplexed immunoassays
Authors: Sung Baek, Elzbieta Izbicka, Robert Streeper, David Campos, Armando Diaz
Journal: Clinical Cancer Research (2007)

A76   Background: Symptoms of lung cancer (LC) often do not appear until the disease is advanced; only 15% of LC cases are discovered while the tumor is in the early stages of development. Carcinogen exposure, asthma and smoking have been determined to be risk factors for the development of LC. Prevention and early detection of LC could have a major impact on the natural history of the disease. The objective of the study was to apply multiplexed immunoassays to identify a panel of biomarkers for early detection of LC.  Methods: Normal (NO) serum controls (n=30) from healthy volunteers and lung cancer (n=30) were acquired from a commercial vendor. Baseline (pre-treatment) serum specimens from individuals with asthma (AST; n=30) and lung cancer risk (LCR; n=73) were available from clinical trials of two novel agents that are being developed by JBNI Inc. for the respective indications. Serum levels of 59 cytokines, growth factors and biologically active peptides were quantified using multiplexed immunoassays using the Luminex platform to identify biomarkers that are expressed in a significantly different manner in individuals with LC, LCR, or AST in comparison with NO subjects. Data were reduced using nearest neighbor cluster analysis with squared Euclidian distance to separate patients into groups across analytes with inter-pathology comparisons determined using Student’s t test.  Results and conclusions: Multiple analytes showed highly significant differences (p
Combination of paclitaxel and LAG3-Ig (IMP321), a novel MHC class II agonist, as a first-line chemoimmunotherapy in patients with metastatic breast carcinoma (MBC): Interim results from the run-in phase of a placebo controlled randomized phase II.
Authors: Francois P. Duhoux, Agnes Jager, Luc Dirix, Manon Thirza Huizing, Guy Heinrich Maria Jerusalem, Peter Vuylsteke, Eveline De Cuypere, Doris Breiner, Christian Mueller, Chrystelle Brignone, Frederic Triebel
Journal: Journal of Clinical Oncology (2017)

1062 Background: IMP321 is a recombinant soluble LAG3-Ig fusion protein that binds to MHC class II molecules and mediates antigen-presenting cell (APC) activation followed by CD8 T-cell activation. The activation of the dendritic cell network with IMP321 the day after a low dose injection of a single agent chemotherapy may lead to stronger anti-tumor CD8 T-cell responses. We report initial results of the safety run-in of a randomized, placebo-controlled phase IIb trial in patients (pts) with hormone receptor positive (HR + ) MBC receiving first-line weekly paclitaxel. Methods: In the safety run-in phase 15 pts with MBC received weekly paclitaxel (80 mg/m 2 ; D1, D8, D15) in a four week cycle in conjunction with either 6 mg (n = 6; cohort 1) or 30 mg (n = 9, cohort 2) IMP321 injections s.c. (D2 and D16) for 6 cycles. Patients without progressive disease could continue with a maintenance phase of 12 additional injections of IMP321 every 4 weeks. Blood samples for pharmacokinetics and immuno-monitoring were taken in cycle 1 and 4 just before and after IMP321 injection. Results: In total 15 pts (median age 53 years) were enrolled between Jan 2016 and Oct 2016. No dose limiting toxicities have been reported. Cytokine release syndrome grade 1 was the only serious adverse event (SAE) related to IMP321 and occurred twice in the same patient. Grade 1 and 2 injection site reactions were the most common related AEs and occurred in 14 pts (93 %). A dose-dependent increase in serum IMP321 concentration was observed among the two dose levels with a C max between 4 and 24 hours. Increased number of circulating monocytes, dendritic cells and increased activation were observed at both dose levels of IMP321, supporting the working hypothesis. Conclusions: The 30 mg s.c. IMP321 given every two weeks in combination with weekly paclitaxel is the recommended phase 2 dose which is used in the ongoing randomized placebo controlled phase II part of the study. Clinical trial information: NCT02614833.