tbuckley/cabot-search huggingface dataset:
Impact of higher-order heme degradation products on hepatic function and hemodynamics
Authors: Raphael A. Seidel, Thierry Claudel, Franziska A. Schleser, Navin K. Ojha, Matthias Westerhausen, Sandor Nietzsche, Christoph Sponholz, Frans Cuperus, Sina M. Coldewey, Stefan H. Heinemann, Georg Pohnert, Michael Trauner, Michael Bauer
Journal: Journal of Hepatology (2017)

Biliverdin and bilirubin were previously considered end products of heme catabolism; now, however, there is evidence for further degradation to diverse bioactive products. Z-BOX A and Z-BOX B arise upon oxidation with unknown implications for hepatocellular function and integrity. We studied the impact of Z-BOX A and B on hepatic functions and explored their alterations in health and cholestatic conditions.Functional implications and mechanisms were investigated in rats, hepatocytic HepG2 and HepaRG cells, human immortalized hepatocytes, and isolated perfused livers. Z-BOX A and B were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in acute and acute-on-chronic liver failure and hereditary unconjugated hyperbilirubinemia.Z-BOX A and B are found in similar amounts in humans and rodents under physiological conditions. Serum concentrations increased ∼20-fold during cholestatic liver failure in humans (p<0.001) and in hereditary deficiency of bilirubin glucuronidation in rats (p<0.001). Pharmacokinetic studies revealed shorter serum half-life of Z-BOX A compared to its regio-isomer Z-BOX B (p=0.035). While both compounds were taken up by hepatocytes, Z-BOX A was enriched ∼100-fold and excreted in bile. Despite their reported vasoconstrictive properties in the brain vasculature, BOXes did not affect portal hemodynamics. Both Z-BOX A and B showed dose-dependent cytotoxicity, affected the glutathione redox state, and differentially modulated activity of Rev-erbα and Rev-erbβ. Moreover, BOXes-triggered remodeling of the hepatocellular cytoskeleton.Our data provide evidence that higher-order heme degradation products, namely Z-BOX A and B, impair hepatocellular integrity and might mediate intra- and extrahepatic cytotoxic effects previously attributed to hyperbilirubinemia.Degradation of the blood pigment heme yields the bile pigment bilirubin and the oxidation products Z-BOX A and Z-BOX B. Serum concentrations of these bioactive molecules increase in jaundice and can impair liver function and integrity. Amounts of Z-BOX A and Z-BOX B that are observed during liver failure in humans have profound effects on hepatic function when added to cultured liver cells or infused into healthy rats.
A two-part phase 2 randomized study of dalantercept and axitinib versus placebo plus axitinib in advanced renal cell carcinoma: Results from the part 1 dose escalation cohorts.
Authors: Michael B. Atkins, Martin Henner Voss, Elizabeth R. Plimack, Brian I. Rini, Robert Alter, Nancy Ann Dawson, J. Thaddeus Beck, Rupal Satish Bhatt, Kristen M. Pappas, Dawn Wilson, Ty McClure, Ravi Kumar, Kenneth M. Attie, Matthew L. Sherman, Shuchi Sumant Pandya
Journal: Journal of Clinical Oncology (2014)

4566 Background: The activity of agents that target the vascular endothelial growth factor (VEGF) pathway in metastatic renal cell cancer (mRCC) may be enhanced in combination with agents that inhibit non-VEGF angiogenesis pathways and may lead to improved outcomes for pts. Activin receptor-like kinase 1 (ALK1) is a type I receptor of the TGFβ superfamily that is expressed on endothelial cells and is involved in blood vessel maturation. Dalantercept (Dal) is an ALK1 receptor-fusion protein that inhibits signaling through ALK1 and has demonstrated additive efficacy with a VEGF receptor (VEGFR) TKI in RCC models. Methods: Part 1 of this randomized 2-part phase 2 study assessed the safety and tolerability of Dal plus axitinib, a VEGFR TKI in pts. with mRCC who had up to 3 prior lines of therapy and determined the recommended phase 2 dose (RP2D). Cohorts of 3-6 pts. each received Dal (0.6, 0.9, or 1.2 mg/kg) SC Q3W and axitinib 5 mg PO BID. An expansion cohort at the RP2D will enroll an additional 10-20 pts. Eligibility criteria include 1 prior VEGFR TKI, ≤ 3 prior tx., and ECOG ≤1. Results: 13 pts. were enrolled in the three cohorts (n= 4, 4, 5) and there were no DLTs within 28 days of the first dose. Of the 13 pts., 46% had ≥ 2 prior tx and 15% had 2 prior anti-VEGF tx. Common Dal-related AEs were grade 1-2 diarrhea, fatigue, anemia, arthralgia, creatinine rise, constipation, nausea, dysphonia, headache, muscle spasms. There have been no Dal associated SAEs. AEs associated with axitinib did not occur with higher than expected frequency or severity. 3 of 12 (25%) evaluable patients (2 at 0.6 mg/kg and 1 at 0.9 mg/kg) 2 of whom had three prior tx, achieved partial responses and were on study for ≥ 10 cycles (7.5 mo). 6 of 11 (55%) evaluable pts. completed ≥ 6 cycles (4.5 mo). Enrollment in the expansion cohort at 1.2mg/kg Dal is ongoing. Conclusions: In this pretreated mRCC population, the combination of Dal and axitinib is well tolerated and associated with clinical activity including disease control in the majority of pts.These data support 1.2 mg/kg as the RP2D of Dal in the randomized double-blind part 2 of this study in which pts. will be randomized to Dal + axitinib vs. placebo + axitinib. Clinical trial information: NCT01727336.
Experience of cetuximab in the salvage treatment for recurrent/metastatic oral squamous cell carcinoma.
Authors: Jin-Ching Lin, Shih-An Liu, Chen-Chi Wang, Ching-Ping Wang
Journal: Journal of Clinical Oncology (2012)

e16006 Background: We investigated the efficacy, toxicity, and prognostic factors of salvage chemotherapy plus cetuximab in patients with recurrent/metastatic oral squamous cell carcinoma (OSCC). Methods: A total of 30 patients with recurrent/metastatic OSCC were treated by an outpatient weekly multi-drug combination chemotherapy plus cetuximab 400 mg/m 2 loading in day 1, then 250 mg/m 2 every week. The major chemotherapy regimen consisted of MEMOCLUB (methotrexate 30 mg/m 2 d1, epirubicin 30 mg/m 2 d1, alternating with mitomycin-C 4 mg/m 2 d8, oncovin 1 mg/m 2 d8, cisplatin 25 mg/m 2 d8, leucovorin 120 mg/m 2 d8, 5-fluorouracil 1000 mg/m 2 d8, and bleomycin 10 mg/m 2 d8) or GV (gemcitabine 1000mg/m 2 d1, and vinorelbine 25 mg/m 2 d8). Results: Baseline characteristics are as followings: median age=45 (range 32-73); male/female=28/2; Karnofsky performance status 80%/70%/60%/50%=7/18/3/2. Most patients had heavily treated history — first recurrence in 11 cases, second recurrence in 6, and third or more recurrence in 13. The disease extent consists of 25 (83.3%) locoregional recurrences, 3 (10.0%) distant metastasis, and 2 (6.7%) locoregional + metastatic diseases. Grade 3/4 toxicity included leucopenia (46.7%), anemia (33.3%), thrombocytopenia (6.7%), mucositis (6.7%) and skin rashes (20.0%). We obtained a high overall response rate of 66.7% (7 CR, 13 PR, 6 SD, 3 PD, and 1 unevaluable). So far, there are 22 deaths and 8 alive. The overall survival time ranges from 48-1365 days with a median of 312 days. One-year overall survival rate is 49%. Two favorable prognostic factors were found by univariate analysis- disease extent (locoregional vs. distant disease, HR=0.1509, 95%CI=0.0008-0.0592) and tumor response (CR+PR vs. SD+PD, HR=0.2255, 95%CI=0.0277-0.2984). Conclusions: Cetuximab plus weekly outpatient multi-drug chemotherapy has a high response rate and encouraging survival with acceptable toxicity in recurrent/metastatic OSCC patients.
Synergistic Immunostimulatory Effects and Therapeutic Benefit of Combined Histone Deacetylase and Bromodomain Inhibition in Non–Small Cell Lung Cancer
Authors: Dennis O. Adeegbe, Yan Liu, Patrick H. Lizotte, Yusuke Kamihara, Amir R. Aref, Christina Almonte, Ruben Dries, Yuyang Li, Shengwu Liu, Xiaoen Wang, Tiquella Warner-Hatten, Jessica Castrillon, Guo-Cheng Yuan, Neermala Poudel-Neupane, Haikuo Zhang, Jennifer L. Guerriero, Shiwei Han, Mark M. Awad, David A. Barbie, Jerome Ritz, Simon S. Jones, Peter S. Hammerman, James Bradner, Steven N. Quayle, Kwok-Kin Wong
Journal: Cancer Discovery (2017)

Effective therapies for non-small cell lung cancer (NSCLC) remain challenging despite an increasingly comprehensive understanding of somatically altered oncogenic pathways. It is now clear that therapeutic agents with potential to impact the tumor immune microenvironment potentiate immune-orchestrated therapeutic benefit. Herein, we evaluated the immunoregulatory properties of histone deacetylase (HDAC) and bromodomain inhibitors, two classes of drugs that modulate the epigenome, with a focus on key cell subsets that are engaged in an immune response. By evaluating human peripheral blood and NSCLC tumors, we show that the selective HDAC6 inhibitor ricolinostat promotes phenotypic changes that support enhanced T-cell activation and improved function of antigen-presenting cells. The bromodomain inhibitor JQ1 attenuated CD4+FOXP3+ T regulatory cell suppressive function and synergized with ricolinostat to facilitate immune-mediated tumor growth arrest, leading to prolonged survival of mice with lung adenocarcinomas. Collectively, our findings highlight the immunomodulatory effects of two epigenetic modifiers that, together, promote T cell-mediated antitumor immunity and demonstrate their therapeutic potential for treatment of NSCLC.Significance: Selective inhibition of HDACs and bromodomain proteins modulates tumor-associated immune cells in a manner that favors improved T-cell function and reduced inhibitory cellular mechanisms. These effects facilitated robust antitumor responses in tumor-bearing mice, demonstrating the therapeutic potential of combining these epigenetic modulators for the treatment of NSCLC. Cancer Discov; 7(8); 852-67. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 783.
Normal esophageal mucosae adjacent to esophageal adenocarcinomas in both Japanese and U.S. patients have a field defect of methylation changes
Authors: M. Nasu, H. Orita, M. Gibson, M. Brock, J. Herman, E. Gabrielson, M. Tsurumaru, A. Forastiere
Journal: Journal of Clinical Oncology (2007)

4636 Background: Esophageal mucosae that reside next to gross cancer are often without histological premalignant changes. We hypothesized that DNA hypermethylation could be detected in “normal” tissues adjacent to esophageal adenocarcinomas (EAC). Methods: A cohort of patients from Japan (J, n=14) and the United States (US, n=41) with locally advanced EAC were evaluated for methylation status. Esophagectomy specimens provided a source of paired normal and tumor tissues. After DNA extraction, methylation specific PCR was used to evaluate the promoters of APC, p16 and MGMT in all samples. Methylation frequency was calculated for each patient and expressed as a percentage of total. Results: Age, gender, pathologic stage and epigenetic analyses of primary tumors were similar in each cohort. Methylation frequency of tumors was: APC (66% US; 70% J). p16 (39% US; 20% J). MGMT (63% US; 75% J). In adjacent histologically “normal” esophageal mucosae, the percentage of patients with methylation at 0, 1, 2 or 3 genes was 79%, 14%, 0%, 7% for the J group and 56%, 44%, 10% and 2% for the U.S. group. In both cohorts, the majority of the normal samples had no methylation changes. In over half of the total cohort, however, there was at least one gene in the adjacent histologically “normal” tissue positive for DNA hypermethylation. Very few samples in either group, however, had more than one gene methylated in histologically “normal” esophageal mucosae. In general, the same methylation pattern present in the “normal” tissue persisted in the primary malignancy. Conclusions: Histologically negative esophageal mucosae adjacent to cancer frequently show at least one hypermethylated gene in a multiple gene panel. These data suggest that for patients with EAC, regardless of nationality, there is a field defect of promoter hypermethylation changes in adjacent esophageal mucosae. These events reflect those of the primary malignancy, and are probably early and cumulative during carcinogenesis. No significant financial relationships to disclose.
Visualization of hepatitis E virus RNA and proteins in the human liver
Authors: Daniela Lenggenhager, Jérôme Gouttenoire, Mohsen Malehmir, Marion Bawohl, Hanna Honcharova-Biletska, Susanne Kreutzer, David Semela, Jörg Neuweiler, Sandra Hürlimann, Patrick Aepli, Montserrat Fraga, Roland Sahli, Luigi Terracciano, Laura Rubbia-Brandt, Beat Müllhaupt, Christine Sempoux, Darius Moradpour, Achim Weber
Journal: Journal of Hepatology (2017)
Prevention and treatment of complications of selective internal radiation therapy: Expert guidance and systematic review
Authors: Bruno Sangro, Diego Martínez‐Urbistondo, Lourens Bester, Jose I. Bilbao, Douglas M. Coldwell, Patrick Flamen, Andrew Kennedy, Jens Ricke, Ricky A. Sharma
Journal: Hepatology (2017)

Selective internal radiation therapy (or radioembolization) by intra-arterial injection of radioactive yttrium-90-loaded microspheres is increasingly used for the treatment of patients with liver metastases or primary liver cancer. The high-dose beta-radiation penetrates an average of only 2.5 mm from the source, thus limiting its effects to the site of delivery. However, the off-target diversion of yttrium-90 microspheres to tissues other than the tumor may lead to complications. The most prominent of these complications include radiation gastritis and gastrointestinal ulcers, cholecystitis, radiation pneumonitis, and radioembolization-induced liver disease, which may occur despite careful pretreatment planning. Thus, selective internal radiation therapy demands an expert multidisciplinary team approach in order to provide comprehensive care for patients. This review provides recommendations to multidisciplinary teams on the optimal medical processes in order to ensure the safe delivery of selective internal radiation therapy. Based on the best available published evidence and expert opinion, we recommend the most appropriate strategies for the prevention, early diagnosis, and management of potential radiation injury to the liver and to other organs. (Hepatology 2017;66:969-982).
Erratum: A new MHC locus that influences class I peptide presentation (Immunity (1997) 7 (641-651))
Authors: Joel D Taurog, K. F. Lindahl, Robert E Hammer, C. A. Slaughter, S. D. Maika, M. Zhou, D. C. Roopenian, G. J. Christianson, S. J. Gaskell, R. C. Jones, R. Bordoli, H. L. Ploegh, B. Galocha, S. G. Summerfield
Journal: Immunity (1999)
Early treatment sensitivity in childhood acute lymphoblastic leukemia is associated with gain of chromosome 21.
Authors: Doris Steinemann, Gunnar Cario, Martin Stanulla, Marcel Tauscher, Anja Weigmann, Tanja Hinrichsen, Gudrun Michaelsen, Susanne Viehmann, Peter Lichter, Martin Schrappe, Brigitte Schlegelberger
Journal: Cancer Research (2006)

5271  Acute lymphoblastic leukemia (ALL) is the most common malignancy in childhood. In vivo response to initial therapy, as assessed by determination of minimal residual disease at 5 and 12 weeks of treatment, has evolved as the strongest prognostic factor in pediatric ALL patients treated according to the BFM regime. In this study, ten patients with a poor treatment response (MRD load > 10-3 at week 12, MRD-high risk, HR), five treatment-sensitive patients (no measurable MRD at weeks 5 and 12, MRD-standard risk, SR) and three patient with an intermediate treatment sensitivity (any MRD positivity at week 5, MRD load
The impact of the Oncotype Dx breast cancer assay in clinical practice: Systematic review and meta-analysis.
Authors: Josh John Carlson, Joshua A. Roth
Journal: Journal of Clinical Oncology (2012)

560 Background: Many studies have evaluated the Oncotype Dx Breast Cancer Assay (ODX) and its impact on adjuvant chemotherapy (ACT) treatment decisions. However, it can be difficult for clinicians and other stakeholders to interpret the collective findings of these studies, as they were conducted in diverse settings and have limited sample sizes. To address this issue, we conducted a systematic review and meta-analysis to synthesize ODX results and provide insights about the utility of ODX in actual clinical practice. Methods: We performed a systematic review of ODX studies using PubMed, Embase, ASCO, and SABCS. Studies were included if patients had ER +, node -, early stage breast cancer, reported use of ODX to inform actual ACT decisions, and reported outcomes of interest, including: 1) distribution of ODX recurrence scores (RS); 2) impact of ODX on ACT recommendations; 3) impact of ODX on ACT use; and 4) proportion of patients following the treatment suggested by the ODX RS. Results: A total of 28 studies met inclusion criteria. The distribution of RS categories was 48.8% low, 39.0% intermediate, and 12.2% high (21 studies, 4,156 patients). ODX changed the clinical-pathological ACT recommendation in 33.4% of patients (8 studies, 1,437 patients). In patients receiving ODX, receipt of ACT was: 28.2% overall, 5.8% low, 37.4% intermediate, and 83.4% high. High RS patients were significantly more likely to follow the treatment suggested by ODX vs. low RS patients RR: 1.07 (1.01–1.14). Conclusions: The pooled results for the impact of ODX on ACT recommendations are consistent with most individual studies to date. However, the proportion of intermediate RS results is nearly 2-fold higher than reported in the ODX development studies by Paik et al., which may have implications for the clinical utility and cost impacts of testing. Also, high RS vs. low RS patients were more likely to follow the ODX results, suggesting a tendency toward aggressive treatment despite a low ODX RS. Finally, there was a lack of studies on the impact of ODX on ACT use vs. standard approaches, suggesting additional studies are warranted. [Table: see text]
Erratum for the Research Article: “Integration of Hedgehog and mutant FLT3 signaling in myeloid leukemia” by Y. Lim, L. Gondek, L. Li, Q. Wang, H. Ma, E. Chang, D. L. Huso, S. Foerster, L. Marchionni, K. McGovern, D. N. Watkins, C. D. Peacock, M. Levis, B. D. Smith, A. A. Merchant, D. Small, W. Matsui
Journal: Science Translational Medicine (2015)
Variability and Reproducibility of Segmental Longitudinal Strain Measurement
Authors: Oana Mirea, Efstathios D. Pagourelias, Jurgen Duchenne, Jan Bogaert, James D. Thomas, Luigi P. Badano, Jens-Uwe Voigt, Luigi P. Badano, James D. Thomas, Jamie Hamilton, Stefano Pedri, Peter Lysyansky, Gunnar Hansen, Yasuhiro Ito, Tomoaki Chono, Jane Vogel, David Prater, Sungwook Park, Jin Yong Lee, Helene Houle, Bogdan Georgescu, Rolf Baumann, Bernhard Mumm, Yashuhiko Abe, Willem Gorissen
Journal: JACC. Cardiovascular imaging (2017)
Thrombin-Induced Podocyte Injury Is Protease-Activated Receptor Dependent
Authors: Ruchika Sharma, Amanda P. Waller, Shipra Agrawal, Katelyn J. Wolfgang, Hiep Luu, Khurrum Shahzad, Berend Isermann, William E. Smoyer, Marvin T. Nieman, Bryce A. Kerlin
Journal: Journal of the American Society of Nephrology (2017)

Nephrotic syndrome is characterized by massive proteinuria and injury of specialized glomerular epithelial cells called podocytes. Studies have shown that, whereas low-concentration thrombin may be cytoprotective, higher thrombin concentrations may contribute to podocyte injury. We and others have demonstrated that ex vivo plasma thrombin generation is enhanced during nephrosis, suggesting that thrombin may contribute to nephrotic progression. Moreover, nonspecific thrombin inhibition has been shown to decrease proteinuria in nephrotic animal models. We thus hypothesized that thrombin contributes to podocyte injury in a protease-activated receptor-specific manner during nephrosis. Here, we show that specific inhibition of thrombin with hirudin reduced proteinuria in two rat nephrosis models, and thrombin colocalized with a podocyte-specific marker in rat glomeruli. Furthermore, flow cytometry immunophenotyping revealed that rat podocytes express the protease-activated receptor family of coagulation receptors in vivo . High-concentration thrombin directly injured conditionally immortalized human and rat podocytes. Using receptor-blocking antibodies and activation peptides, we determined that thrombin-mediated injury depended upon interactions between protease-activated receptor 3 and protease-activated receptor 4 in human podocytes, and between protease-activated receptor 1 and protease-activated receptor 4 in rat podocytes. Proximity ligation and coimmunoprecipitation assays confirmed thrombin-dependent interactions between human protease-activated receptor 3 and protease-activated receptor 4, and between rat protease-activated receptor 1 and protease-activated receptor 4 in cultured podocytes. Collectively, these data implicate thrombinuria as a contributor to podocyte injury during nephrosis, and suggest that thrombin and/or podocyte-expressed thrombin receptors may be novel therapeutic targets for nephrotic syndrome.
RAGE-mediated extracellular matrix proteins accumulation exacerbates HySu-induced pulmonary hypertension
Authors: Daile Jia, Yuhu He, Qian Zhu, Huan Liu, Caojian Zuo, Guilin Chen, Ying Yu, Ankang Lu
Journal: Cardiovascular Research (2017)

Extracellular matrix (ECM) proteins accumulation contributes to the progression of pulmonary arterial hypertension (PAH), a rare and fatal cardiovascular condition defined by high pulmonary arterial pressure, whether primary, idiopathic, or secondary to other causes. The receptor for advanced glycation end products (RAGE) is constitutively expressed in the lungs and plays an important role in ECM deposition. Nonetheless, the mechanisms by which RAGE mediates ECM deposition/formation in pulmonary arteries and its roles in PAH progression remain unclear.Expression of RAGE and its activating ligands, S100/calgranulins and high mobility group box 1 (HMGB1), were increased in both human and mouse pulmonary arterial smooth muscle cells (PASMCs) under hypoxic conditions and were also strikingly upregulated in pulmonary arteries in hypoxia plus SU5416 (HySu)-induced PAH in mice. RAGE deletion alleviated pulmonary arterial pressure and restrained extracellular matrix accumulation in pulmonary arteries in HySu-induced PAH murine model. Moreover, blocking RAGE activity with a neutralizing antibody in human PASMCs, or RAGE deficiency in mouse PASMCs exposed to hypoxia, suppressed the expression of fibrotic proteins by reducing TGF-β1 expression. RAGE reconstitution in deficient mouse PASMCs restored hypoxia-stimulated TGF-β1 production via ERK1/2 and p38 MAPK pathway activation and subsequently increased ECM protein expression. Interestingly, HMGB1 acting on RAGE, not toll-like receptor 4 (TLR4), induced ECM deposition in PASMCs. Finally, in both idiopathic PAH patients and HySu-induced PAH mice, soluble RAGE (sRAGE) levels in serum were significantly elevated compared to those in controls.Activation of RAGE facilitates the development of hypoxia-induced pulmonary hypertension by increase of ECM deposition in pulmonary arteries. Our results indicate that sRAGE may be a potential biomarker for PAH diagnosis and disease severity, and that RAGE may be a promising target for PAH treatment.