tbuckley/cabot-search huggingface dataset:
Interim safety results from a phase II/III trial with 5-FU, oxaliplatin, and docetaxel (FLOT) versus epirubicin, cisplatin, and 5-FU (ECF) in patients with locally advanced, resectable gastric/oesophagogastric junction (OGJ) cancer: A study of the AIO.
Authors: Ulrike Koock, Claudia Pauligk, Kim Barbara Luley, Frank Mayer, Karsten Schulmann, Nils Homann, Harald Schmalenberg, Wael Hozaeel, Ralf Hofheinz, Stephan Probst, Rolf Mahlberg, Michael Koenigsmann, Georg Martin Haag, Johannes Meiler, Nicole Prasnikar, Dirk M. Behringer, Jorg Trojan, Matthias Egger, Elke Jäger, Salah-Eddin Al-Batran
Journal: Journal of Clinical Oncology (2012)

4083 Background: Perioperative ECF is a standard treatment for localized gastric/OGJ adenocarcinoma. However, 5-year survival rate remain below 40%. The FLOT regime is an effective new combination with pathologic response rates in the 15% range. This phase II/III study compares both regimens in resectable stages. Methods: Pts are stratified by different baseline criteria and randomized to either 3 + 3 perioperative cycles of ECF (Epirubicin 50 mg/m 2 , d1 Cisplatin 60 mg/m², d1 5-FU 200 mg/m², d1-d21, qd21) or 4 + 4 cycles of perioperative FLOT (Docetaxel 50mg/m2, d1 5-FU 2600 mg/m², d1 leucovorin 200 mg/m², d1 Oxaliplatin 85 mg/m², d1, qd14). 5-FU can be replaced by Capecitabine in the ECF-arm (ECX). This is a preplanned toxicity analysis after 200 pts in order to decide whether to continue to a phase III trial. Results: 202 pts have been randomized so far. Median age is 62 yrs; 79% of pts are male. The Primaries were Gastric in 43.4%, OGJ in 53.2% and not evaluable/documented in 3.4% of pts. 190 pts were eligible for the safety analyses. Median no. of preoperative cycles was 3 and 4 with ECF/ECX and FLOT, respectively, and 68.7% vs. 66.0% of pts (ECF/ECX vs. FLOT) started postoperative chemotherapy (ct). Grade 3/4 side effects were observed in 52.1% of ECF/ECX and 59.6% of FLOT pts with no significant differences between arms regarding individual grade 3/4 toxicities. Thromboembolic events occurred in 14.5% vs. 8.5% in pts with ECF/ECX vs. FLOT (p=.25). Serious adverse events occurred in 60.3% vs. 39.7% of pts with ECF/ECX vs. FLOT. Preoperative delay/interruptions of ct were observed in 74.0% vs. 61.7% of pts with ECF/ECX vs. FLOT (p=.07). Dose modifications of preoperative ct were performed in 28.1% vs. 22.3% of treatment cycles with ECF/ECX vs. FLOT, respectively. 121 pts underwent surgery. Severe surgical morbidity was similar in both arms (ECF/ECX, 15.8%; FLOT, 14.1%). Surgical mortality was observed in 2 and 1 pts with ECF/ECX and FLOT. Toxic deaths were observed in 1 pt each. Conclusions: Perioperative FLOT is feasible and safe. This supports the continuation of the trial as a phase III.
Abstract P305: Detrimental Effects of Chronic Activation of AKT in Hearts from Ozone-Exposed Healthy Adult Rats
Authors: Rajat Sethi, Ashoka Bandla, Magdalena Ramirez, Shubham Manchanda, Carlos Garcia, David Dostal
Journal: Circulation Research (2011)

Death of cardiomyocytes results in decreased cardiac function, which correlates with overall morbidity and mortality in many different clinical settings. For these reasons, understanding the intracellular signaling pathways that control cardiomyocyte survival has significant clinical implications. Each year in the US 60,000 cardiovascular deaths have been linked to environmental pollutants such as ozone (O 3 ). Earlier studies from our laboratory have shown that myocardial dysfunction, subsequent to chronic O 3 exposure, in normal adult rats. This attenuation of cardiac function was associated with increased myocardial TNF-alpha (TNF-α) levels. Progressive increases in the expression of myocardial TNF-α in 4 and 8 week O 3 exposed animals were followed by decreases in cardiac caveolin-1 levels. Acute activation of the serine-threonine kinase Akt is cardioprotective and reduces both infarction and dysfunction after ischemia/reperfusion injury (IRI). Akt is activated in samples from patients with chronic heart failure, however, less is known about the chronic effects of Akt activation in the hearts from ozone exposed patients. Although caveolin-1 has been shown to negatively regulate AKT expression; a cell survival pathway, regulatory role of AKT in hearts from ozone exposed subjects has never been studied. Sprague Dawley rats were exposed 8 hr/day for 28 and 56 days to filtered air or 0.8 ppm O 3 . In order to assess the chronic effects to O 3 , expressions of AKT and p-AKT were determined by wetern blotting in hearts extracted from rats, 24 hr after termination of air or O 3 exposure. Compared to rats exposed to filtered air, total AKT levels were significantly increased in all O 3 exposed animals. Similar results were seen with pAKT levels. Since earlier studies have determined detrimental effects of chronic activation of AKT in ischemia reperfusion injury, our novel findings suggest the interesting possibility of a mechanism by which chronic Akt activation can become maladaptive after exposure to chronic levels of ozone. It is possible that PI3K-dependent but Akt-independent effectors are required for full cardioprotection. Studies are currently in progress to prove this hypothesis and complete study will be presented at the meeting in New Orleans in 2011.
Repairing Mitochondrial Dysfunction in Disease
Authors: Vincenzo Sorrentino, Keir J. Menzies, Johan Auwerx
Journal: The Annual Review of Pharmacology and Toxicology (2017)

Mitochondria are essential organelles for many aspects of cellular homeostasis, including energy harvesting through oxidative phosphorylation. Alterations of mitochondrial function not only impact on cellular metabolism but also critically influence whole-body metabolism, health, and life span. Diseases defined by mitochondrial dysfunction have expanded from rare monogenic disorders in a strict sense to now also include many common polygenic diseases, including metabolic, cardiovascular, neurodegenerative, and neuromuscular diseases. This has led to an intensive search for new therapeutic and preventive strategies aimed at invigorating mitochondrial function by exploiting key components of mitochondrial biogenesis, redox metabolism, dynamics, mitophagy, and the mitochondrial unfolded protein response. As such, new findings linking mitochondrial function to the progression or outcome of this ever-increasing list of diseases has stimulated the discovery and development of the first true mitochondrial drugs, which are now entering the clinic and are discussed in this review.
The use of primary radiation for ocular adnexal MALTomas.
Authors: Wesley Alan Russell, David Gessert, Jack A. Cohen, Jonathan B. Rubenstein, Arnold M. Herskovic, Stephanie A. Gregory
Journal: Journal of Clinical Oncology (2012)

e18502 Background: Ocular adnexal mucosal associated lymphoid tissue lymphomas (MALTomas) are rare with no phase III trials to guide treatment. Typical management has been primary radiation therapy. This retrospective series aims to report the experience of a single institution and add to the current literature. Methods: Using our electronic medical record systems and available paper charts, we identified patients with MALTomas of the lacrimal gland or sac, conjunctiva, and posterior orbital structures. Records were reviewed to determine pathology, staging, treatment information, local and distant control, salvage treatments, and late toxicity. Results: Sixteen patients with ocular adnexal MALTomas had local radiation between 1992 and 2011 for primary or recurrent disease. 50% had lymphoma in the conjunctiva, 25% in the lacrimal sac/gland, and 25% in the posterior orbit. 75% had stage IAE disease, 6% had stage IIAE, and 19% had a positive bone marrow biopsy. One patient received chemotherapy as part of his initial therapy. The median radiation dose was 30 Gy (25.5-36 Gy) delivered with electrons (31%) or photons (69%). After a median follow-up of 34.78 months, two patients had residual/progressive disease, two had contralateral recurrence, and 1 had a distant failure, for local control of 87.5% and overall disease control of 68.75%. Recurrence/progression occurred at a median of 35.45 months. Two patients with residual/progressive disease and one with a contralateral recurrence were followed, successfully salvaged, and are NED. Fourteen patients are still alive and there were no disease-related/toxicity deaths. Seven patients developed cataracts in the treated eye, 2 had radiation retinopathy, 2 had permanent dry eye syndrome, and 1 had severe keratopathy requiring enucleation. Six patients (3.75%) had worsening visual acuity of unclear etiology. Conclusions: Primary radiation therapy for ocular adnexal MALTomas with a median dose of 30 Gy led to excellent local control. Those patients who did recur were successfully salvaged. Radiation was generally well-tolerated with expected cataractogenesis given the dose required to achieve local control with only one patient developing severe keratopathy after receiving the highest dose in this series.
Abstract B44: Protein interactions involving LARP1 in chemotherapy resistant ovarian cancer cells
Authors: Chara Stavraka, Manuela Mura, Roman Fischer, Marie-Laetitia Thezenas, Sadaf Ghaem Maghami, James Chettle, Laki Buluwela, Benedikt Kessler, Sarah P. Blagden
Journal: Cancer Research (2017)

Abstract Ovarian cancer (OC) is the most lethal gynecological malignancy accounting for 152,000 deaths annually worldwide. Due to the lack of a validated diagnostic tool, patients usually present with disseminated disease and the majority will develop resistance to platinum chemotherapy. Resensitizing OC to cisplatin-based chemotherapy is an unmet clinical need. The RNA-binding protein LARP1 is highly expressed in OC and is a post-transcriptional regulator of cell survival and tumorigenesis. LARP1 depletion using RNA interference (RNAi) restores platinum sensitivity in cisplatin-resistant OC cell lines and shows a synergistic anti-tumour effect with cisplatin. We explored the effect of this resensitization on the efficiency of protein translation using the Surface Sensing of Translation (SUnSET) method. Whilst cisplatin-induced genotoxic stress attenuated de novo protein synthesis in platinum sensitive OVCAR3 cells, this was not observed in platinum-resistant OVCAR8 cells where residual protein synthesis was maintained. However this residual translation was completely abolished after RNAi to LARP1 suggesting that, in the OVCAR8 cells, LARP1 maintains protein synthesis during genotoxic stress. Although LARP1 is known to bind Poly A binding protein (PABP) we questioned whether other interacting partners might also regulate this response. Using immunoprecipitation followed by ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) in OVCAR3 and OVCAR8 cells before and after cisplatin treatment, we identified PABPC1, PABPC4 and YB-1 as strong interactors with LARP1. By western blotting, Duolink Proximity Ligation Assay and Immunofluorescence we then confirmed these candidates as being complexed with LARP1. We are currently elucidating the functional role of these interactions on the LARP1-mediated genotoxic stress response with the overall aim of identifying therapeutic strategies to overcome platinum-resistance in ovarian cancer. Citation Format: Chara Stavraka, Manuela Mura, Roman Fischer, Marie-Laetitia Thezenas, Sadaf Ghaem Maghami, James Chettle, Laki Buluwela, Benedikt Kessler, Sarah P. Blagden. Protein interactions involving LARP1 in chemotherapy resistant ovarian cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr B44.
NOD2 variants as novel genetic risk factors for secondary sclerosing cholangitis in critically ill patients
Authors: C. Jüngst, V. Stadlbauer, M. Reichert, S. Weber, L. Ofner-Ziegenfuß, T. Voigtländer, W. Spindelböck, P. Fickert, G. Kirchner, F. Lammert, T.O. Lankisch, M. Krawczyk
Journal: Journal of Hepatology (2017)
Improved bone and renal safety of switching from tenofovir disoproxil fumarate to tenofovir alafenamide: preliminary results from 2 phase 3 studies in HBeAg-positive and HBeAg-negative patients with chronic hepatitis B
Authors: H.L. Chan, S. Fung, W.K. Seto, E. Gane, J.F. Flaherty, V. Suri, L. Lin, A. Gaggar, G.M. Subramanian, W.L. Chuang, K. Agarwal, H.L. Janssen, M. Buti
Journal: Journal of Hepatology (2017)
Ablation of Notch-signaling via recombination signal binding protein for immunoglobulin kappa j region knockout in liver induces massive damage by impaired intra-hepatic bile duct morphogenesis, cholestasis and necrosis
Authors: U.T. Mathada, T. Seufferlein, F. Oswald, S.-F. Katz, A. Lechel
Journal: Journal of Hepatology (2017)
Rational design of nanoparticles towards targeting antigen-presenting cells and improved T cell priming
Authors: Eva Zupančič, Caterina Curato, Maria Paisana, Catarina Rodrigues, Ziv Porat, Ana S. Viana, Carlos A.M. Afonso, João Pinto, Rogério Gaspar, João N. Moreira, Ronit Satchi-Fainaro, Steffen Jung, Helena F. Florindo
Journal: Journal of Controlled Release (2017)
Abstract P226: Small Heterodimer Partner Negatively Regulates Cardiac Hypertrophy Through Upregulation of GATA6
Authors: Gwang Hyeon Eom, Hosouk Joung, Yoojung Kim, Hae Jin Kee, Sera Shin, Don-Kyu Kim, Nakwon Choe, Duk-hwa Kwon, Kwang-Il Nam, Hueng-Sik Choi, Hyun Kook
Journal: Circulation Research (2011)

Small heterodimer partner (SHP; NR0B2) is an atypical orphan nuclear receptor that regulates a variety of cellular events such as cell proliferation, differentiation and metabolism in liver and bone. However, the role of SHP in heart has not yet been elucidated. In this study, we investigated the functional roles of SHP in cardiac hypertrophy. In rat neonatal cardiomyocytes model, phenylephrine (PE) down-regulated expression of SHP. Transient transfection of SHP decreased the promoter activity of Nppa (natriuretic polypeptide precursor type A). Adenovirus-mediated overexpression of SHP (Ad-SHP) blocked gene expressions of GATA4, GATA6, and serum response factor (SRF). The increase in [ 3 H]-leucine incorporation induced by PE or fetal bovine serum (FBS) was dramatically reduced by Ad-SHP. Likewise, increases in cell size with those hypertrophic stresses were significantly attenuated by Ad-SHP. The expressions of atrial natriuretic factor (ANF), β-myosin heavy chain (βMHC), and skeletal α-actin were significantly higher in hearts of SHP null mice. SHP physically interacted with GATA6 in mammalian cells. SHP significantly decreased the activation of -3003 Nppa promoter induced by GATA6. The action of SHP on Nppa promoter activity was partially recovered by GATA6. Taken together, these results suggest that SHP works as a novel anti-hypertrophic regulator by repressing GATA6.
Anti-claudin 18.2 antibody as new targeted therapy for advanced gastric cancer
Authors: Prabhsimranjot Singh, Sudhamshi Toom, Yiwu Huang
Journal: Journal of Hematology & Oncology (2017)

Targeted therapy and immunotherapy have revolutionized treatment of various cancers in the past decade. Despite targeted therapy with trastuzumab in Her2-positive gastric cancer patients, survival has been dismal, mostly due to disease progression and toxicity related to the treatments. One area of active development is looking for ideal monoclonal antibodies (IMAB) specific to the proteins only on the tumor and hence avoiding unnecessary side effects. Claudin proteins with isoform 2 are one such protein, specific for several cancers, particularly gastric cancer and its metastases, leading to the development of anti-claudin 18.2 specific antibody, claudiximab. This review will highlight the latest development of claudiximab as first in class IMAB for the treatment of gastric cancer.
UK poverty has “devastating” effect on children’s health, doctors warn
Authors: Gareth Iacobucci
Journal: BMJ (2017)

Poverty is damaging the health of children in the UK and must be urgently tackled by the next government, paediatricians have warned.

The Royal College of Paediatrics and Child Health and the Child Poverty Action Group, in a joint report based on an online survey of 266 paediatricians working at 90 NHS trusts in the UK,1 asked doctors for their views on how poverty is affecting the physical and mental health of the children they see and whether things are getting better or worse. …
Trunk and branch drivers in hepatocellular carcinoma: impact of molecular heterogeneity
Authors: A. Moeini, D. Sia, A.N. Harrington, S. Torrecilla, Z. Zhang, G. Camprecios, S. Toffanin, M.I. Fiel, K. Hao, M. Higuera, L. Cabellos, H. Cornella, M. Mahajan, Y. Hoshida, A. Villanueva, S. Florman, M.E. Schwartz, J.M. Llovet
Journal: Journal of Hepatology (2017)
Potassium 2-(l-hydroxypentyl)-benzoate attenuates neuroinflammatory responses and upregulates heme oxygenase-1 in systemic lipopolysaccharide-induced inflammation in mice
Authors: Chunyang Zhao, Weizhen Hou, Hui Lei, Longjian Huang, Shan Wang, Dandan Cui, Changhong Xing, Xiaoliang Wang, Ying Peng
Journal: Acta Pharmaceutica Sinica B (2017)

A neuroinflammatory response is commonly involved in the progression of many neurodegenerative diseases. Potassium 2-(1-hydroxypentyl)-benzoate (PHPB), a novel neuroprotective compound, has shown promising effects in the treatment of ischemic stroke and Alzheimer׳s disease (AD). In the present study, the anti-inflammatory effects of PHPB were investigated in the plasma and brain of C57BL/6 mice administered a single intraperitoneal (i.p.) injection of lipopolysaccharide (LPS). Levels of iNOS and the cytokines TNFα, IL-1β and IL-10 were elevated in plasma, cerebral cortex and hippocampus after LPS injection and the number of microglia and astrocytes in cortex and hippocampus were increased. LPS also upregulated the expression of heme oxygenase-1 (HO-1) in the cortex and hippocampus. PHPB reduced the levels of iNOS and cytokines in the plasma and brain, decreased the number of microglia and astrocytes and further enhanced the upregulation of HO-1. In addition, PHPB inhibited the LPS-induced phosphorylation of ERK, P38 and JNK. These results suggest that PHPB is a potential candidate in the treatment of neurodegenerative diseases through inhibiting neuroinflammation.
Radioguided thyroidectomy for follicular tumors: Multicentric experience
Authors: D. Parmeggiani, C. Gambardella, R. Patrone, A. Polistena, M. De Falco, R. Ruggiero, R. Cirocchi, A. Sanguinetti, V. Cuccurullo, M. Accardo, N. Avenia, G. Docimo, S. Tolone, V. Bassi, L. Docimo, G. Conzo
Journal: International Journal of Surgery (2017)
The Dietary Approaches to Stop Hypertension (DASH) diet, Western diet, and risk of gout in men: prospective cohort study
Authors: Sharan K Rai, Teresa T Fung, Na Lu, Sarah F Keller, Gary C Curhan, Hyon K Choi
Journal: BMJ (2017)

Objective To prospectively examine the relation between the Dietary Approaches to Stop Hypertension (DASH) and Western diets and risk of gout (ie, the clinical endpoint of hyperuricemia) in men.Design Prospective cohort study.Setting The Health Professionals Follow-up Study.Participants 44 444 men with no history of gout at baseline. Using validated food frequency questionnaires, each participant was assigned a DASH dietary pattern score (based on high intake of fruits, vegetables, nuts and legumes, low fat dairy products, and whole grains, and low intake of sodium, sweetened beverages, and red and processed meats) and a Western dietary pattern score (based on high intake of red and processed meats, French fries, refined grains, sweets, and desserts).Main outcome measure Risk of incident gout meeting the preliminary American College of Rheumatology survey criteria for gout, adjusting for potential confounders, including age, body mass index, hypertension, diuretic use, and alcohol intake.Results During 26 years of follow-up, 1731 confirmed cases of incident gout were documented. A higher DASH dietary pattern score was associated with a lower risk for gout (adjusted relative risk for extreme fifths 0.68, 95% confidence interval 0.57 to 0.80, P value for trend <0.001). In contrast, a higher Western dietary pattern score was associated with an increased risk for gout (1.42, 1.16 to 1.74, P=0.005).Conclusion The DASH diet is associated with a lower risk of gout, suggesting that its effect of lowering uric acid levels in individuals with hyperuricemia translates to a lower risk of gout. Conversely, the Western diet is associated with a higher risk of gout. The DASH diet may provide an attractive preventive dietary approach for men at risk of gout.
Abstract B05: Characterization of the pre-ribosomal complex, which mediates the p53 Impaired Ribosome Biogenesis Checkpoint (IRBC)
Authors: Sandra Menoyo, Antonio Gentilella, George Thomas
Journal: Cancer Research (2017)

Abstract Ribosome biogenesis is one of the most energy consuming anabolic processes in a growing tumor cell. For more than a century it has been recognized that the increased size and abnormal morphology of nucleoli, the sites of ribosome biogenesis, are markers of aggressive cancers, particularly sporadic colorectal cancers (sCRC). The TCGA has recently published that over 90% of sCRCs have a mutation in the WNT/APC signaling pathway, leading to persistent c-Myc activation in almost all cases. As c-Myc tumors are addicted to high rates of ribosome biogenesis, recent studies have suggested that impaired ribosome biogenesis, leading to the activation of p53 may serve as an Achilles' heel in the treatment of such tumors. Although a number of ribosomal proteins (RPs) have been implicated in inducing p53 stabilization following impaired ribosome biogenesis, our laboratory has shown that this response is mediated by a ribosomal precursor complex made-up of RPL5, RPL11 and non-coding 5S rRNA, which upon a lesion in ribosome biogenesis is redirected from assembly into nascent 60S ribosomal subunits to the binding and inhibition of Hdm2, leading to p53 stabilization, cell cycle arrest and apoptosis. We have termed this response the Impaired Ribosome Biogenesis Checkpoint (IRBC). However the sequence of molecular events that determine the transition of the RPL5/RPL11/5S rRNA-precursor complex upon impaired ribosome biogenesis into a tumor suppressor, the IRBC complex, are unknown. Here we present the use of a colon cancer cell line endogenously tagged by means of CRISPR/Cas9 with a GFP-fusion moiety placed at the eukaryotic-specific N-terminal extension of one copy of the gene coding for RPL11, which behaves as the wild type allele in terms of ribosome assembly and protein synthesis. We are using cells expressing this allele i) to follow by live imaging the endogenous IRBC complex localization over time under normal growing conditions or upon inducing lesions in ribosome biogenesis known to trigger the IRBC and p53 stabilization and (ii) to determine underlying molecular and biochemical alterations leading to the transition of the RPL5/RPL11/5S rRNA-precursor complex into of the IRBC complex. Citation Format: Sandra Menoyo, Antonio Gentilella, George Thomas. Characterization of the pre-ribosomal complex, which mediates the p53 Impaired Ribosome Biogenesis Checkpoint (IRBC). [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr B05.