tbuckley/cabot-search huggingface dataset:
Human knockouts of<i>PLA2G4A</i>phenocopy NSAID-induced gastrointestinal and renal toxicity
Authors: Sateesh Maddirevula, Mohammed Abanemai, Fowzan S Alkuraya
Journal: Gut (2016)

We read with great interest the study by Brooke and colleagues, in which they revealed that a severe hereditary form of peptic ulcer disease known as ‘cryptogenic multifocal ulcerating stenosing enteritis’ is caused by homozygosity for a truncating mutation in PLA2G4A , causing complete loss of cytosolic phospholipase A2-α (cPLA(2)α).1 We describe below a family with a different truncating mutation to further delineate the PLA2G4A -related phenotype.

The family consists of healthy first cousin parents and 8-year-old triplets, two of whom had been treated for severe peptic ulcer disease since they were 2 years of age. The initial presentation was in the form of abdominal pain, anaemia and blood in stools, and multiple gastric and duodenal ulcers were diagnosed by endoscopy at …
Mutation Analysis of Cell-Free DNA and Single Circulating Tumor Cells in Metastatic Breast Cancer Patients with High Circulating Tumor Cell Counts
Authors: Jacqueline A. Shaw, David S. Guttery, Allison Hills, Daniel Fernandez-Garcia, Karen Page, Brenda M. Rosales, Kate S. Goddard, Robert K. Hastings, Jinli Luo, Olivia Ogle, Laura Woodley, Simak Ali, Justin Stebbing, R. Charles Coombes
Journal: Clinical Cancer Research (2016)

The purpose of this study was to directly compare mutation profiles in multiple single circulating tumor cells (CTC) and cell-free DNA (cfDNA) isolated from the same blood samples taken from patients with metastatic breast cancer (MBC). We aimed to determine whether cfDNA would reflect the heterogeneity observed in 40 single CTCs.
An Evaluation of the Zuccala Cancer Test&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: J. H. Hill, M.D.
Journal: JNCI Journal of the National Cancer Institute (1957)

An Evaluation of the Zuccala Cancer Test Get access J. H. Hill, M.D. J. H. Hill, M.D. Department of Pathology and Oncology, University of Kansas Medical School, Kansas City, Kansas Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 18, Issue 2, February 1957, Pages 301–305, https://doi.org/10.1093/jnci/18.2.301 Published: 01 February 1957 Article history Received: 29 August 1956 Published: 01 February 1957
Mechanism, Consequences, and Therapeutic Targeting of Abnormal IL15 Signaling in Cutaneous T-cell Lymphoma
Authors: Anjali Mishra, Krista La Perle, Sonya Kwiatkowski, Laura A. Sullivan, Gregory H. Sams, Jessica Johns, Douglas P. Curphey, Jing Wen, Kathleen McConnell, Jun Qi, Henry Wong, Giandomenico Russo, Jianying Zhang, Guido Marcucci, James E. Bradner, Pierluigi Porcu, Michael A. Caligiuri
Journal: Cancer Discovery (2016)

Cutaneous T-cell lymphoma (CTCL) is the most common type of primary cutaneous lymphoma. Here, we report that patients with CTCL show increased IL15 in a clinical stage-dependent manner. Mechanistically, we show that ZEB1 is a transcriptional repressor of IL15 in T cells and that hypermethylation of the ZEB1 binding region within the IL15 promoter, as seen in patients with CTCL, prevents ZEB1 binding and causes increased transcription of IL15 Using a transgenic mouse model of IL15, we provide evidence that overexpression of IL15 induces a spontaneous CTCL that mimics the human neoplasm. Excessive autocrine production of IL15 in T cells inhibits an HDAC1-mediated negative autoregulatory loop, resulting in the upregulation of HDAC1 and HDAC6 and transcriptional induction of the onco-miR-21. Interruption of IL15 downstream signaling with isotype-specific HDAC inhibitors halts (HDAC1) or significantly delays (HDAC6) the progression of CTCL in vivo and provides preclinical evidence supporting a hierarchical model of oncogenic signaling in CTCL.To date, CTCL pathogenesis remains unknown, and there are no curative therapies. Our findings not only demonstrate a critical role for IL15-mediated inflammation in cutaneous T-cell lymphomagenesis, but also uncover a new oncogenic regulatory loop in CTCL involving IL15, HDAC1, HDAC6, and miR-21 that shows differential sensitivity to isotype-specific HDAC inhibitors. Cancer Discov; 6(9); 986-1005. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 932.
Risk of hypoglycaemia in users of sulphonylureas compared with metformin in relation to renal function and sulphonylurea metabolite group: population based cohort study
Authors: Judith van Dalem, Martijn C G J Brouwers, Coen D A Stehouwer, André Krings, Hubert G M Leufkens, Johanna H M Driessen, Frank de Vries, Andrea M Burden
Journal: BMJ (2016)

<b>Objective</b>&nbsp;To determine the association between use of sulphonylureas and risk of hypoglycaemia in relation to renal function and sulphonylurea metabolic group compared with use of metformin. <b>Design</b>&nbsp;Population based cohort study using routinely collected data from general practices in England. <b>Setting</b>&nbsp;Clinical Practice Research Datalink (CPRD) database, 2004-12. <b>Participants</b>&nbsp;120 803 new users of a non-insulin antidiabetic agent with at least one prescription and aged 18 years or more. The first prescription defined start of follow-up. Patients were followed until the end of data collection, a record for hypoglycaemia, or a blood glucose level of less than 3.0 mmol/L. <b>Main outcome measures</b>&nbsp;Associations between sulphonylurea dose, renal impairment, type of sulphonylurea used, and risk of hypoglycaemia, were determined using Cox proportional hazard models. Adjustments were made for age, sex, lifestyle, comorbidity, and drug use. <b>Results</b>&nbsp;The risk of hypoglycaemia in current users of sulphonylureas only was significantly increased compared with current users of metformin only (adjusted hazard ratio 2.50, 95% confidence interval 2.23 to 2.82). The higher risk in current users of sulphonylureas only was further increased in patients with an estimated glomerular filtration rate of less than 30 mL/min/1.73 m<sup>2</sup> (4.96, 3.76 to 6.55). The risk of hypoglycaemia was also significantly higher in patients with a high sulphonylurea dose (3.12, 2.68 to 3.62) and in current users of glibenclamide (7.48, 4.89 to 11.44). Gliclazide, the sulphonylurea of first choice, showed a similar risk of hypoglycaemia compared with other sulphonylureas. <b>Conclusions</b>&nbsp;Sulphonylurea treatment in patients with a renal function of less than 30 mL/min/1.73 m<sup>2</sup> should be considered with caution. Moreover, an increased risk of hypoglycaemic events was observed among all users of sulphonylureas. This contrasts with several guidelines that recommend gliclazide as first choice sulphonylurea, and therefore requires further investigation.
First Results of the Multicenter Total Therapy Gimema LAL 1509 Protocol for De Novo Adult Philadelphia Chromosome Positive (Ph+) Acute Lymphoblastic Leukemia (ALL) Patients
Authors: Sabina Chiaretti, Antonella Vitale, Loredana Elia, Silvana Albino, Alfonso Piciocchi, Paola Fazi, Francesco Di Raimondo, Antonella Fornaro, Francesco Fabbiano, Alfonso Maria D'Arco, Giovanni Martinelli, Francesca Ronco, Lidia Edwige Santoro, Nicola Cascavilla, Piero Galieni, Alessandra Tedeschi, Simona Sica, Nicola Di Renzo, Angela Melpignano, Angelo Michele Carella, Felicetto Ferrara, Marco Vignetti, Robin Foa
Journal: Blood (2014)
Multiple Threats to Child Health from Fossil Fuel Combustion: Impacts of Air Pollution and Climate Change
Authors: Frederica P. Perera
Journal: Environmental Health Perspectives (2016)

Background:Approaches to estimating and addressing the risk to children from fossil fuel combustion have been fragmented, tending to focus either on the toxic air emissions or on climate change. Yet developing children, and especially poor children, now bear a disproportionate burden of disease from both environmental pollution and climate change due to fossil fuel combustion.Objective:This commentary summarizes the robust scientific evidence regarding the multiple current and projected health impacts of fossil fuel combustion on the young to make the case for a holistic, child-centered energy and climate policy that addresses the full array of physical and psychosocial stressors resulting from fossil fuel pollution.Discussion:The data summarized here show that by sharply reducing our dependence on fossil fuels we would achieve highly significant health and economic benefits for our children and their future. These benefits would occur immediately and also play out over the life course and potentially across generations.Conclusion:Going beyond the powerful scientific and economic arguments for urgent action to reduce the burning of fossil fuels is the strong moral imperative to protect our most vulnerable populations.Citation:Perera FP. 2017. Multiple threats to child health from fossil fuel combustion: impacts of air pollution and climate change. Environ Health Perspect 125:141–148; http://dx.doi.org/10.1289/EHP299
Evolution of acute myelogenous leukemia stem cell properties after treatment and progression
Authors: Tzu-Chieh Ho, Mark LaMere, Brett M. Stevens, John M. Ashton, Jason R. Myers, Kristen M. O’Dwyer, Jane L. Liesveld, Jason H. Mendler, Monica Guzman, Jennifer D. Morrissette, Jianhua Zhao, Eunice S. Wang, Meir Wetzler, Craig T. Jordan, Michael W. Becker
Journal: Blood (2016)
Is carbamazepine helpful in paroxysmal behavior disorders?
Authors: J C Garbutt, P T Loosen
Journal: American Journal of Psychiatry (1983)

Carbamazepine was used to treat two patients with paroxysmal behavioral episodes and preexisting psychiatric disease. Carbamazepine abolished the paroxysmal episodes. Its effects on the preexisting disease were less clear. These data suggest carbamazepine treatment for paroxysmal behavior.
Unloading Shoes for Self-management of Knee Osteoarthritis
Authors: Rana S. Hinman, Tim V. Wrigley, Ben R. Metcalf, Penny K. Campbell, Kade L. Paterson, David J. Hunter, Jessica Kasza, Andrew Forbes, Kim L. Bennell
Journal: Annals of Internal Medicine (2016)

Background: Appropriate footwear is recommended for self-management of knee osteoarthritis. Shoes that reduce harmful knee loads are available, but symptomatic effects are uncertain. Objective: To evaluate the efficacy of unloading shoes in alleviating knee osteoarthritis symptoms. Design: Participant- and assessor-blinded comparative effectiveness randomized, controlled trial. (Australian New Zealand Clinical Trials Registry: ACTRN12613000851763) Setting: Community. Participants: 164 persons with medial knee osteoarthritis. Intervention: Walking shoes with triple-density, variable-stiffness midsoles and mild lateral-wedge insoles designed to unload the medial knee and worn daily (intervention) versus conventional walking shoes (comparator). Measurements: Primary outcomes were pain with walking (assessed on a numerical rating scale [NRS]) and physical function (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC]) at 6 months. Secondary outcomes were knee pain and stiffness (WOMAC), average pain (NRS), intermittent and constant knee pain (Intermittent and Constant Osteoarthritis Pain questionnaire), quality of life (Assessment of Quality of Life instrument), physical activity (Physical Activity Scale for the Elderly), and global change in pain and function (Likert scales). Results: A total of 160 participants (98%) completed primary outcome measures at 6 months. Changes in pain (mean difference, 0.0 units [95% CI, −0.9 to 0.8 unit]) and function (mean difference, 0.3 unit [CI, −3.2 to 3.7 units]) did not differ between groups at 6 months, with both groups showing clinically relevant improvements in function and the intervention group showing clinically relevant improvements in pain. There were no differences in secondary outcomes. Pain was globally improved in 54% of participants, and function was globally improved in 44% to 48%. Unloading shoes were not associated with increased probability of improvement (odds ratios, 0.99 [CI, 0.53 to 1.86] for pain and 0.85 [CI, 0.45 to 1.61] for function). Limitation: Effects on joint structure were not evaluated. Conclusion: Shoes with modified midsoles to unload the medial knee conferred no additional benefit over conventional walking shoes. Both improved pain and function by clinically relevant amounts. Primary Funding Source: Australian National Health and Medical Research Council.
Vascular tumor burden as a new quantitative CT imaging biomarker for predicting metastatic RCC response to antiangiogenic therapy.
Authors: Andrew Dennis Smith, Xu Zhang, Frederico Souza, Manohar Roda, Haowei Zhang, Jason Bryan
Journal: Journal of Clinical Oncology (2016)

595 Background: Anti-angiogenic (AAG) therapy is designed to devascularize tumors, so we developed methods for measuring the vascular tumor burden (VTB) on CT images. This study was designed to validate initial changes in the VTB as a quantitative CT imaging biomarker for predicting progression-free survival (PFS) in patients with metastatic RCC treated with AAG therapy. Methods: As part of a multi-institutional prospective phase III trial by Motzer et al. NEJM 2009, adult patients with metastatic clear cell RCC were treated with sunitinib (N=375). In this post hoc secondary analysis, quantitative CT imaging software was used to measure the VTB in cm 2 on baseline and initial post-therapy CT images (N=275 with digital images). Enhancing MASS (eMASS) Criteria response groups included Favorable Risk (FR; 30% decrease in VTB), Intermediate Risk (IR; not FR or UR), or Unfavorable Risk (UR; 20% increase in VTB or new metastases). Initial post-therapy CT images were evaluated by eMASS Criteria, RECIST, Choi Criteria and MASS Criteria. Comparison of PFS among response groups was evaluated using log-rank test and Cox-proportional hazards ratio. Results: Median PFS of the cohort was 1.1 years. Median PFS of the response groups from the criteria are depicted in Table 1. The median difference in PFS (MD) and hazard ratio (HR) for eMASS Criteria IR vs FR (MD=1.2, p&lt;0.001; HR=5.24, 95%CI=3.71-7.41, p&lt;0.001) were substantially higher than for RECIST SD vs PR (MD=0.3, p=0.237; HR=1.42, 95%CI=0.79-2.57, p=0.241), Choi Criteria SD vs PR (MD=0.4, p=0.003; HR=1.86, 95%CI=1.22-2.83, p=0.004), or MASS Criteria IR vs FR (MD=0.2, p=0.051; HR=1.37, 95%CI=1.00-1.89, p=0.052), indicating that patients with eMASS IR were 5 times more likely to progress than patients with FR. Conclusions: A quantitative CT imaging biomarker designed to measure initial changes in the vascular tumor burden is highly predictive of PFS in patients with metastatic RCC treated with AAG therapy. [Table: see text]
The kinase TBK1 controls IgA class switching by negatively regulating noncanonical NF-κB signaling
Authors: Jin Jin, Yichuan Xiao, Jae-Hoon Chang, Jiayi Yu, Hongbo Hu, Robyn Starr, George C Brittain, Mikyoung Chang, Xuhong Cheng, Shao-Cong Sun
Journal: Nature Immunology (2012)
Abstract 14888: Lipid Changes 8 Years Post Gastric Bypass in Adolescents With Severe Obesity
Authors: Amy S Shah, Todd Jenkins, Elaine M Urbina, Shelley Kirk, Robert Siegel, Thomas Inge
Journal: Circulation (2015)

Introduction: Severe obesity in adolescents is increasing and few effective treatments exist. Weight loss surgery is one option, but the extent to which surgery influences cardiovascular risk factors such as lipids in youth is not clear. We studied the impact of weight loss surgery in adolescents with severe obesity on lipid parameters in the Follow-up of Adolescent Bariatric Surgery-5+ (FABS-5+) study &gt;5 years postoperatively. Hypothesis: We predicted weight loss surgery would be associated with a greater improvement in lipids compared to no surgery. Methods: Adolescents and young adults who either underwent laparoscopic Roux-en Y gastric bypass (RYGB; “Surgical”) or who were seeking weight loss treatment (“Non-Surgical”) in 2001-2007 were recruited for the FABS-5+ follow-up study between 2011-2013. Baseline (pre-treatment) BMI and fasting lipids and TG/HDL-C ratio (representing small dense LDL particles) were abstracted from charts. Follow-up data were obtained at a research visit. Changes in BMI and lipids were evaluated using paired t-tests and Wilcoxon signed rank tests. Results: At baseline, surgical participants (n=58; 80% of all RYGB cases performed in 2001-2007) were a mean±SD age of 17±2 years and 25±2 at follow-up. 86% were Caucasian and 64% were female. After RYGB, BMI was 29% lower than baseline (p&lt;0.01). All lipids (except total cholesterol) significantly improved with the largest changes in HDL-C and TG/HDL-C ratio. In the non-surgical comparison group (n=30) from baseline to follow up (ages 15±2 and 22±2 years, respectively), BMI increased by 8% but lipid parameters were similar (Table). Conclusions: This is the longest term and most complete follow-up of youth following RYGB. Weight loss was durably maintained and significant improvements in lipid profile were observed. Whether these lipid improvements translate into reductions in atherosclerosis and cardiovascular events overtime remains to be determined.
Comparative effectiveness research in renal cell carcinoma: Lenvatinib with everolimus as a potential new treatment option.
Authors: Gabriel Tremblay, Corey Pelletier, Unnati Majethia, Anna Forsythe
Journal: Journal of Clinical Oncology (2016)

27 Background: Renal cell carcinoma (RCC) is the most common type of kidney cancer and represents about 90% of all kidney cancers. As comprehensive comparison of the efficacy associated with mRCC treatments is not available, the goal of this research was to provide a comparative effectiveness analysis including overall survival (OS) and progression free survival (PFS) for first and second line treatments. Methods: Systematic literature review yielded the following randomized active-controlled studies: lenvatinib + everolimus (LEN+EVE) versus everolimus (EVE), axinitib (AXI) versus sorafenib (SOR), cabozantinib (CAB) versus EVE, nivolumab (NIV) versus EVE, and pazopanib (PAZ) versus sunitinib (SUN). In addition, placebo-controlled studies were identified for EVE, PAZ, and SOR. An indirect treatment comparison (ITC) was performed on OS and PFS hazard ratios (HR). Results: Scenario A presents the HR and confidence intervals (95% CI) generated with ITC of all treatments against EVE. In scenario B, the HR of LEN + EVE are compared to all treatment options. Only LEN + EVE and CAB demonstrated significance against EVE for both OS and PFS. LEN + EVE proved to be significant against EVE, PAZ, SOR, SUN, AXI and NIV for PFS and against EVE, SOR and AXI for OS. The use of crossover trials in the network for the treatment compared to placebo remains a potential bias in the results. Conclusions: Even if limitations exist regarding the use of ITC, the option of LEN+EVE demonstrated a strong comparative effectiveness profile for both OS and PFS. [Table: see text]
Gastrin-releasing Peptide Receptor Imaging in Breast Cancer Using the Receptor Antagonist <sup>68</sup>Ga-RM2 And PET
Authors: Christian Stoykow, Thalia Erbes, Helmut R Maecke, Stefan Bulla, Mark Bartholomä, Sebastian Mayer, Vanessa Drendel, Peter Bronsert, Martin Werner, Gerald Gitsch, Wolfgang A Weber, Elmar Stickeler, Philipp T Meyer
Journal: Theranostics (2016)

Introduction:The gastrin-releasing peptide receptor (GRPR) is overexpressed in breast cancer.The present study evaluates GRPR imaging as a novel imaging modality in breast cancer by employing positron emission tomography (PET) and the GRPR antagonist 68 Ga-RM2.Methods: Fifteen female patients with biopsy confirmed primary breast carcinoma (3 bilateral tumors; median clinical stage IIB) underwent 68 Ga-RM2-PET/CT for pretreatment staging.In vivo tumor uptake of 68 Ga-RM2 was correlated with estrogen (ER) and progesterone (PR) receptor expression, HER2/neu status and MIB-1 proliferation index in breast core biopsy specimens.Results: 13/18 tumors demonstrated strongly increased 68 Ga-RM2 uptake compared to normal breast tissue (defined as PET-positive).All PET-positive primary tumors were ER-and PR-positive (13/13) in contrast to only 1/5 PET-negative tumors.Mean SUV MAX of ER-positive tumors was 10.6±6.0 compared to 2.3±1.0 in ER-negative tumors (p=0.016).In a multivariate analysis including ER, PR, HER2/neu and MIB-1, only ER expression predicted 68 Ga-RM2 uptake (model: r 2 =0.55, p=0.025).Normal breast tissue showed inter-and intraindividually variable, moderate GRPR binding (SUV MAX 2.3±1.0), while physiological uptake of other organs was considerably less except pancreas.Of note, 68 Ga-RM2-PET/CT detected internal mammary lymph nodes with high 68 Ga-RM2 uptake (n=8), a contralateral axillary lymph node metastasis (verified by biopsy) and bone metastases (n=1; not detected by bone scan and CT).Conclusion: Our study demonstrates that 68 Ga-RM2-PET/CT is a promising imaging method in ER-positive breast cancer.In vivo GRPR binding assessed by 68 Ga-RM2-PET/CT correlated with ER expression in primary tumors of untreated patients.
Myeloid cells are required for PD-1/PD-L1 checkpoint activation and the establishment of an immunosuppressive environment in pancreatic cancer
Authors: Yaqing Zhang, Ashley Velez-Delgado, Esha Mathew, Dongjun Li, Flor M Mendez, Kevin Flannagan, Andrew D Rhim, Diane M Simeone, Gregory L Beatty, Marina Pasca di Magliano
Journal: Gut (2016)

Pancreatic cancer is characterised by the accumulation of a fibro-inflammatory stroma. Within this stromal reaction, myeloid cells are a predominant population. Distinct myeloid subsets have been correlated with tumour promotion and unmasking of anti-tumour immunity.The goal of this study was to determine the effect of myeloid cell depletion on the onset and progression of pancreatic cancer and to understand the relationship between myeloid cells and T cell-mediated immunity within the pancreatic cancer microenvironment.Primary mouse pancreatic cancer cells were transplanted into CD11b-diphtheria toxin receptor (DTR) mice. Alternatively, the iKras* mouse model of pancreatic cancer was crossed into CD11b-DTR mice. CD11b+ cells (mostly myeloid cell population) were depleted by diphtheria toxin treatment during tumour initiation or in established tumours.Depletion of myeloid cells prevented KrasG12D-driven pancreatic cancer initiation. In pre-established tumours, myeloid cell depletion arrested tumour growth and in some cases, induced tumour regressions that were dependent on CD8+ T cells. We found that myeloid cells inhibited CD8+ T-cell anti-tumour activity by inducing the expression of programmed cell death-ligand 1 (PD-L1) in tumour cells in an epidermal growth factor receptor (EGFR)/mitogen-activated protein kinases (MAPK)-dependent manner.Our results show that myeloid cells support immune evasion in pancreatic cancer through EGFR/MAPK-dependent regulation of PD-L1 expression on tumour cells. Derailing this crosstalk between myeloid cells and tumour cells is sufficient to restore anti-tumour immunity mediated by CD8+ T cells, a finding with implications for the design of immune therapies for pancreatic cancer.