tbuckley/cabot-search huggingface dataset:
TWEAK-Fn14 Signaling Activates Myofibroblasts to Drive Progression of Fibrotic Kidney Disease
Authors: Ivan G. Gomez, Allie M. Roach, Naoki Nakagawa, Aldo Amatucci, Bryce G. Johnson, Kadeshia Dunn, Mark C. Kelly, Gamze Karaca, Timothy S. Zheng, Suzanne Szak, Claire M. Peppiatt-Wildman, Linda C. Burkly, Jeremy S. Duffield
Journal: Journal of the American Society of Nephrology (2016)

The identification of the cellular origins of myofibroblasts has led to the discovery of novel pathways that potentially drive myofibroblast perpetuation in disease. Here, we further investigated the role of innate immune signaling pathways in this process. In mice, renal injury-induced activation of pericytes, which are myofibroblast precursors attached to endothelial cells, led to upregulated expression of TNF receptor superfamily member 12a, also known as fibroblast growth factor-inducible 14 (Fn14), by these cells. In live rat kidney slices, administration of the Fn14 ligand, TNF-related weak inducer of apoptosis (TWEAK), promoted pericyte-dependent vasoconstriction followed by pericyte detachment from capillaries. In vitro , administration of TWEAK activated and differentiated pericytes into cytokine-producing myofibroblasts, and further activated established myofibroblasts in a manner requiring canonical and noncanonical NF- κ B signaling pathways. Deficiency of Fn14 protected mouse kidneys from fibrogenesis, inflammation, and associated vascular instability after in vivo injury, and was associated with loss of NF- κ B signaling. In a genetic model of spontaneous CKD, therapeutic delivery of anti-TWEAK blocking antibodies attenuated disease progression, preserved organ function, and increased survival. These results identify the TWEAK-Fn14 signaling pathway as an important factor in myofibroblast perpetuation, fibrogenesis, and chronic disease progression.
Surveillance after colonic neoplasia: to die of success
Authors: R. Jover
Journal: Endoscopy (2013)

The main aims of surveillance colonoscopy are to reduce the incidence and mortality of colorectal cancer (CRC), removing adenomas, and detecting early-stage CRC. However, colonoscopy is an expensive and invasive procedure, and therefore surveillance colonoscopy should be targeted toward the patients who are most likely to benefit, and at the minimum frequency required to provide adequate protection against the development of cancer [1]. No studies about postpolypectomy surveillance have directly demonstrated the benefit of a reduction in CRC incidence or mortality; however, some studies have suggested that follow-up colonoscopy appears to be effective in reducing the risk of CRC among patients with previous adenoma [2] [3], and this is the rationale for surveillance colonoscopy. Moreover, surveillance intervals are arbitrary and not based on clinical trials, and available evidence is scarce and of low quality. Although the main outcome indicator used in postpolypectomy surveillance is advanced adenoma, this is only a surrogate marker of the main end point, which is CRC. The rate of progression from advanced adenoma to CRC is also unknown, but is probably low [4].
Comparative Study of Tc-99m MIBI and Tl-201 SPECT in Predicting Chemotherapeutic Response in Non–Small-Cell Lung Cancer
Authors: Y Nishiyama, Y Yamamoto, K Satoh, M Ohkawa, K Kameyama, E Hayashi, J Fujita, M Tanabe
Journal: Clinical Nuclear Medicine (2000)

Purpose: Tc-99m MIBI can be excluded from cytosol against its concentration gradient as a suitable transport substrate by P-glycoprotein. Tc-99m MIBI has also been shown to be more effective than Tl-201 chloride for evaluating the response to chemotherapy in patients with small-cell lung cancer. The relation between Tc-99m MIBI accumulation by the tumor and its response to chemotherapy were evaluated in patients with non–small-cell lung cancer (NSCLC) and compared with the same parameters achieved using Tl-201 chloride. Methods: Thirty-eight patients with NSCLC were examined before chemotherapy was begun. They were classified according to the results of a follow-up computed tomogram into two groups: responders were patients in whom there was a ≥50% decrease and nonresponders were patients in whom there was a <50% decrease in the sum of the product of the maximum perpendicular diameters of all measurable lesions. All patients underwent dual-isotope imaging with Tl-201 chloride and Tc-99m MIBI just before chemotherapy. Regions of interest were placed over the tumor uptake (T) and contralateral normal lung tissue (N) areas on one coronal view with a clearly defined lesion, and the T:N ratio and retention index were calculated. Results: The delayed T:N ratio and retention index for Tc-99m MIBI in the responder group were significantly greater (P < 0.05) than those in the nonresponder group. There was no significant correlation between the T:N ratio and retention index and tumor response using Tl-201 chloride. Conclusion: Tc-99m MIBI SPECT may be more effective than Tl-201 chloride SPECT for evaluating the response to chemotherapy in patients with NSCLC.
A10.01 Too much for too little? a retrospective audit on temporal artery biopsies
Authors: N Okonkwo, LA Selvam
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background</h3> Temporal artery biopsies (TAB) are often performed in suspected cases of sight-threatening arteritis. The results of which often do little to change clinical management. While the American College of Rheumatology (ACR) formed a clinical classification criterion in 1990 for diagnosing GCA to ensure early steroid therapy was commences, they acknowledge TAB should ain in establishing a definitive diagnosis. <h3>Aims</h3> The audit aimed to assess if TABs were performed in accordance with the national ACR guideline and whether their results altered course of treatment in suspected GCA. <h3>Method</h3> A retrospective audit of all patients undergoing TAB at a single DGH between 2010 and 2014, identified from the hostopathology database. Main outcome measures included clinical profile and biochemical criteria associated with positive histology; proportion of negative histology patients who were commenced on steroid therapy; Length of TAB' relationship between ACR score and TAB result. <h3>Conclusion</h3> Raised ESR and higher age may be the most useful diagnostic adjunct of GCA. Many histologically negative TAB individuals were nevertheless clinically diagnosed and managed as GCA. Sub-optimal specimen length may be contributing to lack of diagnostic accuracy. Alternative techniques may be warranted in the near future.
Invaginated ampulla of Vater in synchronous malignant intraductal papillary mucinous neoplasm of the pancreas and common bile duct cancer
Authors: J. Han, S. Jang, D. Ma, S. Yoon, D. Lee
Journal: Endoscopy (2013)

A 61-year-old woman was admitted for upper abdominal pain and fever. Laboratory findings showed raised neutrophil ratio and amylase and lipase levels. Abdominal computed tomography (CT) scan revealed diffuse swelling of the pancreas with peripancreatic fluid, and mild dilatation of the mid-pancreatic duct. Endoscopic retrograde cholangiopancreatography (ERCP) showed dimpling of the ampullary orifice ([Fig. 1]). We inserted an endoscopic retrograde pancreatic drain (ERPD) via a guide wire. A pancreatogram showed pancreatic duct dilatation and deformity ([Fig. 2]) and due to stricture of the pancreatic duct orifice, the ERPD required repositioning. During removal of the ERPD for repositioning, the ampullary orifice, which was invaginated, protruded into the duodenal lumen ([Fig. 3]). A biopsy specimen was taken from the invaginated ampullary orifice, and confirmed to be adenocarcinoma. The patient underwent pylorus-preserving pancreaticoduodenectomy. The postoperative pathology report confirmed the diagnosis of a double primary tumor: the first tumor being a malignant intraductal papillary mucinous neoplasm (IPMN) of the pancreas and the other an adenocarcinoma of the common bile duct (CBD). Histologic exam documented anomalous union of pancreaticobiliary duct with short segment common channel and separated incidental IPMN of main duct in pancreas head. Protruded mass of ampulla of Vater was confirmed as CBD originated.
Staff at NHS regulator are left "broken" by culture of bullying
Authors: M. Limb
Journal: BMJ (2013)

Administration of nonmyeloablative chemotherapeutic agents or total body irradiation (TBI) prior to adoptive transfer of tumor-specific T cells may reduce or eliminate immunosuppressive populations such as T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSC). Little is known about these populations during immune reconstitution. This study was designed to understand the reconstitution rate and function of these populations post TBI in melanoma tumor‑bearing mice. Reconstitution rate and suppressive activity of CD4<sup>+</sup>CD25<sup>+</sup>Foxp3<sup>+</sup> Tregs and CD11b<sup>+</sup>Gr1<sup>+</sup> MDSC following TBI-induced lymphopenia was measured in B16 melanoma tumor‑bearing mice. To ablate the rapid reconstitution of suppressive populations, we treated mice with docetaxel, a known chemotherapeutic agent that targets MDSC, in combination with adoptive T cell transfer and dendritic cell immunotherapy. Both Treg and MDSC populations exhibited rapid reconstitution after TBI-induced lymphopenia. Although reconstituted Tregs were just as suppressive as Tregs from untreated mice, MDSC demonstrated enhanced suppressive activity of CD8<sup>+</sup> T cell proliferation compared with endogenous MDSC from tumor-bearing mice. TBI-induced lymphopenia followed by docetaxel treatment improved the efficacy of adoptive T cell transfer and dendritic cell immunotherapy in melanoma-bearing mice, inducing a significant reduction in tumor growth and enhancing survival. Tumor regression correlated with increased CTL activity and persistence of adoptively transferred T cells. Overall, these findings suggest that TBI-induced MDSC are highly immunosuppressive and blocking their rapid reconstitution may improve the efficacy of vaccination strategies and adoptive immunotherapy.
Management of Insomnia
Authors: David J. Kupfer, Charles F. Reynolds
Journal: New England Journal of Medicine (1997)

Insomnia is a common symptom, and clinicians need a diagnostic approach that allows them to choose from among many different types of therapy. This review focuses on the practical management of insomnia in adults1 and on the scientific basis of current treatments.2,3 Reports of insomnia tend to increase with age4 and are more prevalent among women,5 even though laboratory studies show that older men have more disrupted sleep.6,7 People who are divorced, widowed, or separated report having insomnia more often than married people; lower socioeconomic status is also a correlate of insomnia.8 The course of insomnia can vary . . .
An unusual duodenal polyp: Brunner’s gland hyperplasia
Authors: Lucia Sparano, Pietro Cesari, Mauro Lovera, Fausto Zorzi, Alessandro Paterlini
Journal: Endoscopy (2014)

A 52-year-old man with a 5-day history of black stools (melena) was referred to our digestive endoscopy unit for upper gastrointestinal endoscopy. The patient was not taking aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) and he had never smoked cigarettes. He did however have non-insulin dependent diabetes and hypertension. On admission, the results of blood analysis showed a normochromic, normocytic anemia with a hemoglobin (Hb) level of 9.3 g/dL, mean cell volume (MCV) of 89.7 fL, and mean cell hemoglobin (MCH) of 30.5 pg.
Spending to Save — ACOs and the Medicare Shared Savings Program
Authors: Paul B. Ginsburg
Journal: New England Journal of Medicine (2011)

Before the ink was dry on the proposed rule spelling out requirements for accountable care organizations (ACOs) under the Medicare Shared Savings Program, the criticism began coming fast and furious, much of it claiming that the Centers for Medicare and Medicaid Services (CMS) had set the bar way too high. Common themes of the complaints from health care providers were the disadvantages of not knowing ahead of time which Medicare beneficiaries would be attributed to a particular ACO, the fear that the potential savings would be too low in relation to the needed investments, and the concern that the quality . . .
Acidic chitinase primes the protective immune response to gastrointestinal nematodes
Authors: Kevin M Vannella, Thirumalai R Ramalingam, Kevin M Hart, Rafael de Queiroz Prado, Joshua Sciurba, Luke Barron, Lee A Borthwick, Allen D Smith, Margaret Mentink-Kane, Sandra White, Robert W Thompson, Allen W Cheever, Kevin Bock, Ian Moore, Lori J Fitz, Joseph F Urban, Thomas A Wynn
Journal: Nature Immunology (2016)
A Phosphorus Phthalocyanine Formulation with Intense Absorbance at 1000 nm for Deep Optical Imaging
Authors: Yang Zhou, Depeng Wang, Yumiao Zhang, Upendra Chitgupi, Jumin Geng, Yuehang Wang, Yuzhen Zhang, Timothy R. Cook, Jun Xia, Jonathan F. Lovell
Journal: Theranostics (2016)

Although photoacoustic computed tomography (PACT) operates with high spatial resolution in biological tissues deeper than other optical modalities, light scattering is a limiting factor. The use of longer near infrared wavelengths reduces scattering. Recently, the rational design of a stable phosphorus phthalocyanine (P-Pc) with a long wavelength absorption band beyond 1000 nm has been reported. Here, we show that when dissolved in liquid surfactants, P-Pc can give rise to formulations with absorbance of greater than 1000 (calculated for a 1 cm path length) at wavelengths beyond 1000 nm. Using the broadly accessible Nd:YAG pulse laser emission output of 1064 nm, P-Pc could be imaged through 11.6 cm of chicken breast with PACT. P-Pc accumulated passively in tumors following intravenous injection in mice as observed by PACT. Following oral administration, P-Pc passed through the intestine harmlessly, and PACT could be used to non-invasively observe intestine function. When the contrast agent placed under the arm of a healthy adult human, a PACT transducer on the top of the arm could readily detect P-Pc through the entire 5 cm limb. Thus, the approach of using contrast media with extreme absorption at 1064 nm readily enables high quality optical imaging in vitro and in vivo in humans at exceptional depths.
Abstract 1238: Diagnostic and therapeutic potential of nuclear receptor expression in lung cancer
Authors: Yangsik Jeong, Woochang Lee, Yang Xie, Angie L. Bookout, Bong-hyun Kim, Luc Girard, John D. Minna, David J. Mangelsdorf
Journal: Cancer Research (2010)

Abstract Lung cancer is the leading cause of cancer related death with the highest mortality among cancers. Although several studies have been published on prognostic biomarkers for lung cancer patients, little attention has been given to identify diagnostic biomarkers and new therapeutic targets. Nuclear receptors are druggable targets due to their ligand-controlled activity, and indeed have become well-established therapeutic tools for treating patients with strong estrogen receptor alpha (ERα)-positive breast cancer or androgen-dependent prostate cancer. Our aims in this study were (1) to investigate if the NR superfamily as a whole or individually showed diagnostic potential, (2) to evaluate NRs as therapeutic targets using both in vitro cell lines and in vivo xenografts. Utilizing quantitative real-time PCR (QPCR), we profiled the mRNA expression of the NR superfamily in a panel of 56 lung cell lines, including 5 normal human bronchial epithelial cells, 10 immortalized cell lines, 14 small cell lung cancers (SCLCs), and 27 non-SCLCs. All individual cell lines were characterized by DNA fingerprinting and gene expression using the affymetrix U133 A plus B microarray. Unsupervised cluster analysis of the QPCR profile and the microarray signature of the NR superfamily revealed that the NR superfamily was able to segregate normal/immortalized cells from tumor cell lines, and SCLCs from non-SCLCs. Further analysis identified subsets of NRs responsible for this discriminatory ability. In addition, using publicly available microarray datasets, we found that the NR signature has a predictive power with an accuracy of 79% for lung cancer incidence in smokers (n=129), in which a prediction model was constructed in a training set (n=77) using penalized logistic regression (PLR), and validated in a testing cohort (n=52). Finally, preclinical evaluation of a panel of NRs ¬- androgen receptor, ERα, vitamin D receptor, and peroxisome proliferators-activated receptor gamma - for their therapeutic potential showed receptor-specific and ligand-dependent cell growth responses in lung cancer cell lines. Evaluation of one receptor/ligand pair using a mouse xenograft model confirmed receptor-specific tumor growth response in vivo. Collectively, our study provides preclinical evidence that the expression of the NR superfamily yields theragnostic (therapy plus diagnosis) information for predicting lung cancer type and incidence, while simultaneously offering therapeutic targets for potential lung cancer treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1238.
THU0058 B Cell Receptor Editing in Scleroderma Patients Generates Pathogenic Anti-PDGFR Autoantibodies
Authors: G. Moroncini, A. Grieco, G. Nacci, C. Paolini, C. Tonnini, K. N. Pozniak, S. Mori, S. Svegliati, E. Avvedimento, A. Funaro, A. Gabrielli
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Systemic sclerosis or scleroderma (SSc) is a clinically heterogeneous disease of the connective tissue characterized by vascular, immune/inflammatory and fibrotic manifestations. We have hypothesized that the serum of SSc patients contains stimulatory auto-antibodies (auto-abs) directed to the PDGF receptor (PDGFR) that elicit reactive oxygen species (ROS) and collagen production in human fibroblasts<sup>1</sup>. <h3>Objectives</h3> Aim of this study was to analyze the native immune repertoire of SSc patients. <h3>Methods</h3> Memory B cells of two SSc patients were immortalized and screened for PDGFR-autoreactive clones. RNA was extracted from each PDGFR-autoreactive B cell line, reverse-transcribed, and amplified with a set of primers designed to analyze the human immunoglobulin (Ig) gene repertoire. Ig variable (V) regions identified in these clones were expressed as human IgG monoclonal abs and characterized through binding and functional assays. <h3>Results</h3> PCR analysis of rearranged Ig genes suggested the presence of a large panel of V heavy (H) and light (L) chain subgroups. However, subsequent sequencing showed a small panel of VH and VL chains in each B cell line: the same variable Ig sequences were recovered repeatedly from independent PCR amplifications of different VH and VL subgroups and displayed a high frequency of somatic mutations in the complementarity determining regions (CDRs). Ab engineering revealed that 4 different VL chains identified in one SSc patient conferred diverse biological properties to the unique VH chain identified in the same patient: loss of high affinity binding; PDGFR binding without signaling; PDGFR binding with ROS induction; PDGFR binding with ROS and collagen gene induction. This gain in autoreactivity from the nonbinding monoclonal antibody up to the fully agonistic antibody corresponded to a progressive enrichment in positive charge and higher isoelectric point (pI) of the CDRs. These data are consistent with the notion that B cell receptor editing governs B cell tolerance to endogenous antigens, and suppresses autoreactivity by pairing potentially reactive Ig H chains with non-autoreactive L chains. <h3>Conclusions</h3> The repertoire of PDGFR-autoreactive SSc B cells is restricted and somatically mutated. This suggests the hypothesis of a polarization of the immune response towards the autologous PDGFRa under the influence of a strong antigenic drive, the nature of which awaits identification. Stimulatory and non-stimulatory anti-PDGFRa auto-abs coexist in the same SSc patient, they share a common VH chain and have, therefore, a common origin. The CDRs of the shared VH framework might represent a common trait of SSc patients’ IgG, and be used as novel biomarkers of this disease. <h3>References</h3> Baroni SS, NEJM 2006. <h3>Disclosure of Interest</h3> None Declared
Abstract 3539: Targeting levels and oligomerization of mutant nucleophosmin induces differentiation and loss of survival of human AML cells with mutant NPM1
Authors: Ramesh Balusu, Warren Fiskus, Rekha M. Rao, Sreedhar Venkannagari, Narasimha Nalabothula, Casey Williams, Sunil Abhyankar, Joseph McGuirk, Kapil N. Bhalla
Journal: Cancer Research (2011)

Abstract NPM1 is an oligomeric, nucleolar phosphoprotein that functions as a molecular chaperone for both proteins and nucleic acids. NPM1 plays multiple roles in cell growth and proliferation by participating in diverse biological processes, including ribosome biogenesis and transport, centrosome duplication, DNA repair, transcriptional regulation and histone chaperoning. NPM1 has an N-terminal conserved, hydrophobic, oligomerization domain (residues, 1-110), which is common to all isoforms of NPM1 and critical for its chaperone activity. Recently, NSC348884 was identified as a small molecule inhibitor that disrupts NPM1 dimer/oligomer formation, inducing apoptosis of cancer cells. NPM1 is mutated in approximately one-third of patients with AML. The mutant NPM1c+ contains a 4-base insert that results in extra C-terminal residues encoding a nuclear export signal (NES), which causes NPM1c+ to be aberrantly localized in the cytoplasm. Here, we determined the effects of targeting NPM1 in cultured and primary AML cells. Treatment with siRNA to NPM1, which depleted both NPM1c+ and un-mutated NPM1, significantly induced p21, decreased the % of cells in S-phase of the cell cycle, as well as induced differentiation of the AML OCI-AML3 cells that express both NPMc+ and un-mutated NPM1. This was associated with up-regulation of C/EBPα but attenuation of the levels of HOXA9 and MEIS1. Notably, treatment with NPM1 siRNA sensitized OCI-AML3 more than HL-60 cells (expressing only wild-type NPM1) to all-trans retinoic acid (ATRA) and cytarabine. Moreover, inhibition of NPM1 oligomerization by NSC348884-induced apoptosis and sensitized OCI-AML3 and primary AML cells expressing NPM1c+, but not AML or normal CD34+ progenitor cells expressing wild-type NPM1, to ATRA and cytarbine. NSC348884 was also able to sensitize primary AML cells that expressed NPM1c+ as well as FLT3-ITD to ATRA and cytarbine. Addtionally, co-treatment with NSC384884 sensitized these primary AML cells to the lethal effects of the FLT3 kinase inhibitor PKC412 (Novartis Pharma). These results show that attenuating levels or oligomerization of NPM1 selectively induces apoptosis and sensitizes AML cells expressing NPM1c+ alone or with FLT3-ITD to treatment with ATRA, cytarabine and FLT3 kinase inhibitor. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3539. doi:10.1158/1538-7445.AM2011-3539
Critical Moments — Doctors and Patients
Authors: Lenore M. Buckley
Journal: New England Journal of Medicine (2011)

The pale, thin, anxious 9-year-old boy is in pain, stoic, and not very verbal. Gradually, as he nods in answer to probing questions, the physician realizes that this is one of those critical moments: the boy in front of her is seriously ill; a hard journey is beginning.