tbuckley/cabot-search huggingface dataset:
Gallium‐Loaded Dissolvable Microfilm Constructs that Provide Sustained Release of Ga<sup>3+</sup> for Management of Biofilms
Authors: Maggie Herron, Michael J. Schurr, Christopher J. Murphy, Jonathan F. McAnulty, Charles J. Czuprynski, Nicholas L. Abbott
Journal: Advanced Healthcare Materials (2015)

The persistence of bacterial biofilms in chronic wounds delays wound healing. Although Ga(3+) can inhibit or kill biofilms, precipitation as Ga(OH)3 has prevented its use as a topical wound treatment. The design of a microfilm construct comprising a polyelectrolyte film that releases noncytotoxic concentrations of Ga(3+) over 20 d and a dissolvable micrometer-thick film of polyvinylalcohol that enables facile transfer onto biomedically important surfaces is reported. By using infrared spectroscopy, it is shown that the density of free carboxylate/carboxylic acid and amine groups within the polyelectrolyte film regulates the capacity of the construct to be loaded with Ga(3+) and that the density of covalent cross-links introduced into the polyelectrolyte film (amide-bonds) controls the release rate of Ga(3+) . Following transfer onto the wound-contact surface of a biologic wound dressing, an optimized construct is demonstrated to release ≈0.7 μg cm(-2) d(-1) of Ga(3+) over 3 weeks, thus continuously replacing Ga(3+) lost to precipitation. The optimized construct inhibits formation of P. aeruginosa (two strains; ATCC 27853 and PA01) biofilms for up to 4 d and causes pre-existing biofilms to disperse. Overall, this study provides designs of polymeric constructs that permit facile modification of the wound-contacting surfaces of dressings and biomaterials to manage biofilms.
Origin and evolution of HLA class I pseudogenes.
Authors: A L Hughes
Journal: Molecular Biology and Evolution (1995)

The HLA (human major histocompatibility complex, or MHC) region includes three types of class I MHC genes: (1) class Ia loci (HLA-A, -B, and -C), which are highly expressed and polymorphic; (2) class Ib loci, which have much reduced expression and polymorphism; and (3) unexpressed class I pseudogenes. Phylogenetic analysis suggests that both class Ib loci and class I pseudogenes arose by duplication of class Ia loci. 5' regulatory elements conserved in class Ia genes are not conserved in either class Ib or class I pseudogenes, but the former show evidence of purifying selection at nonsynonymous sites in coding regions that is lacking in the latter. In the HLA class I region, there is little correspondence between map distance and phylogenetic distance, suggesting a complex history of tandem gene duplications. Furthermore, separate phylogenetic analysis of different gene regions suggests that several class I genes are evolutionary chaemeras, which presumably have arisen as a result of a process of interlocus recombination. For example, the 5' flanking region of the HLA-92 pseudogene was donated by a gene related to HLA-B and -C; and the HLA-A gene arose when exons 1-3 (and intervening introns) were donated to a gene related to the HLA-70 pseudogene by a gene related to HLA-B and -C.
Loss of GPR3 reduces the amyloid plaque burden and improves memory in Alzheimer’s disease mouse models
Authors: Yunhong Huang, Aneta Skwarek-Maruszewska, Katrien Horré, Elke Vandewyer, Leen Wolfs, An Snellinx, Takashi Saito, Enrico Radaelli, Nikky Corthout, Julien Colombelli, Adrian C. Lo, Leen Van Aerschot, Zsuzsanna Callaerts-Vegh, Daniah Trabzuni, Koen Bossers, Joost Verhaagen, Mina Ryten, Sebastian Munck, Rudi D’Hooge, Dick F. Swaab, John Hardy, Takaomi C. Saido, Bart De Strooper, Amantha Thathiah
Journal: Science Translational Medicine (2015)

Loss of GPR3 reduced amyloid plaque burden and improved cognition in four mouse models of Alzheimer’s disease, suggesting that GPR3 may be a potential therapeutic target.
Intensive chemoimmunotherapy and bilateral globe irradiation as initial therapy for primary intraocular lymphoma
Authors: Chan Yoon Cheah, Sarah Milgrom, Dai Chihara, Dan S. Gombos, Chelsea C. Pinnix, Bouthaina S. Dabaja, Nathan H. Fowler
Journal: Neuro-Oncology (2015)

Primary intraocular lymphoma is a rare variant of primary CNS lymphoma for which the optimum treatment strategy remains unknown.We performed a retrospective single-center study including patients who underwent uniform management from October 2007 in which patients were offered sequential rituximab, methotrexate, procarbazine, and vincristine (R-MPV) followed by binocular radiotherapy and consolidative high-dose cytarabine.Eleven patients with median age 66 years (range, 48-72) were included. All patients received binocular radiotherapy to a median dose of 36 Gy (range, 30.6-39.6) in 20 fractions. Grade 3+ anemia, thrombocytopenia, and neutropenia occurred in 1 (9%), 2 (18%), and 3 (27%) patients, respectively; raised creatinine and peripheral sensory neuropathy occurred in 4 (36%) and 3 (27%) patients, respectively. Grade 3+ ocular toxicities included cataract formation and keratitis in 6 (54%) and 3 (27%) patients, respectively. Ten patients (91%) achieved complete response and 1 (9%) partial response. After median follow-up of 4.2 years (range, 1.8-7.6), the median progression-free survival was 3.8 years and the estimated 4-year overall survival was 75.8% (95% CI: 30.5%-93.7%). The initial site of disease progression was the CNS in 4 of 7 patients (57%) and within the eye in 3 of 7 (43%). Five patients achieved responses to salvage therapies.Combined modality treatment with R-MPV, binocular radiation, and high-dose cytarabine is effective with moderate toxicity. Both local and CNS relapses occur; however, the achievement of second and subsequent remissions is possible.
Reactivation of p53 by a Cytoskeletal Sensor to Control the Balance Between DNA Damage and Tumor Dissemination
Authors: Cecilia Herraiz, Fernando Calvo, Pahini Pandya, Gaia Cantelli, Irene Rodriguez-Hernandez, Jose L. Orgaz, NaRa Kang, Tinghine Chu, Erik Sahai, Victoria Sanz-Moreno
Journal: JNCI Journal of the National Cancer Institute (2015)

Background:Abnormal cell migration and invasion underlie metastasis, and actomyosin contractility is a key regulator of tumor invasion. The links between cancer migratory behavior and DNA damage are poorly understood.
Reply to P.F. Pinsky, C.P. Crum, and M.W. McIntosh et al
Authors: Usha Menon, Jatinderpal K. Kalsi, Aleksandra Gentry-Maharaj, Andy Ryan, Matthew Burnell, Max Parmar, Lesley Fallowfield, Stuart Campbell, Alistair McGuire, Steven Skates, Ian Jacobs
Journal: Journal of Clinical Oncology (2015)
THE SELF-INFLICTED INJURY
Authors: DAVID J. FLICKER
Journal: American Journal of Psychiatry (1942)

According to Karpman(10), "The material for malingering must come from the unconscious reservoir of the individual.....It is a rather frequent observation that malingerers often press into service a minor experience for the purpose of gaining desired ends." It is a reasonable assumption, I believe, to state that the accidental axe cut last year determined the form and nature of this patient's self-inflicted wound. However, I do not agree with Hulett(3) who says, "It is indeed devastating to recognize as we must that all men are not possessed of manhood and that the yellow streak down the backs of some of our fellows is invisible to the unaided human eye," since I believe more frequently than not that the sufferer of the self-inflicted wound is neither a moral nor a physical coward. He may not agree with what is the accepted community goal. He does show determination and stamina in attaining his personal desire. We have here a man who after a milder form of malingering had failed attempted to produce the desired end by a self-inflicted wound. It is my impression that the man with the self-inflicted wound is a malingerer of the severest type. This act was not a suicidal gesture nor was it performed to obtain sympathy or compensation, but rather merely to obtain release from what was to him an uncomfortable and intolerable environmental situation. I believe that henceforth the definition of malingering with reference to the armed forces should stress the intentional production of disease in addition to exaggeration and simulation.
A two-stage treatment of lentigo maligna using ablative laser therapy followed by imiquimod: excellent cosmesis, but frequent recurrences on the nose
Authors: K. Greveling, K. de Vries, M.B.A. van Doorn, E.P. Prens
Journal: British Journal of Dermatology (2015)

Journal Article A two‐stage treatment of lentigo maligna using ablative laser therapy followed by imiquimod: excellent cosmesis, but frequent recurrences on the nose Get access K. Greveling, K. Greveling Department of Dermatology Erasmus MC University Medical Center Rotterdam Burg s'Jacobplein 51 3015 CA Rotterdam the Netherlands Search for other works by this author on: Oxford Academic Google Scholar K. de Vries, K. de Vries Department of Dermatology University Medical Center Groningen Groningen the Netherlands Search for other works by this author on: Oxford Academic Google Scholar M.B.A. van Doorn, M.B.A. van Doorn Department of Dermatology Erasmus MC University Medical Center Rotterdam Burg s'Jacobplein 51 3015 CA Rotterdam the Netherlands Search for other works by this author on: Oxford Academic Google Scholar E.P. Prens E.P. Prens Department of Dermatology Erasmus MC University Medical Center Rotterdam Burg s'Jacobplein 51 3015 CA Rotterdam the Netherlands Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 174, Issue 5, 1 May 2016, Pages 1134–1136, https://doi.org/10.1111/bjd.14330 Published: 01 May 2016
Antibody Drug Conjugates for Cancer Therapy
Authors: Paul Polakis
Journal: Pharmacological Reviews (2015)

Antibody drug conjugates (ADCs) constitute a family of cancer therapeutics designed to preferentially direct a cytotoxic drug to cells expressing a cell-surface antigen recognized by an antibody. The antibody and drug are linked through chemistries that enable release of the cytotoxic drug or drug adduct upon internalization and digestion of the ADC by the cell. Over 40 distinct ADCs, targeting an array of antigens and utilizing a variety of drugs and linkers, are undergoing clinical evaluation. This review primarily covers ADCs that have advanced to clinical investigation with a particular emphasis on how the individual targets, linker chemistries, and appended drugs influence their behavior.
Local Nerve Blocks for Postoperative Analgesia
Authors: J Edmonds-Seal, G M C Paterson, A B Loach
Journal: Journal of the Royal Society of Medicine (1980)

The effect of local nerve blockade on the relief of postoperative pain is reported in a series of 167 patients who underwent surgery of the arm, knee or foot. In 80% of cases analgesics were not required within 4 hours postoperatively, and in 39% analgesics were not required within 8 hours. Conventional methods of postoperative pain relief are not always effective. Local nerve blockade can be used to provide complete analgesia after limb surgery and is therefore of great value to postoperative care.
Guide to the Internet: Introducing the Internet
Authors: M. Pallen
Journal: BMJ (1995)

The benefits to medical practitioners of using the Internet are growing rapidly as the Internet becomes easier to use and ever more biomedical resources become available on line. The Internet is the largest computer network in the world; it is also a virtual community, larger than many nation states, with its own rules of behaviour or “netiquette.” There are several types of Internet connection and various ways of acquiring a connection. Once connected, you can obtain, free of charge, programs that allow easy use of the Internet's resources and help on how to use these resources; you can access many of these resources through the hypertext references in the on line version of this series (go to http://www.bmj.com/bmj/ to reach the electronic version). You can then explore the various methods for accessing, manipulating, or disseminating data on the Internet, such as electronic mail, telnet, file transfer protocol, and the world wide web. Results from a search of the world wide web for information on the rare condition of Recklinghausen's neurofibromatosis illustrate the breadth of medical information available on the Internet. Imagine a working environment where, without moving from your desk in, say, London, you could:
The Opposing Function of STAT3 as an Oncoprotein and Tumor Suppressor Is Dictated by the Expression Status of STAT3β in Esophageal Squamous Cell Carcinoma
Authors: Hai-Feng Zhang, Ye Chen, Chengsheng Wu, Zhi-Yong Wu, David J. Tweardy, Abdulraheem Alshareef, Lian-Di Liao, Yu-Jie Xue, Jian-Yi Wu, Bo Chen, Xiu-E Xu, Keshav Gopal, Nidhi Gupta, En-Min Li, Li-Yan Xu, Raymond Lai
Journal: Clinical Cancer Research (2015)

Abstract Purpose: STAT3 is known to have both oncogenic and tumor suppressive effects, but the regulation of these opposing effects is elusive. We hypothesized that STAT3β, one of the two STAT3 isoforms, is the key determinant in this context. Experimental Design: The prognostic significance of STAT3β and phospho-STAT3αY705 (pSTAT3αY705) was evaluated in 286 cases of patients with esophageal squamous cell carcinoma (ESCC). STAT3β-induced changes in the chemosensitivity to cisplatin and 5-fluorouracil were assessed both in vitro and in vivo. STAT3β-induced changes in the frequency of cancer stem cells were evaluated using Hoechst and CD44 staining. How STAT3β regulates STAT3α was determined using immunoprecipitation, confocal microscopy, DNA-binding, and chromatin immunoprecipitation-PCR. Results: STAT3β expression is an independent protective prognostic marker in patients with ESCC, which strongly correlated with longer overall survival (P = 0.0009) and recurrence-free survival (P = 0.0001). STAT3β significantly decreased the cancer stem cell population, and sensitized ESCC cells to cisplatin and 5-fluorouracil in tumor xenografts. Mechanistically, STAT3β markedly attenuated the transcription activity of STAT3α via inducing STAT3α:STAT3β heterodimers. However, the heterodimer formation decreased the binding between STAT3α and PTPN9 (better known as PTP-MEG2), a protein tyrosine phosphatase, thereby promoting the phosphorylation of STAT3αY705 and enhancing its nuclear translocation and DNA binding. Correlating with this, high STAT3β expression converts the prognostic value of pSTAT3αY705 from unfavorable to favorable in patients with ESCC. Conclusions: STAT3β suppresses chemoresistance and cancer stemness by blocking the transcriptional activity of STAT3α. The paradoxical increase in pSTAT3αY705 induced by STAT3β carries important implications as to how the biologic and prognostic significance of STAT3 in cancers should be interpreted. Clin Cancer Res; 22(3); 691–703. ©2015 AACR.
The renin–angiotensin system promotes arrhythmogenic substrates and lethal arrhythmias in mice with non-ischaemic cardiomyopathy
Authors: Chinatsu Yamada, Koichiro Kuwahara, Masatoshi Yamazaki, Yasuaki Nakagawa, Toshio Nishikimi, Hideyuki Kinoshita, Yoshihiro Kuwabara, Takeya Minami, Yuko Yamada, Junko Shibata, Kazuhiro Nakao, Kosai Cho, Yuji Arai, Haruo Honjo, Kaichiro Kamiya, Kazuwa Nakao, Takeshi Kimura
Journal: Cardiovascular Research (2015)

AimsThe progression of pathological left ventricular remodelling leads to cardiac dysfunction and contributes to the occurrence of malignant arrhythmias and sudden cardiac death.The underlying molecular mechanisms remain unclear, however.Our aim was to examine the role of the renin -angiotensin system (RAS) in the mechanism underlying arrhythmogenic cardiac remodelling using a transgenic mouse expressing a cardiac-specific dominant-negative form of neuron-restrictive silencer factor (dnNRSF-Tg).This mouse model exhibits progressive cardiac dysfunction leading to lethal arrhythmias. Methods and resultsSubcutaneous administration of aliskiren, a direct renin inhibitor, significantly suppressed the progression of pathological cardiac remodelling and improved survival among dnNRSF-Tg mice while reducing arrhythmogenicity.Genetic deletion of the angiotensin type 1a receptor (AT1aR) similarly suppressed cardiac remodelling and sudden death.In optical mapping analyses, spontaneous ventricular tachycardia (VT) and fibrillation (VF) initiated by breakthroughtype excitations originating from focal activation sites and maintained by functional re-entry were observed in dnNRSF-Tg hearts.Under constant pacing, dnNRSF-Tg hearts exhibited markedly slowed conduction velocity, which likely contributes to the arrhythmogenic substrate.Aliskiren treatment increased conduction velocity and reduced the incidence of sustained VT.These effects were associated with suppression of cardiac fibrosis and restoration of connexin 43 expression in dnNRSF-Tg ventricles. ConclusionRenin inhibition or genetic deletion of AT1aR suppresses pathological cardiac remodelling that leads to the generation of substrates maintaining VT/VF and reduces the occurrence of sudden death in dnNRSF-Tg mice.These findings demonstrate the significant contribution of RAS activation to the progression of arrhythmogenic substrates.
Ofatumumab in relapsed nodular lymphocyte-predominant Hodgkin lymphoma: results of a phase II study from the German Hodgkin study group
Authors: D A Eichenauer, H Goergen, A Plütschow, D Wongso, K Behringer, S Kreissl, I Thielen, T Halbsguth, P J Bröckelmann, M Fuchs, B Böll, B von Tresckow, P Borchmann, A Engert
Journal: Leukemia (2015)
Motif mimetic of epsin perturbs tumor growth and metastasis
Authors: Yunzhou Dong, Hao Wu, H.N. Ashiqur Rahman, Yanjun Liu, Satish Pasula, Kandice L. Tessneer, Xiaofeng Cai, Xiaolei Liu, Baojun Chang, John McManus, Scott Hahn, Jiali Dong, Megan L. Brophy, Lili Yu, Kai Song, Robert Silasi-Mansat, Debra Saunders, Charity Njoku, Hoogeun Song, Padmaja Mehta-D’Souza, Rheal Towner, Florea Lupu, Rodger P. McEver, Lijun Xia, Derek Boerboom, R. Sathish Srinivasan, Hong Chen
Journal: Journal of Clinical Investigation (2015)

Tumor angiogenesis is critical for cancer progression. In multiple murine models, endothelium-specific epsin deficiency abrogates tumor progression by shifting the balance of VEGFR2 signaling toward uncontrolled tumor angiogenesis, resulting in dysfunctional tumor vasculature. Here, we designed a tumor endothelium–targeting chimeric peptide (UPI) for the purpose of inhibiting endogenous tumor endothelial epsins by competitively binding activated VEGFR2. We determined that the UPI peptide specifically targets tumor endothelial VEGFR2 through an unconventional binding mechanism that is driven by unique residues present only in the epsin ubiquitin–interacting motif (UIM) and the VEGFR2 kinase domain. In murine models of neoangiogenesis, UPI peptide increased VEGF-driven angiogenesis and neovascularization but spared quiescent vascular beds. Further, in tumor-bearing mice, UPI peptide markedly impaired functional tumor angiogenesis, tumor growth, and metastasis, resulting in a notable increase in survival. Coadministration of UPI peptide with cytotoxic chemotherapeutics further sustained tumor inhibition. Equipped with localized tumor endothelium–specific targeting, our UPI peptide provides potential for an effective and alternative cancer therapy.
AGS16F Is a Novel Antibody Drug Conjugate Directed against ENPP3 for the Treatment of Renal Cell Carcinoma
Authors: Fernando Doñate, Arthur Raitano, Kendall Morrison, Zili An, Linnette Capo, Hector Aviña, Sher Karki, Karen Morrison, Peng Yang, Jimmy Ou, Ryuichi Moriya, Yuriy Shostak, Faisal Malik, Rossana Nadell, Wendy Liu, Daulet Satpayev, John Atkinson, Ingrid B.J. Joseph, Daniel S. Pereira, Pia M. Challita-Eid, David R. Stover
Journal: Clinical Cancer Research (2015)

New cancer-specific antigens are required for the design of novel antibody-drug conjugates (ADC) that deliver tumor-specific and highly potent cytotoxic therapy.Suppression subtractive hybridization identified ectonucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3 or CD203c) as a potential human cancer-specific antigen. Antibodies targeting the extracellular domain of human ENPP3 were produced and selected for specific binding to ENPP3. Expression of ENPP3 in normal and cancer tissue specimens was evaluated by immunohistochemistry (IHC). ADCs comprising anti-ENPP3 Ab conjugated with maleimidocaproyl monomethyl auristatin F via a noncleavable linker (mcMMAF) were selected for therapeutic potential using binding and internalization assays, cytotoxicity assays, and tumor growth inhibition in mouse xenograft models. Pharmacodynamic markers were evaluated by IHC in tissues and ELISA in blood.ENPP3 was highly expressed in clear cell renal cell carcinoma: 92.3% of samples were positive and 83.9% showed high expression. By contrast, expression was negligible in normal tissues examined, with the exception of the kidney. High expression was less frequent in papillary renal cell carcinoma and hepatocellular carcinoma samples. AGS16F, an anti-ENPP3 antibody-mcMMAF conjugate, inhibited tumor growth in three different renal cell carcinoma (RCC) xenograft models. AGS16F localized to tumors, formed the active metabolite Cys-mcMMAF, induced cell-cycle arrest and apoptosis, and increased blood levels of caspase-cleaved cytokeratin-18, a marker of epithelial cell death.AGS16F is a promising new therapeutic option for patients with RCC and is currently being evaluated in a phase I clinical trial.
P63 Neurological sequelae of acute and chronic HEV genotype 3 infection
Authors: H Dalton, N Kamar, H R Dalton, R Bendall, F Keane, J M Peron, P Cintas, L Pruhomme, J M Mansuy, L Rostaing, S Ijaz, J Izopet
Journal: Gut (2010)

Introduction  HEV is an emerging infection in the developed world. It differs from HEV endemic in developing countries as it is caused by HEV genotype 3, is thought to be a porcine zoonosis, has a predilection for middle aged/elderly males, and can cause chronic infection in the immunosuppressed. Neurological symptoms associated with HEV infection have been described in both developed and developing countries. However, to date, no systematic study of the neurological sequelae of HEV has been undertaken.  Aim  To describe the clinical and laboratory features of the neurological complications of HEV genotype 3 infection.  Method  Retrospective review of 126 patients with locally acquired acute and chronic HEV genotype 3 infection from two University Hospitals: Truro (UK) and Toulouse (France).  Results  Neurological complications were seen in 7/126 (5.5%) of patients with HEV. The neurological complications included inflammatory polyradiculopathy (n=3), Guillain-Barre Syndrome (n=1), bilateral brachial neuritis (n=1), encephalitis (n=1), ataxia/proximal myopathy (n=1). Three cases occurred during acute HEV infection in non-immunocompromised patients and four occurred in immunocompromised patients with chronic HEV infection (three transplant patients, and one HIV-positive patient). HEV RNA was detected in the cerebrospinal fluid (CSF) of all four patients with chronic HEV infection and neurological symptoms. In one of these cases unique HEV quasispecies were documented in the CSF. In patients with acute HEV who had neurological symptoms, HEV RNA was absent in the CSF (n=2). Follow-up was up to 4 years and neurological outcomes were: complete resolution (n=3), improvement with residual neurological deficit (n=3), no improvement (n=1).  Conclusion  Neurological symptoms are an emerging extra-hepatic manifestation of HEV infection. The pathophysiology is not understood, but HEV may be neurotropic, as unique HEV quasispecies were isolated from the CSF of one of our cases.