tbuckley/cabot-search huggingface dataset:
Targeting CD137 enhances the efficacy of cetuximab
Authors: Holbrook E. Kohrt, A. Dimitrios Colevas, Roch Houot, Kipp Weiskopf, Matthew J. Goldstein, Peder Lund, Antonia Mueller, Idit Sagiv-Barfi, Aurelien Marabelle, Ruth Lira, Emily Troutner, Lori Richards, Amanda Rajapaska, Jonathan Hebb, Cariad Chester, Erin Waller, Anton Ostashko, Wen-Kai Weng, Lieping Chen, Debra Czerwinski, Yang-Xin Fu, John Sunwoo, Ronald Levy
Journal: Journal of Clinical Investigation (2014)

Treatment with cetuximab, an EGFR-targeting IgG1 mAb, results in beneficial, yet limited, clinical improvement for patients with head and neck (HN) cancer as well as colorectal cancer (CRC) patients with WT KRAS tumors. Antibody-dependent cell-mediated cytotoxicity (ADCC) by NK cells contributes to the efficacy of cetuximab. The costimulatory molecule CD137 (4-1BB) is expressed following NK and memory T cell activation. We found that isolated human NK cells substantially increased expression of CD137 when exposed to cetuximab-coated, EGFR-expressing HN and CRC cell lines. Furthermore, activation of CD137 with an agonistic mAb enhanced NK cell degranulation and cytotoxicity. In multiple murine xenograft models, including EGFR-expressing cancer cells, HN cells, and KRAS-WT and KRAS-mutant CRC, combined cetuximab and anti-CD137 mAb administration was synergistic and led to complete tumor resolution and prolonged survival, which was dependent on the presence of NK cells. In patients receiving cetuximab, the level of CD137 on circulating and intratumoral NK cells was dependent on postcetuximab time and host FcyRIIIa polymorphism. Interestingly, the increase in CD137-expressing NK cells directly correlated to an increase in EGFR-specific CD8+ T cells. These results support development of a sequential antibody approach against EGFR-expressing malignancies that first targets the tumor and then the host immune system.
Zeroing in on <i>ROS1</i> Rearrangements in Non–Small Cell Lung Cancer
Authors: Magda Stumpfova, Pasi A. Jänne
Journal: Clinical Cancer Research (2012)

Abstract Rimkunas and colleagues report on the development and validation of an immunohistochemical assay evaluating non–small cell lung cancers (NSCLC) for the presence of ROS1 fusions. The diagnostic was validated in a screen of 556 NSCLCs, identifying 9 (1.6%) tumors with oncogenic ROS1 rearrangements. These patients are candidates for ROS1-targeted therapies. Clin Cancer Res; 18(16); 4222–4. ©2012 AACR.
Anti-dsDNA antibodies associated with acute EBV infection in Sjogren's syndrome
Authors: E Y PADALKO
Journal: Annals of the Rheumatic Diseases (2001)

The role of viral infection in the pathogenesis of autoimmune diseases is not clear. Some authors have suggested a role for herpes viruses and retroviruses in the pathogenesis of systemic rheumatic diseases,1-4 whereas others have produced evidence against this idea.5-7 In this report we present a case in which an association was found between Epstein-Barr virus (EBV) infection and anti-DNA antibodies in a patient with Sjogren's syndrome.

A 28 year old woman was diagnosed with Sjogren's syndrome. The clinical presentation …
Challenges from the digital revolution
Authors: M. Dziadzio
Journal: Journal of the Royal Society of Medicine (2006)

We note with interest the recent editorial (January 2006 JRSM1) and letter (January 2006 JRSM2). They reflect facets of the massive growth in communications technology in healthcare. The doctor-patient relationship has been affected by the information available on the Internet and the presence of self-help groups and web sites moderated by expert patients.3 Geographical—but not linguistic—barriers are becoming irrelevant.

Another form of telephone consultation1 of value is the nurse-lead telephone help lines run for patients with chronic conditions by centres of excellence—for instance, the Arthritis Centre, Northwick Park Hospital and the Scleroderma Centre at the Royal Free Hospital, London.

Outsourcing2 is not restricted to moving tasks to lower cost centres: the opposite may occur. For example, on-line journal submission systems have moved tedious data entry away from journals' editorial staff to the submitting authors. Similarly, digital cameras, and easy-to-use software, have allowed physicians to subsume the task of medical photography—albeit at lower quality than qualified medical photographers, who are also scrupulous in obtaining consent and meeting the needs of data protection. Regretfully, medical photography departments are being closed.

The availability of mobile phones with integral digital cameras allows physicians to capture ephemeral signs at the bedside or in the clinic. For instance, a camera phone was used by one of us to acquire an image of a transient rash that allowed the diagnosis of adult onset Still's disease to be reached.

But the use of mobile phones in hospitals remains contentious as they may affect medical equipment.4 Nevertheless, the widespread ownership and reliance on mobile phones makes blanket bans of their use in hospitals unenforceable.

We expect the use of telecommunications in healthcare to expand. It is clear, however, that innovation should be carefully risk assessed and monitored lest the law of unexpected (and unwanted) consequences be invoked.
Nontuberculous mycobacterial disease and Aspergillus-related lung disease in bronchiectasis
Authors: H. Kunst, M. Wickremasinghe, A. Wells, R. Wilson
Journal: European Respiratory Journal (2006)

The aim of the present study was to determine whether patients with bronchiectasis and nontuberculous mycobacteria (NTM) have a higher prevalence of Aspergillus-related lung disease. A series of 30 consecutive patients with bronchiectasis and NTM (cases) were compared with 61 patients with bronchiectasis and no evidence of NTM (controls). Aspergillus serology and computerised tomography of the thorax were used to identify Aspergillus-related lung diseases, including aspergilloma, allergic bronchopulmonary aspergillosis and chronic necrotising pulmonary aspergillosis. The rate of positive Aspergillus serology was higher in cases with NTM disease compared with controls (10 out of 30 versus six out of 61). The radiological features of Aspergillus-related lung disease were also more common among patients with NTM disease than controls (six out of 30 versus none out of 61). This association between NTM disease and Aspergillus-related lung disease remained significant after adjustment for confounding effects of age and lung function (adjusted odds ratio 5.1, 95% confidence interval 1.5-17.0). Patients with bronchiectasis and nontuberculous mycobacterial disease have a higher prevalence of coexisting Aspergillus-related lung disease than patients with bronchiectasis and without nontuberculous mycobacteria. Identification of Aspergillus-related lung disease is important as prognosis amongst undetected cases is invariably poor.
Tubular p53 Regulates Multiple Genes to Mediate AKI
Authors: Dongshan Zhang, Yu Liu, Qingqing Wei, Yuqing Huo, Kebin Liu, Fuyou Liu, Zheng Dong
Journal: Journal of the American Society of Nephrology (2014)

A pathogenic role of p53 in AKI was suggested a decade ago but remains controversial. Indeed, recent work indicates that inhibition of p53 protects against ischemic AKI in rats but exacerbates AKI in mice. One intriguing possibility is that p53 has cell type-specific roles in AKI. To determine the role of tubular p53, we generated two conditional gene knockout mouse models, in which p53 is specifically ablated from proximal tubules or other tubular segments, including distal tubules, loops of Henle, and medullary collecting ducts. Proximal tubule p53 knockout (PT-p53-KO) mice were resistant to ischemic and cisplatin nephrotoxic AKI, which was indicated by the analysis of renal function, histology, apoptosis, and inflammation. However, other tubular p53 knockout (OT-p53-KO) mice were sensitive to AKI. Mechanistically, AKI associated with the upregulation of several known p53 target genes, including Bax, p53-upregulated modulator of apoptosis-α, p21, and Siva, and this association was attenuated in PT-p53-KO mice. In global expression analysis, ischemic AKI induced 371 genes in wild-type kidney cortical tissues, but the induction of 31 of these genes was abrogated in PT-p53-KO tissues. These 31 genes included regulators of cell death, metabolism, signal transduction, oxidative stress, and mitochondria. These results suggest that p53 in proximal tubular cells promotes AKI, whereas p53 in other tubular cells does not.
Early tuberculosis treatment monitoring by Xpert® MTB/RIF: Figure 1–
Authors: Paolo Miotto, Sara Bigoni, Giovanni Battista Migliori, Alberto Matteelli, Daniela M. Cirillo
Journal: European Respiratory Journal (2012)

To the Editors:

Progress made to improve laboratory capacity for tuberculosis (TB) diagnosis led to the development of molecular assays that are now replacing conventional microscopy and culture-based methods on a large scale [1, 2]. Unfortunately, current molecular techniques detect both live and dead bacteria, and a positive result does not imply the viability of the pathogen. Indeed, DNA can persist for a long period after bacterial death and nucleic acid from dead bacteria is equally amplifiable. Therefore, molecular assays are unsuitable for treatment monitoring and/or for infection control purposes.

We report an innovative approach to selectively amplify DNA derived from viable Mycobacterium tuberculosis in clinical specimens, which is useful for monitoring mycobacterial load in pulmonary TB patients during anti-TB treatment.

The protocol is based on pre-treatment of samples with propidium monoazide (PMA; Biotium Inc., Hayward, CA, USA), a chemical compound that can intercalate the DNA of non-viable (or membrane-damaged) organisms but is excluded from viable bacteria. After light activation, PMA binds covalently to the DNA, preventing its amplification by PCR [3]. After light exposure, unbound PMA is not able to interact further with DNA molecules.

The assay was first optimised using acid-fast bacilli (AFB)-negative sputum samples spiked with dead or live mycobacteria at different concentrations. In brief, live Mycobacterium fortuitum cells were added to N -acetyl-cysteine decontaminated sputum specimens negative for AFB by smear microscopy at a final concentration of 106 bacteria·mL−1. An aliquot of this laboratory-made sample was treated to heat kill the M. fortuitum cells. PMA stock solution was prepared and stored at -20°C and protected from light exposure, until use, as recommended by the manufacturers. PMA was added as a pre-treatment at a final concentration of 500 μM and incubated for 30 min at 4°C in the …
Depression, Stress, and Anhedonia: Toward a Synthesis and Integrated Model
Authors: Diego A. Pizzagalli
Journal: Annual Review of Clinical Psychology (2014)

Depression is a significant public health problem, but its etiology and pathophysiology remain poorly understood. Such incomplete understanding likely arises from the fact that depression encompasses a heterogeneous set of disorders. To overcome these limitations, renewed interest in intermediate phenotypes (endophenotypes) has resurfaced, and anhedonia has emerged as one of the most promising endophenotypes of depression. Here, a heuristic model is presented postulating that anhedonia arises from dysfunctional interactions between stress and brain reward systems. To this end, we review and integrate three bodies of independent literature investigating the role of (a) anhedonia, (b) dopamine, and (c) stress in depression. In a fourth section, we summarize animal data indicating that stress negatively affects mesocorticolimbic dopaminergic pathways critically implicated in incentive motivation and reinforcement learning. In the last section, we provide a synthesis of these four literatures, present initial evidence consistent with our model, and discuss directions for future research.
A Novel Variant of Ileal Bile Acid Binding Protein Is Up-regulated through Nuclear Factor-κB Activation in Colorectal Adenocarcinoma
Authors: Changming Fang, Jarrod Dean, Jeffrey W. Smith
Journal: Cancer Research (2007)

Abstract Ileal bile acid binding protein (IBABP) is the only cytosolic protein known to bind and transport bile acids. Because IBABP is reportedly up-regulated in colorectal cancer, it has been suggested as a link between bile acids and the risk of colorectal cancer. However, in this study, we show that IBABP is not up-regulated. Rather, a novel transcript of the IBABP gene, which encodes an additional 49 NH2-terminal amino acid residues, is up-regulated in colorectal cancer (P &amp;lt; 0.001). The novel transcript, called IBABP-L, is also distinct from IBABP because its transcription is controlled by nuclear factor-κB (NF-κB) rather than by the farnesoid X receptor. Most significantly, IBABP-L is necessary for the survival of HCT116 colon cancer cells in the presence of physiologic levels of the secondary bile acid deoxycholate. Collectively, the studies point toward a unique bile acid response pathway involving NF-κB and IBABP-L that could be useful for diagnosis and could potentially be targeted for therapeutic benefit. [Cancer Res 2007;67(19):9039–46]
Levels of plasmacytoid dendritic cells and type-2 myeloid dendritic cells are reduced in peripheral blood of patients with primary Sjögren's syndrome
Authors: Petra Vogelsang, Johan G Brun, Gunnvor Øijordsbakken, Kathrine Skarstein, Roland Jonsson, Silke Appel
Journal: Annals of the Rheumatic Diseases (2009)

Sjögren's syndrome (SS) is a lymphoproliferative autoimmune disease, characterised by dryness of the mouth and eyes. Dendritic cells (DC) are potent antigen-presenting cells crucial for initiating and maintaining primary immune responses. This study quantified interferon-producing plasmacytoid DC (pDC) and two myeloid DC subsets (mDC1 and mDC2) in peripheral blood (PB) from primary SS (pSS) patients and healthy controls.Blood samples from 31 pSS patients and 28 gender and age-matched healthy controls were analysed by flow cytometry using the Miltenyi Blood DC enumeration kit. The presence of pDC in salivary glands (SG) from pSS patients was analysed by immunohistochemistry.Patients with pSS had significantly less pDC and mDC2 in PB compared with healthy controls. Moreover, pDC are present in SG from patients with pSS.Patients with pSS have alterations among DC populations in PB, and pDC are present in the SG, suggesting a potential role of these cells in SS.
Quality of Life in the Antiarrhythmics Versus Implantable Defibrillators Trial
Authors: Eleanor B. Schron, Derek V. Exner, Qing Yao, Louise S. Jenkins, Jonathan S. Steinberg, James R. Cook, Steven P. Kutalek, Peter L. Friedman, Rosemary S. Bubien, Richard L. Page, Judy Powell
Journal: Circulation (2002)

Background — Implantable cardioverter defibrillator (ICD) use reduces mortality in patients with serious ventricular arrhythmias compared with antiarrhythmic drug (AAD) use. However, the relative impact of these therapies on self-perceived quality of life (QoL) is unknown. Methods and Results — Three self-administered instruments were used to measure generic and disease-specific QoL in Antiarrhythmics Versus Implantable Defibrillators trial participants. Generalized linear models were used to assess the relationships between self-perceived QoL and treatment (AAD versus ICD) and adverse symptoms and ICD shocks. To minimize the impact of missing data, only patients surviving 1 year were included in the primary analyses. Baseline characteristics among QoL participants (n=905) and nonparticipants (n=111) were similar, but participants who survived 1 year (n=800) were healthier at baseline than nonsurvivors (n=105). Of the 800 patients in the primary analysis, characteristics of those randomized to AAD (n=384) versus ICD (n=416) were similar. Overall, ICD and AAD use were associated with similar alterations in QoL. The development of sporadic shocks and adverse symptoms were each associated with reduced physical functioning and mental well-being and increased concerns among ICD recipients, whereas development of adverse symptoms was associated with reduced physical functioning and increased concerns among AAD recipients. Conclusions — ICD and AAD therapy are associated with similar alterations in self-perceived QoL over 1-year follow-up. Adverse symptoms were associated with reduced self-perceived QoL in both groups, and sporadic shocks were associated with reduced QoL in ICD recipients.
Comparison of different instruments to obtain nasal epithelial cells from human volunteers
Authors: Andrea Stokes, Elisabeth Kieninger, Brigitte Sandra Kopf, Nicolas Regamey, Marco Alves
Journal: European Respiratory Journal (2012)

Introduction   Nasal epithelial cells have been shown to be good surrogate markers for bronchial epithelial cells. We aimed at comparing different brushing instruments allowing collection of nasal epithelial cells.   Methods   Nasal epithelial cells were obtained by brushing the inferior surface of the middle turbinate of both nostrils using three different instruments: a cytology brush, a flocked nasal swab and a nasal mucosal curette. Cell cultures were established by seeding the cells into medium. Cell count, cell viability, success rate in establishing cell cultures and the acceptability to subjects were compared between groups   Results   60 human subjects (median [IQR] age: 34 [27-36] years) were brushed. Higher number of cells were obtained using brushes (9.8 [6.7-33.5] x 10 5  cells/mL) compared to swabs (2.5 [1.5-4.0] x 10 5  cells/mL, p 5  cells/mL, p 2  cell culture flask) was 90% with brushes, 65% with swabs and 85% with curettes. Pain intensity was similar for all instruments, brushes (3.0 [2.0-5.8] out of 10 on the pain scale), swabs (2.5 [1.0-4.0] and curettes (3.0 [2.0-5.0]).   Conclusion   All three types of instruments allow collection and growth of human nasal epithelial cells, with good acceptability to subjects. The most efficient instrument is the nasal brush.
Do all psychological treatments really work the same in posttraumatic stress disorder?
Authors: Anke Ehlers, Jonathan Bisson, David M. Clark, Mark Creamer, Steven Pilling, David Richards, Paula P. Schnurr, Stuart Turner, William Yule
Journal: Clinical Psychology Review (2009)

A recent meta-analysis by Benish, Imel, and Wampold (2008, Clinical Psychology Review, 28, 746-758) concluded that all bona fide treatments are equally effective in posttraumatic stress disorder (PTSD). In contrast, seven other meta-analyses or systematic reviews concluded that there is good evidence that trauma-focused psychological treatments (trauma-focused cognitive behavior therapy and eye movement desensitization and reprocessing) are effective in PTSD; but that treatments that do not focus on the patients' trauma memories or their meanings are either less effective or not yet sufficiently studied. International treatment guidelines therefore recommend trauma-focused psychological treatments as first-line treatments for PTSD. We examine possible reasons for the discrepant conclusions and argue that (1) the selection procedure of the available evidence used in Benish et al.'s (2008)meta-analysis introduces bias, and (2) the analysis and conclusions fail to take into account the need to demonstrate that treatments for PTSD are more effective than natural recovery. Furthermore, significant increases in effect sizes of trauma-focused cognitive behavior therapies over the past two decades contradict the conclusion that content of treatment does not matter. To advance understanding of the optimal treatment for PTSD, we recommend further research into the active mechanisms of therapeutic change, including treatment elements commonly considered to be non-specific. We also recommend transparency in reporting exclusions in meta-analyses and suggest that bona fide treatments should be defined on empirical and theoretical grounds rather than by judgments of the investigators' intent.
The Phase III Trial in the Era of Targeted Therapy: Unraveling the “Go or No Go” Decision
Authors: Thomas G. Roberts, Thomas J. Lynch, Bruce A. Chabner
Journal: Journal of Clinical Oncology (2003)

To review characteristics of contemporary phase III oncology trials and create an explicit framework to help clinical researchers prioritize novel therapies for phase III testing.We searched the MEDLINE and EMBASE databases for all reviews of phase III trials; cataloged all phase III trials in two national clinical trial databases; and reviewed approval criteria of recently approved oncology drugs from public data provided by the US Food and Drug Administration. Industry data not available elsewhere in the medical literature were obtained from a sourcebook published by a large contract research organization.Phase III oncology trials are the most expensive and time-consuming aspect of the drug development process. The results of these trials continue to exert the greatest influence on the treatment decision of oncologists and remain pivotal to the granting of drug approval. Making optimal decisions about which agents to advance to phase III testing may decrease the overall cost of cancer drug development and limit the number of patients exposed to ineffective drugs. A conceptual decision model for prioritizing novel therapies for phase III testing is presented.Cancer drug development has become more complex and expensive, whereas overall clinical progress remains slow. The transition from phase II to phase III requires a strategic decision that is based on new considerations. A greater investment in phase I and II drug trials may be required to provide the information necessary for phase III planning.
Tumours of the Hand
Authors: H. G. Stack
Journal: BMJ (1960)

The small number of papers published on the incidence of hand tumours, mostly from America, differ con- siderably, and suggest that selection has varied according to the specialized units in which the authors worked.For example, Mason (1954) gives a high incidence of malignant tumours, whereas the clinical impression in this country was that malignant tumours of the hand were uncommon.Therefore it was thought that it would be of value to analyse a series of hand tumours in order to make a practical estimation of the propor- tion of each type.This paper is based on an analysis of 300 tumours of the hand presenting consecutively over a period of three and a quarter years in a casualty and an .orthopaedicdepartment of a big general hospital.All localized swellings that occurred below the level of the radio-carpal joint are included as being in the hand.Warts alone have been excluded, since these cases were usually sent direct to the skin department.Of the 300 cases 61% were ganglia of various types, 10% were epidermoid cysts, and 29% comprised no fewer than 27 other diagnoses (see Table ).There were Tumours of the Hand. 300Consecutive Cases Type 1st 100 2nd 100 3rd 100 Total OGanglion of carpus ..