tbuckley/cabot-search huggingface dataset:
Delivery of NKG2D Ligand Using an Anti-HER2 Antibody-NKG2D Ligand Fusion Protein Results in an Enhanced Innate and Adaptive Antitumor Response
Authors: Hyun-Mi Cho, Joseph D. Rosenblatt, Khaled Tolba, Sarah J. Shin, Daniel S. Shin, Carmen Calfa, Yu Zhang, Seung-Uon Shin
Journal: Cancer Research (2010)

Abstract NKG2D ligands link the innate and adapative immune response by activating the receptors expressed on effector cells of both the innate (NK) and adaptive immune systems (CD8+ T cells). In this study, we explored the potential therapeutic utility of this intersection by fusing the murine NKG2D ligand Rae-1β to the 3′ end of an anti-HER2 IgG3 antibody containing an intact Fc domain (anti-HER2 IgG3-Rae-1β), thereby targeting an NK cell activation signal to HER2+ breast tumor cells. The antitumor efficacy of this anti-HER2-Rae-1β fusion protein was examined in a mouse mammary tumor model engineered to express HER2 (EMT6-HER2 cells). We observed an enhanced cytotoxic response of NK effectors against EMT-HER2 cells in vitro. Mice implanted on one flank with EMT6-HER2 cells and contralaterally with control EMT6 cells exhibited rapid regression of EMT6-HER2 tumors but delayed regression of contralateral EMT6 tumors. IFNγ was implicated, given a lack of antitumor efficacy in IFNγ−/− mice. Depletion of either NK cells or CD8+ T cells abrogated tumor growth inhibition, suggesting essential roles for each in the observed antitumor activity. Mice rejecting EMT6-HER2 tumors after anti-HER2-Rae-1β treatment showed markedly decreased tumor growth when rechallenged with EMT6-HER2 or EMT6 cells, whereas both EMT6 and EMT6-HER2 cells grew in control mice, indicating the development of an adaptive memory response. Our findings demonstrate that administration of an antibody-NKG2D ligand fusion protein can enhance innate and adaptive immune antitumor responses, also evoking additional nontargeted antigens to enhance the potential clinical utility of this approach. Cancer Res; 70(24); 10121–30. ©2010 AACR.
PCR-Induced Sequence Alterations Hamper the Typing of Prehistoric Bone Samples for Diagnostic Achondroplasia Mutations
Authors: C. M. Pusch, M. Broghammer, G. J. Nicholson, A. G. Nerlich, A. Zink, I. Kennerknecht, L. Bachmann, N. Blin
Journal: Molecular Biology and Evolution (2004)

Achondroplasia (ACH) is a skeletal disorder (MIM100800) with an autosomal dominant Mendelian inheritance and complete penetrance. Here we report the screening of ancient bone samples for diagnostic ACH mutations. The diagnostic G→A transition in the FGFR3 gene at cDNA position 1138 was detected in cloned polymerase chain reaction (PCR) products obtained from the dry mummy of the Semerchet tomb, Egypt (first dynasty, ∼4,890–5,050 BP [before present]), and from an individual from Kirchheim, Germany (Merovingian period, ∼1,300–1,500 BP), both of which had short stature. However, these mutations were also reproducibly observed in four ancient control samples from phenotypically healthy individuals (false-positives), rendering the reliable molecular typing of ancient bones for ACH impossible. The treatment of a false-positive DNA extract with uracil N-glycosylase (UNG) to minimize type 2 transitions (G→A/C→T) did not reduce the frequency of the false-positive diagnostic ACH mutations. Recently, it was suggested that ancient DNA extracts may induce mutations under PCR. Contemporary human template DNA from a phenotypically healthy individual was therefore spiked with an ancient DNA extract from a cave bear. Again, sequences with the diagnostic G→A transition in the FGFR3 gene were observed, and it is likely that the false-positive G→A transitions result from errors introduced during the PCR reaction. Amplifications in the presence of MnCl2 indicate that position 1138 of the FGFR3 gene is particularly sensitive for mutations. Our data are in line with previously published results on the occurrence of nonrandom mutations in PCR products of contemporary human mitochondrial HVRI template DNA spiked with ancient DNA extracts.
On the site of absorption of fat from the human small intestine
Authors: B. Borgstrom, A. Dahlqvist, G. Lundh
Journal: Gut (1962)

The results of previous studies of the site of absorption of fat in the human small intestine using a test meal with a water-soluble reference substance have been criticized because of observations which have indicated that fat separates from the water-soluble marker in the stomach. It is now shown that the separation of fat and marker follows a sufficiently well-defined pattern to allow correction of the results obtained. The separation of fat and marker does not invalidate the authors' previous conclusions that the site of absorption of most of the fat fed to man has been the proximal jejunum.
Sonographic erosions of the rheumatoid little toe
Authors: R KLOCKE, D GLEW, N COX, D R BLAKE, W GRASSI, E FILIPPUCCI, A FARINA, F SALAFFI, C CERVINI
Journal: Annals of the Rheumatic Diseases (2001)

We read with interest the pictorial essay on ultrasonography of bone erosions by Grassi and colleagues.1 The presented site-specific comparison of radiographic and sonographic imaging of metacarpophalangeal (MCP) and metatarsophalangeal (MTP) joint sites in rheumatoid subjects suggests strongly a homology of the erosive lesions, as visualised by these different imaging modalities. A recently published study by an independent group,2 comparing radiographic and sonographic imaging of MCP joints in patients with rheumatoid arthritis (RA) supports this impression. The same study observed magnetic resonance imaging (MRI) changes corresponding to specific sites at selected radiograph-negative joints that had sonographic erosions, and found (depending on disease duration) 3.4- to 6.5-fold more erosions with ultrasound than with radiography.

In our experience, based on pilot data on rheumatoid patients with a disease duration of up to six years, sonographic erosions could be shown in half of all 5th MTP joints examined. Fifteen patients with RA, according to standard criteria,3 (median age (range) 48 (23–78) years; eight female; median disease duration (range) 13 (1.5–72) months; 12 rheumatoid …
Potential Use of Imatinib in Ewing's Sarcoma: Evidence for In Vitro and In Vivo Activity
Authors: M. S. Merchant
Journal: JNCI Journal of the National Cancer Institute (2002)

Background: Ewing's sarcoma cells express c-kit, a receptor tyrosine kinase, and its ligand, stem cell factor (SCF), creating a potential autocrine loop that may promote tumor survival. We thus examined whether the specific tyrosine kinase inhibitor imatinib mesylate (hereafter imatinib; formerly STI571) could inhibit the proliferation of Ewing's sarcoma cells in vitro and in vivo. Methods: The effect of imatinib on c-kit expression and phosphorylation in Ewing's sarcoma cells was examined by immunoblotting. The effect of imatinib on cell growth and apoptosis was examined with an MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assay and with a morphologic test and Annexin V staining, respectively. The effect of imatinib oral therapy (every 12 hours for 5–7 days) on primary tumor growth was assessed in Ewing's sarcoma xenografts in SCID/bg mice (5 or 10 mice per group). Results: All Ewing's sarcoma cell lines tested were sensitive to imatinib-mediated apoptosis with a concentration inhibiting growth by 50% (IC50) of 10–12 μM. Imatinib inhibited SCF-mediated c-kit phosphorylation (IC50 = 0.1–0.5 μM). In the xenograft model, imatinib treatment resulted in the regression or control of primary Ewing's sarcomas. After 6 days of treatment, the mean lower extremity volume including xenograft tumor was 3744 mm3 (95% confidence interval [CI] = 3050 to 4437 mm3), 1442 mm3 (95% CI = 931 to 1758 mm3), and 346 mm3 (95% CI = 131 to 622 mm3) in mice treated with carrier alone or with imatinib at 50 mg/kg or at 100 mg/kg, respectively. Conclusions: Imatinib interferes with growth of all Ewing's sarcoma cell lines tested in vitro and in vivo. Targeted inhibition of tyrosine kinase-dependent autocrine loops, therefore, may be a viable therapeutic strategy for Ewing's sarcoma.
Apparent Recombination or Gene Conversion in the Ribosomal ITS Region of a Flammulina (Fungi, Agaricales) Hybrid
Authors: Karen W. Hughes, Ronald H. Petersen
Journal: Molecular Biology and Evolution (2001)

Internally transcribed spacer (ITS) regions of ribosomal DNA are widely used in reconstructing phylogenies at lower taxonomic levels (see, e.g., Vilgalys and Sun 1994;Baldwin et al. 1995).Ribosomal genes are tandemly repeated, and the paralogs are usually identical due to a poorly understood process of concerted evolution.Proposed mechanisms of concerted evolution include unequal crossing over (Schlotterer and Tautz 1994) and biased gene conversion (Hillis et al. 1991;Linares, Bowen, and Dover 1994).Within-individual diversity for the ribosomal ITS region has been observed and has in some cases been attributed to hybridization (Sang, Crawford, and Stuessy 1995;Hugall, Stanton, and Moritz 1999).This report documents an apparent natural hybridization event between two species of Flammulina (F.velutipes and F. rossica) which resulted in a homogenized ribosomal repeat containing elements of both parents.A chromosome carrying the hybrid repeat has apparently introgressed into F. velutipes and persists in nature.Flammulina velutipes is predominantly found in temperate Northern Hemisphere forests but has also been collected in Argentina and New Zealand.Flammulina rossica is a more northern species, so far identified from Alaska, northern Canada, and eastern Russia.Approximately 200 collections of Flammulina worldwide were identified to species on the basis of morphology (Redhead and Petersen 1999), mating studies (Petersen et al. 1999), and restriction fragment length polymorphism (RFLP) patterns (Methven, Hughes, and Petersen 2000).DNA was extracted from geographically diverse collections of each species.The ribosomal ITS region was amplified and sequenced on both strands using primers ITS5 and ITS3 in the forward direction and primers ITS4 and ITS2 in the reverse direction as described by Hughes et al. (1999).This combination of primers provided unambiguous sequence data on both forward and reverse strands.Forward and reverse sequences were compared and corrected manually and aligned with other Flammulina sequences using the Genetics Computer Group (1999) family of programs, and all divergent bases were rechecked against the original sequence files.Sequence alignments were deposited with TreeBASE (accession M641;Hughes et al. 1999).Two of ca. 150 natural dikaryon (diploid) worldwide collections identified morphologically as F.
Expressed Emotion and Relapse of Psychopathology
Authors: Jill M. Hooley
Journal: Annual Review of Clinical Psychology (2007)

Expressed emotion (EE) is a measure of the family environment that predicts worse clinical outcomes for patients with a range of disorders. This article describes the assessment of EE and the evidence linking EE to clinical relapse in patients with psychopathology. This is followed by consideration of the possible explanatory models that might account for the EE-relapse link and a review of the evidence suggesting that EE may play a causal role in the relapse process. The results of studies describing the effect of EE on patients, as well as cross-cultural aspects of the construct, are highlighted. Finally, the possibility that high levels of EE may stress patients by perturbing activity in neural circuits that underlie psychopathology is considered and new directions for EE research are outlined.
Activation of caspase-1 by the NLRP3 inflammasome regulates the NADPH oxidase NOX2 to control phagosome function
Authors: Anna Sokolovska, Christine E Becker, W K Eddie Ip, Vijay A K Rathinam, Matthew Brudner, Nicholas Paquette, Antoine Tanne, Sivapriya K Vanaja, Kathryn J Moore, Katherine A Fitzgerald, Adam Lacy-Hulbert, Lynda M Stuart
Journal: Nature Immunology (2013)
Ideal Cardiovascular Health and the Prevalence and Progression of Coronary Artery Calcification in Adults With and Without Type 1 Diabetes
Authors: Amy C. Alman, David M. Maahs, Marian J. Rewers, Janet K. Snell-Bergeon
Journal: Diabetes Care (2013)

In 2010, the American Heart Association defined seven metrics (smoking, BMI, physical activity, diet, total cholesterol, blood pressure, and fasting plasma glucose) for ideal cardiovascular health (ICH). Subsequent studies have shown that the prevalence of achieving these metrics is very low in the general population. Adults with type 1 diabetes are at increased risk of cardiovascular disease (CVD), but no studies to date have been published on the prevalence of ICH in this population.Data for this analysis were collected as part of the prospective Coronary Artery Calcification in Type 1 Diabetes study. This analysis involved 546 subjects with type 1 diabetes and 631 subjects without diabetes who had complete information for calculating the ICH metrics.Overall, the prevalence of ICH was low in this population, with none meeting the ideal criteria for all seven metrics. The prevalence of ideal physical activity (10.0%) and diet (1.1%) were particularly low. ICH was significantly associated with both decreased prevalence (odds ratio [OR] 0.70; 95% CI 0.62-0.80) and progression (OR 0.77; 95% CI 0.66-0.90) of coronary artery calcification (CAC).ICH is significantly associated with decreased prevalence and progression of CAC; however, prevalence of ICH metrics was low in adults both with and without type 1 diabetes. Efforts to increase the prevalence of ICH could have a significant impact on reducing the burden of CVD.
Mechanisms of cervical spine injury in rugby union: is it premature to abandon hyperflexion as the main mechanism underpinning injury?
Authors: Christopher R Dennison, Erin M Macri, Peter A Cripton
Journal: British Journal of Sports Medicine (2012)

Cervical spine injuries in rugby union have received growing worldwide attention owing to their often catastrophic nature.1,–,3 Kuster et al 4 considered recent changes in the epidemiology as well as the ex vivo biomechanics literature on cervical spine injury during head-first impacts. Kuster postulated that the majority of catastrophic cervical spine injuries before year 2000 occurred through a hyperflexion mechanism in the scrum and since the year 2000, these injuries have occurred during tackles via an axial compression mechanism and related ‘buckling’ of the cervical spine.

Regulators and other stakeholders in the game continually seek to improve understanding of the scope, true incidence and mechanism of these catastrophic injuries. Ideally, a full comprehension of cervical injury mechanisms occurring during rugby would lead to changes in the game, through rule changes or changes in enforcement and/or player coaching or education, which in turn would reduce the incidence of these injuries.2 Achieving such a full comprehension, however, has been elusive.1,–,3 ,5,–,9 For example, recent changes to the rules have led to reduced time spent in scrum and have altered scrum engagement, which subsequently have been associated with a reduction in incidence of scrum-related cervical spine injury (an injury primarily involving forward positions and accounting for 37%–51% of cervical spine injuries).5 ,7 ,8 ,10 ,11 These changes have therefore affected the distribution of players who get injured, with increased percentage of these injuries now being sustained by back positions than prior to these rule changes, and up to 57% of cervical injuries are now occurring …
Exophthalmos in Seminoma
Authors: J. Bradley Taylor
Journal: JAMA (1978)

SYSTEMIC manifestations of seminoma, apart from those directly attributable to metastatic lesions, are rare. To our knowledge, bilateral exophthalmos in association with this testicular tumor has been reported previously in only two cases.<sup>1,2</sup>We report a third case in which exophthalmos was the presenting sign of seminoma, and where removal of the tumor resulted in complete regression of the eye changes. <h3>Report of a Case</h3> A 57-year-old man had a two-week history of progressive protrusion of the eyes, decreasing visual acuity, and lacrimation. He denied any previous ophthalmologic disorder, trauma, allergies, neoplasm, or signs and symptoms suggestive of hyperthyroidism. The results of a physical examination showed a well-developed man with bilateral proptosis with chemosis. Visual acuity was notably decreased, more severely on the right than on the left, and there was appreciable limitation of eye movements in all directions. An afferent pupil defect was also present on the right,
Characterisation of the Escherichia coli strain associated with an outbreak of haemolytic uraemic syndrome in Germany, 2011: a microbiological study
Authors: Martina Bielaszewska, Alexander Mellmann, Wenlan Zhang, Robin Köck, Angelika Fruth, Andreas Bauwens, Georg Peters, Helge Karch
Journal: The Lancet Infectious Diseases (2011)
Phosducin influences sympathetic activity and prevents stress-induced hypertension in humans and mice
Authors: Nadine Beetz, Michael D. Harrison, Marc Brede, Xiangang Zong, Michal J. Urbanski, Anika Sietmann, Jennifer Kaufling, Michel Barrot, Mathias W. Seeliger, Maria Augusta Vieira-Coelho, Pavel Hamet, Daniel Gaudet, Ondrej Seda, Johanne Tremblay, Theodore A. Kotchen, Mary Kaldunski, Rolf Nüsing, Bela Szabo, Howard J. Jacob, Allen W. Cowley, Martin Biel, Monika Stoll, Martin J. Lohse, Ulrich Broeckel, Lutz Hein
Journal: Journal of Clinical Investigation (2009)

Hypertension and its complications represent leading causes of morbidity and mortality. Although the cause of hypertension is unknown in most patients, genetic factors are recognized as contributing significantly to an individual’s lifetime risk of developing the condition. Here, we investigated the role of the G protein regulator phosducin (Pdc) in hypertension. Mice with a targeted deletion of the gene encoding Pdc (Pdc–/– mice) had increased blood pressure despite normal cardiac function and vascular reactivity, and displayed elevated catecholamine turnover in the peripheral sympathetic system. Isolated postganglionic sympathetic neurons from Pdc–/– mice showed prolonged action potential firing after stimulation with acetylcholine and increased firing frequencies during membrane depolarization. Furthermore, Pdc–/– mice displayed exaggerated increases in blood pressure in response to post-operative stress. Candidate gene–based association studies in 2 different human populations revealed several SNPs in the PDC gene to be associated with stress-dependent blood pressure phenotypes. Individuals homozygous for the G allele of an intronic PDC SNP (rs12402521) had 12–15 mmHg higher blood pressure than those carrying the A allele. These findings demonstrate that PDC is an important modulator of sympathetic activity and blood pressure and may thus represent a promising target for treatment of stress-dependent hypertension.
The Role of Diagnosis and Clinical Follow-up of Monoclonal Gammopathy of Undetermined Significance on Survival in Multiple Myeloma
Authors: Elin Edda Sigurdardottir, Ingemar Turesson, Sigrun Helga Lund, Ebba K. Lindqvist, Sham Mailankody, Neha Korde, Magnus Björkholm, Ola Landgren, Sigurdur Y. Kristinsson
Journal: JAMA Oncology (2015)

Multiple myeloma (MM) is consistently preceded by the precursor state, monoclonal gammopathy of undetermined significance (MGUS). The average annual risk of progression from MGUS to multiple myeloma is 0.5% to 1.0%. Current guidelines suggest life-long clinical follow-up of individuals diagnosed as having MGUS depending on risk stratification. The impact of diagnosing and conducting clinical follow-up of MGUS on MM survival is unclear.To estimate the impact of prior knowledge of MGUS diagnosis and comorbidities on MM survival.We conducted a population-based study including all patients with MM (MM patients) diagnosed in Sweden (n = 14,798) from 1976 to 2005 (with follow-up until 2007); 394 (2.7%) had previously been diagnosed as having MGUS. Information on comorbidities was gathered for all patients. We calculated survival rates from the time of MM diagnosis, comparing patients with vs those without prior knowledge of MGUS. Using Cox proportional hazards models, we calculated hazard ratios (HRs) and 95% CIs for risk factors for death. χ2 Tests were used to evaluate differences in comorbidities.Prior knowledge of MGUS among MM patients. In a subanalysis, monoclonal (M)-protein concentration and type were used as exposure.Risk of death and comorbidities.Patients with MM with prior knowledge of MGUS had significantly (HR, 0.86; 95% CI, 0.77-0.96; P < .01) better overall survival (median survival, 2.8 years) than MM patients without prior knowledge of MGUS (median survival, 2.1 years), although MM patients with (vs without) prior knowledge of MGUS had more comorbidities (P < .001). Among MM patients with prior knowledge of MGUS, low M-protein concentration (<0.5 g/dL) at MGUS diagnosis was associated with poorer MM survival (HR, 1.86; 95% CI, 1.13-3.04; P = .01).Patients with MM with prior knowledge of MGUS had better MM survival, suggesting that earlier treatment of MM leads to better survival. The observation that a low M-protein concentration at MGUS diagnosis was associated with poorer MM survival may reflect less frequent clinical follow-up. Our observations stress the importance of clinical follow-up in patients with MGUS, regardless of risk stratification.
Integrinβ6-Targeted Immunoliposomes Mediate Tumor-Specific Drug Delivery and Enhance Therapeutic Efficacy in Colon Carcinoma
Authors: Benjia Liang, Muhammad Shahbaz, Yang Wang, Huijie Gao, Ruliang Fang, Zhengchuan Niu, Song Liu, Ben Wang, Qi Sun, Weibo Niu, Enyu Liu, Jiayong Wang, Jun Niu
Journal: Clinical Cancer Research (2014)

Abstract Purpose: Adjuvant chemotherapy is one of the significant treatments for colon cancer in clinic. However, it does not achieve the desired therapeutic efficacy, largely due to chemotherapeutic resistance. Integrinβ6 (ITGB6) is expressed in malignant colonic epithelia, but not in normal epithelia, and is associated with the progression, metastasis, and chemotherapeutic resistance of colon cancer. Accordingly, it is necessary to design therapeutic approaches for efficient and targeted drug delivery into ITGB6-positive cancer cells to improve chemotherapeutic efficacy in colon cancer. Experimental Design: PEGylated liposomes were employed to design ITGB6-targeted immunoliposomes, which have ITGB6 monoclonal antibodies (mAbs) conjugated. We evaluated the ITGB6-targeted immunoliposomes internalization into colon cancer cells and examined 5-fluorouracil (5-FU)–induced cellular apoptosis produced by ITGB6-targeted immunoliposomes+5-FU. In addition, the biodistribution and antitumor efficiency of ITGB6-targeted immunoliposomes were observed in vivo. Results: ITGB6-targeted immunoliposomes enhanced cellular internalization in ITGB6-positive colon cancer cells compared with liposomes. Furthermore, the ITGB6-targeted immunoliposome internalization was dependent on the ITGB6 expression level on cellular surface. ITGB6-targeted immunoliposomes decreased the 5-FU IC50 more than 90% in HT-29 and SW480β6 cells relative to liposomes. Moreover, when loaded with 5-FU, ITGB6-targeted immunoliposomes produced an approximately 1.5-fold higher 5-FU–induced cellular apoptosis rate than liposomes. In vivo, the therapeutic activity of ITGB6-targeted immunoliposomes+5-FU was significantly superior, resulting in 25% to 35% reduction of tumor weight compared with 5-FU or liposomes+5-FU. Conclusions: ITGB6-targeted immunoliposomes provide a highly efficient approach for targeted drug delivery in colon cancer and thus offer the potential of a novel and promising anticancer strategy for clinical therapy. Clin Cancer Res; 21(5); 1183–95. ©2014 AACR.