tbuckley/cabot-search huggingface dataset:
In vivo imaging of colitis and colon cancer development in mice using high resolution chromoendoscopy
Authors: C Becker
Journal: Gut (2005)

<b>Background:</b> Mouse models of colitis and cancer are indispensable for our understanding of the pathogenesis of these diseases. In the past, mice had to be sacrificed in order to analyse colitis activity and tumour development. We have developed a safe method for high resolution endoscopic monitoring of living mice. <b>Methods:</b> Mice developing colitis or colonic tumours were anaesthetised using avertine and repeatedly examined by endoscopy. A novel miniendoscope (1.9 mm outer diameter), denoted Coloview, was introduced via the anus and the colon was carefully insufflated with an air pump before analysis of the colonic mucosa. An extra working channel allowed the introduction of biopsy forceps or injection needles as well as surface staining with methylene blue in order to visualise the surface of the crypts and the pit pattern architecture. <b>Results:</b> Endoscopic pictures obtained were of high quality and allowed monitoring and grading of disease. Scoring of colitis activity as well as tumour size and growth was possible. In addition, pit pattern analysis using chromoendoscopy permitted discrimination between inflammatory and neoplastic changes. Biopsies yielded enough tissue for molecular and histopathological analyses. <b>Conclusions:</b> In summary, chromoendoscopy in mice allows monitoring of the development of colitis and colon cancer with high resolution. Manipulations such as local injection of reagents or taking biopsies can be performed easily.
Repolarization Gradients in the Canine Left Ventricle Before and After Induction of Short-Term Cardiac Memory
Authors: Michiel J. Janse, Eugene A. Sosunov, Ruben Coronel, Tobias Opthof, Evgeny P. Anyukhovsky, Jacques M.T. de Bakker, Alexei N. Plotnikov, Iryna N. Shlapakova, Peter Danilo, Jan G.P. Tijssen, Michael R. Rosen
Journal: Circulation (2005)

Background— Questions remain about the contributions of transmural versus apicobasal repolarization gradients to the configuration of the T wave in control settings and after the induction of short-term cardiac memory. Methods and Results— Short-term cardiac memory is seen as T-wave changes induced by altered ventricular activation that persists after restoration of sinus rhythm. We studied cardiac memory in anesthetized, open-chest dogs paced from the ventricle for 2 hours. Unipolar electrograms were recorded from as many as 98 epicardial and 144 intramural sites, and activation times and activation-recovery intervals (ARIs) were measured. In separate experiments, epicardial monophasic action potentials were recorded. We found no appreciable left ventricular intramural gradients in repolarization times (activation time+ARI) in either control conditions or after the induction of memory. In controls, there was a left ventricular apicobasal gradient, with the shortest repolarization times in anterobasal regions and longest repolarization times posteroapically. After induction of memory, repolarization times shortened uniformly throughout the ventricular wall. Monophasic action potential duration at 90% repolarization decreased by ≈10 ms after induction of memory. Conclusions— In the intact canine left ventricle at physiological rates, there is no transmural gradient in repolarization. Apicobasal gradients in repolarization time, with shortest repolarization times in anterobasal areas and longest repolarization times in posteroapical regions, are important in the genesis of the T wave. Repolarization times and monophasic action potentials at the 90% repolarization level shorten after the induction of memory. The deeper T wave in the ECG after induction of memory may be explained by the more rapid phase 3 of the action potential.
Recruitment to multicentre trials--lessons from UKCTOCS: descriptive study
Authors: U. Menon, A. Gentry-Maharaj, A. Ryan, A. Sharma, M. Burnell, R. Hallett, S. Lewis, A. Lopez, K. Godfrey, D. Oram, J. Herod, K. Williamson, M. Seif, I. Scott, T. Mould, R. Woolas, J. Murdoch, S. Dobbs, N. Amso, S. Leeson, D. Cruickshank, A. McGuire, S. Campbell, L. Fallowfield, S. Skates, M. Parmar, I. Jacobs
Journal: BMJ (2008)

Objective To describe the factors that contributed to successful recruitment of more than 200 000 women to the UK Collaborative Trial of Ovarian Cancer Screening, one of the largest ever randomised controlled trials. Design Descriptive study. Setting 13 NHS trusts in England, Wales, and Northern Ireland. Participants Postmenopausal women aged 50-74; exclusion criteria included ovarian malignancy, bilateral oophorectomy, increased risk of familial ovarian cancer, active non-ovarian malignancy, and participation in other ovarian cancer screening trials. Main outcome measures Achievement of target recruitment, acceptance rates of invitation, and recruitment rates. Results The trial was set up in 13 centres with 27 adjoining local health authorities. The coordinating centre team was led by one of the senior investigators, who was closely involved in planning and day to day trial management. Of 1 243 282 women invited, 23.2% (288 955) replied that they were eligible and would like to participate. Of those sent appointments, 73.6% (205 090) attended for recruitment. The acceptance rate varied from 19% to 33% between trial centres. Measures to ensure target recruitment included named coordinating centre staff supporting and monitoring each centre, prompt identification and resolution of logistic problems, varying the volume of invitations by centre, using local non-attendance rates to determine the size of recruitment clinics, and organising large ad hoc clinics supported by coordinating centre staff. The trial randomised 202 638 women in 4.3 years. Conclusions Planning and trial management are as important as trial design and require equal attention from senior investigators. Successful recruitment needs constant monitoring by a committed proactive management team that is willing to explore individual solutions for different centres and use central resources to improve local recruitment. Automation of trial processes with web based trial management systems is crucial in large multicentre randomised controlled trials. Recruitment can be further enhanced by using information videos and group discussions. Trial registration Current Controlled Trials [ISRCTN22488978][1]. [1]: /external-ref?link_type=ISRCTN&access_num=ISRCTN22488978
Discussion by George L. Spaeth, MD, Chryssa Terzidou, MD, Anna Bhan, MD
Authors: George L Spaeth, Chryssa Terzidou, Anna Bhan
Journal: Ophthalmology (2002)

People with glaucoma can and do lose vision as a result of deterioration in the field of vision. They also can and do lose vision due to the treatments designed to prevent the loss of field. Were such loss of vision to occur in all people with glaucoma, then vigorous and even potentially damaging treatment would be justified. But Grant and Burke,1 Hattenhauer et al,2 Quigley and colleagues,3 and Eid and Spaeth (Eid TM, Spaeth GL. Long-term follow-up of patients with treated chronic open-angle glaucomas. Presented at the AAO annual meeting, San Francisco, 1997) have shown that by no means do all treated patients with glaucoma become functionally disabled or even symptomatic due to glaucomatous visual field loss. Nevertheless, physicians and patients alike wish to prevent field loss from occurring, and consequently medicinal and surgical treatment are usually advised in patients with glaucoma in order to achieve that goal. The question, of course, is whether these treatments are justified in view of the risks associated with them.
Vitamin C Further Improves the Protective Effect of Glucagon-Like Peptide-1 on Acute Hypoglycemia-Induced Oxidative Stress, Inflammation, and Endothelial Dysfunction in Type 1 Diabetes. Diabetes Care 2013;36:4104–4108
Authors: Antonio Ceriello, Anna Novials, Emilio Ortega, Silvia Canivell, Lucia La Sala, Gemma Pujadas, Loredana Bucciarelli, Maurizio Rondinelli, Stefano Genovese
Journal: Diabetes Care (2014)

In the print version of the article cited above, in the research design and methods section, the sentence “Studies …
The human leukocyte antigen (HLA)-C-specific "activatory" or "inhibitory" natural killer cell receptors display highly homologous extracellular domains but differ in their transmembrane and intracytoplasmic portions.
Authors: R Biassoni, C Cantoni, M Falco, S Verdiani, C Bottino, M Vitale, R Conte, A Poggi, A Moretta, L Moretta
Journal: The Journal of Experimental Medicine (1996)

Natural killer cells express clonally distributed receptors specific for major histocompatibility complex class I molecules. The human leukocyte antigen (HLA)-C-specific receptors have been molecularly identified and cloned. They exist not only as inhibitory (p58) but also as activatory (p50) receptors. Here we show that p50 and p58 are highly homologous in their extracellular regions formed by two Ig-like domains. In contrast, major differences exist in their transmembrane and cytoplasmic portions. Whereas p 58 displays a 76-84-amino acid cytoplasmic tail containing an unusual antigen receptor activation motif, p50 is characterized by a shorter 39-amino acid tail. In addition, whereas p58 has a nonpolar transmembrane portion, p50 contains the charged amino acid Lys. These data strongly suggest that receptors with identical HLA-C allele specificity can mediate functions of opposite sign owing to their different transmembrane/cytoplasmic portions.
The Mysterious Evolutionary Origin for the GNE Gene and the Root of Bilateria
Authors: A. de Mendoza, I. Ruiz-Trillo
Journal: Molecular Biology and Evolution (2011)

Phylogenomic analyses have revealed several important metazoan clades, such as the Ecdysozoa and the Lophotrochozoa. However, the phylogenetic positions of a few taxa, such as ctenophores, chaetognaths, acoelomorphs, and Xenoturbella, remain contentious. Thus, the findings of qualitative markers or "rare genomic changes" seem ideal to independently test previous phylogenetic hypotheses. We here describe a rare genomic change, the presence of the gene UDP-GlcNAc 2-epimerase/N-acetylmannosamine kinase (GNE). We show that GNE is encoded in the genomes of deuterostomes, acoelomorphs and Xenoturbella, whereas it is absent in protostomes and nonbilaterians. Moreover, the GNE has a complex evolutionary origin involving unique lateral gene transfer events and/or extensive hidden paralogy for each protein domain. However, rather than using GNE as a phylogenetic character, we argue that rare genomic changes such as the one presented here should be used with caution.
Immune cell trafficking from the brain maintains CNS immune tolerance
Authors: Mohammad G. Mohammad, Vicky W.W. Tsai, Marc J. Ruitenberg, Masoud Hassanpour, Hui Li, Prue H. Hart, Samuel N. Breit, Paul E. Sawchenko, David A. Brown
Journal: Journal of Clinical Investigation (2014)

In the CNS, no pathway dedicated to immune surveillance has been characterized for preventing the anti-CNS immune responses that develop in autoimmune neuroinflammatory disease. Here, we identified a pathway for immune cells to traffic from the brain that is associated with the rostral migratory stream (RMS), which is a forebrain source of newly generated neurons. Evaluation of fluorescently labeled leukocyte migration in mice revealed that DCs travel via the RMS from the CNS to the cervical LNs (CxLNs), where they present antigen to T cells. Pharmacologic interruption of immune cell traffic with the mononuclear cell-sequestering drug fingolimod influenced anti-CNS T cell responses in the CxLNs and modulated experimental autoimmune encephalomyelitis (EAE) severity in a mouse model of multiple sclerosis (MS). Fingolimod treatment also induced EAE in a disease-resistant transgenic mouse strain by altering DC-mediated Treg functions in CxLNs and disrupting CNS immune tolerance. These data describe an immune cell pathway that originates in the CNS and is capable of dampening anti-CNS immune responses in the periphery. Furthermore, these data provide insight into how fingolimod treatment might exacerbate CNS neuroinflammation in some cases and suggest that focal therapeutic interventions, outside the CNS have the potential to selectively modify anti-CNS immunity.
AN HETEROPHILE FACTOR IN RAGWEED POLLEN
Authors: F. Eastty Sammis
Journal: The Journal of Experimental Medicine (1940)

1. There is serological evidence that ragweed pollen antigen contains a factor which causes an increased hemolysin titre for sheep cells, when injected into rabbits. 2. It remains questionable whether the antigen absorbs normal rabbit hemolysins. It does, however, absorb anti-ragweed hemolysins, as demonstrated by hemolysis inhibition test. 3. Dilution and lyophilization (Mudd-Flosdorf method) of antigen-antibody mixture shows that one hemolytic unit of anti-ragweed rabbit serum combines with 0.00007 mg. of low ragweed total N. There were three zones of inhibition of hemolysis demonstrated. 4. The immune hemolysins are completely absorbed by sheep cells and by Forssman antigen, but not by human cells of groups A or B. 5. Although Forssman antigen was able to absorb anti-ragweed hemolysin, the ragweed antigen was not able to absorb Forssman antibody. 6. Human ragweed sensitive sera from 22 cases with hay fever, before treatment, did not show increased titre of heat-labile or heat-stable hemolysin. There was no change after treatment. 7. Among the human cases there were encountered blood groups A, B, and O. Heat-labile hemolysins for sheep cells were present in nineteen of the twenty-two sera regardless of blood groups.
Fibroblast-Specific Protein 1/S100A4–Positive Cells Prevent Carcinoma through Collagen Production and Encapsulation of Carcinogens
Authors: Jinhua Zhang, Lin Chen, Xiaoman Liu, Thomas Kammertoens, Thomas Blankenstein, Zhihai Qin
Journal: Cancer Research (2013)

Stromal restraints to cancer are critical determinants of disease but they remain incompletely understood. Here, we report a novel mechanism for host surveillance against cancer contributed by fibroblast-specific protein 1 (FSP1)+ /S100A4+ fibroblasts. Mechanistic studies of fibrosarcoma formation caused by subcutaneous injection of the carcinogen methylcholanthrene (MCA) had suggested that IFN-γ receptor signaling may restrict MCA diffusion by inducing expression of collagen (foreign body reaction). We tested the hypothesis that this reaction encapsulated MCA and limited carcinogenesis by determining whether its ability to induce fibrosarcomas was impaired in the absence of proliferating fibroblasts. We found that FSP1+ /S100A4+ fibroblasts accumulated around the carcinogen where they produced collagens, encapsulating MCA and protecting epithelial cells from DNA damage. Ablation of these cells at the site of MCA injection by local administration of ganciclovir in FSP-TK transgenic mice altered tumor morphology to an epithelial phenotype, indicating that, in the absence of encapsulating fibroblasts, MCA targeted epithelial cells. Notably, we showed that destruction of the fibrous capsule around the MCA by local injection of collagenase induced rapid tumor development in mice that were otherwise durably tumor free. Our findings demonstrate that the FSP1+ /S100A4+ fibroblasts prevent epithelial malignancy and that collagen encapsulation of carcinogens protects against tumor development. Together, this study provides a novel mechanism for host surveillance against cancer.
Simulation Modeling of Health Care Policy
Authors: Sherry Glied, Nicholas Tilipman
Journal: Annual Review of Public Health (2010)

Simulation modeling of health reform is a standard part of policy development and, in the United States, a required element in enacting health reform legislation. Modelers use three types of basic structures to build models of the health system: microsimulation, individual choice, and cell-based. These frameworks are filled in with data on baseline characteristics of the system and parameters describing individual behavior. Available data on baseline characteristics are imprecise, and estimates of key empirical parameters vary widely. A comparison of estimated and realized consequences of several health reform proposals suggests that models provided reasonably accurate estimates, with confidence bounds of ∼30%.
Was a manual gesturing stage really necessary?
Authors: Ralph L. Holloway
Journal: Behavioral and Brain Sciences (2003)

Given the primate propensity to make noise, it is unclear why a manual gestural stage would have been necessary in the development of either language or right-handedness. Cortical asymmetries are present in australopithecines but become clearly human-like with the appearance of Homo about two million years ago, including Broca's cap regions. Stone tool-making is still our only empirical entry into past cognitive processes.
Synthetic Lethality in ATM-Deficient <i>RAD50</i>-Mutant Tumors Underlies Outlier Response to Cancer Therapy
Authors: Hikmat Al-Ahmadie, Gopa Iyer, Marcel Hohl, Saurabh Asthana, Akiko Inagaki, Nikolaus Schultz, Aphrothiti J. Hanrahan, Sasinya N. Scott, A. Rose Brannon, Gregory C. McDermott, Mono Pirun, Irina Ostrovnaya, Philip Kim, Nicholas D. Socci, Agnes Viale, Gary K. Schwartz, Victor Reuter, Bernard H. Bochner, Jonathan E. Rosenberg, Dean F. Bajorin, Michael F. Berger, John H.J. Petrini, David B. Solit, Barry S. Taylor
Journal: Cancer Discovery (2014)

Abstract Metastatic solid tumors are almost invariably fatal. Patients with disseminated small-cell cancers have a particularly unfavorable prognosis, with most succumbing to their disease within two years. Here, we report on the genetic and functional analysis of an outlier curative response of a patient with metastatic small-cell cancer to combined checkpoint kinase 1 (CHK1) inhibition and DNA-damaging chemotherapy. Whole-genome sequencing revealed a clonal hemizygous mutation in the Mre11 complex gene RAD50 that attenuated ATM signaling which in the context of CHK1 inhibition contributed, via synthetic lethality, to extreme sensitivity to irinotecan. As Mre11 mutations occur in a diversity of human tumors, the results suggest a tumor-specific combination therapy strategy in which checkpoint inhibition in combination with DNA-damaging chemotherapy is synthetically lethal in tumor cells but not normal cells with somatic mutations that impair Mre11 complex function. Significance: Strategies to effect deep and lasting responses to cancer therapy in patients with metastatic disease have remained difficult to attain, especially in early-phase clinical trials. Here, we present an in-depth genomic and functional genetic analysis identifying RAD50 hypomorphism as a contributing factor to a curative response to systemic combination therapy in a patient with recurrent, metastatic small-cell cancer. Cancer Discov; 4(9); 1014–21. ©2014 AACR. See related commentary by Peng et al., p. 988 This article is highlighted in the In This Issue feature, p. 973
Is There a Link Between Liraglutide and Pancreatitis? A Post Hoc Review of Pooled and Patient-Level Data From Completed Liraglutide Type 2 Diabetes Clinical Trials
Authors: Troels M. Jensen, Kishore Saha, William M. Steinberg
Journal: Diabetes Care (2014)

OBJECTIVE To report the incidence of pancreatitis in type 2 diabetes trials of liraglutide and details of all pancreatitis cases. RESEARCH DESIGN AND METHODS Data from Novo Nordisk–sponsored trials with liraglutide (phase 2 and 3; NN2211 identifiers) completed by 19 April 2013 were pooled. All pancreatitis cases were reviewed. RESULTS Total exposure to liraglutide and active comparators was 5,021 and 1,354 patient-years, respectively (n = 6,345 and 1,846, respectively). Eight cases of acute pancreatitis (AP) with liraglutide and one with any comparator (glimepiride) were found. The incidence of AP was 1.6 cases/1,000 patient-years exposure (PYE) for liraglutide vs. 0.7 cases/1,000 PYE for total active comparators. One of the eight AP cases reported with liraglutide did not meet diagnostic criteria for AP. In six of these eight cases, recognized risk factors for AP were present and/or the onset of AP occurred &amp;gt;6 months after liraglutide initiation. All patients were receiving multiple medications. Four cases of chronic pancreatitis (CP) with liraglutide and none with comparators were found. One of these four cases fulfilled diagnostic criteria for CP; these criteria were not met or information was missing in the remaining three. CONCLUSIONS Based on the small number of cases observed, the incidences of reported AP and CP were numerically greater with liraglutide than with comparators. Not all cases fulfilled diagnostic criteria, and confounding variables were present in 75% of the AP cases with liraglutide therapy, precluding firm conclusions.
Phase II Multicenter Trial of Bevacizumab Plus Fluorouracil and Leucovorin in Patients With Advanced Refractory Colorectal Cancer: An NCI Treatment Referral Center Trial TRC-0301
Authors: Helen X. Chen, Margaret Mooney, Matthew Boron, Don Vena, Kimberly Mosby, Louise Grochow, Carl Jaffe, Lawrence Rubinstein, James Zwiebel, Richard S. Kaplan
Journal: Journal of Clinical Oncology (2006)

To provide bevacizumab (BV) -based therapy to patients with advanced colorectal cancers (CRC) who had exhausted standard chemotherapy options, and to evaluate the response to BV combined with fluorouracil (FU) and leucovorin (LV) in this patient population.This was a multicenter, single-arm treatment trial conducted under the National Cancer Institute Treatment Referral Center network nationwide. Patients were treated with BV 5 mg/kg every 2 weeks combined with FU/LV; FU was administered by bolus or continuous infusion. Eligibility criteria included advanced CRC that had progressed after irinotecan- and oxaliplatin-based chemotherapy, Eastern Cooperative Oncology Group performance status 0 to 2, and absence of thromboembolism. The primary end point was objective response rate (RR) in the first 100 assessable patients. All patients received follow-up for toxicity and survival.Due to rapid accrual, a total of 350 patients were enrolled at 32 participating sites nationwide by October 2003. In the initially planned cohort of 100 assessable patients, the objective RR was 4% (95% CI, 1.1% to 9.9%) by investigators' assessment and 1% (95% CI, 0% to 5.5%) based on independent review; median progression-free survival was 3.5 months and median overall survival was 9.0 months. The safety profile was similar to prior BV trials in CRC. Grade 3 to 4 hemorrhage occurred in 5% of patients, including 3.8% with bleeding in the GI tract. Other adverse events such as hypertension, thrombosis, and bowel perforation were also observed at rates consistent with other studies.For patients with advanced CRC that had progressed after both irinotecan-based and oxaliplatin-based chemotherapy regimens, the combination of BV and FU/LV was associated with rare objective responses.