tbuckley/cabot-search huggingface dataset:
The Evolutionary Origin of an Altruistic Gene
Authors: Aurora M. Nedelcu, Richard E. Michod
Journal: Molecular Biology and Evolution (2006)

Although the conditions favoring altruism are being increasingly understood, the evolutionary origins of the genetic basis for this behavior remain elusive. Here, we show that reproductive altruism (i.e., a sterile soma) in the multicellular green alga, Volvox carteri, evolved via the co-option of a life-history gene whose expression in the unicellular ancestor was conditioned on an environmental cue (as an adaptive strategy to enhance survival at an immediate cost to reproduction) through shifting its expression from a temporal (environmentally induced) into a spatial (developmental) context. The gene belongs to a diverged and structurally heterogeneous multigene family sharing a SAND-like domain (a DNA-binding module involved in gene transcription regulation). To our knowledge, this is the first example of a social gene specifically associated with reproductive altruism, whose origin can be traced back to a solitary ancestor. These findings complement recent proposals that the differentiation of sterile castes in social insects involved the co-option of regulatory networks that control sequential shifts between phases in the life cycle of solitary insects.
Insulin-Like Growth Factor-1 Sustains Stem Cell–Mediated Renal Repair
Authors: Barbara Imberti, Marina Morigi, Susanna Tomasoni, Cinzia Rota, Daniela Corna, Lorena Longaretti, Daniela Rottoli, Federica Valsecchi, Ariela Benigni, Jun Wang, Mauro Abbate, Carla Zoja, Giuseppe Remuzzi
Journal: Journal of the American Society of Nephrology (2007)

In mice with cisplatin-induced acute kidney injury, administration of bone marrow-derived mesenchymal stem cells (MSC) restores renal tubular structure and improves renal function, but the underlying mechanism is unclear. Here, we examined the process of kidney cell repair in co-culture experiments with MSC and cisplatin-injured proximal tubular epithelial cells (PTEC). Exposure of PTEC to cisplatin markedly reduced cell viability at 4 days, but co-culture with MSC provided a protective effect by promoting tubular cell proliferation. This effect was mediated by insulin-like growth factor-1 (IGF-1), highly expressed by MSC as mRNA and protein, since blocking the growth factor's function with a specific antibody attenuated cell proliferation of PTEC. Confirming this, knocking down IGF-1 expression in MSC by small interfering-RNA also resulted in a significant decrease in PTEC proliferation and increased apoptosis. Furthermore, in the murine model of cisplatin-induced kidney injury, administering IGF-1 gene-silenced MSC limited their protective effect on renal function and tubular structure. These findings indicate that MSC exert beneficial effects on tubular cell repair in acute kidney injury by producing the mitogenic and pro-survival factor IGF-1.
A clinical and genetic study of X-linked recessive ichthyosis and contiguous gene defects
Authors: D.G. PAIGE, G.G. EMILION, P.M.G. BOULOUX, J.I. HARPER
Journal: British Journal of Dermatology (1994)

X‐linked recessive ichthyosis (XLI) is caused by a deletion, or mutation, of the steroid sulphatase gene on the distal short arm of the X chromosome (Xp22.3). This region of the X chromosome is particularly susceptible to deletions. Such deletions can occasionally extended to involve neighbouring genes, causing a contiguous gene defect. Therefore, XLI may be associated with Kallmann's syndrome (KS), mental retardation, X‐linked recessive chondrodysplasia punctata and short stature. We have reviewed 33 patients with XLI. Nine showed evidence of contiguous gene defects. A further four had neurological deficit sustained at the time of birth. This study highlights the importance of screening patients with X‐linked recessive ichthyosis for neighbouring genetic disorders and, in particular, the early identification of KS, as delay in diagnosis may lead to infertility and osteoporosis. Parents should be warned about possible obstetric complications due to prolonged labour in future pregnancies.
Mortality Associated With Acute Charcot Foot and Neuropathic Foot Ulceration
Authors: Juliette van Baal, Richard Hubbard, Fran Game, William Jeffcoate
Journal: Diabetes Care (2010)

To compare the mortality of patients with an acute Charcot foot with a matched population with uninfected neuropathic foot ulcers (NFUs).Data were extracted from a specialist departmental database, supplemented by hospital records. The findings were compared with the results of earlier populations with Charcot foot and uninfected NFUs managed from 1980. Finally, the results of all patients with acute Charcot foot and all control subjects managed between 1980 and 2007 were compared with normative mortality data for the U.K. population.A total of 70 patients presented with an acute Charcot foot (mean age 57.4 +/- 12.0 years; 48 male [68.6%]) between 2001 and 2007; there were 66 matched control subjects. By 1 October 2008, 13 (eight male; 18.6%) patients with a Charcot foot had died, after a median of 2.1 years (interquartile range 1.1-3.3). Twenty-two (20 male; 33.3%) control subjects had also died after a median of 1.3 years (0.6-2.5). There was no difference in survival between the two groups (log-rank P > 0.05). Median survival of all 117 patients with acute Charcot foot managed between 1980 and 2007 was 7.88 years (4.0-15.4) and was not significantly different from the control NFU patients (8.43 years [3.4-15.8]). When compared with normative U.K. population data, life expectancy in the two groups was reduced by 14.4 and 13.9 years, respectively.These data confirm that the mortality in patients presenting to our unit with either an acute Charcot foot and an uninfected neuropathic ulcer was unexpectedly high.
Ankylosing spondylitis and risk of ischaemic heart disease: a population-based cohort study
Authors: Ivette Essers, Carmen Stolwijk, Annelies Boonen, Marie L De Bruin, Marloes T Bazelier, Frank de Vries, Astrid van Tubergen
Journal: Annals of the Rheumatic Diseases (2014)

To investigate the incidence and risk of ischaemic heart disease (IHD) and acute myocardial infarction (AMI), including the role of non-steroidal anti-inflammatory drugs (NSAID), in patients with ankylosing spondylitis (AS) compared with population controls.All patients with newly diagnosed AS (n=3809) from the British Clinical Practice Research Datalink (1987-2012) were matched with up to seven persons without AS by year of birth, gender and practice (n=26 197). Incidence rate ratios (IRR) and HRs for development of IHD and AMI were calculated. Stepwise analyses were performed adjusting for age, gender, comorbidity and drug use, including NSAIDs.At baseline, 4.3% of the patients had IHD and 1.8% had AMI compared with 3.4% and 1.4% of the controls, respectively. After exclusion of pre-existing IHD or AMI, the IRRs were 1.18 (95% CI 0.96 to 1.46) and 0.91 (95% CI 0.65 to 1.27) for IHD and AMI, respectively. Compared with controls, the age-gender adjusted HR for developing IHD was 1.20 (95% CI 0.97 to 1.48), and for AMI 0.91 (95% CI 0.65 to 1.28). In female patients, the risk of developing IHD was increased (HR 1.88, 95% CI 1.22 to 2.90), but after adjustment for all possible risk factors only a non-significant trend was found (HR 1.31, 95% CI 0.83 to 2.08). In particular, NSAID use explained this change (HR IHD adjusted for age-gender-NSAID use 1.57, 95% CI 0.99 to 2.48).Female patients with AS had an increased age-adjusted risk of developing IHD, but after adjustment for NSAID use only a non-significant trend towards increased risk was found.
Treatment of Polycythemia Vera With Hydroxyurea and Pipobroman: Final Results of a Randomized Trial Initiated in 1980
Authors: Jean-Jacques Kiladjian, Sylvie Chevret, Christine Dosquet, Christine Chomienne, Jean-Didier Rain
Journal: Journal of Clinical Oncology (2011)

Purpose The overall impact of hydroxyurea (HU) or pipobroman treatments on the long-term outcome of patients with polycythemia vera (PV) has not been assessed in randomized studies. We report final analyses from the French Polycythemia Study Group (FPSG) study, which randomly assigned HU versus pipobroman as first-line therapy in 285 patients younger than age 65 years. Patients and Methods The full methodology has been described previously. FPSG results were updated with a median follow-up of 16.3 years. Statistical analysis was performed by using competing risks on the intention-to-treat population and according to main treatment received. Results Median survival was 17 years for the whole cohort, 20.3 years for the HU arm, and 15.4 years for the pipobroman arm (P = .008) and differed significantly from that in the general population. At 10, 15, and 20 years, cumulative incidence of acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) was 6.6%, 16.5%, and 24% in the HU arm and 13%, 34%, and 52% in the pipobroman arm (P = .004). Cumulative myelofibrosis incidence at 10, 15, and 20 years according to main treatment received was 15%, 24%, and 32% with HU versus 5%, 10%, and 21% with pipobroman (P = .02). Conclusion Data from this unique randomized trial comparing HU with another cytoreductive drug in PV showed that (1) survival of patients with PV treated with conventional agents differed from survival in the general population, (2) evolution to AML/MDS is the first cause of death, (3) pipobroman is leukemogenic and is unsuitable for first-line therapy, and (4) incidence of evolution to AML/MDS with HU is higher than previously reported, although consideration should be given to the natural evolution of PV.
MicroRNAs and their isomiRs function cooperatively to target common biological pathways
Authors: Nicole Cloonan, Shivangi Wani, Qinying Xu, Jian Gu, Kristi Lea, Sheila Heater, Catalin Barbacioru, Anita L Steptoe, Hilary C Martin, Ehsan Nourbakhsh, Keerthana Krishnan, Brooke Gardiner, Xiaohui Wang, Katia Nones, Jason A Steen, Nicholas A Matigian, David L Wood, Karin S Kassahn, Nic Waddell, Jill Shepherd, Clarence Lee, Jeff Ichikawa, Kevin McKernan, Kelli Bramlett, Scott Kuersten, Sean M Grimmond
Journal: Genome biology (2011)

Abstract Background Variants of microRNAs (miRNAs), called isomiRs, are commonly reported in deep-sequencing studies; however, the functional significance of these variants remains controversial. Observational studies show that isomiR patterns are non-random, hinting that these molecules could be regulated and therefore functional, although no conclusive biological role has been demonstrated for these molecules. Results To assess the biological relevance of isomiRs, we have performed ultra-deep miRNA-seq on ten adult human tissues, and created an analysis pipeline called miRNA-MATE to align, annotate, and analyze miRNAs and their isomiRs. We find that isomiRs share sequence and expression characteristics with canonical miRNAs, and are generally strongly correlated with canonical miRNA expression. A large proportion of isomiRs potentially derive from AGO2 cleavage independent of Dicer. We isolated polyribosome-associated mRNA, captured the mRNA-bound miRNAs, and found that isomiRs and canonical miRNAs are equally associated with translational machinery. Finally, we transfected cells with biotinylated RNA duplexes encoding isomiRs or their canonical counterparts and directly assayed their mRNA targets. These studies allow us to experimentally determine genome-wide mRNA targets, and these experiments showed substantial overlap in functional mRNA networks suppressed by both canonical miRNAs and their isomiRs. Conclusions Together, these results find isomiRs to be biologically relevant and functionally cooperative partners of canonical miRNAs that act coordinately to target pathways of functionally related genes. This work exposes the complexity of the miRNA-transcriptome, and helps explain a major miRNA paradox: how specific regulation of biological processes can occur when the specificity of miRNA targeting is mediated by only 6 to 11 nucleotides.
Comparative analysis of murine marrow–derived dendritic cells generated by Flt3L or GM-CSF/IL-4 and matured with immune stimulatory agents on the in vivo induction of antileukemia responses
Authors: Brenda J. Weigel, Narender Nath, Patricia A. Taylor, Angela Panoskaltsis-Mortari, Wei Chen, Arthur M. Krieg, Kenneth Brasel, Bruce R. Blazar
Journal: Blood (2002)
Combination of surgery and chemotherapy and the role of targeted agents in the treatment of patients with colorectal liver metastases: recommendations from an expert panel
Authors: B. Nordlinger, E. Van Cutsem, T. Gruenberger, B. Glimelius, G. Poston, P. Rougier, A. Sobrero, M. Ychou
Journal: Annals of Oncology (2009)
Heparin treatment of thromboembolic disease
Authors: G. De Takats
Journal: JAMA (1967)

To the Editor:—  Dr. Gurewich and his associates can only be applauded for the emphasis on massive heparinization in acute thromboembolic disease ( 199 :116, 1967). Intermittent intravenous administration of heparin in 100- to 150-mg doses, four to six times a day in the acute phase of thromboembolism, has been employed by us since 1941 ( JAMA  142 :527, 1950, and the fact that the patient's response to heparin fluctuates from resistance to sensitivity was demonstrated in 1943 by a simple in vivo heparin tolerance test ( Surg Gynec Obstet  77 :39, 1943).  I would strongly differ, however, with their recommendation for the maintenance of two to three times normal control value for the continued treatment of thromboembolism. In my experience, the initial massive doses of 60,000 to 100.000 units a day lead often to clotting times well exceeding one hour without any evidence of bleeding. However, the dosage of heparin has to
A prospective, randomised, placebo-controlled study to identify biomarkers associated with active treatment in psoriatic arthritis: effects of adalimumab treatment on synovial tissue
Authors: A W R van Kuijk, D M Gerlag, K Vos, G Wolbink, M de Groot, M A de Rie, A H Zwinderman, B A C Dijkmans, P P Tak
Journal: Annals of the Rheumatic Diseases (2008)

<h3>Objective:</h3> To determine which of the changes in synovial tissue correlates best with clinical response associated with effective therapy (adalimumab) to facilitate the planning of future studies with therapeutic agents for psoriatic arthritis (PsA). <h3>Methods:</h3> A total of 24 patients with active PsA were randomised to receive adalimumab (n = 12) or placebo (n = 12) for 4 weeks. Synovial biopsies were obtained before and after 4 weeks of treatment. Immunohistochemical analysis was performed to characterise the cell infiltrate, expression of cytokines and matrix metalloproteinases (MMPs) and vascularity. Sections were analysed by digital image analysis. Statistical analysis was performed using covariance analysis. <h3>Results:</h3> The mean Disease Activity Score in 28 joints (DAS28) after 4 weeks was 1.92 units lower (95% confidence interval (CI) 1.07 to 2.77) after adalimumab therapy compared with placebo. Paired pretreatment and post-treatment synovial samples were available from 19 patients. Many cell types were reduced after adalimumab treatment compared to placebo. After applying a ranked analysis of covariance (ANCOVA) model to correct for baseline imbalances, a significant effect of treatment was observed on CD3-positive cells: there was a median reduction of 248 cells/mm<sup>2</sup> after adalimumab versus placebo treatment (p = 0.035). In addition, the expression of MMP13 was significantly reduced after active treatment: the integrated optical density (IOD)/mm<sup>2</sup> was 18 190 lower after adalimumab treatment as compared to placebo (p = 0.033). <h3>Conclusion:</h3> Adalimumab therapy in PsA is associated with a marked reduction in T cell infiltration and MMP13 expression in synovial tissue, suggesting that these parameters could be used as biomarkers that are sensitive to change after active treatment in small proof of concept studies in PsA.
The development of the EULAR-OMERACT rheumatoid arthritis MRI reference image atlas
Authors: P Bird
Journal: Annals of the Rheumatic Diseases (2005)

Based on a previously developed rheumatoid arthritis MRI scoring system (OMERACT 2002 RAMRIS), the development team agreed which joints, MRI features, MRI sequences, and image planes would best illustrate the scoring system in an atlas. After collecting representative examples for all grades for each abnormality (synovitis, bone oedema, and bone erosion), the team met for a three day period to review the images and choose by consensus the most illustrative set for each feature, site, and grade. A predefined subset of images (for example, for erosion—all coronal slices through the bone) was extracted. These images were then re-read by the group at a different time point to confirm the scores originally assigned. Finally, all selected images were photographed and formatted by one centre and distributed to all readers for final approval.
Illuminating Cancer Systems with Genetically Engineered Mouse Models and Coupled Luciferase Reporters<i>In Vivo</i>
Authors: Brandon Kocher, David Piwnica-Worms
Journal: Cancer Discovery (2013)

Bioluminescent imaging (BLI) is a powerful noninvasive tool that has dramatically accelerated the in vivo interrogation of cancer systems and longitudinal analysis of mouse models of cancer over the past decade. Various luciferase enzymes have been genetically engineered into mouse models (GEMM) of cancer, which permit investigation of cellular and molecular events associated with oncogenic transcription, posttranslational processing, protein-protein interactions, transformation, and oncogene addiction in live cells and animals. Luciferase-coupled GEMMs ultimately serve as a noninvasive, repetitive, longitudinal, and physiologic means by which cancer systems and therapeutic responses can be investigated accurately within the autochthonous context of a living animal.
ADAM-17: A Target to Increase Chemotherapeutic Efficacy in Colorectal Cancer?
Authors: Adam M. Lee, Robert B. Diasio
Journal: Clinical Cancer Research (2010)

Abstract Chemotherapy-induced activation of ADAM-17 results in increased growth factor shedding and activation of growth factor receptor-mediated pro-survival response. Enhanced ADAM-17 activity and HER ligand shedding results in resistance to chemotherapy in CRC. Therapies that decrease ADAM-17 activity in conjunction with current treatments may enhance response rates in advanced CRC patients. Clin Cancer Res; 16(13); 3319–21. ©2010 AACR.
Cellular and Connective Tissue Changes in Alveolar Septal Walls in Emphysema
Authors: GORDANA VLAHOVIC, MICHAEL L. RUSSELL, ROBERT R. MERCER, JAMES D. CRAPO
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

Emphysema is commonly defined as enlargement of airspaces distal to terminal bronchioles accompanied by destruction of alveolar walls, but without obvious fibrosis. Morphometric techniques were used to correlate changes in components of the alveolar septa surrounding enlarged airspaces in human emphysema with the mean linear intercept (Lm) of those airspaces. Alveolar and capillary surface density decreased with increased Lm, but the ratio of these surface densities to each other remained close to normal for mild to moderate increases in Lm. This suggests that the decreased gas exchange observed in emphysema is initiated by a total loss of septa and not by selective pathological changes of the microvasculature. Increases in septal wall thickness directly correlated with increases in Lm. For the mild to moderate emphysema lesions included in this study, an increase of 100% in Lm correlated with a 130% increase in the relative volume of the alveolar septal interstitium. Significant increases occurred in both elastin (0.14 to 0.56 μ m3/ μ m2 basement membrane [BM]) and collagen (0.49 to 1.63 μ m3/ μ m2 BM). The increase in elastin and collagen raises the possibility of a remodeling process in the connective matrix in alveolar walls. Whether or not the new connective tissue represents a disordered, nonfunctional regional response needs to be determined. Vlahovic G, Russell ML, Mercer RR, Crapo JD. Cellular and connective tissue changes in alveolar septal walls in emphysema.
Cognitive Dysfunction Is Associated With Poor Diabetes Control in Older Adults
Authors: Medha Munshi, Laura Grande, Mellody Hayes, Darlene Ayres, Emmy Suhl, Roberta Capelson, Susan Lin, William Milberg, Katie Weinger
Journal: Diabetes Care (2006)

OBJECTIVE—To evaluate the association between cognitive dysfunction and other barriers and glycemic control in older adults with diabetes. RESEARCH DESIGN AND METHODS—Patients over the age of 70 years presenting to a geriatric diabetes clinic were evaluated for barriers to successful diabetes management. Patients were screened for cognitive dysfunction with the Mini Mental State Examination (MMSE) and a clock-drawing test (CDT) scored by 1) a method validated by Mendez et al. and 2) a modified CDT (clock in a box [CIB]). Depression was evaluated with the Geriatric Depression Scale. Interview questionnaires surveyed activities of daily living (ADLs) and instrumental ADLs (IADLs), as well as other functional disabilities. RESULTS—Sixty patients (age 79 ± 5 years, diabetes duration 14 ± 13 years) were evaluated. Thirty-four percent of patients had low CIB (≤5), and 38% of patients had low CDT (≤13). Both CIB as well as CDT were inversely correlated with HbA1c, suggesting that cognitive dysfunction is associated with poor glycemic control (r = −0.37, P &amp;lt; 0.004 and r = −0.38, P &amp;lt; 0.004, respectively). Thirty-three percent of patients had depressive symptoms with greater difficulty completing the tasks of the IADL survey (5.7 ± 1.7 vs. 4.6 ± 2.0; P &amp;lt; 0.03). These older adults with diabetes had a high incidence of functional disabilities, including hearing impairment (48%), vision impairment (53%), history of recent falls (33%), fear of falls (44%), and difficulty performing IADLs (39%). CONCLUSIONS—Older adults with diabetes have a high risk of undiagnosed cognitive dysfunction, depression, and functional disabilities. Cognitive dysfunction in this population is associated with poor diabetes control.