tbuckley/cabot-search huggingface dataset:
In vivo characterization of site-specific phosphorylation in human topoisomerase IIβ
Authors: Adrian G. Grozav, Kenichi Chikamori, Dale R. Grabowski, Yan Xu, Michael Kinter, Ram Ganapathi, Mahrukh K. Ganapathi
Journal: Cancer Research (2005)

2405  The two highly homologous human topoisomerase II (topo II) isoforms, topoIIα and topoIIβ, alter DNA topology by creating double-stranded breaks. These enzymes are also targets for several clinically effective anti-tumor agents. Multiple phosphorylation sites that are cell cycle regulated have been identified in the C-terminal domain of topoIIα. More recently, phosphorylation of serine (Ser)-1106 in the catalytic domain of topo IIα has been reported to affect enzymatic activity and drug sensitivity. A potential functional role for site-specific phosphorylation in topoIIβ is suggested by our observations on hyperphosphorylation of topoIIβ in doxorubicin-resistant HL-60 cells and following all-trans retinoic acid induced differentiation of wild-type HL-60 cells. To identify phosphorylation sites in topoIIβ, proteomic analysis of the immunoprecipitated protein from wild-type or doxorubicin resistant HL-60 cells was carried out. Purified topoIIβ was subjected to successive cyanogen bromide (CNBr)/trypsin digestions followed by phosphopeptide detection using liquid chromatography-tandem mass spectrometry. This approach allowed us to reproducibly detect three in vivo phosphorylated amino acids - Ser-1550, Ser-1400 and Tyr-661. The residue Tyr-661 is located in the DNA binding/cleavage domain and conserved (Tyr-640 in α) between α and β topo II isoforms. The phosphorylated Ser residues identified lie in highly predicted phosphorylation contexts: KVKAS1400PITN with prediction score (p.s.) = 0.954 (max. value: 1), and KRKAS1550GSEN with p.s. = 0.998. Alignment of the amino acid sequences of the two human topo II proteins showed identity between Ser-1550 in topoIIβ and Ser-1469 in topoIIα (reported as a substrate for casein kinase II). Determination of the functional significance of Ser-1550 phosphorylation revealed that purified recombinant human topoIIβ containing a Ser-1550 to alanine substitution was ∼1.5-fold less active than the wild type protein in decatenating kinetoplast DNA. Single, double and triple mutants of identified phosphorylation sites are being tested for alterations in function. We also determined cell cycle regulation of expression and phosphorylation of topoIIβ isoform. TopoIIβ expression was not cell cycle regulated. However, the topoIIβ 2D-phosphopeptide maps of synchronized (G1, S, G2/M and M) cell fractions from wild-type HL-60 cells metabolically labeled with 32P-orthophosphoric acid were distinctly different; at least 5 major phosphopeptides were specific to cells in M phase. These results provide insights on site specific phosphorylation of topoIIβ and the possible functional role during cell cycle progression.
Implant-forming polymeric 19F MRI-tracer with tunable dissolution
Authors: Kristyna Kolouchova, Daniel Jirak, Ondrej Groborz, Ondrej Sedlacek, Natalia Ziolkowska, Martin Vit, Eva Sticova, Andrea Galisova, Pavel Svec, Jiri Trousil, Milan Hajek, Martin Hruby
Journal: Journal of Controlled Release (2020)
Microbial involvement in Alzheimer disease development and progression
Authors: Hannah R. Bulgart, Evan W. Neczypor, Loren E. Wold, Amy R. Mackos
Journal: Molecular Neurodegeneration (2020)

Abstract Alzheimer disease (AD) is the most prominent form of dementia and the 5th leading cause of death in individuals over 65. AD is a complex disease stemming from genetic, environmental, and lifestyle factors. It is known that AD patients have increased levels of senile plaques, neurofibrillary tangles, and neuroinflammation; however, the mechanism(s) by which the plaques, tangles, and neuroinflammation manifest remain elusive. A recent hypothesis has emerged that resident bacterial populations contribute to the development and progression of AD by contributing to neuroinflammation, senile plaque formation, and potentially neurofibrillary tangle accumulation (Fig. 1). This review will highlight recent studies involved in elucidating microbial involvement in AD development and progression.
Abstract 13034: Pivotal Role of Chitinase-3-like Protein 1, a Novel Myokine in Exercise Training-Induced Protection Against Cardiomyocyte Apoptosis and Promotion of Angiogenesis After Myocardial Infarction in Rats
Authors: Zhenjun Tian, Zhuo Li, Lei Xi
Journal: Circulation (2019)

Introduction: Chitinase-3-like protein 1 (CHI3L1) is a newly identified myokine involving tissue remodeling and inflammatory processes. CHI3L1 and its receptor protease-activated receptor 2 (PAR2) ...
SAT0223 Lyme meningoradiculitis in an endemic zone: clinical signs
Authors: F Roux, L Artru, B Haettich, J Esparbes, X Puéchal
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Neuroborreliosis has been called "the new great imitator". <h3>Objectives</h3> The aim of this study was to define the symptoms of meningoradiculitis. <h3>Methods</h3> We collected prospective data from all patients admitted to hospital with Lyme meningoradiculitis between June 1st, 1998 and December 31st, 1999 in an endemic zone located in western France. Diagnosis was based on lymphocytic meningitis associated with either intrathecal specific antibody synthesis or high serum titers of specific IgM in ELISA and western Blot analysis. <h3>Results</h3> Eleven patients (9 women, 2 men), with a mean age of 62 years (range: 37 to 87) were included during the study period. Two thirds of these patients were admitted to rheumatology wards during the summer. The onset of symptoms was preceded, 5 to 60 days earlier, by a tick bite in 64% of cases or erythema migrans in 55% of cases. In 18% of patients, neither a tick bite nor erythema was observed. Non specific symptoms were recorded in 82% of cases, with transient fever or flu syndrome in 45% of all cases. Cervical radiculoneuritis was observed in 4 cases, symptoms affecting several nerve roots of the lower limbs in 3 cases, femoral neuropathy in 2 cases, a bilateral sensory radiculoneuritis T11–12 in one case and poorly localised paresthesias in the lower limbs in one case. The meningeal signs and symptoms were minimal or, more frequently, absent. A peripheral motor paresis was observed in one quarter of the cases, but without Bell's palsy or encephalic or medullary signs. In half the patients, there was associated spinal pain not relieved by rest. All patients reported nocturnal exacerbation in pain. The electrocardiographic abnormalities included first-degree atrioventricular block in 2 patients. The course of the disease was consistently favourable on ceftriaxone IV treatment, with rapid effective relief of pain. <h3>Conclusion</h3> A diagnosis of Lyme meningoradiculitis should be considered in endemic zones in all cases of spine pain and/or radiculitis with nocturnal exacerbation, especially in the summer period.
SAT0214 Os calcis densitometry (pixi) for osteoporosis screening in postmenopausal women
Authors: JA Román-Ivorra, L Abad, JJ Alegre-Sancho, C Fernández-Carballido, S Fernández
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> To determine t-score values which should be applied for the screening of osteoporosis in postmenoapusal women when using a peripheral os calcis densitometer (PIXI). <h3>Methods</h3> Heel bone mineral density (BMD) was measured in 81 postmenopausal women with a PIXI densitometer (LUNAR). Results (t-score values) were classified according to the WHO definition and to the manufacturer recommendations (LUNAR): normal &gt;-0,6; osteopenia from -0,6 to -1,6 and osteoporosis &lt;-1,6. Hip BMD measurements (DEXA) were used as to compare the results. <h3>Results</h3> <h3>Conclusion</h3> False-negative results for osteoporosis become reduced when t-score classification recommended by the manufacturer are used as cut-off points in heel densitometry. An accurate collection of osteoporosis risk factors can help to identify those patients with hip osteoporosis among patients with heel osteopenia.
High rates of stillbirth and preterm delivery in women with covid-19 and the efficacy of ECMO in pregnancy
Authors: Elizabeth V Kingston
Journal: BMJ (2020)

The initial data reported by the UK Obstetric Surveillance System study were of great interest, and the findings have been discussed in our multidisciplinary maternity team.1

The rates of pregnancy loss, stillbirth, and preterm delivery seem considerably higher than those reported elsewhere. As noted by Magee and colleagues,2 the stillbirth rate among women with covid-19 admitted to hospital, 11.5 per 1000 maternities, is much higher than the most recently reported rate of 4.1 per 1000 completed …
The <scp><i>CYB5R3</i><sup>c</sup></scp><sup>.<scp>350C</scp>&gt;G</sup> and <scp><i>G6PD</i></scp> A alleles modify severity of anemia in malaria and sickle cell disease
Authors: Victor R. Gordeuk, Binal N. Shah, Xu Zhang, Philip E. Thuma, Stenford Zulu, Rodgers Moono, N. Scott Reading, Jihyun Song, Yingze Zhang, Mehdi Nouraie, Andrew Campbell, Caterina P. Minniti, Sohail R. Rana, Deepika S. Darbari, Gregory J. Kato, Mei Niu, Oswaldo L. Castro, Roberto Machado, Mark T. Gladwin, Josef T. Prchal
Journal: American Journal of Hematology (2020)

Genetic modifiers of anemia in Plasmodium falciparum infection and sickle cell disease (SCD) are not fully known. Both conditions are associated with oxidative stress, hemolysis and anemia. The CYB5R3 gene encodes cytochrome b5 reductase 3, which converts methemoglobin to hemoglobin through oxidation of NADH. CYB5R3
A colorimetric RT-LAMP assay and LAMP-sequencing for detecting SARS-CoV-2 RNA in clinical samples
Authors: Viet Loan Dao Thi, Konrad Herbst, Kathleen Boerner, Matthias Meurer, Lukas PM Kremer, Daniel Kirrmaier, Andrew Freistaedter, Dimitrios Papagiannidis, Carla Galmozzi, Megan L. Stanifer, Steeve Boulant, Steffen Klein, Petr Chlanda, Dina Khalid, Isabel Barreto Miranda, Paul Schnitzler, Hans-Georg Kräusslich, Michael Knop, Simon Anders
Journal: Science Translational Medicine (2020)

A colorimetric isothermal RNA amplification method was shown to detect SARS-CoV-2 RNA in clinical samples with excellent sensitivity and specificity.
AB0234 Objektiv functional performance tests in patients with low back pain. review
Authors: K Hanusch, S Hoffmann, I Satkauskas, R Theiler
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> In the past few decades, a large number of physical performance (PP) tests for clinical assessment of patients with low back pain (LBP) have been introduced. Knowledge is limited, however, on the their appropriateness for treatment outcome, clinical and epidemiological studies, which require a high level of reliability and validity of measurements. <h3>Objectives</h3> Our review focus on the psychometric properties and clinical usefulness of physical performance measurements in patients with LBP. <h3>Methods</h3> In order to comprehensively identify instruments of physical performance measurement in LBP patients and studies on their reliability, validity and clinical usefulness, MEDLINE searches were performed for the time interval from 1998 to 2000 using the following controlled vocabulary: low back pain, measurement (s), outcome, tests, function, physical performance, muscle strength, range of motion, reliability, sensitivity, validity. In the second step reference lists of the retrieved papers were used for identification further studies, which were not included in MEDLINE database. The literature about sophisticated, special equipment requiring functional measurements, which application due to cost and time demand in daily clinical practise is restricted, was excluded from analysis. <h3>Results</h3> 162 papers reporting on physical performance tests in patients with low back pain were analysed. Validity and reliability has been more comprehensively studied for ?Timed-up-and-go?, ?Loaded reach? and ?Sit-to-stand? tests. The high level of reliability of these test were reported (correlation coefficients ranged from r = 0,89 to r = 0.99). No one prospective follow-up study on responsiveness of PP tests was found. <h3>Conclusion</h3> In our literature search we found that all validated PP tests were designed as a discriminative instruments, whose purpose was to measure differences between the people. In order to use them as a qualitative clinical outcome measurement instruments, their psychometric property such a responsiveness should be investigated. Available in our rewiev.
FRI0240 Laser nucleolysis for the treatment of lombosciatica. results in a cohort of 30 patients with a 6 months follow up
Authors: R Dupuis, B Lavignolles, L Salanon, JR Vigne, D Liguoro, F San Galli, M Dautheribes, J Dehais, J Guérin
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Since 1986, laser is used for percutaneous treatment of discal herniation. Due to a thermic effect, it infers an evaporation of the nucleus pulposus and allows a discal decompression that seems to be responsible for the improvement of the patients. <h3>Objectives</h3> To estimate the efficacy of the laser nucleolysis on pain, functional incapacity and quality of life of patients suffering of lombosciatica due to dics herniation. <h3>Methods</h3> Thirty patients suffering from lombosciatica due to a disc herniation for more than three months were selected on clinical and radiological criteria. All were not relieved although they underwent a well-driven medical treatment. They were treated with percutaneous way with a laser diode 940 nm. All were followed prospectively for six months by an examiner different from the operator. Evaluation criteria consisted of level of lumbar and radicular pain (VAS), level of functional incapacity (Oswestry) and quality of life (SF-36). <h3>Results</h3> 30 patients were included in this study. 6 months after the intervention 23 of them (76.6%) were relieved of their radicular pain (EVA &lt; 20%). Lumbar pain and level of functional incapacity decreased whereas the quality of life increased. The patients who failed to improve three months after the procedure (23.4%) were all relieved later after a surgical discectomy. <h3>Conclusion</h3> Laser nucleolysis allows a significant decrease at month 6 of pain, functional incapacity and an increase of the quality of life in a group of selected patients suffering from lombosciatica resistant to the medical treatment.
Makorin rings the kisspeptin bell to signal pubertal initiation
Authors: Ali Abbara, Waljit S. Dhillo
Journal: Journal of Clinical Investigation (2020)

The signals maintaining quiescence of the reproductive endocrine axis during childhood before its reawakening at puberty had been enigmatic. Studies in patients with abnormal puberty have illuminated the identity of the signals; kisspeptin has emerged as a major stimulator of puberty, and makorin RING finger protein 3 (MKRN3) as an inhibitory signal that prevents premature initiation of puberty. In this issue of the JCI, Abreu et al. investigated the mechanism by which MKRN3 regulates pubertal onset. The authors found that a reduction in MKRN3 alleviated the constraint on kisspeptin-expressing neurons to allow pubertal initiation, a phenomenon observed across species, including nonhuman primates. Further, the ubiquitinase activity of MKRN3 required its RING finger domain, in order to repress the promoter activity of genes encoding kisspeptin and neurokinin B. These data advance our understanding of the regulation of kisspeptin-expressing neurons by MKRN3 to initiate puberty.
Targeting MAD2 modulates stemness and tumorigenesis in human Gastric Cancer cell lines
Authors: Natalia Pajuelo-Lozano, Sonia Alcalá, Bruno Sainz, Rosario Perona, Isabel Sanchez-Perez
Journal: Theranostics (2020)

Rationale: Gastric cancer (GC) is a solid tumor that contains subpopulations of cancer stem cells (CSCs), which are considered drivers of tumor initiation and metastasis; responsible for therapeutic resistance; and promoters of tumor relapse.The balance between symmetric and asymmetric division is crucial for stem cell maintenance.The objective of this study is to evaluate the role of MAD2, a key protein for proper mitotic checkpoint activity, in the tumorigenesis of GC.Methods: Gastric cancer stem cells (GCSCs) were obtained from MKN45, SNU638 and ST2957 cell lines.Pluripotency and stemness markers were evaluated by RT-qPCR and autofluorescence and membrane markers by flow cytometry.Relevant signal transduction pathways were studied by WB.We analysed cell cycle progression, migration and invasion after modulation of MAD2 activity or protein expression levels in these in vitro models.In vivo assays were performed in a nude mouse subcutaneous xenograft model.Results: We found that NANOG, CXCR4 and autofluorescence are common and consistent markers for the GCSCs analysed, with other markers showing more variability.The three main signalling pathways (Wnt/β-catenin; Hedgehog and Notch) were activated in GCSCs.Downregulation of MAD2 in MKN45 CSCs decreased the expression of markers CXCR4, CD133, CD90, LGR5 and VIM, without affecting cell cycle profile or therapy resistance.Moreover, migration, invasion and tumor growth were clearly reduced, and accordingly, we found that metalloprotease expression decreased.These results were accompanied by a reduction in the levels of transcription factors related with epithelial-to-mesenchymal transition.Conclusions: We can conclude that MAD2 is important for GCSCs stemness and its downregulation in MKN45 CSCs plays a central role in GC tumorigenesis, likely through CXCR4-SNAI2-MMP1.Thus, its potential use in the clinical setting should be studied as its functions appear to extend beyond mitosis.
Abstract IA15: Tissue-agnostic development of TRK inhibitors for pediatric cancer
Authors: Theodore W. Laetsch
Journal: Cancer Research (2020)

Abstract Fusions involving in the NTRK1, NTRK2, and NTRK3 genes that encode the TRKA, TRKB, and TRKC neurotrophin receptors (TRK fusions) occur across a wide range of cancers in children and adults. These fusions result in constitutive expression and ligand-independent activation of the TRK kinase. TRK fusions are pathognomonic for certain rare cancers, including infantile fibrosarcoma and cellular congenital mesoblastic nephroma, and occur at a lower frequency across a range of more common cancers in children including soft-tissue sarcomas, gliomas, and leukemias. Recently, larotrectinib was FDA approved for the treatment of TRK fusion solid tumors in children and adults, representing the first kinase inhibitor to receive FDA histology-agnostic approval for the treatment of cancer. This approval was based on a combined analysis of three clinical trials, including an ongoing pediatric phase 1/2 trial that demonstrated a 94% response rate in 34 children with TRK fusion-positive solid tumors. Remarkably, due to nearly concurrent development in pediatrics and adults, more than 30% of the patients with TRK fusion solid tumors treated with larotrectinib on clinical trials to date have been children. Other TRK inhibitors are also in pediatric development, including entrectinib and LOXO-195, and clinical trials of additional agents including repotrectinib are planned. Entrectinib, which also antagonizes ROS1 and ALK, was reported to induce responses in 11/11 children whose tumors harbored fusions of the TRK, ROS1 or ALK genes. LOXO-195 and repotrectinib have the potential to antagonize resistance mutations that can develop during treatment with first-generation TRK inhibitors, and we reported a 45% response rate to LOXO-195 among 20 patients enrolled to either single-patient treatment protocols or an ongoing pediatric and adult phase 1 study who harbored a TRK kinase resistance mutation. In this talk, I will review the data on the use of TRK inhibitors for TRK fusion cancers in children, discuss unanswered questions related to the use of TRK inhibitors in children and planned clinical trials designed to address these, and highlight the challenges and opportunities that arise when studying novel therapies for rare, molecularly defined diseases. Citation Format: Theodore W. Laetsch. Tissue-agnostic development of TRK inhibitors for pediatric cancer [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr IA15.
Incidence of Hip Fracture Over 4 Decades in the Framingham Heart Study
Authors: Jay Swayambunathan, Abhijit Dasgupta, Philip S. Rosenberg, Marian T. Hannan, Douglas P. Kiel, Timothy Bhattacharyya
Journal: JAMA Internal Medicine (2020)

Age-adjusted hip fracture incidence is decreasing in the US. The decrease has been attributed to osteoporosis treatment, but the cause is unknown.To examine the decrease in hip fracture incidence over the past 40 years in the US.A population-based cohort study using participants in the Framingham Heart Study was conducted. A total of 4918 men and 5634 women were followed up prospectively for the first hip fracture between January 1, 1970, and December 31, 2010. Data were analyzed from May 1, 2019, to May 30, 2020.Incidence of hip fracture and contemporaneous prevalence of risk factors for hip fractures analyzed with age-period-cohort models.The study contained more than 105 000 person-years in 10 552 individuals with a gradual shift toward the offspring participants in the 1980s and 1990s. Women represented more than 55% of the study sample over the years. Adjusted for age, the incidence of hip fracture decreased by 4.4% (95% CI, 6.8%-1.9%) per year from 1970 to 2010. Both period associations (P < .001) and birth cohort associations (P < .001) were statistically significant. For example, in persons aged 85 to 89 years, the incidence of hip fracture was 759 per 100 000 person-years in the offspring group compared with 2018 per 100 000 person-years in the original cohort. The decrease in hip fracture incidence was coincident with a decrease in smoking and heavy drinking. Smoking decreased from 38% in the 1970s to 15% in the late 2000s, while heavy drinking decreased from 7.0% to 4.5%. The prevalence of other risk factors for hip fracture, such as underweight (body mass index <18.5), obesity (body mass index >30), and early menopause (age <45 years) were stable over the study period. When persons who never smoked were evaluated, a change in the incidence of -3.2% (95% CI, -6.0% to -0.4%) per year was observed. The difference between the decrease of the entire population and nonsmokers of 1.5% per year was similar to the hazard ratio conferred by smoking (hazard ratio, 1.5; 95% CI, 1.14-1.96).In this study, individuals born more recently appeared to have a low risk for hip fracture. Reductions in smoking and heavy drinking were the risk factor changes coincident with the observed decrease in hip fracture. Attributing the decrease in hip fracture incidence up to 2010 solely to better treatment is not supported by these data, emphasizing the need to treat patients with osteoporosis while continuing to encourage public health interventions for smoking cessation and heavy drinking.