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Huang, Y., Y. Liu, Q. Huang, W. Deng, and T. W. Li. "POS0133 MONOSODIUM URATE CRYSTALS REDUCE HUMAN LIGAMENT CELLS VIABILITY THROUGH INCREASE OF ROS PRODUCTION." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 278.1–278. http://dx.doi.org/10.1136/annrheumdis-2021-eular.2316.
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Background:Ligament destruction is a frequent complication of gout and is strongly associated with tophi. Ligament fibroblasts are important cellular mediators of ligament remodeling. None of study has paid attention to the effects of monosodium urate (MSU) crystals on ligament fibroblasts.Objectives:The study aims to investigate the effects and mechanism of MSU crystals on ligament fibroblasts.Methods:MSU crystals were added to human ligament fibroblasts(HLFs) cultures or primary ligament cells cultures. Cell counting kit-8 (CCK-8) assay, cell migration assay, Annexin V-FITC/PI assay were conducted. Reactive Oxygen Species(ROS) was tested by ROS Assay Kit.Results:The higher concentrations of MSU crystals (0.5-1mg/mL) reduced the viability of HLFs or primary ligament cells after 24 h as assessed by CCK8 assays, with a further reduction in viability observed at the 48 h time point. When observed under light microscopy, HLFs cultured with MSU crystals (0.5mg/mL) appeared unhealthy with fewer cells present. The cell migration ability of HLFs was decreased significantly on MSU crystals (0.5mg/mL). According to the result of Annexin V-FITC/PI assay, the survival rate of HLFs on MSU crystals (0.5mg/mL) was lower than that of 0.25mg/ml and 0 mg/ml at 72h. ROS assay results showed that the production of ROS increased as the concentrations of MSU crystals increased.Conclusion:MSU crystals inhibit human ligament cells viability through the increase of ROS production. It may contribute to disordered ligament remodeling in gout patients with ligament destruction.References:[1]Ashika Chhana, et al. Monosodium urate crystals reduce osteocyte viability and indirectly promote a shift in osteocyte function towards a proinflammatory and proresorptive state. Arthritis Res Ther. 2018, 20(1): 208.Figure 1.MSU crystals reduce human ligament fibroblasts and primary human ligament cells viability over time. A: CCK-8 assay; B: Observation of HLFs morphology; C: Annexin V-FITC/PI assay.Disclosure of Interests:None declared
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Jiang, Hui, Feng Chen, DianZe Song, Xiaoqin Zhou, Long Ren, and Mei Zeng. "Dynamin-Related Protein 1 Is Involved in Mitochondrial Damage, Defective Mitophagy, and NLRP3 Inflammasome Activation Induced by MSU Crystals." Oxidative Medicine and Cellular Longevity 2022 (October 25, 2022): 1–22. http://dx.doi.org/10.1155/2022/5064494.
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Excessive generation of reactive oxygen species (ROS) has great impacts on MSU crystal-induced inflammation. Drp1-dependent mitochondrial fission is closely associated with mitochondrial ROS levels. However, whether Drp1 signaling contributes to MSU crystal-induced inflammation remains unclear. Mice bone marrow-derived macrophages (BMDMs) were primed with LPS and then stimulated with MSU suspensions for 12 h. The protein levels associated with mitochondrial dynamics, oxidative stress, and mitophagy were detected by Western blot. BMDMs were loaded with MitoTracker Green probe to detect mitochondrial morphology. To measure mitochondrial reactive oxygen species (ROS) and total ROS levels, cells were loaded, respectively, with MitoSOX and DHE probes. The effects of Mito-TEMPO, an antioxidant that targets the mitochondria or DRP1 inhibitor (Mdivi-1) on MSU crystal-induced peritonitis and arthritis mouse models, were evaluated. Our study revealed that MSU crystal stimulation resulted in elevation of mitochondrial fragmentation of BMDMs. Treatment with Mito-TEMPO or Drp1 knockdown significantly ameliorated the mitochondrial damage induced by MSU crystals. BMDMs exposure to MSU crystals increased the expression of auto/mitophagy marker proteins and promoted the fusion of mitophagosomes with lysosomes, leading to accumulation of mitolysosomes. Drp1 knockdown alleviated defective mitophagy and activation of the NLRP3 inflammasome in MSU crystal-treated BMDMs. This study indicates that there is crosstalk between mitochondrial ROS and Drp1 signaling in MSU crystal-induced inflammation. Drp1 signaling is involved in MSU crystal-induced mitochondrial damage, impaired mitophagy and NLRP3 inflammasome activation.
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Abe, Hiroyuki, Robert Anthony Antonia, and Sadayoshi Toh. "Large-scale structures in a turbulent channel flow with a minimal streamwise flow unit." Journal of Fluid Mechanics 850 (July 6, 2018): 733–68. http://dx.doi.org/10.1017/jfm.2018.434.
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Direct numerical simulations are used to examine large-scale motions with a streamwise length$2\sim 4h$($h$denotes the channel half-width) in the logarithmic and outer regions of a turbulent channel flow. We test a minimal ‘streamwise’ flow unit (Toh & Itano,J. Fluid Mech., vol. 524, 2005, pp. 249–262) (or MSU) for larger Kármán numbers ($h^{+}=395$and 1020) than in the original work. This flow unit consists of a sufficiently long (${L_{x}}^{+}\approx 400$) streamwise domain to maintain near-wall turbulence (Jiménez & Moin,J. Fluid Mech., vol. 225, 1991, pp. 213–240) and a spanwise domain which is large enough to represent the spanwise behaviour of inner and outer structures correctly; as$h^{+}$increases, the streamwise extent of the MSU domain decreases with respect to$h$. Particular attention is given to whether the spanwise organization of the large-scale structures may be represented properly in this simplified system at sufficiently large$h^{+}$and how these structures are associated with the mean streamwise velocity$\overline{U}$. It is shown that, in the MSU, the large-scale structures become approximately two-dimensional at$h^{+}=1020$. In this case, the streamwise velocity fluctuation$u$is energized, whereas the spanwise velocity fluctuation$w$is weakened significantly. Indeed, there is a reduced energy redistribution arising from the impaired global nature of the pressure, which is linked to the reduced linear–nonlinear interaction in the Poisson equation (i.e. the rapid pressure). The logarithmic dependence of$\overline{ww}$is also more evident due to the reduced large-scale spanwise meandering. On the other hand, the spanwise organization of the large-scale$u$structures is essentially identical for the MSU and large streamwise domain (LSD). One discernible difference, relative to the LSD, is that the large-scale structures in the MSU are more energized in the outer region due to a reduced turbulent diffusion. In this region, there is a tight coupling between neighbouring structures, which yields antisymmetric pairs (with respect to centreline) of large-scale structures with a spanwise spacing of approximately$3h$; this is intrinsically identical with the outer energetic mode in the optimal transient growth of perturbations (del Álamo & Jiménez,J. Fluid Mech., vol. 561, 2006, pp. 329–358).
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Goo, Bonhyuk, Jeeyoun Lee, Chansol Park, Taeyoung Yune, and Yeoncheol Park. "Bee Venom Alleviated Edema and Pain in Monosodium Urate Crystals-Induced Gouty Arthritis in Rat by Inhibiting Inflammation." Toxins 13, no. 9 (September 16, 2021): 661. http://dx.doi.org/10.3390/toxins13090661.
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Bee venom (BV) acupuncture has anti-inflammatory and analgesic effects; therefore, it was used as a traditional Korean medicine for various musculoskeletal disorders, especially arthritis. In this study, we investigated the effect of BV on monosodium urate (MSU) crystal-induced acute gouty rats. An intra-articular injection of MSU crystal suspension (1.25 mg/site) was administered to the tibiotarsal joint of the hind paw of Sprague Dawley rats to induce MSU crystal-induced gouty arthritis. Colchicine (30 mg/kg) was orally administered 1 h before MSU crystal injection as a positive control, and BV (0.5 mg/kg) was injected into the tibiotarsal joint immediately after MSU crystal injection. The ankle thickness, mechanical allodynia, and expression of proinflammatory cytokines (TNF-α, IL-1β, IL6, COX2 and iNOS) and chemokines (MIP-1α, MIP-1β, MCP-1, GRO-α, MIP-2α) were then evaluated. BV reduced the expression of proinflammatory cytokines and chemokines, which are important mediators of MSU crystal-induced inflammatory responses. This anti-inflammatory effect was also confirmed histologically to attenuate synovitis and neutrophil infiltration. We demonstrated that BV markedly ameliorated ankle edema and mechanical allodynia in gouty rats. These results suggest that BV acupuncture is a potential clinical therapy for acute gouty management.
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Cherian, Mathew, Pankaj Mehta, Shriram Varadharajan, Santosh Poyyamozhi, Elango Swamiappan, Jenny Gandhi, and Nithin Theckumparampil. "Retrospective Review and Proof of Concept of Asia’s First Mobile Stroke Unit Experience in Kovai Medical Center and Hospital." Journal of Stroke Medicine 3, no. 2 (December 2020): 116–23. http://dx.doi.org/10.1177/2516608520968418.
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Background: We review our initial experience of India’s and Asia’s first mobile stroke unit (MSU) following the completion of its first year of operation. We outline the clinical care pathway integrating the MSU services using a case example taking readers along our clinical care workflow while highlighting the challenges faced in organizing and optimizing such services in India. Methods: Retrospective review of data collected for all patients from March 2018 to February 2019 transported and treated within the MSU during the first year of its operation. Recent case example is reviewed highlighting complete comprehensive acute clinical care pathway from prehospital MSU services to advanced endovascular treatment with focus on challenges faced in developing nation for stroke care. Results: The MSU was dispatched and utilized for 14 patients with clinical symptoms of acute stroke. These patients were predominantly males (64%) with median age of 59 years. Ischemic stroke was seen in 7 patients, hemorrhagic in 6, and 1 patient was classified as stroke mimic. Intravenous tissue plasminogen activator was administered to 3 patients within MSU. Most of the patients’ treatment was initiated within 2 h of symptom onset and with the median time of patient contact (rendezvous) following stroke being 55 mins. Conclusion: Retrospective review of Asia’s first MSU reveals its proof of concept in India. Although the number of patients availing treatment in MSU is low as compared to elsewhere in the world, increased public awareness with active government support including subsidizing treatment costs could accelerate development of optimal prehospital acute stroke care policy in India.
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Pascart, T., P. Carpentier, L. Norberciak, J. Legrand, E. Houvenagel, F. Becce, and J. F. Budzik. "OP0175 IDENTIFYING PERIPHERAL VASCULAR MONOSODIUM URATE CRYSTAL DEPOSITION WITH DUAL-ENERGY CT: FACT OR FICTION? THE VASCURATE STUDY." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 109.2–109. http://dx.doi.org/10.1136/annrheumdis-2020-eular.4522.
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Background:The close relationship between gout and cardiovascular diseases is well established. A growing hypothesis explaining this association would be that monosodium urate (MSU) crystals are deposited within vessel walls. Dual-energy computed tomography (DECT) can identify and quantify MSU crystal deposition in soft tissues. It remains unclear whether vascular spots exhibiting DECT attenuation characteristics of MSU are artefacts or true MSU crystal deposits.Objectives:The objectives of this study were to determine whether the presence of peripheral vascular MSU crystal deposition identified with DECT is associated with the extent of MSU deposits in joint soft tissues, and if this association persists over time under urate-lowering therapy.Methods:Patients with a clinical suspicion or established gout diagnosis prospectively underwent DECT for identification and quantification of the MSU crystal burden in their knees and feet. Some of these patients were also enrolled in the GOUT-DECTUS longitudinal study, and thus underwent follow-up DECT scans of their knees and feet at 6, 12 and 24 months. DECT scans were examined for the presence of vascular spots ≥0.01 cm3 classified as MSU crystal deposits according to the default post-processing settings. Multiple linear regressions adjusting on serum urate levels and gout diagnosis were implemented to determine the association between DECT MSU crystal volume in joint soft tissues, and the presence of vascular MSU deposits. Mixed linear models were used to compare DECT volumes of MSU crystal deposition in soft tissues between vascular MSU positive and negative patients during follow-up.Results:A total of 169 patients were included, of which 140 had a final diagnosis of gout, including 15 also included in the longitudinal study. Patients were mostly male (78.8%) and were 65.5 ± 14.6 years old. Among gout patients, disease duration was 9.3 ± 9.9 years and 56.5% were urate lowering therapy-naive. A total of 11/29 (37.9%) controls and 40/140 (28.6%) gout patients presented with a least one vascular spot of DECT MSU deposition, with an average volume of 0.02 ± 0.02 cm3, and all subjects also presented at least one vascular calcification. In the feet, patients positive for vascular DECT MSU crystal deposition had an MSU volume of 3.81 ± 10.06 cm3 in joint soft tissues, compared with 1.85 ± 7.72 cm3 for those without vascular MSU deposition (p=0.018). In the knees, patients with vascular MSU deposition had an MSU crystal volume of 6.03 ± 24.13 cm3 in joint soft tissues, compared with 0.83 ± 2.88 cm3 for those without vascular evidence of MSU deposition. In the longitudinal subgroup analysis, coefficients of the fixed effects for the presence of vascular MSU deposits on the MSU crystal volume in joint soft tissues was 0.4 (p=0.35) in the feet and 1.21 (p=0.03) in the knees. The presence of vascular DECT MSU deposits was associated with a 3.4-fold increase in MSU crystal volume in knee joint soft tissues throughout follow-up.Conclusion:This study suggests that some vascular spots identified with DECT as MSU crystal deposition may be real and not artefacts. This correlation remains throughout follow-up in the knees. However, the comparable prevalence of vascular DECT MSU deposits between gout patients and controls, the systematic co-existence of vascular calcifications and the uneven regression under urate-lowering therapy requires further analysis to determine which DECT spots are artefacts and which are not.References:[1]Dual-Energy Computed Tomography Detection of Cardiovascular Monosodium Urate Deposits in Patients With Gout. Klauser AS, Halpern EJ, Strobl S, Gruber J, Feuchtner G, Bellmann-Weiler R, Weiss G, Stofferin H, Jaschke W.Disclosure of Interests:Tristan Pascart Grant/research support from: Research Grant Horizon Pharma, Consultant of: Novartis, BMS, Sanofi, Pfizer,, Speakers bureau: Novartis, BMS, Paul Carpentier: None declared, Laurène Norberciak: None declared, Julie Legrand: None declared, Eric Houvenagel Speakers bureau: Janssen, Novartis, Fabio Becce: None declared, Jean-François Budzik: None declared
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Powers, Nicholas E., Benjamin Swartzwelter, Carlo Marchetti, Dennis M. de Graaf, Alexandra Lerchner, Martin Schlapschy, Rajiv Datar, et al. "PASylation of IL-1 receptor antagonist (IL-1Ra) retains IL-1 blockade and extends its duration in mouse urate crystal-induced peritonitis." Journal of Biological Chemistry 295, no. 3 (December 9, 2019): 868–82. http://dx.doi.org/10.1074/jbc.ra119.010340.
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Interleukin-1 (IL-1) is a key mediator of inflammation and immunity. Naturally-occurring IL-1 receptor antagonist (IL-1Ra) binds and blocks the IL-1 receptor-1 (IL-1R1), preventing signaling. Anakinra, a recombinant form of IL-1Ra, is used to treat a spectrum of inflammatory diseases. However, anakinra is rapidly cleared from the body and requires daily administration. To create a longer-lasting alternative, PASylated IL-1Ra (PAS–IL-1Ra) has been generated by in-frame fusion of a long, defined-length, N-terminal Pro/Ala/Ser (PAS) random-coil polypeptide with IL-1Ra. Here, we compared the efficacy of two PAS–IL-1Ra molecules, PAS600–IL-1Ra and PAS800–IL-1Ra (carrying 600 and 800 PAS residues, respectively), with that of anakinra in mice. PAS600–IL-1Ra displayed markedly extended blood plasma levels 3 days post-administration, whereas anakinra was undetectable after 24 h. We also studied PAS600–IL-1Ra and PAS800–IL-1Ra for efficacy in monosodium urate (MSU) crystal-induced peritonitis. 5 days post-administration, PAS800–IL-1Ra significantly reduced leukocyte influx and inflammatory markers in MSU-induced peritonitis, whereas equimolar anakinra administered 24 h before MSU challenge was ineffective. The 6-h pretreatment with equimolar anakinra or PAS800–IL-1Ra before MSU challenge similarly reduced inflammatory markers. In cultured A549 lung carcinoma cells, anakinra, PAS600–IL-1Ra, and PAS800-IL-Ra reduced IL-1α–induced IL-6 and IL-8 levels with comparable potency. In human peripheral blood mononuclear cells, these molecules suppressed Candida albicans–induced production of the cancer-promoting cytokine IL-22. Surface plasmon resonance analyses revealed significant binding between PAS–IL-1Ra and IL-1R1, although with a slightly lower affinity than anakinra. These results validate PAS–IL-1Ra as an active IL-1 antagonist with marked in vivo potency and a significantly extended half-life compared with anakinra.
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Alessi, A., G. Buscarino, S. Agnello, F. Messina, L. Sciortino, M. Cannas, and F. M. Gelardi. "Effects of Pressure, Thermal Treatment, and O2 Loading in MCM41, MSU-H, and MSU-F Mesoporous Silica Systems Probed by Raman Spectroscopy." Journal of Physical Chemistry C 119, no. 49 (December 2, 2015): 27434–41. http://dx.doi.org/10.1021/acs.jpcc.5b10206.
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Kwok, Jun Sheng, Kate Fox, Cees Bil, Francesca Langenberg, Anna H. Balabanski, Angela Dos Santos, Andrew Bivard, et al. "Bringing CT Scanners to the Skies: Design of a CT Scanner for an Air Mobile Stroke Unit." Applied Sciences 12, no. 3 (January 31, 2022): 1560. http://dx.doi.org/10.3390/app12031560.
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Stroke is the second most common cause of death and remains a persistent health challenge globally. Due to its highly time-sensitive nature, earlier stroke treatments should be enforced for improved patient outcome. The mobile stroke unit (MSU) was conceptualized and implemented to deliver the diagnosis and treatment to a stroke patient in the ultra-early time window (<1 h) in the pre-hospital setting and has shown to be clinically effective. However, due to geographical challenges, most rural communities are still unable to receive timely stroke intervention, as access to specialized stroke facilities for optimal stroke treatment poses a challenge. Therefore, the aircraft counterpart (Air-MSU) of the conventional road MSU offers a plausible solution to this shortcoming by expanding the catchment area for regional locations in Australia. The implementation of Air-MSU is currently hindered by several technical limitations, where current commercially available CT scanners are still oversized and too heavy to be integrated into a conventional helicopter emergency medical service (HEMS). In collaboration with the Australian Stroke Alliance and Melbourne Brain Centre, this article aims to explore the possibilities and methodologies in reducing the weight and, effectively, the size of an existing CT scanner, such that it can be retrofitted into the proposed search and rescue helicopter—Agusta Westland AW189. The result will be Australia’s first-ever customized CT scanner structure designed to fit in a search-and-rescue helicopter used for Air-MSU.
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He, Menglin, Cheng Hu, Meijuan Chen, Qian Gao, Liqiu Li, and Weiqian Tian. "Effects of Gentiopicroside on activation of NLRP3 inflammasome in acute gouty arthritis mice induced by MSU." Journal of Natural Medicines 76, no. 1 (September 29, 2021): 178–87. http://dx.doi.org/10.1007/s11418-021-01571-5.
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AbstractAcute gouty arthritis is a self-limiting inflammatory disease resulting from the deposition of monosodium urate (MSU) crystals. It has been shown that Gentiopicroside (GPS) possesses anti-inflammatory and analgesic functions. The aim of this study was to parse out whether GPS has an effect on acute gouty arthritis. We established an acute gouty arthritis model by the injection of MSU into the paw, and found that GPS relieves MSU-induced mechanical, thermal hyperalgesia, and paw swelling. Furthermore, GPS down-regulated the release of pro-inflammatory cytokines in paw tissues, including IL-1β, IL-6, IL-18, and TNF-α. The results of H&E staining and MPO activity measurement showed that GPS inhibits neutrophil infiltration. And the over-expressions of NOD-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and Caspase-1 induced by MSU were inhibited by treatment with GPS. These results revealed that GPS can treat acute gouty arthritis based on anti-inflammatory and analgesic properties in vivo, which might be ascribed to the inhibition on NLRP3 inflammasome. Furthermore, we performed in vitro study to confirm the results of in vivo study. Consistently, the results proved that GPS could inhibit the activation of NLRP3 inflammasome in RAW264.7 macrophages stimulated by LPS-MSU. In conclusion, this study provides an experimental basis for the application of GPS and expands the potential value of GPS in the therapy of acute gouty arthritis.
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Xia, Hong, and Bingsi Liu. "High H2O-resistance CaO-MnO /MSU-H sorbents for hot coal gas desulfurization." Journal of Hazardous Materials 324 (February 2017): 281–90. http://dx.doi.org/10.1016/j.jhazmat.2016.10.058.
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Yu, Wei Hua, Han Bin Zhao, Dong Shen Tong, Chun Hui Zhou, and Ping Shao. "Immobilization of lipase onto aminopropyl-functionalized MSU-H type mesoporous silica and esterification." Korean Journal of Chemical Engineering 32, no. 8 (April 28, 2015): 1694–700. http://dx.doi.org/10.1007/s11814-014-0391-x.
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Toprover, M., M. Mechlin, A. Slobodnick, V. C. Pike, C. Oh, C. Davis, T. Fields, F. Becce, and M. H. Pillinger. "POS0134 INCREASED PREVALENCE OF LUMBAR SPINE MONOSODIUM URATE DEPOSITION AMONG GOUT PATIENTS ON DUAL-ENERGY CT." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 278.2–279. http://dx.doi.org/10.1136/annrheumdis-2021-eular.2733.
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Background:Gout affecting the spine is reported as a rare event presenting with neuropathy, spinal compression and acute back pain (1). Cases are often diagnosed by tissue confirmation of monosodium urate (MSU) deposition. The frequency of gout involving the spine asymptomatically or with milder, non-specific symptoms is likely higher than reported.Objectives:Using dual-energy CT (DECT), we are determining prevalence/extent of MSU deposition in the lumbosacral spines of patients with gout and tophaceous gout, compared to non-gout controls.Methods:We are recruiting 25 controls, 25 non-tophaceous and 25 tophaceous gout patients, 45-80 years old. Exclusion criteria include CPPD disease, RA, spondyloarthropathy or spinal malignancy. All gout subjects meet ACR gout classification criteria with entry serum urate (sU) of >6.8 mg/dL, or sU >6.0 mg/dL on ULT for <6 months. Demographics, gout history, Aberdeen back pain scale, sU, ESR, and CRP are collected. DECT of the lumbosacral spine is used to assess MSU deposition and osteoarthritic changes.Results:63 subjects are enrolled and analyzed to date (25 control, 23 non-tophaceous and 15 tophaceous gout). Control, non-tophaceous gout, and tophaceous gout subjects have similar mean age in years (controls 61.8±3.8, non-tophaceous 64.0±6.2, tophaceous 63.5±9.2, p=0.45), but differ in BMI (controls 28.3±6.5 kg/m2, non-tophaceous 32.1±6.7 kg/m2, tophaceous 29.1±4.3 kg/m2, p=0.01) and creatinine (controls 1.0±0.2 mg/dL, non-tophaceous 1.4±0.6 mg/dL, tophaceous 1.7±0.9 mg/dL, p=0.048). Mean sU and ESR are higher in gout subjects (sU-controls 5.3±1 mg/dL, non-tophaceous 8.3±1.4 mg/dL, tophaceous 8.4±2.0 mg/dL, p<0.05; ESR-controls 13.7±13.8 mm/h, non-tophaceous 25.2±18.7 mm/h, tophaceous 22.5±15.1 mm/h, p<0.05). Using default threshold settings for MSU visualization, greater MSU deposition is observed in the spine of gout patients (controls 2.2±1.2 cm3, non-tophaceous 4.5±4.3 cm3, tophaceous 8.5±12.5 cm3, p<0.05; Table 1). Reanalysis of several scans using narrower threshold settings to limit possible artifact confirms increased MSU signal among gout patients. Although many subjects in each group do not have excessive MSU deposition, deposition is more common in both gout groups. No subject demonstrated a frank spinal tophus.Conclusion:Based on preliminary results, gout patients have higher inflammatory markers and greater spinal MSU deposition than controls. Preliminary analyes with more stringent DECT threshold settings suggests these differences are not artifact, but analysis is ongoing. These data suggest that MSU deposition in the spine occurs in a subset of gout patients.References:[1]Toprover M, Krasnokutsky S, Pillinger MH. Gout in the Spine: Imaging, Diagnosis, and Outcomes. Curr Rheumatol Rep. 2015;17(12):70.Figure 1.DECT of the spine. (A) Patient with tophaceous gout (SU 8.9mg/dL, DECT volume 39.76cm3). (B) Control patient (SU 4.5mg/dL, DECT volume 0.70cm3).Table 1.Baseline characteristics and mean DECT deposition volumes. Bold font indicates statistical significance.CharacteristicControlNon-tophaceous GoutTophaceous GoutP-valueNumber of subjects252315Age in years, mean ± SD61.8 ± 3.864.0 ± 6.263.5 ± 9.20.45Male sex, n (%)23 (92.0)23 (100.0)13 (86.7)0.23Race:0.52 -White, n (%)18 (72.0)14 (60.9)7 (46.7) -Black, n (%)6(24.0)6 (26.1)6 (40.0) -Hispanic, n (%)1 (4.0)3 (13.0)2 (13.3)BMI, mean ± SD28.3 ± 6.532.1 ± 6.729.1 ± 4.30.01Chronic kidney disease, n (%)0 (0.0)6 (26.1)3 (20.0)0.03Diabetes mellitus type II, n (%)3 (12.0)5 (21.7)2 (13.3)0.62Hyperlipidemia, n (%)14 (56.0)15 (65.2)7 (46.7)0.52History of myocardial infarction, n (%)1 (4.0)2 (8.7)1 (6.7)0.80Mean sU, mg/dL ± SD5.31 ± 0.988.25 ± 1.48.42 ± 2.0<0.001Mean ESR, mm/hr ± SD (normal 0-10)13.7 ± 13.825.2 ± 18.722.53 ± 15.10.04Mean CRP, mg/L ± SD (normal 0-5)2.7 ± 4.77.6 ± 12.54.1 ± 5.00.13Mean serum creatinine, mg/dL ± SD0.97 ± 0.181.36 ± 0.581.70 ± 0.880.048Mean DECT volume, cm32.2 ± 1.24.5 ± 4.38.5 ± 12.5p<0.05Acknowledgements:Supported by an investigator-initiated grant from Horizon TherapeuticsDisclosure of Interests:Michael Toprover Consultant of: Horizon Pharmaceuticals, Michael Mechlin: None declared, Anastasia Slobodnick: None declared, Virginia C. Pike: None declared, Cheongeun Oh: None declared, Claudine Davis: None declared, Theodore Fields Consultant of: Horizon Pharmaceuticals, Avion Pharmaceuticals, Fabio Becce Consultant of: Horizon Therapeutics, Michael H. Pillinger Consultant of: Horizon Pharmaceuticals, Grant/research support from: Horizon Pharmaceuticals
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Shi, Jishu, Liqiong Lan, Shelly Aono, Edward Morrison, and Wuyuan Lu. "Defensins block the release but not the processing of IL-1beta and IL-18 from human monocytes (38.13)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 38.13. http://dx.doi.org/10.4049/jimmunol.182.supp.38.13.
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Abstract We have previously shown that human defensins can block the release of IL-1beta from LPS-primed human monocytes stimulated with ATP. The objective of this study is to determine whether defensins can inhibit the release IL-1beta and IL-18 from LPS-primed human monocytes stimulated with other inflammasome activators. LPS-activated (20 ng/ml, 2 h), 35S-methionine-labeled (1 h) human monocytes were treated with human defensin HD-5 in the presence or absence of ATP, monosodium urate (MSU), nigericin (Nig) for 90 min. Media and cell-associated fractions were harvested separately. IL-1beta was recovered from each by immunoprecipitation and caspase-1 was examined by western blot analysis. Mature IL-1beta and active caspase-1 were detected in the cytosol fraction from cells treated with HD-5. Thus, HD-5 blocked the release of mature IL-1beta from cells treated with ATP, MSU, or Nig. However, HD-5 did not inhibit ATP-, MSU-, or Nig-induced caspase-1 activation and processing of IL-1beta. In addition, HD-5 also blocked the release of IL-18 from LPS-primed human monocytes stimulated with ATP. To our knowledge, HD-5 is the first known endogenous inhibitor of IL-1beta and IL-18 release. These studies suggest that processing and release of IL-1beta are independent processes.
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Vikhanskiy, Oleg. "G. Popov’s Scientific School of Management." Moscow University Economics Bulletin 2016, no. 5 (October 30, 2016): 132–48. http://dx.doi.org/10.38050/01300105201658.
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The objective of the article is the systematic description of emergence and development at economic faculty of MSU G. H. Popov’s Scientific School of Management. The subject of the article is the dynamics of development of this Scientific School. The methodological basis of the research are author’s personal observations as a participant of the proses of creation of scientific school and analysis of scientific and teaching materials published in 60th–70th of previous century. In the article is show that Scientific School of management of social production was established at economic faculty of Moscow State University in the 70-th of the previous century. During 20 years Scientific School was headed by its founder G. H. Popov. The theoretical statements presented by him in his book «Problems of theory of management» played the role of methodological basis of Popov’s Scientific School. The organizational form of Scientific School there was a Center for the problems of management at Economic faculty of MSU.
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Joosten, Leo A. B., Tania O. Crişan, Tania Azam, Maartje C. P. Cleophas, Marije I. Koenders, Frank L. van de Veerdonk, Mihai G. Netea, Soohyun Kim, and Charles A. Dinarello. "Alpha-1-anti-trypsin-Fc fusion protein ameliorates gouty arthritis by reducing release and extracellular processing of IL-1β and by the induction of endogenous IL-1Ra." Annals of the Rheumatic Diseases 75, no. 6 (July 14, 2015): 1219–27. http://dx.doi.org/10.1136/annrheumdis-2014-206966.
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ObjectivesIn the present study, we generated a new protein, recombinant human alpha-1-anti-trypsin (AAT)-IgG1 Fc fusion protein (AAT-Fc), and evaluated its properties to suppress inflammation and interleukin (IL)-1β in a mouse model of gouty arthritis.MethodsA combination of monosodium urate (MSU) crystals and the fatty acid C16.0 (MSU/C16.0) was injected intra-articularly into the knee to induce gouty arthritis. Joint swelling, synovial cytokine production and histopathology were determined after 4 h. AAT-Fc was evaluated for inhibition of MSU/C16.0-induced IL-1β release from human blood monocytes and for inhibition of extracellular IL-1β precursor processing.ResultsAAT-Fc markedly suppressed MSU/C16.0-induced joint inflammation by 85–91% (p<0.001). Ex vivo production of IL-1β and IL-6 from cultured synovia were similarly reduced (63% and 65%, respectively). The efficacy of 2.0 mg/kg AAT-Fc in reducing inflammation was comparable to 80 mg/kg of plasma-derived AAT. Injection of AAT-Fc into mice increased circulating levels of endogenous IL-1 receptor antagonist by fourfold. We also observed that joint swelling was reduced by 80%, cellular infiltration by 95% and synovial production of IL-1β by 60% in transgenic mice expressing low levels of human AAT. In vitro, AAT-Fc reduced MSU/C16.0-induced release of IL-1β from human blood monocytes and inhibited proteinase-3-mediated extracellular processing of the IL-1β precursor into active IL-1β.ConclusionsA single low dose of AAT-Fc is highly effective in reducing joint inflammation in this model of acute gouty arthritis. Considering the long-term safety of plasma-derived AAT use in humans, subcutaneous AAT-Fc emerges as a promising therapy for gout attacks.
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Watanabe, Azuma, Muhammad Adnan Sohail, Dawidson Assis Gomes, Ardeshir Hashmi, Jun Nagata, Fayyaz Shiraz Sutterwala, Shamail Mahmood, et al. "Inflammasome-mediated regulation of hepatic stellate cells." American Journal of Physiology-Gastrointestinal and Liver Physiology 296, no. 6 (June 2009): G1248—G1257. http://dx.doi.org/10.1152/ajpgi.90223.2008.
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The inflammasome is a cytoplasmic multiprotein complex that has recently been identified in immune cells as an important sensor of signals released by cellular injury and death. Analogous to immune cells, hepatic stellate cells (HSC) also respond to cellular injury and death. Our aim was to establish whether inflammasome components were present in HSC and could regulate HSC functionality. Monosodium urate (MSU) crystals (100 μg/ml) were used to experimentally induce inflammasome activation in LX-2 and primary mouse HSC. Twenty-four hours later primary mouse HSC were stained with α-smooth muscle actin and visualized by confocal microscopy, and TGF-β and collagen1 mRNA expression was quantified. LX-2 cells were further cultured with or without MSU crystals for 24 h in a transwell chemotaxis assay with PDGF as the chemoattractant. We also examined inhibition of calcium (Ca2+) signaling in LX-2 cells treated with or without MSU crystals using caged inositol 1,4,5-triphosphate (IP3). Finally, we confirmed an important role of the inflammasome in experimental liver fibrosis by the injection of carbon tetrachloride (CCl4) or thioacetamide (TAA) in wild-type mice and mice lacking components of the inflammasome. Components of the inflammasome are expressed in LX-2 cells and primary HSC. MSU crystals induced upregulation of TGF-β and collagen1 mRNA and actin reorganization in HSCs from wild-type mice but not mice lacking inflammasome components. MSU crystals inhibited the release of Ca2+ via IP3 in LX-2 cells and also inhibited PDGF-induced chemotaxis. Mice lacking the inflammasome-sensing and adaptor molecules, NLRP3 and apoptosis-associated speck-like protein containing CARD, had reduced CCl4 and TAA-induced liver fibrosis. We concluded that inflammasome components are present in HSC, can regulate a variety of HSC functions, and are required for the development of liver fibrosis.
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Li, Dandan, Qing Liu, Huajun Yin, Yiqi Luo, and Dafeng Hui. "Differential Responses and Controls of Soil CO2 and N2O Fluxes to Experimental Warming and Nitrogen Fertilization in a Subalpine Coniferous Spruce (Picea asperata Mast.) Plantation Forest." Forests 10, no. 9 (September 17, 2019): 808. http://dx.doi.org/10.3390/f10090808.
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Emissions of greenhouse gases (GHG) such as CO2 and N2O from soils are affected by many factors such as climate change, soil carbon content, and soil nutrient conditions. However, the response patterns and controls of soil CO2 and N2O fluxes to global warming and nitrogen (N) fertilization are still not clear in subalpine forests. To address this issue, we conducted an eight-year field experiment with warming and N fertilization treatments in a subalpine coniferous spruce (Picea asperata Mast.) plantation forest in China. Soil CO2 and N2O fluxes were measured using a static chamber method, and soils were sampled to analyze soil carbon and N contents, soil microbial substrate utilization (MSU) patterns, and microbial functional diversity. Results showed that the mean annual CO2 and N2O fluxes were 36.04 ± 3.77 mg C m−2 h−1 and 0.51 ± 0.11 µg N m−2 h−1, respectively. Soil CO2 flux was only affected by warming while soil N2O flux was significantly enhanced by N fertilization and its interaction with warming. Warming enhanced dissolve organic carbon (DOC) and MSU, reduced soil organic carbon (SOC) and microbial biomass carbon (MBC), and constrained the microbial metabolic activity and microbial functional diversity, resulting in a decrease in soil CO2 emission. The analysis of structural equation model indicated that MSU had dominant direct negative effect on soil CO2 flux but had direct positive effect on soil N2O flux. DOC and MBC had indirect positive effects on soil CO2 flux while soil NH4+-N had direct negative effect on soil CO2 and N2O fluxes. This study revealed different response patterns and controlling factors of soil CO2 and N2O fluxes in the subalpine plantation forest, and highlighted the importance of soil microbial contributions to GHG fluxes under climate warming and N deposition.
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Crișan, Tania O., Maartje C. P. Cleophas, Marije Oosting, Heidi Lemmers, Helga Toenhake-Dijkstra, Mihai G. Netea, Tim L. Jansen, and Leo A. B. Joosten. "Soluble uric acid primes TLR-induced proinflammatory cytokine production by human primary cells via inhibition of IL-1Ra." Annals of the Rheumatic Diseases 75, no. 4 (February 3, 2015): 755–62. http://dx.doi.org/10.1136/annrheumdis-2014-206564.
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ObjectivesThe study of the proinflammatory role of uric acid has focused on the effects of its crystals of monosodium urate (MSU). However, little is known whether uric acid itself can directly have proinflammatory effects. In this study, we investigate the priming effects of uric acid exposure on the cytokine production of primary human cells upon stimulation with gout-related stimuli.MethodsPeripheral blood mononuclear cells (PBMCs) were harvested from patients with gout and healthy volunteers. Cells were pretreated with or without uric acid in soluble form for 24 h and then stimulated for 24 h with toll-like receptor (TLR)2 or TLR4 ligands in the presence or absence of MSU crystals. Cytokine production was measured by ELISA; mRNA levels were assessed using qPCR.ResultsThe production of interleukin (IL)-1β and IL-6 was higher in patients compared with controls and this correlated with serum urate levels. Proinflammatory cytokine production was significantly potentiated when cells from healthy subjects were pretreated with uric acid. Surprisingly, this was associated with a significant downregulation of the anti-inflammatory cytokine IL-1 receptor antagonist (IL-1Ra). This effect was specific to stimulation by uric acid and was exerted at the level of gene transcription. Epigenetic reprogramming at the level of histone methylation by uric acid was involved in this effect.ConclusionsIn this study we demonstrate a mechanism through which high concentrations of uric acid (up to 50 mg/dL) influence inflammatory responses by facilitating IL-1β production in PBMCs. We show that a mechanism for the amplification of IL-1β consists in the downregulation of IL-1Ra and that this effect could be exerted via epigenetic mechanisms such as histone methylation. Hyperuricaemia causes a shift in the IL-1β/IL-1Ra balance produced by PBMCs after exposure to MSU crystals and TLR-mediated stimuli, and this phenomenon is likely to reinforce the enhanced state of chronic inflammation.
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Liu, Y., Y. Huang, S. Sun, W. Deng, and T. W. LI. "POS1135 MONOSODIUM URATE CRYSTALS REDUCE SCHWANN CELLS VIABILITY." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 847.1–847. http://dx.doi.org/10.1136/annrheumdis-2021-eular.1989.
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Background:The prevalence of peripheral neuropathy in patients with gout almostly reaches 25%[1]. Demyelination caused by Schwann cell (SCs) injury and apoptosis is the major pathological feature of peripheral[2]. None of study has focused on the effects of monosodium urate (MSU) crystals on SCs.Objectives:To assess the effect of MSU crystals on SCs.Methods:Mouse-derived Schwann cells (RSC96) are stimulated with different concentrations of MSU crystals (0mg/ml,0.25mg/ml,0.5mg/ml) and time (24h,48h,72h). The migration ability of Schwann cells is evaluated by acratch assay, the proliferation level is assessed by the cell counting kit-8 (CCK-8) assay, and the apoptosis rate is detected by flow cytometry.Results:The acratch assay showed that the migration ability of SCs was worsened, CCK-8 assay suggested that proliferation of SCs was reduced in a dose-dependent manner (P<0.05). According to the result of flow cytometry, the survival rate of SCs at 0.5mg/ml(78.60%±2.26%) was lower than that 0.25mg/ml(87.50%±0.95%)and 0mg/ml (98.80%±0.26%)(p<0.05) at 24h. When the stimulation time increased to 72h, the survival rate at 0.5mg/ml(47.90%±11.70%) dropped significantly, which was significantly different from the other two groups(p<0.05).Conclusion:MSU crystals can cause damage to Schwann cells. It may help to explain the reason of peripheral neuropathy in gout patients.References:[1]López-López, C.O., et al., Peripheral neuropathies in rheumatic diseases: More diverse and frequent than expected. A cross-sectional study. International journal of rheumatic diseases, 2020. 23(2): p. 226-232.[2]Liu, Y., S. Shao and H. Guo, Schwann cells apoptosis is induced by high glucose in diabetic peripheral neuropathy. Life sciences, 2020. 248: p. 117459.Figure 1.Flow cytometry assays of RSC96 on MSU crystals at 72hDisclosure of Interests:None declared.
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Tseuguem, Pius Pum, Télesphore Benoît Nguelefack, Basile Ngnanmegne Piégang, and Sorelle Mbankou Ngassam. "Aqueous and Methanol Extracts of Paullinia pinnata (Sapindaceae) Improve Monosodium Urate-Induced Gouty Arthritis in Rat: Analgesic, Anti-Inflammatory, and Antioxidant Effects." Evidence-Based Complementary and Alternative Medicine 2019 (December 5, 2019): 1–12. http://dx.doi.org/10.1155/2019/5946291.
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The profound modification of lifestyle and food habits has led to an important increase in the prevalence of gout. Unfortunately, there are current unmet needs for the treatment of this disease, prompting the search for new alternatives. Paullinia pinnata is a plant used to treat various diseases including arthritis. The present work aimed to investigate the antigouty activities of the aqueous (AEPP) and methanolic (MEPP) extracts of P. pinnata as well as their in vivo antioxidant properties. The gouty arthritis was induced by injecting 50 μl of monosodium urate (MSU, 100 mg/ml) in the left hind ankle of rats. P. pinnata extracts were administered orally at the doses of 100 and 200 mg/kg/day for 6 days, starting 24 h after MSU injection. Allopurinol 5 mg/kg/day was used as reference drug. Inflammation and hyperalgesia were daily monitored from 24 hours after treatment initiation and for the 6 consecutive days. Myeloperoxidase (MPO) quantification was done in collected synovial fluid. Nitrite oxide (NO), malondialdehyde (MDA), and superoxide dismutase (SOD) were evaluated in the spinal cord and the brain. The serum content of SOD was additionally quantified. AEPP and MEPP significantly (p<0.001) reduce MSU-induced inflammation (22.41% to 93.65%) and hyperalgesia (33.33% to 64.44%) in both ankle and paw. AEPP and MEPP significantly (p<0.001) reduce synovial MPO production with the percentage ranging from 76.30% to 85.19%. AEPP and MEPP significantly (p < 0.001) reduce serum, spinal, left and right hemispheres NO, and MDA and increase the SOD activity (p<0.001). P. pinnata leaf extracts possess potent curative effects against MSU-induced gouty arthritis that combines analgesic, anti-inflammatory, and antioxidant activities. These findings support the use of P. pinnata leaves extracts in the treatment of gouty arthritis and further present the plant as a potent source of efficient antigouty medicine.
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Kim, Seong Su, Abhijeet Karkamkar, Thomas J. Pinnavaia, Michal Kruk, and Mietek Jaroniec. "Synthesis and Characterization of Ordered, Very Large Pore MSU-H Silicas Assembled from Water-Soluble Silicates." Journal of Physical Chemistry B 105, no. 32 (August 2001): 7663–70. http://dx.doi.org/10.1021/jp010773p.
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Chang, Xiaoqian, Bingsi Liu, Hong Xia, and Roohul Amin. "High catalytic activity and stability of Ni/CexZr1−xO2/MSU-H for CH4/CO2 reforming reaction." Applied Surface Science 442 (June 2018): 342–51. http://dx.doi.org/10.1016/j.apsusc.2018.02.068.
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Hiyoshi, Norihito, Katsunori Yogo, and Tatsuaki Yashima. "Adsorption of Carbon Dioxide on Amine-modified MSU-H Silica in the Presence of Water Vapor." Chemistry Letters 37, no. 12 (December 5, 2008): 1266–67. http://dx.doi.org/10.1246/cl.2008.1266.
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Gakhal, Baldeesh, and Sharon Oddie. "Bullying behaviours among mentally disordered offenders in a medium secure unit." Journal of Forensic Practice 16, no. 2 (May 6, 2014): 156–65. http://dx.doi.org/10.1108/jfp-03-2013-0020.
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Purpose – The purpose of this paper is to explore the nature and prevalence of bullying behaviours and victimisation experiences among mentally disordered offenders within a medium secure unit (MSU). Design/methodology/approach – In all, 35 adult male patients completed the Direct and Indirect Patient behaviour Checklist-Hospital Version (DIPC-H). Findings – Indirect aggression was reported more frequently than direct aggression, although there was no statistically significant difference between the prevalence estimates. The most prevalent DIPC-H categories were the pure victim and not involved categories followed by bully/victim and pure bully. Membership of the pure bully category was predicted by being on a particular ward. Research limitations/implications – Given that the study was a preliminary investigation into the nature and prevalence of bullying behaviours in a MSU, the sample size is limited. Consequently, it is difficult to generalise the findings. It would be useful for future research to focus on differences between levels of security using larger sample sizes to enable a greater understanding of the prevalence of bullying in secure settings and associated factors. Practical implications – Further evidence is provided by the current research that indirect bullying and victimisation behaviours are reported more frequently by patients. The importance of anti-bullying procedures and interventions in secure settings is emphasised and recommendations that can be applied across various forensic settings are described. Better-informed interventions can then be implemented with the aim to manage bullying behaviours in secure settings. The one “pure bully” in the current study was on a rehabilitation ward. This highlights that such behaviours occur on lesser secure wards and serves as an important reminder to ensure that staff do not become complacent. Originality/value – As there is only one published study to date that has focused on bullying behaviours in a MSU, the current study will contribute to the dearth of literature in this area and assist professionals working in secure settings to better understand the nature and prevalence of bullying behaviours among mentally disordered offenders.
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Santana, E. A., G. Godoy-Lutz, J. C. Nin, F. Saladin, J. S. Beaver, D. P. Coyne, and J. R. Steadman. "Development of Five Tropically Adapted Disease Resistant Dry Bean Varieties." HortScience 33, no. 3 (June 1998): 499d—499. http://dx.doi.org/10.21273/hortsci.33.3.499d.
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Diseases are a primary constraint affecting yield and seed quality of dry beans (Phaseolus vulgaris) in the Dominican Republic. A collaborative dry bean breeding program to develop resistance to one or more diseases in different dry bean types was conducted in the Dominican Republic (DR) under a US-AID Title XII Bean/Cowpea CRSP involving breeders and pathologists in the Ministry of Agriculture, DR, Univ. of Nebraska, Lincoln, and the Univ. of Puerto Rico, Mayaguez. The origin and some characteristics of the five new dry bean varieties released in 1988 are described here. The black seeded `Arroyo Loro Negro' (MUS-N-4-H) (Type II a growth habit) was derived from the cross H-270 (MSU/UPR) X XAN-223 and has resistance to web blight and rust. The pedigree of the white seeded `Anacaona' (L-8020) (Type II a growth habit) is (2b-5-1/2 × NEP-2/Black Turtle Soup) X BON 355 (MSU). `Anacaona' is moderately resistant to web blight. The three red-mottled determinate Pompadour varieties were developed from the following crosses; `Saladin-97' (PC-21-SME) and `CIAS-95' (PC-21-SMA) from `PC-50'(DR) X BAT 1274 (CIAT) and `JB-178' (PR-JB-178) from `Jose Beta' (DR) X C1308 in Puerto Rico. These new high yielding Pompadour varieties have a higher level of field resistance to Andean pathotypes of rust in the DR than does `PC-50' the predominate variety.
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Liu, Ren-Hao, Wantong Shi, Yu-Xiang Zhang, Min Zhuo, and Xu-Hui Li. "Selective inhibition of adenylyl cyclase subtype 1 reduces inflammatory pain in chicken of gouty arthritis." Molecular Pain 17 (January 2021): 174480692110478. http://dx.doi.org/10.1177/17448069211047863.
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Lack of uricase leads to the high incidence of gout in humans and poultry, which is different from rodents. Therefore, chicken is considered to be one of the ideal animal models for the study of gout. Gout-related pain caused by the accumulation of urate in joints is one type of inflammatory pain, which causes damage to joint function. Our previous studies have demonstrated the crucial role of calcium-stimulated adenylyl cyclase subtype 1 (AC1) in inflammatory pain in rodents; however, there is no study in poultry. In the present study, we injected mono-sodium urate (MSU) into the left ankle joint of the chicken to establish a gouty arthritis model, and tested the effect of AC1 inhibitor NB001 on gouty arthritis in chickens. We found that MSU successfully induced spontaneous pain behaviors including sitting, standing on one leg, and limping after 1–3 h of injection into the left ankle of chickens. In addition, edema and mechanical pain hypersensitivity also occurred in the left ankle of chickens with gouty arthritis. After peroral administration of NB001 on chickens with gouty arthritis, both the spontaneous pain behaviors and the mechanical pain hypersensitivity were effectively relieved. The MSU-induced edema in the left ankle of chickens was not affected by NB001, suggesting a central effect of NB001. Our results provide a strong evidence that AC1 is involved in the regulation of inflammatory pain in poultry. A selective AC1 inhibitor NB001 produces an analgesic effect (not anti-inflammatory effect) on gouty pain and may be used for future treatment of gouty pain in both humans and poultry.
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Flood, R., D. Kane, and R. Mullan. "SAT0561 METATARSOPHALANGEAL JOINT MEDIAL COLLATERAL LIGAMENT MEASUREMENT, A NOVEL ULTRASOUND FEATURE OF MONOSODIUM URATE DEPOSITION IN THE JOINT." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1238.1–1239. http://dx.doi.org/10.1136/annrheumdis-2020-eular.2182.
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Background:Acute gouty arthritis most commonly initially affects the first metatarsophalangeal joint (MT1). (1) Musculoskeletal ultrasound (US) is a reliable tool for detecting monosodium urate crystal (MSU) deposition in gout and hyperuricemia with validated, ultrasound features of double contour (DC) sign, tophus, and erosions. (2, 3) The collateral ligaments of MT1, which originate on the medial and lateral epicondyles of the metatarsals and extend to the proximal phalanx, function to stabilize the joint. (4) While tophus deposition typically occurs between the medial collateral ligament (MCL) and head of MT1, small MSU aggregates may be indistinguishable from surrounding tissue. In this study using US, we propose that an increased vertical depth between the superficial surface of the MCL to cortical surface of MT1 (dMC-MT) is indicative of MSU deposition (see figure 1). The aim was to evaluate associations of dMC-MT with serum uric-acid level (sUA) in a cohort of individuals with hyperuricaemia and non-episodic foot pain. We propose a novel sonographic feature of MSU crystal deposition in the MT joint.Objectives:1.)To evaluate the association between sUA and dMC-MT2.)To record the presence/absence of classical features of MSU deposition including; double contour sign, erosions and tophi in a cohort of patients with hyperuricaemia and foot pain.3.)To evaluate the associations between sUA and dMC-MT in those with\without classical features of MSU deposition (DC, erosion, tophi).Methods:Following informed consent, hyperuricaemic patients (n = 52) underwent bilateral US of the 1MT using LogiqE9 at 15 MHz. Features of MSU deposition including DC sign, tophus and juxta-articular erosion were recorded. The dMC-MT was measured as the mean of the perpendicular distance between the superficial surface of the midpoint of the MCL to the MT1 head. Statistical analysis was performed using SPSS V.25 software. Data presented as MEAN ± S.E unless otherwise indicated.Results:DC sign, tophus and erosion occurred in 31%, 20.7% and 19% of cases, respectively. Mean sUA was higher in tophus positive (540 ± 36) versus non tophus (470 ± 16) (p<0.01) and erosion positive (522 ± 32) versus non erosion (477± 17) patients. dMC-MT was significantly greater in tophus positive patients (0.34cm ± 0.17cm) versus non tophus (0.27cm ± 0.01cm) (p < 0.01). dMC-MT was significantly greater in erosion positive patients (0.31cm ± 0.18cm) versus non erosion (0.28cm +0.01cm) (p < 0.05). In DC negative patients dMC-MT was significantly correlated with increasing sUA (r = 0.34 p = <0.05). No correction between dMC-MT and sUA was seen in DC positive patients.Conclusion:dMC-MT is significantly greater both in patients with tophus and erosions indicating its role as an additional marker of MSU crystal deposition. Furthermore a significant association between dMC-MT and sUA in DC negative patients suggests that dMC-MT may be a more sensitive indicator of early urate deposition in a subset of patients where the earliest site of urate deposition has not occurred directly on to articular hyaline cartilage. dMC-MT may therefore be a sensitive tool for very early urate deposition. Further studies clarifying a role for dMC-MT are now required.References:[1]Wallace SL, Robinson H, Masi AT, Decker JL, Mccarty DJ, Yü T -f. Preliminary criteria for the classification of the acute arthritis of primary gout. Arthritis Rheum. 1977;20(3):895–900.[2]Howard RG, Pillinger MH, Gyftopoulos S, Thiele RG, Swearingen CJ, Samuels J. Reproducibility of musculoskeletal ultrasound for determining monosodium urate deposition: Concordance between readers. Arthritis Care Res. 2011;63(10):1456–62.[3]Stewart S, Dalbeth N, Vandal AC, Rome K. Characteristics of the first metatarsophalangeal joint in gout and asymptomatic hyperuricaemia: A cross-sectional observational study. J Foot Ankle Res. 2015;8(1):1–8.[4]Finney FT, Cata E, Holmes JR, Talusan PG. Anatomy and Physiology of the Lesser Metatarsophalangeal Joints. Foot Ankle Clin. 2018;23(1):1–7.Disclosure of Interests:None declared
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Cipolletta, E., A. DI Matteo, W. Grassi, and E. Filippucci. "OP0209 SONOGRAPHIC ESTIMATION OF MONOSODIUM URATE BURDEN PREDICTS THE FULFILMENT OF THE 2016 REMISSION CRITERIA FOR GOUT: A 12-MONTH STUDY." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 125.2–126. http://dx.doi.org/10.1136/annrheumdis-2021-eular.495.
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Background:Preliminary remission criteria for gout include the following five domains: serum uric acid (SUA) levels <360 µmol/l, absence of subcutaneous tophi, absence of gouty flares, pain (due to gout) <2/10 and patient global assessment of disease activity <2/10 [1]. To achieve remission, all criteria must be fulfilled at least twice in a 12-month period [1]. Although imaging techniques allow to visualise monosodium urate (MSU) deposits and to estimate their burden, an imaging domain was not included.Objectives:To investigate whether baseline MSU burden estimated by ultrasonography (US) predicts the achievement of remission according to these criteria [1] over 12 months.Methods:In this 12-month prospective, observational and monocentric study, patients with gout according to the 2015 ACR/EULAR criteria and on urate-lowering therapy for at least the preceding 6 months were consecutively recruited. After the baseline clinical assessment, only patients fulfilling all domains of the remission criteria [1] (and therefore amenable to achieve the remission at 12 months) were followed up at 6-month intervals for one year.The US findings indicative of MSU deposits were identified according to the OMERACT definitions. The following joints were included in the US scanning protocol: elbows, wrists, 2nd metacarpophalangeal joints, knees, ankles and 1st metatarsophalangeal joints. Sum scores of aggregates, double contour (DC) signs, and tophi were calculated separately, and a total score resulting from the sum of all elementary US findings was recorded.Results:Seventy patients with gout were recruited; of these, 20 (28.6%) were excluded at baseline because 13 (18.6%) did not satisfy the SUA domain, 11 (15.7%) tophus domain, 7 (10.0%) pain domain and 5 (7.1%) disease activity domain.In the enrolled patients (Age: 59.9±14.8 years, female/male ratio: 1/49, disease duration: 6.5±6.6 years), remission criteria were fulfilled in 21 (42.0%) of 50 patients over 12 months.No significant difference was found between patients fulfilling and not fulfilling the remission criteria at 12 months in all clinical and laboratory data except for the gout flare prophylaxis (7, 33.3% vs 20, 69.0%; p=0.02).The baseline US MSU burden was significantly lower (total score 1.9±1.8) in patients in remission than in those not in remission at 12 months (total score 5.1±3.1) (p<0.01). The fulfilment of the remission criteria at 12 months was recorded in 87.5% of the patients without baseline US evidence of MSU deposits and in only 33.0% of those with at least one US finding indicating MSU deposits (p<0.01).US scores and gout flare prophylaxis were the only significant predictors of remission in the univariate analyses (Table 1).Table 1.Predictive values of baseline data for the remission at 12 months.OR (95%CI)P valueOngoing flare prophylaxis0.23 (0.07-0.75)0.02Total score=010.83 (1.14-102.59)0.04Aggregate score=05.53 (1.34-22.76)<0.01DC sign score=07.33 (1.71-31.44)<0.01Tophus score=03.88 (1.08-13.92)0.0295%CI: 95% confidence interval; OR: odds ratio.The risk of not fulfilling the remission criteria increased with the US burden of MSU deposits. For each 1-point increase in total score, aggregate score, DC sign score and tophus score, the risk increased by 1.81- (95%CI: 1.27-2.60), 1.73- (95%CI: 1.14-2.64), 4.16- (95%CI: 1.55-11.3) and 1.95-fold (95%CI: 1.07-3.56), respectively (Figure 1).Conclusion:Baseline US estimation of MSU burden is an independent predictor of gout clinical remission at 12 months. The absence of US MSU deposits was the most significant predictor of remission, whereas the US detection of DC sign in at least one joint of not achieving remission. Thus, performing an US examination in patients amenable to fulfil the remission criteria after 12 months may improve risk-stratification and inform management of these patients.References:[1]de Lautour H, et al. Development of Preliminary Remission Criteria for Gout Using Delphi and 1000Minds Consensus Excersices. Arthritis Care Res 2016;68:667–72Disclosure of Interests:Edoardo Cipolletta: None declared, Andrea Di Matteo: None declared, Walter Grassi Speakers bureau: Walter Grassi has received speaking fees from AbbVie, Celgene, Grünenthal, Pfizer and Union Chimique Belge Pharma., Emilio Filippucci Speakers bureau: Emilio Filippucci. has received speaking fees from AbbVie, Bristol-Myers Squibb, Janssen-Cilag, Novartis, Pfizer, Roche and Union Chimique Belge Pharma
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Guamán-Balcázar, María del Cisne, Antonio Montes, Diego Valor, Yorky Coronel, Desireé M. De los Santos, Clara Pereyra, and Enrique J. Martínez de la Ossa. "Inclusion of Natural Antioxidants of Mango Leaves in Porous Ceramic Matrices by Supercritical CO2 Impregnation." Materials 15, no. 17 (August 27, 2022): 5934. http://dx.doi.org/10.3390/ma15175934.
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Mango is one of the most important, medicinal tropical plants in the world from an economic point of view due to the presence of effective bioactive substances as co-products in its leaves. The aim of this work was to enhance the impregnation of natural antioxidants from mango leaves into a porous ceramic matrix. The effects of pressure, temperature, impregnation time, concentration of the extract and different porous silica on impregnation of phenolic compounds and antioxidant activity were analyzed. The volume of the pressurized fluid extract and amount of porous ceramic matrix remained constant. The best impregnation conditions were obtained at 6 h, 300 bar, 60 mg/mL, 35 °C and with MSU-H porous silica. The results indicated that increasing the pressure, concentration of the extract and temperature during impregnation with phenolic compounds such as gallic acid and iriflophenone 3-C (2-O-p-hydroxybenzolyl)-β-D-glucoside increased the antioxidant activity and the amount of total phenols.
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Adekunle, O. O., O. J. Idris, A. A. Wahab, and A. M. Adekanle. "Antibiotic Susceptibility and Detection of Resistance Genes of E. coli among Healthy Pregnant Women in Designated Hospitals around Osogbo, Osun State, Nigeria." Journal of Applied Sciences and Environmental Management 26, no. 6 (June 30, 2022): 1151–55. http://dx.doi.org/10.4314/jasem.v26i6.23.
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Treatment of E. coli is now a challenge globally, due to continuous increase in resistance towards commonly prescribed antibiotics, thus posing a threat to treatment. Hence, the aim of the study is to determine antibiotics sensitivity and resistance genes of E.coli from apparently healthy pregnant women in Osogbo, Osun State, Nigeria using standard methods. A cross-sectional study design was used to collect 150 mid-stream urine (MSU) samples from apparently healthy pregnant women. Standard inoculating loop technique was used by culturing 0.001 ml of MSU on Cysteine Lactose Electrolyte Deficient (CLED) agar, Blood agar and MacConkey agar and incubated at 37 °C for 24 h. A standard agar disc diffusion method was used to determine antimicrobial susceptibility pattern of the isolates. The molecular detection of resistance genes was done using PCR techniques. The ages of women enrolled in this study ranged from 22 to 42 years (mean ± standard deviation = 31 ± 4.7 years). Eight isolates were positive for E. coli. Escherichia coli showed high percentage of resistance to ampicillin and low resistance to ciprofloxacin and penicillin. All the E. coli isolates were sensitive to levofloxacin, and most were resistant to Meropenem. Multiple drug resistance was observed in all the isolates. Resistance genes in VIM 390bp, bla ctx-M 585bp and TEM 517bp were detected in some of the representative E. coli isolates profiled. This study identified the presence of Multi-drug resistance genes in E. coli associated UTI among pregnant women in Osogbo.
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Yu, Wei Hua, Dong Shen Tong, Mei Fang, Ping Shao, and Chun Hui Zhou. "Immobilization of Candida rugosa lipase on MSU-H type mesoporous silica for selective esterification of conjugated linoleic acid isomers with ethanol." Journal of Molecular Catalysis B: Enzymatic 111 (January 2015): 43–50. http://dx.doi.org/10.1016/j.molcatb.2014.11.003.
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Sinicrope, F. A., M. Garrity, R. L. Rego, A. J. French, N. R. Foster, D. J. Sargent, R. M. Goldberg, et al. "Alterations in cell proliferation and apoptosis in human colon cancers with microsatellite instability." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 10022. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.10022.
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10022 Background: Patients with colon cancers displaying high frequency microsatellite instability (MSI-H) are reported to have a favorable prognosis compared to microsatellite stable (MSS) tumors. However, prognostic factors underlying this observation are poorly understood. We studied apoptotic and proliferative indices and their relationship to MSI status, clinicopathological features, and patient survival rates. Methods: Archival Dukes’ stage B2 (n=83) and C (n=246) primary colon adenocarcinomas from patients enrolled in five 5-fluorouracil-based adjuvant therapy trials were analyzed for MSI using a PCR-based assay (MSI-H: ≥30% of loci with instability), and expression of hMLH1, hMSH2 and p53 proteins by immunostaining. Apoptosis was analyzed by the TUNEL assay and the proliferative index (PI: S phase + G2M) and DNA ploidy by flow cytometry. Correlations between markers and associations with overall survival (OS) censored at 8 yrs were sought. Results: MSI-H (n=58.18%) tumors were more likely proximal, diploid, high grade, p53 negative (vs. MSS/MSI-L; all p<0.0001), and from women (p=0.002). Of 58 MSH-H cases tested, 54 showed loss of hMLH1 (n=50) or hMSH2 (n=4) proteins. Median proliferative index (PI) [12.6 vs. 17.4; p=0.0002] was reduced in MSI-H versus MSS/MSI-L tumors. Lower PI was associated with diploidy (p<0.0001) and negative p53 expression (p=0.003). Apoptotic indices (AIs) were increased in MSI-H cancers (vs. MSS/MSI-L, p=0.082), as was the AI/PI ratio (p=0.0065). Interestingly, AI (p=0.02) and AI/PI (p<0.0001) were significantly increased in diploid versus nondiploid tumors, and after removal of MSI-H cases, relationships held for PI and AI/PI with ploidy. Better OS was related to MSI-H (p=0.032), loss of hMLH1 or hMSH2 (p=0.024), diploidy (p=0.0015), and lower PI (p=0.078), but not AI, AI/PI, nor p53 (adjusting for stage, grade, treatment and stratifying by study). Conclusions: MSI-H tumors are characterized by reduced proliferative indices and a higher ratio of apoptosis to proliferation, reflecting slower tumor growth rates compared to MSS/MSI-L tumors. These features may contribute to their better survival. Lower PI and increased AI/PI are also features of diploid MSS cancers. [Table: see text]
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Lyu, Shang, Ruowen Ding, Peng Liu, Hui OuYang, Yulin Feng, Yi Rao, and Shilin Yang. "LC-MS Analysis of Serum for the Metabolomic Investigation of the Effects of Pulchinenoside b4 Administration in Monosodium Urate Crystal-Induced Gouty Arthritis Rat Model." Molecules 24, no. 17 (August 30, 2019): 3161. http://dx.doi.org/10.3390/molecules24173161.
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Gouty arthritis (GA) is commonly caused by deposition of monosodium urate (MSU) crystals within the joint capsule, bursa, cartilage, bone, or other periarticular tissues after chronic hyperuricemia. Clinically, GA is characterized by acute episodes of joint inflammation, which is most frequently encountered in the major joints, and also has a significant impact on quality of life. Pulchinenoside b4(P-b4) has a wide range of biological activities, including antitumor, anti-inflammatory, antiviral and immunomodulatory activities. Currently, the anti-GA activity and metabolomic profiles after being treated by P-b4 have not been reported. In this paper, for the first time, we have performed a non-targeted metabolomics analysis of serum obtained from an MSU crystal-induced GA rat model intervened by P-b4, using ultra-performance liquid chromatography coupled to quadrupole time-of-flight tandem mass spectrometry. In this study, the main pharmacodynamics of different dosing methods and dosages of P-b4 was firstly investigated. Results have shown that P-b4 possesses high anti-inflammatory activity. These results demonstrated changes in serum metabolites with 32 potential biomarkers. Arachidonic acid, sphingolipid, and glycerophospholipid metabolism are considered to be the most relevant metabolic pathway with P-b4 treatment effect in this study. Moreover, the changes of metabolites and the self-extinction of model effects within 24 h reveals important information for GA diagnostic criteria: The regression of clinical symptoms or the decline of some biochemical indicators cannot be regarded as the end point of GA treatment. Furthermore, our research group plans to conduct further metabolomics research on the clinical course of GA.
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Crişan, Tania O., Maartje C. P. Cleophas, Boris Novakovic, Kathrin Erler, Frank L. van de Veerdonk, Hendrik G. Stunnenberg, Mihai G. Netea, Charles A. Dinarello, and Leo A. B. Joosten. "Uric acid priming in human monocytes is driven by the AKT–PRAS40 autophagy pathway." Proceedings of the National Academy of Sciences 114, no. 21 (May 8, 2017): 5485–90. http://dx.doi.org/10.1073/pnas.1620910114.
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Metabolic triggers are important inducers of the inflammatory processes in gout. Whereas the high serum urate levels observed in patients with gout predispose them to the formation of monosodium urate (MSU) crystals, soluble urate also primes for inflammatory signals in cells responding to gout-related stimuli, but also in other common metabolic diseases. In this study, we investigated the mechanisms through which uric acid selectively lowers human blood monocyte production of the natural inhibitor IL-1 receptor antagonist (IL-1Ra) and shifts production toward the highly inflammatory IL-1β. Monocytes from healthy volunteers were first primed with uric acid for 24 h and then subjected to stimulation with lipopolysaccharide (LPS) in the presence or absence of MSU. Transcriptomic analysis revealed broad inflammatory pathways associated with uric acid priming, with NF-κB and mammalian target of rapamycin (mTOR) signaling strongly increased. Functional validation did not identify NF-κB or AMP-activated protein kinase phosphorylation, but uric acid priming induced phosphorylation of AKT and proline-rich AKT substrate 40 kDa (PRAS 40), which in turn activated mTOR. Subsequently, Western blot for the autophagic structure LC3-I and LC3-II (microtubule-associated protein 1A/1B-light chain 3) fractions, as well as fluorescence microscopy of LC3-GFP–overexpressing HeLa cells, revealed lower autophagic activity in cells exposed to uric acid compared with control conditions. Interestingly, reactive oxygen species production was diminished by uric acid priming. Thus, the Akt–PRAS40 pathway is activated by uric acid, which inhibits autophagy and recapitulates the uric acid-induced proinflammatory cytokine phenotype.
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Smitley, D. R., T. W. Davis, and K. A. Kearns. "Eastern Tent Caterpillar Control, Michigan, 1990." Insecticide and Acaricide Tests 16, no. 1 (January 1, 1991): 268. http://dx.doi.org/10.1093/iat/16.1.268a.
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Abstract Pin Cherry trees with active tent caterpillar colonies were selected among open woodlot trees at the MSU horticulture farm in E. Lansing. Precounts were made on 4 May. Applications were made at 1:00 PM to the tents and to the foliage around the tents. Each treatment was replicated 5 times. The insecticides were applied with a R&D Sprayer with a single 8003 flat-fan nozzle at 50 psi. The postcounts were evaluated on 9 May. Caterpillars were counted by walking around each tree and observing the tents and surrounding branches. The larvae were 2nd and 3rd instars at the time of the experiment. Heavy rain (0.78 inch) fell 10 h after application. More rain fell on 9 May (0.5 inch) and 12 May (0.65 inch).
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Zapotocny, Tom H., W. Paul Menzel, James A. Jung, and James P. Nelson. "A Four-Season Impact Study of Rawinsonde, GOES, and POES Data in the Eta Data Assimilation System. Part II: Contribution of the Components." Weather and Forecasting 20, no. 2 (April 1, 2005): 178–98. http://dx.doi.org/10.1175/waf838.1.
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Abstract The impact of in situ rawinsonde observations (raob), remotely sensed Geostationary Operational Environmental Satellite (GOES), and Polar-Orbiting Operational Environmental Satellite (POES) observations routinely used in NCEP’s Eta Data Assimilation/Forecast System (EDAS) is studied for extended-length time periods during four seasons. This work examines the contribution of nine individual components of the total observing system. The nine data types examined include rawinsonde mass and wind observations, GOES mass and wind observations, POES observations from the Microwave Sounding Unit (MSU), the Advanced Microwave Sounding Unit (AMSU-A and AMSU-B), the High Resolution Infrared Radiation Sounder (HIRS), and column total precipitable water and low-level wind observations from the Special Sensor Microwave Imager (SSM/I). The results are relevant for users of the Eta Model trying to compare/contrast the overall forecast impact of traditional, largely land-based rawinsonde observations against remotely sensed satellite observations, which are available domainwide. The case studies chosen consist of 15-day periods during fall 2001, winter 2001/02, spring 2002, and summer 2002. Throughout these periods, a November 2001 32-km version of the EDAS is run 10 times at both 0000 and 1200 UTC. The 10 runs include a control run, which utilizes all data types routinely used in the EDAS, and 9 experimental runs in which one of the component data types noted above is denied. Differences between the experimental and control runs are then accumulated over the 15-day periods and analyzed to demonstrate the 00-h sensitivity and 24-h forecast impact of these individual data types in the EDAS. The diagnostics are computed over the entire horizontal model domain and a subsection covering the continental United States (CONUS) and adjacent coastal waters on isobaric surfaces extending into the lower stratosphere. The 24-h forecast impact results show that a positive forecast impact is achieved from most of the nine component data sources during all four time periods. HIRS, MSU, and SSM/I wind observations yield only a slight positive forecast impact to all fields. Rawinsonde and GOES wind observations have the largest positive forecast impact for temperature over both the entire model domain and the extended CONUS. The same data types also provide the largest forecast impact to the u component of the wind, while GOES wind observations provide the largest forecast impact to moisture.
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Cipolletta, E., A. DI Matteo, G. Brunori, A. Moretti, W. Grassi, and E. Filippucci. "THU0407 THE VALUE OF SONOGRAPHY IN THE INTERCRITICAL PHASE OF GOUT." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 441.1–441. http://dx.doi.org/10.1136/annrheumdis-2020-eular.1339.
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Background:Disease remission is the goal of therapy for many chronic rheumatic diseases. In 2016, provisional gout remission criteria were proposed (1). To the best of our knowledge, no studies have compared ultrasound (US) findings in gouty patients with and without remission.Objectives:To determine the prevalence of US pathologic findings in patients with gout fulfilling and not fulfilling the provisional remission criteria and to investigate the value of the US findings as predictors of a gouty flare within 6 months.Methods:Patients with a diagnosis of gout according to the 2015 classification criteria (2) were recruited in this prospective, monocentric study. The following clinical information was recorded at baseline and after 6 months: number of gouty flares in the preceding 6 months, number of subcutaneous tophi, current serum urate level, and patient reported outcomes (pain visual analogue scale and patient global assessment visual analogue scale). Bilateral US assessment of the following anatomical areas was performed (3): elbow, wrist, II metacarpophalangeal joint, knee, ankle and I metatarsophalangeal joint. US evidence of tophi, aggregates, double contour sign and synovitis were recorded according to the correspondent OMERACT definitions.Results:Forty-nine patients with gout were consecutively enrolled. The remission criteria were satisfied in 9 (18.4%) patients. Monosodium urate (MSU) deposits and findings of synovitis were observed by US less frequently in patients in remission (55.6% and 22.2%), compared with those not fulfilling the criteria (100.0% and 72.5%) (p values<0.01). The US MSU total score was 1.0; 0.0–2.0 (median and inter-quartile range) for patients in remission, compared with 6.0; 5.0–7.0 for those not fulfilling the criteria (p<0.01). US synovitis total score was significantly correlated with patient global assessment (R=0.55, p<0.01), patient pain (R=0.51, p<0.01) and number of gouty attacks in the previous 6 months (R=0.36, p=0.03), whereas MSU total score was associated with the number of gouty attacks in the previous 6 months (R=0.49, p<0.01), the number of subcutaneous tophi (R=0.45, p<0.01), patient pain (R=0.41, p=0.01), patient global assessment (R=0.41, p<0.01). At logistic regression analysis, the presence of subcutaneous tophi (OR=2.8, p=0.02), CRP level (OR=6.5, p=0.04) and US synovitis score (OR=2.0, p=0.04) and were predictors of subsequent development of gouty flare within 6 months.Conclusion:This study provides new insights into the inter-critical phase of gout, highlighting the clinical relevance of US synovitis as a predictor of subsequent development of gouty flare and joint pain. Despite MSU deposits are still detectable in patients satisfying the 2016 provisional remission criteria for gout, the remission is associated with less US detected MSU deposits.References:[1]de Lautour H, et al. Development of preliminary Remission Criteria for Gout Using Delphi and 1000Minds Consensus Exercises. Arthritis Care Res 2016[2]Neogi T, et al. 2015 Gout classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis 2015[3]Naredo E, et al. Ultrasound-detected musculoskeletal urate crystal deposition: which joints and what findings should be assessed for diagnosing gout? Ann Rheum Dis 2014Disclosure of Interests: :Edoardo Cipolletta: None declared, Andrea Di Matteo Grant/research support from: the publication was conducted while Dr. Di Matteo was an ARTICULUM fellow, Giada Brunori: None declared, Antonella Moretti: None declared, Walter Grassi Speakers bureau: Prof. Grassi reports personal fees from AbbVie, personal fees from Celgene, personal fees from Grünenthal, personal fees from Pfizer, personal fees from Union Chimique Belge Pharma, outside the submitted work., Emilio Filippucci Speakers bureau: Dr. Filippucci reports personal fees from AbbVie, personal fees from Bristol-Myers Squibb, personal fees from Celgene, personal fees from Roche, personal fees from Union Chimique Belge Pharma, personal fees from Pfizer, outside the submitted work.
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Ushiki, Ikuo, Naoto Takahashi, Taichi Shimizu, Yoshiyuki Sato, Masaki Ota, Richard L. Smith, and Hiroshi Inomata. "Adsorption equilibria of rhodium acetylacetonate with MCM-41, MSU-H, and HMS silica substrates in supercritical carbon dioxide for preparing catalytic mesoporous materials." Journal of Supercritical Fluids 120 (February 2017): 240–48. http://dx.doi.org/10.1016/j.supflu.2016.05.032.
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An, Hyung Bum, Sung Hoon Park, Sung Hwa Jhurng, Jong Soo Jurng, Gwi-Nam Bae, Jong-Ki Jeon, and Young-Kwon Park. "Benzene Oxidation with Ozone Over MnOx/MSU-H and MnOx/Mesoporous-SAPO-34 Catalysts." Journal of Nanoscience and Nanotechnology 15, no. 1 (January 1, 2015): 454–58. http://dx.doi.org/10.1166/jnn.2015.8361.
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Meza Sánchez, A. V., C. Hernandez-Diaz, C. Duarte-Salazar, R. E. Barbosa-Cobos, I. Romero-Vazquez, L. Ventura, and G. Lugo-Zamudio. "AB0260 ASSOCIATION BETWEEN INFLAMMATION AND DEPRESSIVE SYMPTOMS IN RHEUMATOID ARTHRITIS PATIENTS." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 1257.1–1257. http://dx.doi.org/10.1136/annrheumdis-2022-eular.1643.
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BackgroundRheumatoid arthritis (RA) is an autoimmune, progressive disease characterized by an inflammatory process mediated by CD4+T lymphocytes leading to damage of the synovial membrane1. Its prevalence is estimated between 0.2 and 1.2% worldwide, affecting women in the fourth and fifth decades2. In 2013, the Mexican College of Rheumatology estimated a 1.6% prevalence3 in Mexico.RA may affect patients´ social, psychological, economic and physical areas. Among its psychological implications, depression is one of the most important (with a prevalence of 40%) beyond the general population4. Several studies assess either prevalence or prognosis, despite its higher prevalence and a lesser likelihood of remission in these patients. Some investigations looked for a relationship between inflammation and depressive symptoms considering only clinical or biochemical parameters, despite the evidence supporting better results with imaging methods, such as musculoskeletal ultrasound (MSU).ObjectivesTo identify the association between MSU demonstrated inflammation and the presence of depressive symptoms in RA patients.MethodsIn 2021 a cross-sectional study on RA patients (according to ACR/EULAR 2010 criteria) was conducted. The subjects were from the Instituto Nacional de Rehabilitación “Luis Guillermo Ibarra Ibarra” and Hospital Juárez de México Rheumatology out-patient clinic. Each patient underwent a clinical (SDAI, CDAI, and EVA), psychological (PHQ9 and InCaViSa questionnaires), and MSU assessment (7 joints score). Data described with central tendency and dispersion measures for quantitative variables and frequencies and proportions for qualitative variables. Kruskal Wallis, U Mann-Whitney and Spearman correlation tests for analysis done.ResultsFifty-two patients (94% women) were evaluated, with a mean age of 56.06 (±12.31) years and duration of disease 13.66 (±9.44) years. Depression prevalence was 54%. Patients with disease activity had the highest depression scores (p=0.009), those with triggering events in the last six months (p=0.177), the leading event was the death of a close relative in 30% of the patients. A moderate correlation between the depression score (PHQ9) and clinical disease activity scores (SDAI, CDAI, VAS, and painful joints) (rho=0.553 [p<0.001], 0.559 [p<0.001], 0.492 [p<0.001], and 0.57 [p<0.001], respectively) were found. Furthermore, we found a moderate correlation between depression scores and psychological, social and physical quality of life. A mild correlation between MSU synovitis and depression scores (rho=0.315 [p=0.03]) found.ConclusionPatients with disease activity reported higher depression scores in comparison to remission patients. We demonstrated a relationship between depressive symptoms, social factors, disease perception and ultrasound synovitis. It is crucial to conduct longitudinal studies with a large number of patients, including a control group, and perform an adequate stratification of the demographic characteristics of the patients and their confounding variables.References[1]Karimzadeh H, Karami M, Bazgir N, Karimifar M, Yadegarfar G, Mohammadzadeh Z. Ultrasonographic findings of rheumatoid arthritis patients who are in clinical remission. J Res Med Sci 2018;23(1):38.[2]García de Yébenes M de J, Loza E. Artritis reumatoide: epidemiología e impacto sociosanitario. Reumatol Clin Supl 2018;14(2):3–6.[3]Hérnandez L del C, Querol J, De la Garza AL, Férnandez C. Artritis Reumatoide su impacto social y económico. Boletín Epidemiológico 2016;33(12):1–4.[4]Maldonado G, Ríos C, Paredes C, Ferro C, Intriago MJ, Aguirre C, et al. Depresión en artritis reumatoide. Rev Colomb Reumatol 2017;24(2):84–91.Disclosure of InterestsNone declared
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LI, Enxiao, Ying Hu, Wenbo Han, Tianshu Liu, Fang Lv, Lili Zhao, Yang Liu, Yanhui Chen, and Henghui Zhang. "The mutational landscape of MSI-H and MSS colorectal cancer." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e15122-e15122. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e15122.
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e15122 Background: The microsatellite instability-high (MSI-H) phenotype confers good prognosis and greater response to immunotherapy in colorectal cancer(CRC). The mutational landscape of MSI-H CRC is unclear. This study was designed to illustrate the difference mutation profile between the MSI-H and microsatellite stable (MSS) CRC. Methods: Tumor tissue and matched blood samples from 40 patients with colorectal cancer were collected. Microsatellite instability (MSI) status were detected by PCR-amplified for five mononucleotide repeat markers (BAT-25, BAT-26, NR-21, NR-24 and MONO-27). Mutation profiles were sequenced by a cancer gene-targeted NGS panel. Results: The tumor mutation burden(TMB) of the MSI-H CRC patients was significantly higher than those MSS CRC patients. Compared with the MSS CRC, MSI-H CRC involved more genes and pathways. Furthermore, we found the copy number variation (CNV) was different between the two groups. The copy number instability (CNI) score of MSI-H CRC patients was significantly lower than those MSS CRC patients. MSI-H CRC patients showed a higher frequency of TP53 gene CNV gain compared with MSS CRC (41% (7/17) in MSI-H CRC versus 13% (3/23) in MSS CRC). Conclusions: The mutational landscape are different between the MSI-H and MSS colorectal cancer. Compared with MSS colorectal cancer, the MSI-H colorectal cancer patients have higher tumor mutation burden(TMB) and lower copy number instability (CNI) score. Keywords: colorectal cancer, microsatellite instability, tumor mutation burden, copy number instability. Abbreviations CRC, colorectal cancer; TMB, tumor mutation burden; MSI-H, The microsatellite instability-high; MSS, microsatellite stable; CNV, copy number variation.
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Kim, Chang-gon, Joong Bae Ahn, Minkyu Jung, Seung Hoon Beom, Joo Hoon Kim, Su Jin Heo, Ji Hyung Kim, and Sang Joon Shin. "Patterns of recurrence by microsatellite instability in colorectal cancer." Journal of Clinical Oncology 34, no. 4_suppl (February 1, 2016): 501. http://dx.doi.org/10.1200/jco.2016.34.4_suppl.501.
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501 Background: Although colorectal cancer (CRC) with microsatellite instability (MSI) has a more favorable prognosis than microsatellite stable (MSS) CRC, patterns of recurrence has not been precisely investigated. We aim to explore patterns of recurrence and prognosis of CRC with MSI-H (high-frequency MSI) in comparison to MSI-L (low-frequency of MSI)/MSS. Methods: Patients with stage I-III colorectal cancer who received complete surgical resection were included using retrospective cohort of Yonsei Cancer Center. Patients were categorized to MSI status (MSI-H vs. MSS-L/MSS). Patterns of recurrence, disease free survival (DFS) and overall survival (time from diagnosis to death as OS1 and time from recurrence to death as OS2) between two groups were compared. Results: A total of 2944 patients were evaluated. Of all, 263 patients (8.9%) has MSI-H tumor. Patients with MSI-L/MSS tumor experienced more systemic recurrence events than patients with MSI-H tumor (13.1% vs. 4.6%). In patients who experienced recurrence, MSI-H tumor has tendency toward young age, proximal location and poorly differentiated histology. MSI-H tumor is more likely to recur as peritoneal metastasis (33.3% vs. 8.0%, p-value 0.002) and lymph node metastasis (25.0% vs. 7.7%, p-value 0.033). In contrast, MSI-L/MSS tumor is more likely to recur as lung metastasis (37.1% vs. 0.0%, p-value 0,008). There was no difference in DFS [hazard ratio (HR) = 0.753, p-value 0.241] and OS1 [HR = 1.486, p-value 0.203]. However, OS2 was marginally inferior in MSI-H tumor [HR = 1.779, p-value 0.064]. Conclusions: Patterns of recurrence in MSI-H CRC is different from that of MSI-L/MSS and modification of surveillance strategy in MSI-H CRC should be considered. In addition, prognosis of recurred MSI-H CRC is not superior than MSI-L/MSS and prognostic value of MSI in this circumstance should be evaluated using larger sample size.
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Jermy, B. Rabindran, Mohammed Salahuddin, Gazali Tanimu, Hatim Dafalla, Sarah Almofty, and Vijaya Ravinayagam. "Design and Evaluation of Pegylated Large 3D Pore Ferrisilicate as a Potential Insulin Protein Therapy to Treat Diabetic Mellitus." Pharmaceutics 15, no. 2 (February 9, 2023): 593. http://dx.doi.org/10.3390/pharmaceutics15020593.
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An iron-based SBA-16 mesoporous silica (ferrisilicate) with a large surface area and three-dimensional (3D) pores is explored as a potential insulin delivery vehicle with improved encapsulation and loading efficiency. Fe was incorporated into a framework of ferrisilicate using the isomorphous substitution technique for direct synthesis. Fe3+ species were identified using diffuse reflectance spectroscopy. The large surface area (804 m2/g), cubic pores (3.2 nm) and insulin loading were characterized using XRD, BET surface area, FTIR and TEM analyses. For pH sensitivity, the ferrisilicate was wrapped with polyethylene glycol (MW = 400 Daltons) (PEG). For comparison, Fe (10 wt%) was impregnated on a Korea Advanced Institute of Science and Technology Number 6 (KIT-6) sieve and Mesocellular Silica Foam (MSU-F). Insulin loading was optimized, and its release mechanism was studied using the dialysis membrane technique (MWCO = 14,000 Da) at physiological pH = 7.4, 6.8 and 1.2. The kinetics of the drug’s release was studied using different structured/insulin nanoformulations, including Santa Barbara Amorphous materials (SBA-15, SBA-16), MSU-F, ultra-large-pore FDU-12 (ULPFDU-12) and ferrisilicates. A different insulin adsorption times (0.08–1 h), insulin/ferrisilicate ratios (0.125–1.0) and drug release rates at different pH were examined using the Korsmeyer–Peppas model. The rate of drug release and the diffusion mechanisms were obtained based on the release constant (k) and release exponent (n). The cytotoxicity of the nanoformulation was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay using human foreskin fibroblast (HFF-1) cells. A low cytotoxicity was observed for this nanoformulation starting at the highest concentrations used, namely, 400 and 800 μg. The hypoglycemic activity of insulin/ferrisilicate/PEG on acute administration in Wistar rats was studied using doses of 2, 5 and 10 mg/kg body weight. The developed facile ferrisilicate/PEG nanoformulation showed a high insulin encapsulation and loading capacity with pH-sensitive insulin release for potential delivery through the oral route.
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Ivanova, Oleksandra, Yuri Skorov, Igor Luk'yanyk, Dušan Tomko, Marek Husárik, Jürgen Blum, Oleg Egorov, and Olga Voziakova. "Activity of (6478) Gault during 2019 January 13–March 28." Monthly Notices of the Royal Astronomical Society 496, no. 3 (June 9, 2020): 2636–47. http://dx.doi.org/10.1093/mnras/staa1630.
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ABSTRACT We present the results of photometric observations of active asteroid (6478) Gault performed at heliocentric distances from 2.46 to 2.30 au and geocentric distances from 1.79 to 1.42 au between 2019 January 15 and March 28. Observations were carried out at the 2.5-m telescope of SAI MSU (Caucasian Mountain Observatory) on 2019 January 15 and at the 1.3 and 0.61-m telescopes (SPb) on 2019 February 6 and March 28, respectively. The direct images of the asteroid were obtained with the broad-band B, V, and R filters. Comet-like structures were detected at all observation dates. Colour maps were built and colour variations along the tail for the observation made on 2019 January 15 were analysed. The Afρ was calculated for the R filter, and the evaluated value varies from 47 to 32 cm for the period from 2019 January to the end of March. The rotational period of the body is estimated from the light curve by different methods and is about 1.79 h. Possible mechanisms of triggering Gault's activity are discussed.
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Okamoto, Wataru, Yoshiaki Nakamura, Manabu Shiozawa, Yoshito Komatsu, Tadamichi Denda, Hiroki Hara, Yoshinori Kagawa, et al. "Microsatellite instability status in metastatic colorectal cancer and effect of immune checkpoint inhibitors on survival in MSI-high metastatic colorectal cancer." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e15106-e15106. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e15106.
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e15106 Background: Tumor mismatch repair (MMR) predicts benefit of immune checkpoint inhibitors (ICIs) in metastatic colorectal cancer (mCRC). We conducted a large-scale prospective observational trial on microsatellite instability (MSI) status in mCRC: SCRUM-Japan GI-SCREEN CRC-MSI. Methods: mCRC patients (pts) appropriate for systemic chemotherapy were eligible. Paired tumor and normal DNA extracted from FFPE samples were analyzed by the MSI Analysis System, which includes 5 mononucleotide markers. Tumors exhibiting ≥2 unstable markers were defined as MSI-H, while those with ≤1 were labelled MSI-L/MSS. Results: From 2/2016 to 3/2018, 1,711 pts were enrolled, and 1,696 samples were submitted. MSI status was determined in 1,676 pts (98.8%); 51 pts (3.0%) were MSI-H. For MSI-H vs. MSI-L/MSS pts: Median age (years) 64/64; male gender (%) 51.0 vs. 43.8, p=0.31; right-sided primary (%) 70.6 vs. 25.0, p<0.001; and poorly differentiated histology (%) 33.3 vs. 8.9, p<0.001. Of the 864 pts who received parallel NGS testing, median tumor mutation burdens (TMB) in MSI-H and MSI-L/MSS were 32.8 and 12.6 mt/Mb, p<0.001. High TMB, defined as >20 mt/Mb, was observed in 27/29 (93.1%) MSI-H pts. The frequency of representative gene mutations (%) for MSI-H vs. MSI-L/MSS pts were: TP53 17.2 vs. 66.1, p<0.001; PIK3CA 48.3 vs. 13.2, p<0.001; BRAF 34.5 vs. 7.5, p<0.001; MSH2 17.2 vs. 0, p<0.001; CTNNB1 17.2 vs. 0.6, p<0.001; and ERBB2 10.3 vs. 1.4, p<0.001. ERBB2 amplification was detected only in MSI-L/MSS pts (2.3%). Two-year survival rates from first-line systemic therapy in 389 pts with MSI-L/MSS, 5 pts with MSI-H treated with ICI in any-line, and 5 pts with MSI-H not treated with ICI, were 77.7, 100, and 33.3%, respectively. Conclusions: MSI-H mCRC tumors were more frequent in right-sided colon primaries and with poorly differentiated histology. Median TMB was significantly greater in MSI-H pts, and a very high burden was frequently seen. Survival in MSI-H mCRC was poor before ICIs; these agents may improve outcomes for MSI-H pts. Clinical trial #UMIN000020437.
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Luo, Peng, Anqi Lin, and Jian Zhang. "Crosstalk between the MSI status and tumor microenvironment in colorectal cancer." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e15236-e15236. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e15236.
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e15236 Background: In recent years, cancer immunotherapy has been extensively studied, and colorectal cancer (CRC) patients have also derived clinical benefits from immunotherapy, especially CRC patients with mismatch repair deficiency (dMMR)/microsatellite instability-high (MSI-H), whose sensitivity to immune checkpoint inhibitors (ICIs) is significantly higher than that of patients with microsatellite-stable (MSS)/microsatellite instability-low (MSI-L) disease. This study suggests that patients with MSI-H CRC have a higher mutational burden and more immune cell infiltration than those with MSS/MSI-L disease. However, most studies have not systematically evaluated the immune characteristics and immune microenvironments of MSI-H and MSS/MSI-L CRC. Methods: A published CRC cohort with mutation and immunotherapy-related prognostic data was collected. We analyzed the relationship between the MSI status and prognosis of ICI treatment in an immunotherapy cohort. We then further used mutation data for the immunotherapy and The Cancer Genome Atlas (TCGA)-CRC (colon adenocarcinoma (COAD) + rectum adenocarcinoma (READ) cohorts. For mRNA expression, mutation data analysis of the immune microenvironment and immunogenicity under different MSI status was performed. Results: Compared with MSS/MSI-L CRC patients, patients with MSI-H CRC significantly benefited from ICI treatment. We found that MSI-H CRC had more immune cell infiltration, higher expression of immune-related genes and higher immunogenicity than MSS/MSI-L disease. The MANTIS score used to predict the MSI status was positively correlated with immune cells, immune-related genes, and immunogenicity. In addition, subtype analysis showed that COAD and READ might have different tumor immune microenvironments. Conclusions: MSI-H CRC may have an inflammatory tumor microenvironment and increased sensitivity to ICIs. Unlike those of MSI-H READ, the immune characteristics of MSI-H COAD may be consistent with those of MSI-H CRC. Furthermore, the possible mechanism underlying the prognostic differences among CRC patients receiving ICIs in relation to the immune microenvironment were elucidated to provide theoretical guidance for further improving the curative effect of ICIs treatment on MSI-H CRC patients in the future and solve the problems underlying why MSS/MSI-L CRC patients do not benefit from ICIs treatment.
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Wang, Jingyuan, Joanne Xiu, Anthony Frank Shields, Axel Grothey, Benjamin Adam Weinberg, John Marshall, Emil Lou, et al. "Comprehensive molecular analysis of microsatellite-stable (MSS) tumors with high mutational burden in gastrointestinal (GI) cancers." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 3631. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.3631.
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3631 Background: Mutational signatures contributing to high tumor mutation burden (TMB-H) independent from microsatellite instability-high (MSI-H) status are not well-studied. We aimed to characterize specific molecular features of a large cohort of GI tumors with TMB-H & MSS. Methods: We sequenced23392 GI tumors, including 2707 gastroesophageal (GE), 11616 colorectal (CRC), and 9069 others. Samples were analyzed using Next-generation sequencing (NGS) and immunohistochemistry (IHC) (Caris Life Sciences, Phoenix, AZ). MMR/MSI status was evaluated by a combination of IHC, Fragment Analysis and NGS. Tumors with TMB ≥ 17 mutations/Mb were defined as TMB-H. PD-L1 was tested by IHC [22C3 (CPS score, positivity: CPS ≥ 1%) in GE tumors and SP142 (Positivity: TPS ≥ 5%) in other cancers]. Findings were compared in four groups (TMB-H/L & MSI-H/MSS) using Fisher-Exact or Chi-square and adjusted for multiple comparison by Benjamini-Hochberg. Significance was determined by adjusted (adj) p < .05. Results: Overall, TMB-H & MSS was observed in 1% of patients (pts) (n = 237, including 45 GE, 124 CRC, 68 others), while TMB-H & MSI-H, TMB-L & MSS, TMB-L & MSI-H were observed in 4% (n = 936), 94.4% (n = 22089) and 0.6% (n = 130) respectively. Compared to other groups, TMB-H & MSS showed the most prevalent amplifications (AMPs), including CCND1 (5.6%), FGF3/4/19 (4.9%, 4.3%, 4.4%) , MYC (4.3%) (Top 5, adj p < .05), and the highest mutation rates in POLE (21.6%), RB1 (13.1%), CDC73 (10.3%), RUNX1 (6.5%), and genes involved in PI3K & MAPK ( PIK3R1 17%, mTOR 3.4%, MAP2K1 3.8% , MAP2K4 5.6%) and Wnt ( APC 48.5% , SMAD2 6.5% , TCF7L2 3.8%) pathways (adj p < .05). The rates of HER2 AMP and high-expression (IHC) were the highest in TMB-H & MSS, followed by TMB-L & MSS, TMB-H & MSI-H, TMB-L & MSI-H (adj p< .0001); PD-L1 positive rate was similar between TMB-H & MSS and TMB-L & MSI-H, while the highest and lowest in TMB-H & MSI-H and TMB-L & MSS respectively in GE and other GI cancers (adj p < .01) (Table). Conclusions: This is the largest study to investigate the special molecular landscape of pts with TMB-H & MSS in GI cancers. Our data may provide novel insights for pt selection and more effective targeted combination immunotherapies (e.g. HER2, PI3K inhibitors) in GI cancers. [Table: see text]
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Goksu, Suleyman Yasin, Mohammad Faizan Zahid, Muhammet Ozer, Nina Niu Sanford, Aravind Sanjeevaiah, Salwan Al Mutar, Udit Verma, et al. "Clinicopathologic variables and outcomes in elderly colorectal cancer patients with microsatellite instability and multiple primary malignancies." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e15516-e15516. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e15516.
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e15516 Background: The biology of microsatellite instability-high (MSI-H) in elderly colorectal cancer (CRC) patients is attributed to hypermethylation of promoter region of genes coding for mismatch repair proteins. It is unknown if such patients are predisposed to other malignancies. It is also unknown if the presence or absence of multiple primary malignancies affects elderly MSI-H CRC patients' survival. We aimed to evaluate the clinicopathologic features and outcomes in elderly CRC patients with MSI-H and multiple primary malignancies. Methods: We analyzed the National Cancer Database and included elderly (≥ 65 years) patients with CRC diagnosed between 2010-2016. MSI status was determined using genetic and immunohistochemical testing and categorized as microsatellite stable (MSS) and MSI-H. We further categorized the population into single primary malignancy versus multiple primary malignancies. We compared the baseline characteristics using the Chi-square test. Kaplan-Meier and log-rank tests were performed to calculate the overall survival (OS). Results: Among 52,494 elderly CRC patients, 78.0% were MSS, and 22.0% were MSI-H. The probability of MSI-H disease increased with increasing age, female gender, and non-Hispanic White ethnicity (all p < .001). MSI-H patients were associated with elevated CEA, wild-type KRAS, multiple neoplasms, right-sided tumors, stage II disease, and grade III/IV histology. The proportion of patients with multiple primary malignancies was higher in the MSI-H population versus MSS (36% vs. 31%, p < 0.001). The rate of multiple primary malignancies increased with age in both groups. Among MSI-H CRC patients, the factors associated with multiple primary malignancies included female gender (61.6%), non-Hispanic White ethnicity (86.3%), comorbidity index ≥ 2 (14.8%), and right-sided tumors (77.2%). Multiple primary malignancies were more frequently associated with stage I-III CRC as compared to metastatic CRC. For stage III-IV elderly MSI-H patients, the utilization of chemotherapy was 57.8% overall, but it was not significantly different between single primary malignancy versus multiple primary malignancies groups. MSI-H patients with single primary malignancy had the highest OS, followed by MSS patients with single primary malignancy, MSI-H patients with multiple primary malignancies, and MSS patients with multiple primary malignancies (74.7, 66.7, 58.1, 54.8 mos, respectively) (log-rank p < 0.001). Conclusions: Elderly CRC patients with MSI-H had a higher rate of multiple primary malignancies than MSS. This was associated with female gender, non-Hispanic White ethnicity, and right-sided tumor. MSI-H patients with single primary malignancy had the highest survival while the presence of multiple primary malignancies adversely affected survival in both MSI-H and MSS populations.
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Latham Schwark, Alicia, Preethi Srinivasan, Yelena Kemel, Jinru Shia, Chaitanya Bandlamudi, Diana Mandelker, Marianne Dubard-Gault, et al. "Pan-cancer microsatellite instability to predict for presence of Lynch syndrome." Journal of Clinical Oncology 36, no. 18_suppl (June 20, 2018): LBA1509. http://dx.doi.org/10.1200/jco.2018.36.18_suppl.lba1509.
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LBA1509 Background: The success of immunotherapy in microsatellite unstable (MSI-H) and/or DNA mismatch repair deficient (MMR-D) tumors has resulted in routine MSI-H/MMR-D testing in advanced solid tumors. Unlike colorectal (CRC) and endometrial cancer (EC), where this has long been undertaken, the characterization of Lynch syndrome (LS) across heterogeneous MSI-H/MMR-D tumors is unknown. Methods: Through a targeted NGS panel, MSI status was determined via MSIsensor. Scores of < 3, ≥3 to < 10, or ≥10 designated Microsatellite stable (MSS), MSI-Indeterminate (MSI-I) or MSI-H status, respectively. Germline mutations were assessed in MLH1, MSH2, MSH6, PMS2, EPCAM. Immunohistochemical staining (IHC) for MMR-D and tumor signatures in LS patients were assessed. Clinical variables were correlated with MSI and compared via Chi square or T-test. Results: Of 15,045 tumors spanning > 50 cancers , 93.2% were MSS, 4.6% MSI-I, and 2.2% MSI-H. Germline mutations were identified in 0.3% (37/14,020), 1.9% (13/699), and 16.3% (53/326) in the MSS, MSI-I, and MSI-H groups, respectively (p-value < 0.001). 25% of 1,025 MSI-H/MSI-I tumors were CRC/EC, but 50% (33/66) of LS patients had MSI-H/MSI-I tumors less commonly or not previously associated with LS (mesothelioma, sarcoma, adrenocortical, melanoma, ovarian germ cell). LS pts with MSI-H/MSI-I non-CRC/EC tumors only met testing criteria in 63.6% of cases, had lower MSIsensor scores, and were more likely to be MSI-I (MSI-I: non-CRC/EC, 30.3% (10/33) vs CRC/EC 9.1% (3/33); p-value = 0.03). IHC was completed in 86.4% (57/66) of LS MSI-H/MSI-I tumors, with 98.3% MMR-D-concordance. Of LS pts with MSS tumors, 78% had MSH6/PMS2 mutations, but 71% of LS pts with MSI-H/MSI-I tumors had MLH1/MSH2/EPCAM mutations(p-value < 0.001). 89% (33/37) of MSS tumors of LS pts had non-MMR-D signatures. Conclusions: MSI-H/MMR-D is predictive of LS across tumor types and suggests a more heterogeneous spectrum of LS-associated cancers than previously appreciated. Nearly 40% of LS pts with MSI-H/MMR-D non-CRC/EC tumors did not meet clinical criteria for genetic testing, suggesting that MSI-H/MMR-D tumors, regardless of cancer type or family history, should prompt germline testing for the evaluation of LS.