Journal articles on the topic 'CMMC'
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Dickson, Eamonn J., Dante J. Heredia, and Terence K. Smith. "Critical role of 5-HT1A, 5-HT3, and 5-HT7 receptor subtypes in the initiation, generation, and propagation of the murine colonic migrating motor complex." American Journal of Physiology-Gastrointestinal and Liver Physiology 299, no. 1 (July 2010): G144—G157. http://dx.doi.org/10.1152/ajpgi.00496.2009.
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The colonic migrating motor complex (CMMC) is necessary for fecal pellet propulsion in the murine colon. We have previously shown that 5-hydroxytryptamine (5-HT) released from enterochromaffin cells activates 5-HT3 receptors on the mucosal processes of myenteric Dogiel type II neurons to initiate the events underlying the CMMC. Our aims were to further investigate the roles of 5-HT1A, 5-HT3, and 5-HT7 receptor subtypes in generating and propagating the CMMC using intracellular microelectrodes or tension recordings from the circular muscle (CM) in preparations with and without the mucosa. Spontaneous CMMCs were recorded from the CM in isolated murine colons but not in preparations without the mucosa. In mucosaless preparations, ondansetron (3 μM; 5-HT3 antagonist) plus hexamethonium (100 μM) completely blocked spontaneous inhibitory junction potentials, depolarized the CM. Ondansetron blocked the preceding hyperpolarization associated with a CMMC. Spontaneous CMMCs and CMMCs evoked by spritzing 5-HT (10 and 100 μM) or nerve stimulation in preparations without the mucosa were blocked by SB 258719 or SB 269970 (1–5 μM; 5-HT7 antagonists). Both NAN-190 and (S)-WAY100135 (1–5 μM; 5-HT1A antagonists) blocked spontaneous CMMCs and neurally evoked CMMCs in preparations without the mucosa. Both NAN-190 and (S)-WAY100135 caused an atropine-sensitive depolarization of the CM. The precursor of 5-HT, 5-hydroxytryptophan (5-HTP) (10 μM), and 5-carboxamidotryptamine (5-CT) (5 μM; 5-HT1/5/7 agonist) increased the frequency of spontaneous CMMCs. 5-HTP and 5-CT also induced CMMCs in preparations with and without the mucosa, which were blocked by SB 258719. 5-HT1A, 5-HT3, and 5-HT7 receptors, most likely on Dogiel Type II/AH neurons, are important in initiating, generating, and propagating the CMMC. Tonic inhibition of the CM appears to be driven by ongoing activity in descending serotonergic interneurons; by activating 5-HT7 receptors on AH neurons these interneurons also contribute to the generation of the CMMC.
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Dickson, Eamonn J., Dante J. Heredia, Conor J. McCann, Grant W. Hennig, and Terence K. Smith. "The mechanisms underlying the generation of the colonic migrating motor complex in both wild-type and nNOS knockout mice." American Journal of Physiology-Gastrointestinal and Liver Physiology 298, no. 2 (February 2010): G222—G232. http://dx.doi.org/10.1152/ajpgi.00399.2009.
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Colonic migrating motor complexes (CMMCs) propel fecal contents and are altered in diseased states, including slow-transit constipation. However, the mechanisms underlying the CMMCs are controversial because it has been proposed that disinhibition (turning off of inhibitory neurotransmission) or excitatory nerve activity generate the CMMC. Therefore, our aims were to reexamine the mechanisms underlying the CMMC in the colon of wild-type and neuronal nitric oxide synthase (nNOS)−/− mice. CMMCs were recorded from the isolated murine large bowel using intracellular recordings of electrical activity from circular muscle (CM) combined with tension recording. Spontaneous CMMCs occurred in both wild-type (frequency: 0.3 cycles/min) and nNOS−/− mice (frequency: 0.4 cycles/min). CMMCs consisted of a hyperpolarization, followed by fast oscillations (slow waves) with action potentials superimposed on a slow depolarization (wild-type: 14.0 ± 0.6 mV; nNOS−/−: 11.2 ± 1.5 mV). Both atropine (1 μM) and MEN 10,376 [neurokinin 2 (NK2) antagonist; 0.5 μM] added successively reduced the slow depolarization and the number of action potentials but did not abolish the fast oscillations. The further addition of RP 67580 (NK1 antagonist; 0.5 μM) blocked the fast oscillations and the CMMC. Importantly, none of the antagonists affected the resting membrane potential, suggesting that ongoing tonic inhibition of the CM was maintained. Fecal pellet propulsion, which was blocked by the NK2 or the NK1 antagonist, was slower down the longer, more constricted nNOS−/− mouse colon (wild-type: 47.9 ± 2.4 mm; nNOS−/−: 57.8 ± 1.4 mm). These observations suggest that excitatory neurotransmission enhances pacemaker activity during the CMMC. Therefore, the CMMC is likely generated by a synergistic interaction between neural and interstitial cells of Cajal networks.
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Gross, Steven, Brad Foulk, Jaymala Patel, Mark Connelly, and Marielena Mata. "Automated Enumeration and Characterization of Circulating Multiple Myeloma Cells in Blood." Blood 118, no. 21 (November 18, 2011): 1825. http://dx.doi.org/10.1182/blood.v118.21.1825.1825.
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Abstract Abstract 1825 Detection of circulating Multiple Myeloma cells (CMMC) by flow cytometry is an indicator of active disease. In addition, circulating plasma cells can be detected in earlier stages of disease, including MGUS and Smoldering Multiple Myeloma, and appear to correlate with prognosis. The capture and characterization of these circulating plasma cells from peripheral blood may provide novel biomarkers for the management of Multiple Myeloma patients, particularly in monitoring minimal residual disease and in progression from MGUS or Smoldering Multiple Myeloma to active disease. The enumeration and characterization of circulating tumor cells (CTC) in patients with metastatic breast, prostate or colorectal cancer using the CellSearch® technology, has been shown to provide clinically relevant prognostic and predictive information. Here we describe the development of an automated assay for detecting circulating normal plasma cells (CPC) and multiple myeloma cells (CMMC) in blood using CellSearch. Assay results from Multiple Myeloma, MGUS patients, and from an aged matched control population are presented. The CellTracks® AutoPrep® System and CellTracks Analyzer II® systems were used to capture and enumerate CPC and CMMC. Magnetic particles conjugated to anti-CD138 are used to capture myeloma cells from 4.0mL of blood. Enriched cells are then stained with the nucleic acid dye DAPI and anti-CD38-Phycoerythrin (PE) antibody. Allophycocyanine (APC) conjugated anti-CD45 and anti-CD19 were used to exclude leukocytes and B-cells. In addition, FITC labeled anti-CD56 was added as a biomarker. The enriched and stained cells were transferred to a CellTracks® cartridge and MagNest® for magnetic mounting. The cartridge was scanned using the CellTracks Analyzer II®. Individual images of cells were presented to the operator for review, and scored as CMMCs, based on fluorescence and cell morphology. In a model spike-in system the assay consistently recovered ∼60% of the cells from the Multiple Myeloma cell line H929 spiked into 4.0mL of blood from healthy donors. The assay was linear over the tested range of from 0 to 2000 spiked H929 cells (r2 0.98, slope 0.50, intercept 10). The assay was validated using blood from age matched healthy donors (n=22) and patients with Multiple Myeloma (n=66) and MGUS (n=7). In 4.0mL blood from normal donors, 0 CPC were detected in 12/22 (55%) and low numbers (1–6 CPC) were detected in 10/22 (45%) samples. Interestingly, one CD56 positive CPC (CMMC?) was found in a normal donor. CMMC in Multiple Myeloma patients ranged from 0 – 17,000 /4.0mL blood. One or more CMMC were detected in 91% of the patients, > 5 in 68%, > 10 in 58% and > 100 in 35%. Expression of CD56 was highly variable in the patient population. CMMC in MGUS patients ranged from 0 – 112 /4.0mL blood. One or more CMMC were detected in 6/7 of the patients, > 5 in 4/6, > 10 in 2/6 and > 100 in 1/6. To further characterize CMMC, and differentiate CPC from CMMC, an interphase fluorescent in situ hybridization (FISH) assay was developed to be used with the capture and detection system described above. A four color FISH probe was used to simultaneously detect high risk mutations including two recurrent translocations of the IgH locus (t(4;14)(p16;q32) and t(14;16)(q32;q23)) as well as deletion of the TP53 locus (Δ17p13). The FISH assay was verified on cell lines H929, MM1s, and U266, which showed mutations at t(4;14), t(14;16) and Δ17p13, respectively. The FISH assay was tested on 9 CMMC patient samples and 8 samples yielded evaluable results. Two samples showed t(4;14)fusions, 3 patients showed aberrant FISH signal patterns indicating aneuploidy of chromosome 4 or 14 and the remaining patients showed normal FISH patterns. Well controlled prospective clinical studies are needed to establish the prognostic and predictive value of the presence, and characteristics, of CMMC in multiple myeloma or MGUS. In addition, as with CTC, this automated CMMC assay should prove useful in evaluating the effectiveness of new treatments as well as the assessment of potential treatment targets on CMMC in this difficult disease. Disclosures: Gross: Johnson and Johnson: Employment, Equity Ownership. Foulk:Johnson and Johnson: Employment, Equity Ownership. Patel:Johnson and Johnson: Employment, Equity Ownership. Connelly:Johnson and Johnson: Employment, Equity Ownership. Mata:Johnson and Johnson: Employment, Equity Ownership.
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Apsite, Anita, Aleksandra Konevnina, and Diana Neperte. "THE USE OF COMPULSORY MEASURES OF MEDICAL CHARACTER (CMMC) IN LATVIA – PROBLEMS AND SOLUTIONS." Health Sciences 29, no. 4 (August 13, 2019): 127–30. http://dx.doi.org/10.35988/sm-hs.2019.068.
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The authors in their report give a description of the types of CMMC in Latvia. Particular attention is paid to the problem of carrying out psyciatric expertise in Latvia, as well as to the peculiarities of legislation that can cause inaccuracies in conducting and monitoring CMMC. As one of the main problems is identified CMMC in outpatient practice: how are CMMC controlled, who is responsible for control, cooperation between doctor and law enforcement agencies, financing issues.
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Dutta, Ankit K., Elizabeth D. Lightbody, Ziao Lin, Jean-Baptiste Alberge, Romanos Sklavenitis-Pistofidis, Tarek H. Mouhieddine, Annie Cowan, et al. "Non-Invasive Liquid Biopsy to Quantify and Molecularly Characterize Circulating Multiple Myeloma Cells in the Assessment of Precursor Disease Pathology." Blood 138, Supplement 1 (November 5, 2021): 78. http://dx.doi.org/10.1182/blood-2021-150622.
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Abstract Introduction: Multiple Myeloma (MM) is an incurable hematologic malignancy characterized by the abnormal growth of clonal plasma cells in the bone marrow (BM). In most cases MM develops from early, asymptomatic disease stages known as Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering Multiple Myeloma (SMM). Despite effective new therapies, most MM patients inevitably relapse and require further treatment, highlighting the need for better early detection methods for precursor patients and targeted interventions to prevent early disease from progressing. The initial diagnosis of MGUS/SMM remains an incidental process following the identification of increased clonal immunoglobulin in the blood. BM biopsy is the gold standard for diagnosis and monitoring of MM progression, but is intrusive, painful, and comes with possible secondary complications for patients. Consequently, repeated assessment is not a feasible option for MGUS and SMM patients who are asymptomatic. Here we tested the utility of circulating multiple myeloma cells (CMMCs) from non-invasive blood biopsy to accompany BM as a method to monitor disease development, by enumerating CMMCs from MGUS/SMM patients. Methods: Peripheral blood from 185 precursor patients (75 MGUS and 110 SMM) from the Dana-Farber Cancer Institute observational PCROWD study (IRB #14-174) was collected in CellRescue TM Preservative Tubes and processed on the CellSearch CellTracks Autoprep system using the CMMC assay kit using 4mL of blood. This assay employs the enrichment of CMMCs through the immunophenotype of CD138 +CD45 -19 -, and leukocyte exclusion based on CD45 +CD19 +. Nucleated cells were identified using DAPI staining. The CellTracks Analyzer II fluorescence microscope system was subsequently used to scan captured CMMC cartridges, with software allowing the automated scoring and enumeration of CMMCs. Additional molecular analyses were carried out on SMM patients. Briefly, minipools of CMMCs were sorted by DEPArray and underwent whole genome amplification using Ampli1 kit, PCR-free library construction, quantification and low pass whole genome sequencing (~0.5x) on the Illumina HiSeq2500. To assess whether molecular analyses can be performed to detect hyperdiploidy as a genomic biomarker of MM disease, ichorCNA analyses was performed to determine copy number variant (CNV) events and infer tumour fraction. Results: CMMCs were detected in 27% of MGUS patients collected, with a median count of 2 CMMCs (range 0 to 1328). Comparably, CMMCs were detected in 57% of SMM patients, with a median enumeration of 13 CMMCs (range 0 to 43836). Enumeration of CMMCs illustrated a correlation with clinical measure of disease including the International Myeloma Working Group 2/20/20 risk stratification model. A higher CMMC count was associated with increasing risk group based on the 3-risk factor model, with a median of 5, 29 and 59 CMMCs detected at low, intermediate, and high-risk SMM groups, respectively. CMMC counts were significantly increased at intermediate (P = 5.0 x 10 -4) and high-risk stages (P = 3.7 x 10 -3) compared to low-risk. While enumeration provides a correlative measure of CMMCs that may be of tumor origin, downstream molecular characterization can confirm MM-associated genetic alterations. At the precursor stages, a low tumour burden is evident clinically, thus both normal and malignant plasma cells are present. Therefore, to determine the concordance between bone marrow and peripheral blood CMMCs, we performed genomic analyses to identify arm level gain or loss events. Molecular analyses of CMMCs was carried out in patients who had matched BM and clinical fluorescent in situ hybridization (FISH) results. We showed that CMMCs can capture 100% of clinically annotated BM FISH CNV events. Furthermore, CMMC samples identified additional yield, with further CNVs identified that were not observed by FISH. In cases that did not have BM biopsy results, sequencing of CMMCs revealed the existence of genetic aberrations. Conclusion: Our results demonstrate clinical correlation and molecular characterization of CMMCs from MGUS/SMM patients. This study provides a foundation for non-invasive detection, enumeration and genomic interrogation of rare CMMCs from the peripheral blood of MGUS/SMM, illustrating the clinical potential of using liquid biopsies for monitoring and managing disease in the precursor setting of MM. Disclosures Getz: IBM, Pharmacyclics: Research Funding; Scorpion Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy.
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Zagorodnyuk, Vladimir P., Melinda Kyloh, Simon J. Brookes, Sarah J. Nicholas, and Nick J. Spencer. "Firing patterns and functional roles of different classes of spinal afferents in rectal nerves during colonic migrating motor complexes in mouse colon." American Journal of Physiology-Gastrointestinal and Liver Physiology 303, no. 3 (August 1, 2012): G404—G411. http://dx.doi.org/10.1152/ajpgi.00047.2012.
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The functional role of the different classes of visceral afferents that innervate the large intestine is poorly understood. Recent evidence suggests that low-threshold, wide-dynamic-range rectal afferents play an important role in the detection and transmission of visceral pain induced by noxious colorectal distension in mice. However, it is not clear which classes of spinal afferents are activated during naturally occurring colonic motor patterns or during intense contractions of the gut smooth muscle. We developed an in vitro colorectum preparation to test how the major classes of rectal afferents are activated during spontaneous colonic migrating motor complex (CMMC) or pharmacologically induced contraction. During CMMCs, circular muscle contractions increased firing in low-threshold, wide-dynamic-range muscular afferents and muscular-mucosal afferents, which generated a mean firing rate of 1.53 ± 0.23 Hz ( n = 8) under isotonic conditions and 2.52 ± 0.36 Hz ( n = 17) under isometric conditions. These low-threshold rectal afferents were reliably activated by low levels of circumferential stretch induced by increases in length (1–2 mm) or load (1–3 g). In a small proportion of cases (5 of 34 units), some low-threshold muscular and muscular-mucosal afferents decreased their firing rate during the peak of the CMMC contractions. High-threshold afferents were never activated during spontaneous CMMC contractions or tonic contractions induced by bethanechol (100 μM). High-threshold rectal afferents were only activated by intense levels of circumferential stretch (10–20 g). These results show that, in the rectal nerves of mice, low-threshold, wide-dynamic-range muscular and muscular-mucosal afferents are excited during contraction of the circular muscle that occurs during spontaneous CMMCs. No activation of high-threshold rectal afferents was detected during CMMCs or intense contractile activity in naïve mouse colorectum.
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Habibi, Zohreh, Farideh Nejat, Parvin Tajik, Syed S. Kazmi, and Abdol-Mohammad Kajbafzadeh. "Cervical Myelomeningocele." Neurosurgery 58, no. 6 (June 1, 2006): 1168–75. http://dx.doi.org/10.1227/01.neu.0000215955.18762.32.
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Abstract OBJECTIVE: Cervical myelomeningocele (cMMC) is a rare disease. Only a few series have been published regarding cMMC. Different issues regarding the etiology, classification, clinical, surgical, and pathological aspects of cMMC are still a matter of conflict. METHODS: Sixteen children operated on for cMMC between July 2000 and 2003 were followed by the neurosurgical service at Children's Hospital Medical Center in Tehran. The patients were followed up for 2 to 5 years (median, 3 yr). RESULTS: The studied patients were nine boys and seven girls, ages 1 day to 4 months. Neurological examination was normal in all but two patients. All children had a normal anal fold, could void spontaneously, and showed no evidence of gross orthopedic deformity. We found eight patients with hydrocephalus, four patients with Chiari II malformation, two patients with syringomyelia, one patient with diastematomyelia at the level of cervical hemimyelomeningocele, and one patient with associated sacral myeloschisis. A thorough urological evaluation was planned for 13 patients, which confirmed bladder dysfunction in 10 (71%) patients. All infants had midline lesions, which consisted of a protruding sac from the back of neck, covered with purplish rudimentary or dysplastic skin at the dome. All patients underwent surgical resection of the sac and intradural exploration to release any adhesion and to exclude other associated anomalies. CONCLUSION: Cervical myelomeningocele differs structurally and clinically from myelomeningocele in distal areas and has a more favorable outcome. We think that some trivial neurological deficits in cMMC are caused by the late and limited neurulation abnormality during its development. We advise thorough preoperative evaluation of the brain, spinal column, and urinary system. Intradural exploration to release any potential adhesion bands as well as correcting associated anomalies is recommended in all cMMC operations.
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Adel, Heba Mohamed, and Raghda Abulsaoud Ahmed Younis. "Using co-creating mass-customisation and innovation climate for enhanced value." Journal of Humanities and Applied Social Sciences 1, no. 1 (June 11, 2019): 25–42. http://dx.doi.org/10.1108/jhass-05-2019-002.
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Purpose This paper aims to study the impact of innovation climate (IC) on co-creating modular mass-customisation (CMMC) in terms of cost effectiveness, volume effectiveness, responsiveness, product modularity and collaborative assembly. Additionally, this research paper investigates the effect of IC and CMMC on the value to customer (VC) in a modular jewellery emerging market that includes international companies. Design/methodology/approach After conducting a comprehensive literature review, the authors suggested a conceptual framework and examined it using mixed methods approach. In addition to qualitative focus groups, questionnaires were filled – across five-point Likert scale format – through 63 depth interviews carried out with subject-matter-experts working at 14 international organisations in the Egyptian modular jewellery market. SmartPLS software was used for structural equation modelling analysis. Findings Results showed that CMMC positively and significantly affects VC. Furthermore, IC positively and significantly affects both CMMC and VC. Practical implications Recent industrial developments that can be observed in such international modular jewellery sector can be enhanced by the empirical evidence of this research regarding the importance of developing IC for more creative manufacturing approach of modular mass-customisation and better VC. Originality/value To the best of our knowledge, it is the first empirical study that investigates the relationship between CMMC, IC and VC in a unique jewellery market, which recently generated high customer involvement in the assembly/reassembly processes. Conceptually and empirically, it consolidates and adds to the literature of production and operations management (mass-customisation), organisational studies and innovation science (organisational climate for innovation) and applied social sciences.
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Levy, Yair, and Ruti Gafni. "Towards the quantification of cybersecurity footprint for SMBs using the CMMC 2.0." Online Journal of Applied Knowledge Management 10, no. 1 (September 6, 2022): 43–61. http://dx.doi.org/10.36965/ojakm.2022.10(1)43-61.
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Organizations, small and big, are faced with major cybersecurity challenges over the past several decades, as the proliferation of information systems and mobile devices expand. While larger organizations invest significant efforts in developing approaches to deal with cybersecurity incidents, Small and Medium Businesses (SMBs) are still struggling with ways to both keep their businesses alive and secure their systems to the best of their abilities. When it comes to critical systems, such as defense industries, the interconnectivities of organizations in the supply-chain have demonstrated to be problematic given the depth required to provide a high-level cybersecurity posture. The United States (U.S.) Department of Defense (DoD) with the partnership of the Defense Industry Base (DIB) have developed the Cybersecurity Maturity Model Certification (CMMC) in 2020 with a third-party mandate for Level 1 certification. Following an outcry from many DIB organizations, a newly revised CMMC 2.0 was introduced in late 2021 where Level 1 (Fundamental) was adjusted for annual self-assessment. CMMC 2.0 provides the 17 practices that organizations should self-assess. While these 17 practices provide initial guidance for assessment, the specific level of measurement and how it impacts their overall cybersecurity posture is vague. Specifically, many of these practices use non-quantifiable terms such as “limit”, “verify”, “control”, “identify”, etc. The focus of this work is to provide SMBs with a quantifiable method to self-assess their Cybersecurity Footprint following the CMMC 2.0 Level 1 practices. This paper outlines the foundational literature work conducted in support of the proposed quantification Cybersecurity Footprint Index (CFI) using 26 elements that correspond to the relevant CMMC 2.0 Level 1 practices.
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Weiss, Brendan, Kate Sasser, Chandra Rao, Brad Foulk, Steven Gross, Gayle Mallon, Colleen Erb, et al. "Circulating Multiple Myeloma Cells (CMMCs): A Novel Method for Detection and Molecular Characterization of Peripheral Blood Plasma Cells in Multiple Myeloma Precursor States." Blood 124, no. 21 (December 6, 2014): 2031. http://dx.doi.org/10.1182/blood.v124.21.2031.2031.
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Abstract Background Circulating plasma cells (PCs) have been identified as a prognostic factor in patients with myeloma precursor states (MGUS and SMM) and active multiple myeloma (MM). Enumeration of circulating PCs by available methods is not suitable for widespread use and does not provide molecular characterization. We developed and evaluated a novel method for enumeration and molecular characterization of circulating PCs (circulating multiple myeloma cells, “CMMC”), based on the CELLSEARCH® System (Janssen Diagnostics LLC, Raritan, NJ), an automated technology for the capture, enumeration and characterization of rare cells in the peripheral blood. Methods We are performing a prospective study of patients with MGUS and SMM to evaluate CMMCs as biomarker for progression to active MM. Utilizing the CELLSEARCH® System CMMCs were captured by CD138 ferrofluid magnetic particles and identification was defined as CD38+ and CD19-, CD45-. Nonviable cells were excluded by DAPI. Isolated CMMCs were stored and FISH for t(4:14), t(14;16) and del17 was performed. Results We have enrolled 16 patients, MGUS = 3, SMM = 11, and newly diagnosed MM = 2. The Mayo Risk stratification for MGUS patients was: low risk = 2, low-intermediate = 1. All SMM patients were low risk by Mayo Model incorporating serum free light chains. The median number of bone marrow plasma cells for MGUS patients was 7 (range 7-9) and for SMM patients was 15 (range 10-40). The median CMMCs for MGUS = 6 (range 2-55), median CMMCs for SMM = 31 (5-1918). The two patients with NDMM had 5870 and 5 CMMCs, respectively. A single patient with SMM progressed with a symptomatic solitary lumbar plasmacytoma and had CMMCs of 5 and 3 at baseline and progression, respectively. Abnormalities by FISH were detected in both bone marrow and CMMCs. Accrual is ongoing and additional data will be presented at the meeting. Conclusions The CELLSEARCH® CMMC assay can detect, quantify and provide molecular characterization of circulating PCs in MGUS/SMM/MM; longer prospective follow-up is needed to test the prognostic value of CMMCs. Disclosures Weiss: Janssen: Consultancy, Research Funding. Sasser:Janssen: Employment. Rao:Janssen: Employment, Equity Ownership. Foulk:Janssen: Employment. Gross:Johnson & Johnson: Employment, Equity Ownership. Cohen:Janssen: Membership on an entity's Board of Directors or advisory committees. Vogl:Celgene Corporation: Consultancy; Amgen: Consultancy; Millennium/Takeda: Research Funding; GSK: Research Funding; Acetylon: Research Funding. Stadtmauer:Janssen: Consultancy.
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Udompanit, Nattadon, Panyawat Wangyao, Suparoek Henpraserttae, and Yuttanant Boonyongmaneerat. "Wear Response of Composition-Modulated Multilayer Ni-W Coatings." Advanced Materials Research 1025-1026 (September 2014): 302–9. http://dx.doi.org/10.4028/www.scientific.net/amr.1025-1026.302.
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The present studies investigate the wear response of composition-modulated multilayer Ni-W coatings as fabricated by electrodeposition. By regulating the pulse waveforms of the applied currents, the chemical composition, grain size, and the individual layer thickness of the electrodeposited Ni-W CMMC can be tailored. The ball-on-disc test and the subsequent microstructural analysis indicates that the wear resistance and friction coefficient of Ni-W CMMC are influenced by the composition and the thickness of the individual alternating layer. The decrement of interlayer’s size monotoically increase wear resistance and friction coefficient.
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Gruber, David. "The extent of engagement, the means of invention: measuring debate about mirror neurons in the humanities and social sciences." Journal of Science Communication 15, no. 02 (February 16, 2016): A01. http://dx.doi.org/10.22323/2.15020201.
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Mirror neurons (MN) — or neurons said to be able to "mirror" the sensed environment — have been widely popularized and referenced across many academic fields. Yet, MNs have also been the subject of considerable debate in the neurosciences. Using a criterion based sampling method and a citation analysis, this paper examines the extent of engagement with the neuroscience literature about MNs, looking specifically at the frequency of "MN debate sources" within articles published in the JSTOR and Communication and Mass Media (CMMC) databases. After reporting the results, the paper reviews characteristic examples in context and, ultimately, shows that MN debates remain largely absent from peer-reviewed articles published in JSTOR and CMMC. However, the paper suggests that this happens for good reason and that MNs retain the potential for inventive animations even though debates have gone largely unrecognized.
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Wang, Runnan, Xuewei Yan, Zhonglin Li, Qingyan Xu, and Baicheng Liu. "Effect of Construction Manner of Mould Cluster on Stray Grain Formation in Dummy Blade of DD6 Superalloy." High Temperature Materials and Processes 36, no. 4 (April 1, 2017): 399–409. http://dx.doi.org/10.1515/htmp-2016-0138.
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AbstractA dummy blade of Ni-based single crystal (SX) superalloy was modelled to investigate the stray grain (SG) defect by both experiment and simulation. Three construction manners of mould cluster (CMMC) with 0°, 45° and 90° assembling angle were considered. The experimental results reveal a strong dependence of SG sensitivity upon CMMC. Profuse SGs took place in the case of 0°, but almost no one shown in those of 45° and 90°. The FEM simulation results indicate that SG occurrence is not only determined by critical nucleation undercooling, but also the geometrical characteristic, shape of liquidus isotherm and other three important effects (shadow effect, channel effect and dimension effect). The tendency of SG formation increases with the increase of number of these effects. By means of the combination effect consisting of the above three effects, SG occurrence can be qualitatively predicted and process window is more accurately modified.
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Machado, Laís Del Prá Netto, Marcelo A. Molinari, Larissa dos Santos, and Caio M. M. de Cordova. "Performance of four commercial kits for laboratory diagnosis of urogenital mollicute infection." Canadian Journal of Microbiology 60, no. 9 (September 2014): 613–17. http://dx.doi.org/10.1139/cjm-2014-0112.
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We have empirical evidence for the unsatisfactory performance of the most accessible commercial kits for mollicute culture. We aimed to evaluate the performance of the 4 commercial kits available for diagnosis of urogenital mollicute infections, compared with culture media (CMMC) produced in our research laboratory. We demonstrated that the NewProv kit had a sensitivity of 17% for Ureaplasma sp. and 33% for Mycoplasma hominis. The Laborclin kit presented a sensitivity of 25% for Ureaplasma sp., although M. hominis isolation was not observed during its evaluation. The kits from bioMérieux and International Microbio/Elitech each presented a sensitivity of 100% compared to the CMMC media. We also observed an important level of mollicute resistance (37.5%) to the main antibiotics used in treatment. The lack of diagnostic sensitivity of some commercial systems has consequences for antibiotic resistance, since it may lead to inadequate treatment of urogenital mollicute infections.
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Hussein, Belal, Moustafa Gouda, Walid Fathall, and Sherin Arabi. "Europium-(7-carboxymethoxy-4-methyl coumarin)2 Complex based Electrochemical Probe for DNA based on the Interaction between Them." Journal of New Materials for Electrochemical Systems 20, no. 4 (September 25, 2017): 189–95. http://dx.doi.org/10.14447/jnmes.v20i4.445.
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The interaction of Eu(III) ion with 7-carboxymethoxy-4-methylcoumarin (CMMC) has been investigated using the potentiometric method in the ethanol-water mixture solvent (0.15 volume fraction). The formation of the different binary, ternary complexes is confirmed by the corresponding pH-potentiometric curves. SUPERQUAD computer program has been used for the refinement of all the calculated constants in our present study. Electroanalytical techniques have been used to confirm the formation of different binary and ternary complexes under investigation. The binding constant of the ternary complex Eu(III)-CMMC-DNA calculated by cyclic voltammetry (CV) and differential pulse (DP) was found to be 1.8 and 2.5x 105 M-1 in Tris-HCl, respectively. The changes in the current intensity have been used for the quantitative determination of DNA over a linear concentration range with LOD of 1.0-1.3 µg/ ml in 0.1 M Tris-HCl buffer.
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Moriyama, T., M. Fujibayashi, Y. Fujiwara, T. Kaneko, C. Xia, E. Imai, T. Kamada, A. Ando, and N. Ueda. "Angiotensin II stimulates interleukin-6 release from cultured mouse mesangial cells." Journal of the American Society of Nephrology 6, no. 1 (July 1995): 95–101. http://dx.doi.org/10.1681/asn.v6195.
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Interleukin-6 (IL-6) is a multifunctional cytokine exerting a wide variety of biologic responses, including cell proliferation. Recently, IL-6 has been known to play a role in the pathogenesis of mesangial proliferative glomerulonephritis. IL-6 is now recognized as an autocrine growth factor for glomerular mesangial cells, and various inflammatory mediators have been shown to promote IL-6 release from mesangial cells. However, little is known about the noninflammatory stimuli of IL-6 release from mesangial cells. In this study, it was hypothesized that angiotensin II (AngII) is one of the noninflammatory mediators of IL-6 release in mesangial cells, and the effects of AngII on IL-6 release and mRNA expression in cultured mouse mesangial cells (CMMC) were investigated. It was demonstrated that AngII (10(-7) M or higher) caused IL-6 release and mRNA accumulation in CMMC. IL-6 release was detected at 4 h and reached a plateau at 8 h after the addition of AngII, whereas IL-6 mRNA expression peaked at 4 h. The effects of AngII on IL-6 release and gene expression were completely blocked by the AngII receptor type 1 (AT1 receptor) antagonist CV-11974. AngII and IL-6 were both shown to stimulate DNA synthesis in CMMC, and the blockade of IL-6 signaling with anti-IL-6 receptor antibody abolished the enhanced DNA synthesis induced by AngII. These results raise a possibility that the growth-promoting effect of AngII on mesangial cells is at least partially mediated by IL-6 released from mesangial cells.
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Nannapaneni, Siddhartha, Jennifer Silvis, Karleigh Curfman, Timothy Chung, Thomas Simunich, Shawna Morrissey, and Russell Dumire. "Bronchoscopy Decreases Ventilator-Associated Pneumonia in Trauma Patients." American Surgeon 88, no. 4 (December 8, 2021): 653–57. http://dx.doi.org/10.1177/00031348211058639.
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Health care-associated pneumonias (HAPs) are a significant comorbidity seen in hospitalized patients. Traumatic injury is a known independent risk factor for the development of HAP. Trauma-related injuries also contribute to an increase in the rate of pneumonia in mechanically ventilated patients requiring intensive care unit (ICU) treatment. In 2011, the ventilator-associated pneumonia (VAP) rate among ICU patients at our institution (CMMC) increased dramatically. As a result, our infection control specialists performed a focused review of these patients and found a likely association between these infections and patients requiring pre-hospital intubation. Their determination prompted a July 2012 revision of the CMMC Trauma/Surgery Admission ICU protocol for ventilated patients to include bronchoscopy for all patients who have been intubated pre-hospital providing no contraindications were present. Our aim was to ascertain any influence of the protocol change on the rate of VAP. We conducted a retrospective medical record review of trauma patients who were intubated in the field or ED and seen at our institution (an accredited Level 1 trauma center) from 2012 to 2018. Applying the current definition of VAP from the Centers for Disease Control and Prevention (CDC) to data collected from the CMMC trauma registry, we observed a 13% lower VAP rate in the bronchoscopy group ( YB) as compared to the group that did not receive bronchoscopy (NB) ( P < .025). Based on our results, we determined that bronchoscopy performed in this setting does support a statistically significant decrease in the rate of ventilator-associated pneumonia.
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Raspadori, Andrea, Claudio Forcato, Petrini Edoardo, Francesca Marzia Papadopulos, Alberto Ferrarini, Valentina Del Monaco, Mario Terracciano, et al. "A High-Throughput Workflow for the Detection, Isolation and Genomic Analysis of Single Circulating Multiple Myeloma Cells." Blood 132, Supplement 1 (November 29, 2018): 5574. http://dx.doi.org/10.1182/blood-2018-99-112871.
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Abstract Introduction: Multiple myeloma (MM) is a malignancy of terminally differentiated plasma cells. The high heterogeneity of MM cells is one of the major cause of disease relapse. Detection of circulating MM cells (CMMC) from peripheral blood is a useful procedure to investigate tumor heterogeneity and provides a painless alternative to the classic bone marrow biopsy to monitor disease progression. Here we demonstrate that the synergy between CellSearch® (CS) and DEPArray™ (DA) technologies can be used to identify, isolate and characterize at the genetic level single and pure CMMCs . Methods: 4.0 ml of peripheral blood samples were obtained from 3 patients with MM. Putative CMMCs were enriched with CS using anti-CD138 or anti-CD138/CD38 as positive selection marker and subsequently stained with CD38-PE, CD19/CD45-APC immunofluorescent probes. Cells detection and enumeration was performed based on the co-localization of nuclei DAPI staining and CD38-PE. Single CMMCs (CD38+/CD19- and CD45-/DAPI+) and White Blood Cells (WBCs: CD38-/CD19+ or CD45+/DAPI+) were then isolated using the DA NxT system. Single cells genomic DNA was amplified using Ampli1™ Whole Genome Amplification (WGA) kit and Illumina®-compatible libraries were obtained using Ampli1™ LowPass kit and a high-throughput, customized automated protocol using Hamilton STARLet Liquid handler. Highly-multiplexed, genome-wide single-cell Low-Pass Copy Number Alteration (LPCNA) analysis was performed using HiSeq 2500 Illumina® platform. Results: CS and DA workflow* enabled the isolation of 215 single CMMC, selected for LPCNA analysis. 42 single WBCs were also included as normal controls. Copy-number profiles of single CMMCs showed relevant gains and losses of chromosomal segments, as result of a high-level genomic instability. Notably, intra-patient CMMCs revealed overall conserved CNA patterns with subclonal alterations, suggesting a certain level of branched tumor evolution. Conversely, a higher degree of heterogeneity in CMMCs CNA profiles was observed among different patients. Interestingly, CNAs detected in all patients are located in regions containing genes involved in cell cycle regulation (MAPK, NOTCH pathways) and cell signaling (IL6R), which might be involved in proliferative processes and immuno-surveillance escape. Conclusion: The combination of CS and DA workflow* with a streamlined automated protocol allowed to obtain hundreds of genomic libraries from pure single CMMCs. The presented workflow constitutes a non-invasive, rapid and high-throughput approach for characterizing MM tumor heterogeneity and progression, suggesting a possible future implementation in clinical applications. *For Research Use Only. Not for use in diagnostic procedures. Disclosures Raspadori: Menarini Silicon Biosystems: Employment. Forcato:Menarini Silicon Biosystems: Employment. Edoardo:Menarini Silicon Biosystems: Employment. Papadopulos:Menarini Silicon Biosystems: Employment. Ferrarini:Menarini Silicon Biosystems: Employment. Del Monaco:Menarini Silicon Biosystems: Employment. Terracciano:Menarini Silicon Biosystems: Employment. Morano:Menarini Silicon Biosystems: Employment. Gross:Menarini Silicon Biosystems: Employment. Bolognesi:Menarini Silicon Biosystems: Employment. Buson:Menarini Silicon Biosystems: Employment. Fontana:Menarini Silicon Biosystems: Employment. Connelly:Menarini Silicon Biosystems, Inc.: Employment, Other: Chief R&D Officer, USA. Simonelli:Menarini Silicon Biosystems: Employment. Medoro:Menarini Silicon Biosystems: Employment. Manaresi:Menarini Silicon Biosystems: Employment.
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Lohr, Jens G., Sora Kim, Joshua Gould, Birgit Knoechel, Yotam Drier, Daniel Gray, Nicole Birrer, et al. "Comprehensive Genetic Interrogation of Circulating Multiple Myeloma Cells at Single Cell Resolution." Blood 128, no. 22 (December 2, 2016): 800. http://dx.doi.org/10.1182/blood.v128.22.800.800.
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Abstract Continuous genomic evolution has been a major limitation to curative treatment of multiple myeloma (MM). Frequent monitoring of the genetic heterogeneity in MM from blood, rather than serial bone marrow (BM) biopsies, would therefore be desirable. We hypothesized that genomic characterization of circulating MM cells (CMMCs) recapitulates the genetics of MM in BM biopsies, enables MM classification, and is feasible in the majority of MM patients with active disease. Methods: To test these hypotheses, we developed a method to enrich, purify and isolate single CMMCs with a sensitivity of at least 1:10(5). We then performed DNA- and RNA-sequencing of single CMMCs and compared them to single BM-derived MM cells. We determined CMMC numbers in 24 randomly selected MM patient samples and compared them to numbers of circulating MM cells obtained by flow cytometry. We performed single-cell whole genome amplification of single cells from 10 MM patients, and targeted sequencing of the 35 most recurrently mutated loci in MM. A total of 568 single primary cells representing CMMCs, BM MM cells, CD19+ B lymphocytes, CD45+CD138- WBC from these patients were subjected to DNA-sequencing. By processing 80 single cells from four MM cell lines with known mutations we determined the mean sensitivity of mutation detection in single cells to be 93 ± 9%. In addition to DNA-sequencing we also isolated 57 single MM cells from the BM and peripheral blood of two MM patients and performed whole transcriptome single cell RNA-sequencing. Results: In 24 randomly selected MM patient samples we detected >12 CMMCs per 1ml of blood in all 24 patients. In comparison, by flow cytometry, we detected ≥10 CMMCs per 10(5) white blood cells in 10/24 cases (42%), ≥1 CMMC but ≤ 10 CMMCs in 13/24 cases (54%), and < 1 CTCs in 1/24 patients (4%). Mutational analysis of 35 recurrently mutated loci in 335 high quality single MM cells from the blood and BM of 10 patients, including one MGUS patient, revealed the presence of a total of 12 mutations (in KRAS, NRAS, BRAF, IRF4 and TP53). All targeted mutations that were detected by clinical-grade genotyping of bulk BM were also detected in single cell analysis of CMMCs. While in most patients, the fraction of mutated single cells was similar between blood and BM, in three patients, the proportion of MM cells harboring TP53 R273C, BRAF G469A and NRAS G13D mutations was significantly higher in the blood than in the BM, suggesting a different clonal composition. We developed an analytical model to predict whether a genetic locus underwent loss of heterozygosity, using the distribution of known allelic fractions of previously described mutations in MM cell lines as a benchmark. In two patients who simultaneously harbored two mutations, we predicted a BRAF G469E and a KRAS G12C mutation to be heterozygous, whereas the loci harboring a TP53 R273C and a TP53 R280T mutation were predicted to be associated with LOH with high statistical confidence. Whole transcriptome single cell RNA-sequencing of 57 MM cells from the BM and peripheral blood of two patients showed >3,700 transcripts per cell. Single-cell RNA-sequencing allowed for a clear distinction between normal plasma cells and MM cells, either based on analysis of CD45, CD27, and CD56 alone, or by unsupervised hierarchical clustering of detected transcripts in single cells. In addition, single cell CMMC expression analysis could be used to infer the existence of key MM chromosomal translocations. For example, CCND1 and CCND3 were highly upregulated in single MM cells from the blood and BM of two patients, whose MM was found by FISH analysis to harbor a t(11;14) and a t(6;14) translocation, respectively. Conclusion: We demonstrate that extensive genomic characterization of MM is feasible from very small numbers of CMMCs with single cell resolution. Interrogation of single CMMCs faithfully reproduces the pattern of somatic mutations present in MM in the BM, identifies actionable oncogenes, and reveals if somatic mutated loci underwent loss of heterozygosity. Single CMMCs also reveal mutations that are not detectable in the BM either by single cell sequencing or clinical grade bulk sequencing. Single cell RNA-sequencing of CMMCs provides robust transcriptomic profiling, allowing for class-differentiation and inference of translocations in MM patients. Disclosures Raje: Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Eli Lilly: Research Funding.
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Khwaja, Nadeem, Saroj Sharma, Julian Wong, David Murray, Jonathan Ghosh, Michael O. Murphy, Anastassi T. Halka, and Michael G. Walker. "Interpreter Services in An Inner City Teaching Hospital: A 6-Year Experience." Annals of The Royal College of Surgeons of England 88, no. 7 (November 2006): 659–62. http://dx.doi.org/10.1308/003588406x130606.
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INTRODUCTION Being able to communicate effectively with patients is essential not only from a medicolegal standpoint but more importantly from clinical governance perspectives. Issues such as informed consent and patient choice within the NHS are currently being highlighted; for these to be available to patients, their language requirements are paramount. PATIENTS AND METHODS An audit was performed by the Linkworkers office at the Central Manchester & Manchester Children's Hospital NHS (CMMC) Trust on the total number of attendances and refusals per language in the period 1998–2003. RESULTS In the CMMC Trust, Urdu/Punjabi, Bengali, Cantonese, Somali, Arabic and French represent the majority of the workload, comprising almost 80% of cases in 2003. In the same year, an increase in demand for languages of Eastern European countries became evident. Finding interpreters for these languages even via agencies can be extremely difficult. CONCLUSIONS If the current trend continues, requirement for these services will increase exponentially. For this demand to be met adequately these issues must be kept at the forefront of NHS planning.
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DRYHUSZ, Adam, and Kazimierz KOWALSKI. "THE HIGH-SPEED MILITARY TRACKED VEHICLE MAINTENACE SYSTEM - MODIFICATION IS NEEDED." Scientific Journal of the Military University of Land Forces 158, no. 4 (October 1, 2010): 71–83. http://dx.doi.org/10.5604/01.3001.0002.2736.
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The maintenance system of high-speed military tracked vehicles and the graphic original interpretation of maintenance activity (mainly maintenance) are described. A modification of the maintenance system of the above-mentioned vehicles based on dependability-oriented maintenance (Reliability Cantered Maintenance – RCM) is proposed. Additionally, the use of the statistical analysis of maintenance cases and the development of Computerised Maintenance Management System – CMMC are proposed as well.
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Gould, Thomas W., William A. Swope, Dante J. Heredia, Robert D. Corrigan, and Terence K. Smith. "Activity within specific enteric neurochemical subtypes is correlated with distinct patterns of gastrointestinal motility in the murine colon." American Journal of Physiology-Gastrointestinal and Liver Physiology 317, no. 2 (August 1, 2019): G210—G221. http://dx.doi.org/10.1152/ajpgi.00252.2018.
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The enteric nervous system in the large intestine generates two important patterns relating to motility: 1) propagating rhythmic peristaltic smooth muscle contractions referred to as colonic migrating motor complexes (CMMCs) and 2) tonic inhibition, during which colonic smooth muscle contractions are suppressed. The precise neurobiological substrates underlying each of these patterns are unclear. Using transgenic animals expressing the genetically encoded calcium indicator GCaMP3 to monitor activity or the optogenetic actuator channelrhodopsin (ChR2) to drive activity in defined enteric neuronal subpopulations, we provide evidence that cholinergic and nitrergic neurons play significant roles in mediating CMMCs and tonic inhibition, respectively. Nitrergic neurons [neuronal nitric oxide synthase (nNOS)-positive neurons] expressing GCaMP3 exhibited higher levels of activity during periods of tonic inhibition than during CMMCs. Consistent with these findings, optogenetic activation of ChR2 in nitrergic neurons depressed ongoing CMMCs. Conversely, cholinergic neurons [choline acetyltransferase (ChAT)-positive neurons] expressing GCaMP3 markedly increased their activity during the CMMC. Treatment with the NO synthesis inhibitor Nω-nitro-l-arginine also augmented the activity of ChAT-GCaMP3 neurons, suggesting that the reciprocal patterns of activity exhibited by nitrergic and cholinergic enteric neurons during distinct phases of colonic motility may be related. NEW & NOTEWORTHY Correlating the activity of neuronal populations in the myenteric plexus to distinct periods of gastrointestinal motility is complicated by the difficulty of measuring the activity of specific neuronal subtypes. Here, using mice expressing genetically encoded calcium indicators or the optical actuator channelrhodopsin-2, we provide compelling evidence that cholinergic and nitrergic neurons play important roles in mediating coordinated propagating peristaltic contractions or tonic inhibition, respectively, in the murine colon.
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Tsai, Wei-Chun, Chung-Feng Liu, Hung-Jung Lin, Chien-Chin Hsu, Yu-Shan Ma, Chia-Jung Chen, Chien-Cheng Huang, and Chia-Chun Chen. "Design and Implementation of a Comprehensive AI Dashboard for Real-Time Prediction of Adverse Prognosis of ED Patients." Healthcare 10, no. 8 (August 9, 2022): 1498. http://dx.doi.org/10.3390/healthcare10081498.
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The emergency department (ED) is at the forefront of medical care, and the medical team needs to make outright judgments and treatment decisions under time constraints. Thus, knowing how to make personalized and precise predictions is a very challenging task. With the advancement of artificial intelligence (AI) technology, Chi Mei Medical Center (CMMC) adopted AI, the Internet of Things (IoT), and interaction technologies to establish diverse prognosis prediction models for eight diseases based on the ED electronic medical records of three branch hospitals. CMMC integrated these predictive models to form a digital AI dashboard, showing the risk status of all ED patients diagnosed with any of these eight diseases. This study first explored the methodology of CMMC’s AI development and proposed a four-tier AI dashboard architecture for ED implementation. The AI dashboard’s ease of use, usefulness, and acceptance was also strongly affirmed by the ED medical staff. The ED AI dashboard is an effective tool in the implementation of real-time risk monitoring of patients in the ED and could improve the quality of care as a part of best practice. Based on the results of this study, it is suggested that healthcare institutions thoughtfully consider tailoring their ED dashboard designs to adapt to their unique workflows and environments.
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Kim, Dong-Sun, and Yeon-Seung Ryu. "A study on the improvement of the integrated real state investigation system for coping with the US CMMC system." Journal of the Korean Association of Defense Industry Studies 29, no. 3 (December 31, 2022): 51–61. http://dx.doi.org/10.52798/kadis.2022.29.3.4.
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Hemanth, Joel. "Quartz (SiO2p) reinforced chilled metal matrix composite (CMMC) for automotive applications." Materials & Design 30, no. 2 (February 2009): 323–29. http://dx.doi.org/10.1016/j.matdes.2008.04.064.
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Balasuriya, Gayathri K., Mitra Mohsenipour, Kurt Brassington, Aleksandar Dobric, Simone N. De Luca, Kevin Mou, Huei Jiunn Seow, et al. "Ebselen prevents cigarette smoke-induced gastrointestinal dysfunction in mice." Clinical Science 134, no. 22 (November 2020): 2943–57. http://dx.doi.org/10.1042/cs20200886.
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Abstract Gastrointestinal (GI) dysfunction is a common comorbidity of chronic obstructive pulmonary disease (COPD) for which a major cause is cigarette smoking (CS). The underlying mechanisms and precise effects of CS on gut contractility, however, are not fully characterised. Therefore, the aim of the present study was to investigate whether CS impacts GI function and structure in a mouse model of CS-induced COPD. We also aimed to investigate GI function in the presence of ebselen, an antioxidant that has shown beneficial effects on lung inflammation resulting from CS exposure. Mice were exposed to CS for 2 or 6 months. GI structure was analysed by histology and immunofluorescence. After 2 months of CS exposure, ex vivo gut motility was analysed using video-imaging techniques to examine changes in colonic migrating motor complexes (CMMCs). CS decreased colon length in mice. Mice exposed to CS for 2 months had a higher frequency of CMMCs and a reduced resting colonic diameter but no change in enteric neuron numbers. Ten days cessation after 2 months CS reversed CMMC frequency changes but not the reduced colonic diameter phenotype. Ebselen treatment reversed the CS-induced reduction in colonic diameter. After 6 months CS, the number of myenteric nitric-oxide producing neurons was significantly reduced. This is the first evidence of colonic dysmotility in a mouse model of CS-induced COPD. Dysmotility after 2 months CS is not due to altered neuron numbers; however, prolonged CS-exposure significantly reduced enteric neuron numbers in mice. Further research is needed to assess potential therapeutic applications of ebselen in GI dysfunction in COPD.
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Heredia, Dante J., Nathan Grainger, Conor J. McCann, and Terence K. Smith. "Insights from a novel model of slow-transit constipation generated by partial outlet obstruction in the murine large intestine." American Journal of Physiology-Gastrointestinal and Liver Physiology 303, no. 9 (November 1, 2012): G1004—G1016. http://dx.doi.org/10.1152/ajpgi.00238.2012.
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The mechanisms underlying slow-transit constipation (STC) are unclear. In 50% of patients with STC, some form of outlet obstruction has been reported; also an elongated colon has been linked to patients with STC. Our aims were 1) to develop a murine model of STC induced by partial outlet obstruction and 2) to determine whether this leads to colonic elongation and, consequently, activation of the inhibitory “occult reflex,” which may contribute to STC in humans. Using a purse-string suture, we physically reduced the maximal anal sphincter opening in C57BL/6 mice. After 4 days, the mice were euthanized (acutely obstructed), the suture was removed (relieved), or the suture was removed and replaced repeatedly (chronically obstructed, over 24–31 days). In partially obstructed mice, we observed increased cyclooxygenase (COX)-2 levels in muscularis and mucosa, an elongated impacted large bowel, slowed transit, nonpropagating colonic migrating motor complexes (CMMCs), a lack of mucosal reflexes, a depolarized circular muscle with slow-wave activity due to a lack of spontaneous inhibitory junction potentials, muscle hypertrophy, and CMMCs in mucosa-free preparations. Elongation of the empty obstructed colon produced a pronounced occult reflex. Removal of the obstruction or addition of a COX-2 antagonist (in vitro and in vivo) restored membrane potential, spontaneous inhibitory junction potentials, CMMC propagation, and mucosal reflexes. We conclude that partial outlet obstruction increases COX-2 leading to a hyperexcitable colon. This hyperexcitability is largely due to suppression of only descending inhibitory nerve pathways by prostaglandins. The upregulation of motility is suppressed by the occult reflex activated by colonic elongation.
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Smith, Terence Keith, and Sang Don Koh. "A model of the enteric neural circuitry underlying the generation of rhythmic motor patterns in the colon: the role of serotonin." American Journal of Physiology-Gastrointestinal and Liver Physiology 312, no. 1 (January 1, 2017): G1—G14. http://dx.doi.org/10.1152/ajpgi.00337.2016.
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We discuss the role of multiple cell types involved in rhythmic motor patterns in the large intestine that include tonic inhibition of the muscle layers interrupted by rhythmic colonic migrating motor complexes (CMMCs) and secretomotor activity. We propose a model that assumes these motor patterns are dependent on myenteric descending 5-hydroxytryptamine (5-HT, serotonin) interneurons. Asynchronous firing in 5-HT neurons excite inhibitory motor neurons (IMNs) to generate tonic inhibition occurring between CMMCs. IMNs release mainly nitric oxide (NO) to inhibit the muscle, intrinsic primary afferent neurons (IPANs), glial cells, and pacemaker myenteric pacemaker interstitial cells of Cajal (ICC-MY). Mucosal release of 5-HT from enterochromaffin (EC) cells excites the mucosal endings of IPANs that synapse with 5-HT descending interneurons and perhaps ascending interneurons, thereby coupling EC cell 5-HT to myenteric 5-HT neurons, synchronizing their activity. Synchronized 5-HT neurons generate a slow excitatory postsynaptic potential in IPANs via 5-HT7 receptors and excite glial cells and ascending excitatory nerve pathways that are normally inhibited by NO. Excited glial cells release prostaglandins to inhibit IMNs (disinhibition) to allow full excitation of ICC-MY and muscle by excitatory motor neurons (EMNs). EMNs release ACh and tachykinins to excite pacemaker ICC-MY and muscle, leading to the simultaneous contraction of both the longitudinal and circular muscle layers. Myenteric 5-HT neurons also project to the submucous plexus to couple motility with secretion, especially during a CMMC. Glial cells are necessary for switching between different colonic motor behaviors. This model emphasizes the importance of myenteric 5-HT neurons and the likely consequence of their coupling and uncoupling to mucosal 5-HT by IPANs during colonic motor behaviors.
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Sinadinovic, Danka, Irena Aleksic-Hajdukovic, and Stevan Mijomanovic. "Doctor-patient communication in medicine and dental medicine." Serbian Dental Journal 67, no. 1 (2020): 50–59. http://dx.doi.org/10.2298/sgs2001050s.
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Doctor-patient communication is a type of institutional communication which distinct linguistic features can significantly affect patient satisfaction and treatment outcome. A medical encounter has a clearly defined structure that has been shifting from clinician-centred to patient-centred. Therefore, it is of utter importance for prospective doctors and dentists to be aware of the role of language when communicating with their patients. Given the fact that working in a medical/dental practice has become increasingly international, the paper focuses on the role of the English language. New communicative models and environments such as Computer-Mediated Medical Communication (CMMC) and Video Interaction Guidance (VIG) are also presented.
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Verma, Deeksha, Khuram Shehzad, Danial Khan, Sung Jin Kim, Young Gun Pu, Sang-Sun Yoo, Keum Cheol Hwang, Youngoo Yang, and Kang-Yoon Lee. "A Design of Low-Power 10-bit 1-MS/s Asynchronous SAR ADC for DSRC Application." Electronics 9, no. 7 (July 6, 2020): 1100. http://dx.doi.org/10.3390/electronics9071100.
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A design of low-power 10-bit 1 MS/s asynchronous successive approximation register analog-to-digital converter (SAR ADC) is presented in this paper. To improve the linearity of the digital-to-analog converter (DAC) and energy efficiency, a common mode-based monotonic charge recovery (CMMC) switching technique is proposed. The proposed switching technique consumes only 63.75 CVREF2 switching energy, which is far less as compared to the conventional switching technique without dividing or adding additional switches. In addition, bootstrap switching is implemented to ensure enhanced linearity. To reduce the power consumption from the comparator, a dynamic latch comparator with a self-comparator clock generation circuit is implemented. The proposed prototype of the SAR ADC is implemented in a 55 nm CMOS (complementary metal-oxide-semiconductor) process. The proposed architecture achieves a figure of merit (FOM) of 17.4 fJ/conversion, signal-to-noise distortion ratio (SNDR) of 60.39 dB, and an effective number of bits (ENOB) of 9.74 bits with a sampling rate of 1 MS/s at measurement levels. The implemented SAR ADC consumes 14.8 µW power at 1 V power supply.
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Xiao, Xizhu, Danielle Ka Lai Lee, Rachel Min Wong, and Porismita Borah. "The Impact of Theory in HPV Vaccination Promotion Research: A Systematic Review and Meta-Analysis." American Journal of Health Promotion 35, no. 7 (May 5, 2021): 1002–14. http://dx.doi.org/10.1177/08901171211012524.
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Objective: Numerous studies examined HPV vaccination promotional strategies. However, an overview of theory use, a synthesis of strategies’ effectiveness and an examination of the moderating influence of theory are absent. Data Source: We retrieved studies from Academic Search Complete, Business Source Complete, PubMed, PsycINFO, Web of Science, CMMC, CINAHL, and MEDLINE. Study Inclusion and Exclusion Criteria: 1) peer-reviewed articles written in English, 2) experimental or quasi-experimental, 3) measure HPV vaccination-related outcomes, 4) had to contain a control condition and report statistics necessary for conversion (for meta-analysis only). Data Extraction: 70 and 30 studies were included for the systematic review and meta-analysis respectively. Data Synthesis: Four major categories were coded: study information, theory use, type of theory, and outcomes. Two independent coders coded the sample (Cohen’s Kappa ranged from .8 to 1). Results: Most of the studies were based in the U.S. (77%, k = 54) with convenient samples (80%, k = 56), targeted toward females (46%, k = 32), and around a quarter did not employ any theories (47%, k = 33). Among theory-driven studies, the most commonly used were Framing (22%, k = 19), Health Belief Model (HBM; 13%, k = 12), and Narrative (7%, k = 6). Among controlled studies, promotional strategies were significantly more effective compared to the control (r+ = .25, p < .001). Strategies guided by the information, motivation, behavioral skills model (IMB) were more effective (r+ = .75, p < .001) than studies guided by framing theory (r+ = −.23, p < .001), HBM (r+ = .01, p < .001), and other theories (r+ = .11, p < .001). Conclusion: This review contributes to HPV vaccination promotion literature by offering a comprehensive overview of promotional strategies and practical suggestions for future research and practices.
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dos Santos, Rodrigo Pinheiro, Kathia Marçal de Oliveira, and Wander Pereira da Silva. "Evaluating the service quality of software providers appraised in CMM/CMMI." Software Quality Journal 17, no. 3 (October 7, 2008): 283–301. http://dx.doi.org/10.1007/s11219-008-9065-4.
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Calvo, Xavier, Ivonne Parraga, Lourdes Florensa, Sara Montesdeoca Romero, Anna Puiggros, Marta Salido, Blanca Espinet, et al. "Immunophenotypic Characteristics of Olygomonocytic Chronic Myelomonocytic Leukemia Support Its Diagnosis As a Distinctive Entity in the Continuum of Chronic Myelomonocytic Leukemia." Blood 132, Supplement 1 (November 29, 2018): 5520. http://dx.doi.org/10.1182/blood-2018-99-119906.
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Abstract INTRODUCTION The diagnosis of chronic myelomonocytic leukemia (CMML) according to WHO 2017 requires the presence of ≥1x109/L and ≥10% of monocytes in peripheral blood (PB). Presence of dysplasia is frequent but not always present. Recently, Geyer et al. described olygomonocytic CMML (O-CMML) as those MDS cases with relative monocytosis (≥10% monocytes) and monocyte count 0.5-<1x109/L. The authors showed that molecular signature and outcome of O-CMML were similar to overt CMML, suggesting that this represents an early-phase of dysplastic CMML (D-CMML). The study of peripheral monocyte subsets by flow cytometry (FC) has gained interest for the diagnosis of CMML. As showed by Selimoglu-Buet, the increase in the fraction of classical monocytes (Mo1) to >94% of total monocytes is a highly sensitive and specific diagnostic marker for CMML. We assessed peripheral monocyte subsets by FC in 11 O-CMML cases and compared those with 20 CMML cases, 14 D-CMML and 6 proliferative CMML (P-CMML). In addition, we studied the aberrant expression of CD56, CD2 and CD7 in monocytes. As mentioned, O-CMML may be considered an early-phase of D-CMML and some D-CMML may progress to P-CMML, an entity with an ominous prognosis. We compared the percentage of Mo1 and non-classical monocytes (Mo3) among O-CMML, D-CMML and P-CMML in order to evaluate if a progressive accumulation of Mo1 and a progressive decrease in Mo3 could be appreciated among these entities. In our view, Mo1 could be considered as a marker of tumor burden, while Mo3, formerly considered as a specific type of dendritic cell, could be related with immunosurveillance. In order to reinforce this hypothesis we evaluated if the reduction in Mo3 would be also accompanied by a decrease in plasmocytoid dendritic cells (pDC). METHODS Twenty CMML and 11 O-CMML were prospectively studied from 02/2016 to 04/2018. Patients' characteristics are summarized in Table 1. We performed FC study of monocyte subsets in PB describing Mo1 (CD14bright/CD16-), intermediate monocytes (Mo2) (CD14bright/CD16+) and Mo3 (CD14dim or -/CD16bright). In addition, we assessed the expression of CD56, CD2 and CD7 in monocyte population and quantified pDC (CD123bright/HLA-DR+). Comparisons were evaluated by Chi-Square test, Man-Whitney U-test or by Kruskall-Wallis test as appropriate. RESULTS & DISCUSSION 1) 6/11 (55%) O-CMML showed an increase in the fraction of Mo1>94% of total monocytes. In contrast, 12/14 (86%) D-CMML and 6/6 (100%) P-CMML showed a percentage of Mo1>94% of total monocytes. Considering together all overt CMML, 18/20 (90%) presented Mo1>94% of total monocytes. This result was almost identical to that reported in the original study by Selimoglu-Buet. 2) The median percentage of Mo1 and Mo3 monocytes was statistically different among these three entities (Mo1, p=0,005; Mo3, p=0,002). Table 2. Interestingly, the median percentage of Mo1 (% Mo1) was significantly lower in O-CMML when compared to P-CMML (p=0,004) and a clear trend was observed when compared to D-CMML. In the same way, % Mo1 was significantly lower in D-CMML when compared to P-CMML (p=0,017). Moreover, the median percentage of Mo3 (% Mo3) was significantly higher in O-CMML when compared to P-CMML (p=0,002) and a clear trend was observed when compared to D-CMML. In the same line, % Mo3 was significantly higher in D-CMML when compared to P-CMML (p=0,002). Likewise, the median percentage of pDC (% pDC) was significantly higher in O-CMML when compared to P-CMML (p=0,004). A clear trend was observed when O-CMML was compared with D-CMML, and D-CMML with P-CMML. These data reinforce the hypothesis that progression from O-CMML to D-CMML and P-CMML could be guided by a progressive accumulation of Mo1 ("tumor burden increase") and by a progressive reduction of Mo3 and pDC ("immunosurveillance decrease"). 3) Expression of CD56, CD2 and CD7 in monocytes is depicted in Table 3. No aberrant expression of CD7 was observed in any case. In contrast, CD56 expression was observed in 9/11 O-CMML, 7/14 D-CMML and 5/6 P-CMML. Considering together all overt CMML, 12/20 expressed CD56. CD56 expression in monocytes is a common finding in CMML and has been rarely described in other myeloid disorders. This may be interpreted as another indicator that O-CMML is in the continuum of CMML. CONCLUSIONS O-CMML presents flow cytometric immunophenotypic characteristics in line with overt CMML. These data support that O-CMML is in the biological continuum of overt CMML. Disclosures No relevant conflicts of interest to declare.
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Liu, Sha, Kai-Wei Fan, and Prasun Sinha. "CMAC." ACM Transactions on Sensor Networks 5, no. 4 (November 2009): 1–34. http://dx.doi.org/10.1145/1614379.1614381.
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Roman-Bravo, David, Leonor Arenillas, Maria Teresa Asensi, Nieves Garcia-Gisbert, Juan Jose Rodriguez-Sevilla, Brayan Merchan, Sara García Ávila, et al. "Clinical Outcomes of Oligomonocytic Chronic Myelomonocytic Leukemia (OM-CMML) and Predictive Factors of Evolution of OM-CMML into Overt Chronic Myelomonocytic Leukemia (CMML)." Blood 138, Supplement 1 (November 5, 2021): 1533. http://dx.doi.org/10.1182/blood-2021-146447.
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Abstract INTRODUCTION Recent studies have shown that OM-CMML and CMML have a similar clinical and biological profile. Since the proliferative-CMML (P-CMML) is the last-stage of CMML proliferative continuum and shows poor outcomes, it is expected that OM-CMML presents the best outcomes of these entities, as it represents an early-stage of dysplastic-CMML (D-CMML). In this sense, although a high percentage of OM-CMML evolve to CMML, some of them die before evolving. Therefore, identifying predictive factors of evolution into CMML may be valuable since, OM-CMML that evolves to CMML show shorter overall survival (OS) (Calvo X et al. Blood Adv 2020). AIM To analyze clinical outcomes of 41 OM-CMML patients and to compare them to that of 182 overt CMML (141 D-CMML and 41 P-CMML), and to assess predictive factors of evolution of OM-CMML into overt CMML. RESULTS OM-CMML showed longer OS than D-CMML and P-CMML (Figure 1). OM-CMML also showed longer AML-free survival than D-CMML (median OS: 131.8m vs. 43.47m; P=0.001) and P-CMML (median OS: 23m; P<0.01). These outcomes were retained after multivariate adjustment by CPSS (HR:0.38, 95%CI 0.21-0.70, P=0.002; HR:2.53, 95%CI 1.64-3.91, P=<0.001), CPSS-P (HR:0.42, 95%CI 0.23-0.78, P=0.005; HR:2.82, 95%CI 1.92-4.14, P=<0.001), and Mayo-prognostic-model (HR:0.41, 95CI 0.23-0.75, P=0.04; HR:3.45, 95%CI 2.29-5.20, P=<0.001). At a median follow-up of 45 months, 29% of D-CMML evolved to P-CMML. There was no difference in OS between D-CMML patients that evolved to P-CMML than those who did not. Nevertheless, from the moment of evolution, they had a very short survival (median OS: 10.2 months). This suggests that P-CMML evolution is the latest stage of a biological continuum that initiates in OM-CMML. Reinforcing this idea, mutations associated with proliferation (i.e: ASXL1 and RAS-pathway) were identified as independent prognostic factors for OS in our series (HR ASXL1:2.47, 95%CI 1.13-5.37, P=0.023; HR RAS-pathway:3.91, 95%CI 1.74-8.77, P=0.001). As previously commented, OM-CMML patients who evolved to overt CMML showed an inferior OS than did those who did not. At a median follow-up of 42 months, 30% OM-CMML evolved to CMML. Patients with more than 3 mutated genes (HR: 4.24, 95%CI 1.08-16.71, P=0.039) and a proportion of monocytes above 20% in peripheral blood (HR: 3.48, 95%CI 1.05-11.47, P=0.041) showed a significant shorter time to CMML. These two variables were faced in a multivariate analysis and maintained their significance for predicting time to CMML (HR: 4.33, 95%CI 1.23-15.20, P=0.022; and HR:5.82, 95%CI 1.32-25.7 , P=0.02). Moreover, these variables were also independent adverse prognostic factors for OS in our series of 94 patients with available molecular data (41 OM-CMML and 53 CMML) (HR:4.39, 95%CI 1.99-9.68 , P<0.001; HR:3.05 , 95%CI 1.27-7.34 , P=0.013). Figure 2 depicts univariate survival analysis. Given the similar HR for predicting time to CMML of both variables, we implemented a model for predicting time to CMML: 0 points (none of them), 1 (one of them) or 2 points (both). This model offered an excellent predictive power (C-index: 0.82). CONCLUSIONS 1. The clinical outcomes of OM-CMML support its consideration as the first step in the proliferative continuum of CMML. 2. OM-CMML with higher molecular complexity and higher relative monocytosis are at greater risk of CMML evolution. Figure 1 Figure 1. Disclosures Bellosillo: Thermofisher Scientific: Consultancy, Speakers Bureau; Roche: Research Funding, Speakers Bureau; Qiagen: Consultancy, Speakers Bureau.
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Tan, Kien Thiam, Chia-Ling Wu, Yen-Jung Lu, Ka-Po Tse, and Chien-Feng L. Li. "Abstract 5103: Characterization of the genomic landscape and actionable mutations in Taiwanese prostate cancer patients." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5103. http://dx.doi.org/10.1158/1538-7445.am2022-5103.
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Abstract Background: Prostate Cancer (PCa) is the second most common male cancer worldwide and the most common cancer in males over 65 years old. PCa is the sixth most common cancer in Taiwan, and its incidence rate has increased gradually over the past 30 years. PAPR inhibitors are the only type of targeted drug approved by the FDA to treat advanced castration-resistant prostate cancer (CRPC) that has grown after the hormone therapy drugs. This study aimed to characterize the genomic profile of Taiwanese PCa and explore whether there are potential treatment guidances derived. Methods: Formalin-fixed paraffin-embedded (FFPE) tumor tissues from 99 patients diagnosed with PCa and collected at Chi-Mei Medical Center (CMMC) were subject to next-generation sequencing using ACTOnco® CGP panel that cover coding regions of 440 cancer-related genes. Genomic alterations (GAs) and signatures, including single nucleotide variations (SNVs), short insertions and deletions (InDels), copy-number variations (CNVs), fusion genes, tumor mutations burden (TMB), and microsatellite instability (MSI) status were retrieved. The gene mutation prevalence was compared with the Western population using the TCGA prostate cancer dataset. Results: A total of 1558 variants was identified, including 215 SNVs, 22 InDels, 1178 CN gain and 135 homozygous deletions. Similar to the Western population, the most frequently mutated genes were SPOP (21.2%), KMT2C (10.1%), MUC16 (8.1%), TP53 (6.1%), ARID2 (5.1%), IDH1 (5.1%), PTGS2 (5.1%). Further analysis showed that 12 patients harbored deleterious/likely deleterious mutations in genes implicated in homologous recombination (HRR) DNA repair pathway, including three BRCA2, two CDK12, BRAD1 and ARID1A, respectively, and one ATR, ATM and PALB2, respectively. All BRCA2 mutations were predicted to be germline origin and only one-third of 12 HRR mutants had a biallelic gene loss. Median TMB calculated from NGS data is 0.6 muts/Mb (range 0 to 4.5) and all samples are microsatellite-stable (MSS). Therapeutically actionable gene and pathway analysis revealed that up to 24.2% of patients harbored at least one aberration against FDA-approved targeted drugs, such as MET copy number (CN) gain (11.1%), mTOR pathway aberration (6.1%), HRR gene biallelic loss (4%), BRAF activating mutation (4%), IDH1 activating mutations (4%), EGFR CN gain (3.0%), FGFR1 CN gain (2.0%), MET fusion (1.0%) and BRAF fusion (1%). Conclusion: This CGP study unraveled the genomic profile of Taiwanese prostate cancers, and the results showed that GAs identified could serve as a potential biomarker to guide personalized, targeted therapies in one-fourth of patients. Citation Format: Kien Thiam Tan, Chia-Ling Wu, Yen-Jung Lu, Ka-Po Tse, Chien-Feng L Li. Characterization of the genomic landscape and actionable mutations in Taiwanese prostate cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5103.
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Staib, E., K. Leuchte, M. Thelen, P. Gödel, A. Lechner, P. Zentis, M. Garcia-Marquez, et al. "P02.03 Microwave ablation enhances tumor-specific immune response in patients with hepatocellular carcinoma." Journal for ImmunoTherapy of Cancer 8, Suppl 2 (October 2020): A21.1—A21. http://dx.doi.org/10.1136/jitc-2020-itoc7.39.
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BackgroundThermal ablative therapies, such as microwave ablation (MWA) or radiofrequency ablation (RFA), are standard treatments for HCC. In addition to the local tumor destruction, abscopal effects (a reduction of a tumor mass in areas that were not included in the thermal ablation) could be observed. These systemic effects may be mediated by anti-tumor immune response, which has been described for RFA. MWA is rapidly replacing RFA, but systemic immunostimulatory effects of MWA treatment have been poorly studied.Materials and MethodsPatients receiving MWA for localized HCC were included in this study. Effects of MWA on peripheral blood mononuclear cells (PBMC) of HCC patients treated with MWA were analyzed by multicolor flow cytometry. Tumor-specific immune responses against 7 shared tumor antigens were analyzed using peptide pools in 3-color Fluorospot assays (Interferon-y/Interleukin-5/Interleukin-10). The impact of type, density and localization of tumor-infiltrating lymphocytes was assessed by immunohistochemistry (IHC) of CD3, CD4, CD8, FoxP3, CD38 and CD20 and digital image analyses (Immunoscore) of tumor specimens in an additional cohort of patients who received combined surgical resection and thermal ablation.ResultsWhile comprehensive flow cytometric analyses in sequential samples (day 0, 7 and 90) of a prospective patient cohort (n=23) demonstrated only moderate effects of MWA on circulating immune cell subsets, Fluorospot analyses revealed de novo or enhanced tumor-specific immune responses in 30% of these patients. This anti-tumor immune response was related to tumor control. Interferon-y and Interleukin-5 T cell responses against cancer testis antigens were more frequent in patients with a long-time remission (>12 months) after MWA (7/16) compared to patients suffering from an early relapse (0/13 patients). Presence of tumor-specific T cell response (Interferon-y and/or Interleukin-5) was associated to longer progression-free survival (15.0 vs. 10.0 months). Immunohistochemical analyses of resected tumor samples revealed that a high T cell infiltration in a second tumor lesion at the time of thermal ablation was associated with superior disease-free survival (37.4 vs. 13.1 months).ConclusionsOur data demonstrates remarkable immune-related effects of MWA in HCC patients. This study and provides additional evidence for a combination of thermal ablation and immunotherapy in this challenging disease.Funding‘Koeln Fortune’ and ‘CAP-CMMC’ local research grant (to P.G. and H.A.S.) supported our research.Disclosure InformationE. Staib: None. K. Leuchte: None. M. Thelen: None. P. Gödel: None. A. Lechner: None. P. Zentis: None. M. Garcia-Marquez: None. D. Waldschmidt: None. R.R. Datta: None. R. Wahba: None. C. Wybranski: None. T. Zander: None. A. Quaas: None. U. Drebber: None. D.L. Stippel: None. C. Bruns: None. K. Wennhold: None. M. von Bergwelt-Baildon: None. H.A. Schlösser: None.
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Heibl, Sonja, Bettina Gisslinger, Eva Jäger, Agnes Barna, Michael Gurbisz, Maike Stegemann, Peter Bettelheim, et al. "Clinical, Hematologic, Biologic and Molecular Characteristics of Patients with Myeloproliferative Neoplasms and a Chronic Myelomonocytic Leukemia-Like Phenotype." Cancers 12, no. 7 (July 14, 2020): 1891. http://dx.doi.org/10.3390/cancers12071891.
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Patients with a myeloproliferative neoplasm (MPN) sometimes show a chronic myelomonocytic leukemia (CMML)-like phenotype but, according to the 2016 WHO classification, a documented history of an MPN excludes the diagnosis of CMML. Forty-one patients with an MPN (35 polycythemia vera (PV), 5 primary myelofibrosis, 1 essential thrombocythemia) and a CMML-like phenotype (MPN/CMML) were comprehensively characterized regarding clinical, hematologic, biologic and molecular features. The white blood cell counts in MPN/CMML patients were not different from CMML patients and PV patients. The hemoglobin values and platelet counts of these patients were higher than in CMML but lower than in PV, respectively. MPN/CMML patients showed myelomonocytic skewing, a typical in vitro feature of CMML but not of PV. The mutational landscape of MPN/CMML was not different from JAK2-mutated CMML. In two MPN/CMML patients, development of a CMML-like phenotype was associated with a decrease in the JAK2 V617F allelic burden. Finally, the prognosis of MPN/CMML (median overall survival (OS) 27 months) was more similar to CMML (JAK2-mutated, 28 months; JAK2-nonmutated 29 months) than to PV (186 months). In conclusion, we show that patients with MPN and a CMML-like phenotype share more characteristics with CMML than with PV, which may be relevant for their classification and clinical management.
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Wibisono, Septian Bagus, and Dana Indra Sensuse. "COMBINATION OF CMMI-DEV AND CMMI-SVC TO MEASURE IMPLEMENTATION MATURITY OF E-GOVERNMENT: A SYSTEMATIC LITERATURE REVIEW." Masyarakat Telematika Dan Informasi : Jurnal Penelitian Teknologi Informasi dan Komunikasi 9, no. 1 (December 30, 2018): 39. http://dx.doi.org/10.17933/mti.v9i1.97.
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AbstrakGagasan utama implementasi e-government adalah memberikan pelayanan yang optimal kepada warga melalui penerapan TIK. Untuk mengukur kematangan implementasi e-government dapat digunakan model pengukuran CMMI. CMMI dipilih karena memiliki model pengukuran sesuai dengan implementasi e-government, yaitu CMMI-DEV, yang berorientasi pada proses pembangunan, dan CMMI-SVC, yang berorientasi pada layanan. Selain itu, model pengukuran CMMI dapat dinilai sesuai dengan tingkat kematangannya. Tulisan ini bertujuan untuk meninjau secara sistematis proses spesifik pada CMMI-DEV dan CMMI-SVC yang dapat digunakan untuk mengukur kematangan implementasi e-government. Dalam tulisan ini digunakan metode tinjauan literatur sistematis dengan framework PRISMA, melalui pencarian artikel sebagai bukti bahwa proses spesifik CMMI-DEV dan CMMI-SVC dapat diukur dalam implementasi e-government. Proses review merekomendasikan agar semua proses spesifik dalam CMMI-DEV digunakan untuk ukuran kematangan implementasi e-government, namun hanya beberapa proses spesifik di CMMI-SVC yang direkomendasikan untuk dijadikan ukuran kematangan tersebut. AbstractThe main idea of e-government implementation is to provide an optimal service to the citizen through the application of ICT. To measure the maturity of e-government implementation, it can be used CMMI measurement model. CMMI is chosen because it has a measurement model in accordance with the implementation of e-government, namely CMMI-DEV which oriented to development process, and CMMI-SVC which is service-oriented. In addition, CMMI measurement model can be assessed in accordance with its maturity level. This paper aims to systematically review specific processes on CMMI-DEV and CMMI-SVC which can be used to measure the maturity of e-government implementation. A systematic literature review method with PRISMA frameworks is used as a method of composing this paper, by searching for articles as evidence that the specific processes of CMMI-DEV and CMMI-SVC can be measured in e-government implementation. The review process recommends that all specific processes in CMMI-DEV are measured to show maturity in e-government implementation, but only a few specific processes in CMMI-SVC are recommended to serve as a measurement of that purpose.
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Calvo, Xavier, Nieves Garcia-Gisbert, Ivonne Parraga, Joan Gibert, Lourdes Florensa, Marcio Andrade-Campos, Brayan Merchan, et al. "Oligomonocytic and overt chronic myelomonocytic leukemia show similar clinical, genomic, and immunophenotypic features." Blood Advances 4, no. 20 (October 27, 2020): 5285–96. http://dx.doi.org/10.1182/bloodadvances.2020002206.
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Abstract Oligomonocytic chronic myelomonocytic leukemia (OM-CMML) is defined as those myelodysplastic syndromes (MDSs) or myelodysplastic/myeloproliferative neoplasms, unclassifiable with relative monocytosis (≥10% monocytes) and a monocyte count of 0.5 to <1 × 109/L. These patients show clinical and genomic features similar to those of overt chronic myelomonocytic leukemia (CMML), although most of them are currently categorized as MDS, according to the World Health Organization 2017 classification. We analyzed the clinicopathologic features of 40 patients with OM-CMML with well-annotated immunophenotypic and molecular data and compared them to those of 56 patients with overt CMML. We found similar clinical, morphological, and cytogenetic features. In addition, OM-CMML mirrored the well-known complex molecular profile of CMML, except for the presence of a lower percentage of RAS pathway mutations. In this regard, of the different genes assessed, only CBL was found to be mutated at a significantly lower frequency. Likewise, the OM-CMML immunophenotypic profile, assessed by the presence of >94% classical monocytes (MO1s) and CD56 and/or CD2 positivity in peripheral blood monocytes, was similar to overt CMML. The MO1 percentage >94% method showed high accuracy for predicting CMML diagnosis (sensitivity, 90.7%; specificity, 92.2%), even when considering OM-CMML as a subtype of CMML (sensitivity, 84.9%; specificity, 92.1%) in our series of 233 patients (39 OM-CMML, 54 CMML, 23 MDS, and 15 myeloproliferative neoplasms with monocytosis and 102 reactive monocytosis). These results support the consideration of OM-CMML as a distinctive subtype of CMML.
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Calvo, Xavier, Nieves Garcia-Gisbert, Ivonne Parraga, Lourdes Florensa, Sara Montesdeoca, Concepción Fernández, Marta Salido, et al. "Oligomonocytic Chronic Myelomonocytic Leukemia (O-CMML) and Chronic Myelomonocytic Leukemia (CMML) Show Similar Clinical, Morphological, Immunophenotypic and Molecular Features." Blood 134, Supplement_1 (November 13, 2019): 4266. http://dx.doi.org/10.1182/blood-2019-130445.
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INTRODUCTION The 2017 WHO classification requires the presence of ≥1x109/L and ≥10% of monocytes in peripheral blood (PB) for the diagnosis of CMML. Recently, Geyer et al. defines oligomonocytic CMML (O-CMML) as those MDS cases with relative monocytosis (≥10% monocytes) and monocyte count 0.5<1x109/L. The authors showed that clinicopathologic and mutational profile of OCMML were similar to overt CMML. The study of PB monocyte subsets by flow cytometry (FC) has gained interest for CMML diagnosis. As showed by Selimoglu-Buet et al, the increase of classical monocytes (Mo1) >94% is a highly sensitive and specific diagnostic marker for CMML. In the extent of our knowledge, there are no data about PB monocyte subset distribution by FC in O-CMML. Moreover, CD2 and CD56 expression is common in CMML and rarely observed in MDS, the group where O-CMML are currently included. Furthermore, we compared: the molecular profile; cytogenetic abnormalities; cytopenias; BM dysplasia; BM blast and monocyte percentage; PB monocyte percentage, and monocyte and leukocyte counts. METHODS 50 CMML and 33 O-CMML from a single institution were prospectively studied from 02/2016 to date. Table 1 summarizes morphologic, cytogenetic, molecular and clinical findings. We studied PB monocyte subsets by FC: Mo1 (CD14bright/CD16-), Mo2 (CD14bright/CD16+) and Mo3 (CD14dim or -/CD16bright). In addition, we assessed the expression of CD56 and CD2 in monocytes (positivity ≥ 20%). Finally, targeted NGS of the entire exonic sequence of 25 genes recurrently mutated in myeloid malignancies was performed (VAF sensitivity: 2%). Chi-Square, Fisher exact or Man-Whitney U tests were used as appropriate. RESULTS AND DISCUSSION The Mo1 percentage (%) was significantly inferior in O-CMML (P=0.007), but it is noteworthy that median and mean of Mo1% in O-CMML were upper the cutoff of 94% (median: 96.1 vs 98.1; mean: 94.7 vs 96.9). Moreover, the % of patients with >94% Mo1 was no significantly different when comparing O-CMML and CMML although a clear trend was observed (72% vs 90%; P=0.082). This result is impressive since, as previously reported, the specificity of the Mo1 >94% test is around 90-95% and only 5-10% of false positive rate (FP) should be expected. However, in O-CMML a 72% of FP was observed since following 2017 WHO recommendation these patients should be considered as MDS. No differences were observed neither in the % of patients showing CD56+ monocytes (65.6% vs 66.7%; P=0.923) nor in the % of them showing CD2+ (28.1% vs 37.5%; P=0.53) when comparing O-CMML and CMML. We observed no significant differences in platelet count, hemoglobin, BM dyserythropoiesis, BM dysgranulopoiesis, BM dysmegacaryopoiesis, BM blast %, percentage of abnormal karyotypes, and Spanish cytogenetic risk stratification. The main differences were observed in leukocyte count, monocyte count, PB monocyte %, BM monocyte %, and BM promonocyte percentage. Table 1. There were no differences in the number of mutated genes or in the number of mutations between CMML and O-CMML (Table 1). As expected, TET2 and SRSF2 were the most frequently mutated genes in both groups. Moreover, no significant difference was observed in the presence of TET2/SRSF2 co-mutation, the gene signature of CMML (32% vs 26% in CMML). The genes mutated at a frequency >10% in O-CMML were: TET2 (79%), SRSF2 (36%), SF3B1 (29%), ZRSR2 (25%), DNMT3A (15%), and ASXL1 (14%). The genes mutated at a frequency >10% in CMML were: TET2 (81%), SRSF2 (28%), ASXL1 (23%), CBL (23%), SF3B1 (16%), and NRAS (14%). Only two genes were mutated at a significant different frequency: CBL (4% vs 23% in CMML, P=0.041) and ZRSR2 (25% vs 7% in CMML, P=0.043). As expected, CMML showed a higher % of RAS pathway mutations (CBL, NRAS or KRAS) since these have been associated with proliferative features (4% vs 40%, P=0.001). This is especially evident in proliferative CMML in which genes associated with proliferation are present at higher frequencies: CBL (4% vs 39% in CMML, P=0.01), NRAS (0 vs 23% in CMML, P=0.029) and ASXL1 (14% vs 62% in CMML, P=0.004). A significant lower percentage of O-CMML with ZRSR2mut presented Mo1 >94% (33% vs 86%, P=0.024). As shown, O-CMML without ZRSR2mut showed this feature in a similar percentage than CMML (86% vs 90%). At a median follow-up of 31.2 months, 19% of O-CMML evolved to CMML showing a median time to evolution of 34 months. CONCLUSION Our data support the diagnosis of O-CMML as a distinctive subtype of CMML. Table 1 Disclosures Bellosillo: Qiagen: Consultancy, Speakers Bureau; TermoFisher Scientific: Consultancy, Speakers Bureau.
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Alfaraj, Hussain M., and Shaowen Qin. "Operationalising CMMI: integrating CMMI and CoBIT perspective." Journal of Engineering, Design and Technology 9, no. 3 (October 11, 2011): 323–35. http://dx.doi.org/10.1108/17260531111179933.
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Xu, Yin, Aine Yung, Brian Kwok, Karen Macdonell, Bashar Dabbas, and Prashanti Reddy. "Chronic Myelomonocytic Leukemia With Preexisting Myelodysplastic Syndrome Or Myeloproliferative Neoplasm: Two Stages Of One Disease With Poor Prognosis." Blood 122, no. 21 (November 15, 2013): 1342. http://dx.doi.org/10.1182/blood.v122.21.1342.1342.
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Abstract Introduction Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic malignancy characterized by persistent monocytosis with features of a myelodysplastic syndrome (MDS) and/or myeloproliferative neoplasm (MPN). While most cases present as de novo disease, a subset of CMML has been described in the literature to evolve from a preexisting MDS (MDS-CMML). CMML with preexisting MPN (MPN-CMML) has not been characterized to our knowledge. It is uncertain whether CMML patients with preexisting MDS or MPN have one or more disease processes and if such patients behave differently from patients who present with de novo CMML. In an attempt to address these questions, we compared the clinicopathologic features between groups of MDS-CMML, MPN-CMML, and de novo CMML in the present study. Methods 126 cases with newly diagnosed CMML were retrieved from our database over a 3-year period. 22 cases had preexisting MDS (n=15) or MPN (n=7). Prior diagnoses of MDS included refractory anemia (n=5), refractory anemia with ring sideroblasts (n=2), MDS with isolated 5q deletion (n=1), refractory cytopenia with multilineage dysplasia (n=6), and refractory anemia with excess blasts-1 (n=1). Prior diagnoses of MPN included essential thrombocythemia (n=1), primary myelofibrosis (n=3), and MPN NOS (n=3). Cytogenetic studies were performed in all cases. Other parameters obtained included age, gender, hemoglobin, white blood cell count, monocytes, platelets, bone marrow blasts and histology, and JAK2/MPL mutations. 22 consecutive cases of de novo CMML were included for comparative analysis. Results CMML with preexisting MDS or MPN comprised 17% of CMML (22/126 patients). Among these 22 patients, 15 were male and 7 female with a median age of 79 (range 61-86) years. Median age of the patients at CMML stage was similar to that of patients with de novo CMML (77 years; range 65-89). The median time between disease presentation as MDS or MPN and CMML was 22 months. Patients presented with marked monocytosis at the CMML stage (mean: 23% and 4564/uL) as compared to the stage of MDS (mean: 13% and 794/uL; p<0.001) or MPN (mean: 6.4% and 1216/uL; p<0.001); and the monocyte count was similar to that present in de novo CMML (mean: 24% and 4313/uL). Marrow blasts were significantly increased at the CMML stage as compared to the stage of MDS (mean: 5.3 vs. 1.6; p=0.017), MPN (mean: 5.1 vs. 1.9; p=0.048), or de novo CMML (5.2 vs. 1.9; p=0.009). There was no significant difference in average hemoglobin, platelet count or marrow cellularity between cases at the two disease stages or among the MDS-CMML and MPN-CMML subgroups. However, the marrows of MPN-CMML showed significantly increased diffuse reticulin fibrosis (p=0.002) and marked megakaryocytic hyperplasia (p=0.002) as compared to MDS-CMML. CMML with preexisting MDS or MPN is more frequently associated with cytogenetic abnormalities than de novo CMML (50% vs. 23%), although this difference did not reach statistical significance (p=0.116). 8 (36%) cases had chromosome abnormalities at the MDS or MPN stages; 7 (87%) of the 8 cases demonstrated persistent chromosome abnormalities at the CMML stage. In addition, 4 (18%) patients acquired chromosome abnormalities at the CMML stage. JAK2 mutation was seen in 1 (7%) of 15 cases of MDS-CMML and 4 (57%) of 7 cases of MPN-CMML. Notably, 2 cases of JAK2 positive MPN became JAK2 negative at the CMML stage; one of the patients had been previously treated with a JAK2 inhibitor. No MPL mutation was found in any case. Conclusions CMML with preexisting MDS or MPN is not uncommon. The majority of cases exhibit persistent chromosomal abnormalities from the preexisting MDS or MPN, supporting the notion of one disease with two stages of presentation. The findings of a higher frequency of cytogenetic abnormalities and occasional cytogenetic evolution may suggest that chromosome alteration is one of the mechanisms involved in triggering disease progression to CMML. JAK2 V617F was more frequent in MPN-CMML, which correlated with myelofibrosis and megakaryocytic hyperplasia. However, loss of JAK2 mutation can occur at CMML stage. Loss/inhibition of JAK2 activity may contribute to a change in disease course. Our study revealed that CMML with preexisting MDS or MPN is characterized by more advanced disease with increased marrow blasts and therefore may be associated with a poorer prognosis. Disclosures: No relevant conflicts of interest to declare.
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Castaño-Díez, Sandra, Monica Lopez-Guerra, Daniel Esteban, Francesca Guijarro, Alex Bataller Torralba, Paola Charry, Carlos Castillo, et al. "Myeloproliferative/Myelodysplastic Neoplasms Presenting All Diagnostic Criteria of Chronic Myelomonocytic Leukemia but with Absolute Peripheral Blood Monocytosis 0.5-1× 109/L Should be Classified As CMML." Blood 136, Supplement 1 (November 5, 2020): 10–11. http://dx.doi.org/10.1182/blood-2020-142819.
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Introduction Current diagnosis of chronic myelomonocytic leukemia (CMML) requires peripheral blood (pb) monocytosis ≥1×109/L. Accordingly, cases which fulfill other diagnostic criteria of CMML but not reaching the required pb monocytosis threshold would be classified as MDS or unclassifiable MPN/MDS according to WHO classification (Arber et al, Blood 2016) Recently, a group of authors (Geyer et al, Modern Pathology 2017) proposed the term oligomonocytic CMML (OM-CMML) for these patients with blood monocytes ≥10% of the WBCs, but only accounting for 0.5-1 × 109/L as an absolute value and fulfilling all other criteria of CMML and suggested that they should be managed as other patients with classical CMML despite lacking pb monocytosis ≥1×109/L. To address clinical value of this proposed newly entity, we analyzed the incidence, clinico-biological characteristics and outcome of a series of patients fulfilling the proposed criteria for OM-CMML from a single center with a long follow-up. Methods We included patients diagnosed between 1997 and 2019 who gathered the proposed criteria for OM-CMML (Geyer et al, Modern Pathology 2017). These patients were compared with a cohort of patients from the same study period diagnosed with classical CMML. Statistical analyses were performed using Rv3.1 and SPSS v20. Next generation targeted sequencing (NGS) was performed with Ion Ampliseq AML Research and Oncomine Myeloid Research Assay panel Results Overall, we included in the study 213 patients, including 35 (16%) who fulfilled the proposed criteria for OM-CMML. Median follow-up of alive patients was 42 months. In the OM-CMML group, 71% were males, median age was 74 years (51-92). OM-CMML patients presented at diagnosis with a lower leucocyte count (WBC) (median value, 4.6(2.2-7.5)x109/L vs 10(3-119)x109/L, p<0.001), neutrophil count (2(0.7-5.7)x109/Lvs5.1(0.5-57)x109/L; p<0.001), and monocyte count, both in terms of absolute figures (0.75(0.5-0.9)x109/Lvs1.9(0.6-33)x109/L;p<0.001) and relative percentage (15% (10-30) vs 20% (1.8-51);p<0.001). All OM-CMML patients corresponded to FAB non-leucocytosis, CMML-Myelodysplastic type (CMML-MD), whereas 62% of c-CMML patients were diagnosed as a CMML-MD subtype p<0.001). No other different clinical characteristic were observed (Table 1). Cytogenetic analysis showed an abnormal karyotype in 23% of OM-CMML patients. NGS at diagnosis was available in 26 pt, without observing significant differences regarding gene mutation frequency. At diagnosis 17% of OM-CMML patients were transfusion-dependent and the distribution according to CPSS categories was: low (48%), int-1 (23%), int-2 (26%) and high (3%) risk, without difference with c-CMML (Table 1). Progression to a c-CMML was observed in 67% (24) of OM-CMML pts with a median time to progression of 7 months (m) (1-149 m). We did not observe differences in transformation rate to AML (AML-t; 10 (28.5%) vs 44 (24.7%) among OM-CMML and c-CMML group, p=0.6) or cumulative incidence (CI) of AML-t between OM-CMML and c-CMML patients (50m-CI AML-t: 35%±7 vs 21±12, p=0.3) (Fig 1). Eight out of the 10 pt (80%) who developed an AML previously presented a c-CMML phase. Median time to AML-t was longer in OM-CMML pt: 60m (3-219) vs 13.7m (0.8-124), p=0.011. The percentage of patients who received treatment in OM-CMML cohort was similar to that of c-CMML pts: (28% vs 21%, p=0.37, respectively). Moreover, time to treatment requirement was similar in both patient cohorts (15m (0.9-211m) vs 10m (0.1-112), p=0.5, respectively). Finally, overall survival of OM-CMML did not differ from that of c-CMML (5-year Overall Survival: 45±16% vs 30±7%; p=0.31, Figure 2). Conclusion: Clinical features and evolution of patients with OM-CMML were comparable to that of patients with c-CMML, supporting similar classification and management criteria. Acknowledgement: PI16/01027 (JE; MDB), PI19/01476 (JE; MDB) Disclosures No relevant conflicts of interest to declare.
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Yamazaki, Sho, Kazuki Taoka, Shunya Arai, Masashi Miyauchi, Keisuke Kataoka, Akihide Yoshimi, and Mineo Kurokawa. "Patient-Derived Induced Pluripotent Stem Cells Identified SLITRK4 As a Causative Gene of Chronic Myelomonocytic Leukemia." Blood 128, no. 22 (December 2, 2016): 1134. http://dx.doi.org/10.1182/blood.v128.22.1134.1134.
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Abstract Chronic myelomonocytic leukemia (CMML), the most frequent disease entity of myelodysplastic syndrome/myeloproliferative neoplasm is a clonal hematopoietic malignancy that is characterized by persistent monocytosis, morphologic myeloid dysplasia, and progression to acute myeloid leukemia. The pathogenesis of CMML remains entirely elusive because of the lack of suitable mouse models and the difficulties in the establishment of CMML cell lines. We have previously reported that we established induced pluripotent stem cells (iPSC) from CMML CD34 positive leukemic cells (CMML-iPSC) as a new disease model. Co-cultured with C3H10T1/2 stromal cells in the presence of vascular endothelial growth factor, CMML-iPSC generated CD34 CD43 double-positive hematopoietic progenitor cells (CMML-HPC). CMML-HPC have recapitulated important disease features of parental CMML cells in terms of genetic abnormalities, acceleration of cell proliferation, and aberrant surface markers expression. In addition, a novel human CMML xenograft mouse model has been established through secondary transplantation of human HPCs from CMML-iPSC-derived teratomas. This model produced HPCs that mimicked the properties of CMML in vivo. To identify key molecular abnormalities that contribute to the pathophysiology of CMML, we conducted comprehensive gene expression and DNA methylation profiling analyses of normal and CMML parental CD34 positive cells, iPSC, and their hematopoietic progenies, respectively. Correlation analysis revealed that gene expression and DNA methylation status between normal and CMML iPSC-derived HPC exhibited similar pattern (R2 = 0.92 and 0.96, respectively), although normal and CMML parental CD34 positive cells were quite different (R2 = 0.72 and 0.90, respectively), indicating that reprogramming followed by re-differentiation may enable to obtain more homogenous population of normal and CMML cells that reside in almost the same differentiation stage. These results allowed us to determine the difference in the genetic and epigenetic status between normal and CMML iPSC-derived HPC, which remained through reprogramming and re-differentiation, in order to find out causative genes in the pathogenesis of CMML. Using these combined omics platforms, we identified SLIT and NTRK like family member 4 (SLITRK4) as a candidate gene involving in pathogenesis of CMML, whose expression was enhanced and whose promoters were hypo-methylated in CMML-HPC. In other CMML patients' CD34 positive leukemic cells, the expression of SLITRK4 was up-regulated compared to healthy CD34 positive bone marrow cells and other leukemia cells. In addition, we revealed SLITRK4 had pro-proliferative activity as the knockdown of SLITRK4 inhibited proliferation of leukemic cell lines OCI-AML3. To elucidate whether SLITRK4 exert any biological functions in CMML, we established CMML-iPSC clones harboring hetero-knockout (wt/-) or homo-knockout (-/-) of SLITRK4 gene by CRISPR/Cas9 system. Although SLITRK4 (wt/-) and (-/-) clones did not exhibit any morphological and proliferative difference in CMML-iPSC, the production of HPC from CMML-iPSC was dramatically attenuated in SLITRK4-dependent manner. Therefore, while little has been known about the roles of SLITRK molecules in tumorigenesis, we demonstrated SLITRK4 was indispensable for generation of CMML leukemic cells and suggested the possibility of novel molecular therapy targeting SLITRK4, based on the findings obtained from our combined omics platforms. In summary, we identified SLITRK4 as a novel candidate gene responsible for the pathogenesis of CMML through our combined omics platform using patient-derived iPSC. This platform may provide a potential to trace causative genes in a variety of diseases. Disclosures Kataoka: Kyowa Hakko Kirin: Honoraria; Boehringer Ingelheim: Honoraria; Yakult: Honoraria.
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Loghavi, Sanam, Dawen Sui, Peng Wei, Guillermo Garcia-Manero, Sherry Pierce, Mark J. Routbort, Elias J. Jabbour, et al. "Validation of the 2017 revision of the WHO chronic myelomonocytic leukemia categories." Blood Advances 2, no. 15 (July 27, 2018): 1807–16. http://dx.doi.org/10.1182/bloodadvances.2018019224.
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Onida, Francesco, Servida Federica, Soligo Davide, Ricci Clara, Pasquini Maria Cristina, Vismara Alessandro, Cortelezzi Agostino, and Lambertenghi Deliliers Giorgio. "Intracytoplasmic Concentration of GM-CSF and Intensity of the GM-CSF Membrane Receptor Are Significantly Higher in Proliferative Than in Dysplastic Variant of CMML and Could Explain the Higher In Vivo and In Vitro Growth Pattern." Blood 106, no. 11 (November 16, 2005): 2602. http://dx.doi.org/10.1182/blood.v106.11.2602.2602.
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Abstract Chronic myelomonocytic leukemia (CMML) is a heterogeneous hematological malignancy, which has been included in a new category of MDS/MPD disorders in the last WHO classification of myeloid malignancies. An arbitrarily chosen leukocyte count has been proposed by the FAB group to differentiate between a “dysplastic” type (MD-CMML, with ≤12 x 109 WBC/L) and a “proliferative” type (MP-CMML, with >12 x 109 WBC/L) of CMML. However, apart from the WBC count, no biological difference has been identified to support distinction between these two disease-entities. Among factors that have been implicated in pathogenesis of CMML, GM-CSF produced by either autocrine or paracrine mechanisms has been shown to be a major growth determinant. In this study, peripheral blood samples from normal controls and from patients affected by proliferative and dysplastic variants of CMML were used to investigate expression of intracytoplasmic GM-CSF and expression of GM-CSF membrane receptor. Briefly, mononuclear cells (MNC) were isolated on Ficoll-Paque density gradient and cryopreserved in FCS 10% DMSO. In a first set of experiments samples from 5 healthy controls, 11 MP-CMML and 8 MD-CMML were thawed, permeabilized and stained with GM-CSF PE (Caltag) to evaluate expression of the intracytoplasmic cytokine by FACSCalibur flow cytometer (BD). Mean percentage of GM-CSF expression was 0.1 (range 0–0.5) in normal controls, 59.8 (range 14.5–90.7) in MP-CMML and 2.27 (range 0–9.3) in MD-CMML. The difference between MP and MD disease was statistically significant. To further investigate the possible role of GM-CSF cytokine in the pathogenesis of CMML, in a second set of experiments, MNC from 8 normal controls, 14 MP-CMML and 11 MD-CMML samples were thawed and stained with GM-CSFR (CD116 Pharmingen) and then with Goat Anti-Mouse FITC (BD) to evaluate the expression of the cytokine receptor. Mean percentage of expression of GM-CSFR was significantly higher in CMML samples (41.3, range 9.5–69) than in normal controls (20.3, range 16.4–27.3). No difference was detected between subtypes of MP-CMML and MD-CMML. When we considered median intensity of GM-CSFR expression, we observed a significantly higher values in MP-CMML than in MD-CMML (123.2 and 51.4, respectively), whereas no significant difference was detected between normal samples and MD-CMML. In this study, we also assessed "in vitro" spontaneous colony growth of PB-MNC from patients with both variants of CMML. The number of CFU-GM was higher in the MP-CMML than in MD-CMML (57 vs 17/5x10e5 cells plated) and a significant correlation with intracytoplasmic GM-CSF expression was observed (p <0.05). The higher levels of intracytoplasmic GM-CSF and the increased density of the cytokine receptor in MP-CMML suggest a possible role of GM-CSF in malignant cell proliferation of CMML patients. If our results will be confirmed, these findings could be utilized as a possible biological marker to distinguish proliferative and dysplastic variants of the disease. Further studies are warranted to investigate possible therapeutic applications.
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Matti, Nawar, Ruifang Zheng, Khalid Algarrahi, Albert Alhatem, Xinlai Sun, Jie-Gen Jiang, and Rutgers NJMS. "Cytogenetic and Molecular Profile Analysis in Hispanic Chronic Myelomonocytic Leukemia Patients From Puerto Rico." American Journal of Clinical Pathology 152, Supplement_1 (September 11, 2019): S106. http://dx.doi.org/10.1093/ajcp/aqz121.005.
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Abstract Objectives Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic malignancy with both myelodysplastic and myeloproliferative features. The clinical and pathological features of CMML are highly heterogeneous. It was reported that Hispanic whites had an age-adjusted lower incidence rate of CMML compared to non-Hispanic whites. The aim of this study is to define the cytogenetic and genomic landscape of Hispanic CMML patients and explore their potential clinical significance. Methods Clinically relevant cytogenetic results and 40-gene molecular profiles of Hispanic CMML patients in Puerto Rico (PR) from 2009 to 2018 were obtained retrospectively. Results Total 111 Hispanic CMML patients from PR were diagnosed in our institute from 2009 to 2018. The age range was from 46 to 96 years with a median age of 74. Sixty-five were male and 46 were female. The epidemiological features are similar to that in a general CMML patient population. In total, 107 patients had karyotypes available; 17 patients had abnormal karyotype (17/107, ~16%). Compared with general CMML patients, Hispanic CMML patients had a significantly lower rate of cytogenetic abnormalities (30% vs 16%). Among total 111 Hispanic CMML patients, 40-gene myeloid molecular profiles were performed in 56 CMML patients. Fifty-five out of 56 patients had mutations identified (~98.2%). The most frequent mutated genes were TET2, SRSF2, ASXL1, NRAS, and ZRSR2. Twenty-six of 56 patients (~46.4%) had mutated TET2/wild-type ASXL1. Previous studies indicated that mutated ASXL1, NRAS, RUNX1, and SETBP1 likely associate with an unfavorable prognosis in a general CMML patient population. Mutated TET2 with wild-type ASXL1 (muTET2/wtASXL1) may associate with a favorable prognosis. Compared with general CMML patients, Hispanic CMML patients in this study had relatively lower mutational rates in ASXL1 (30.4% vs 37.0%), NRAS (10.7% vs 11.7%), RUNX1 (5.3% vs 7.9%), and SETBP1 (5.3% vs 8.9%) and a higher rate of muTET2/wtASXL1 (46.4% vs 37.8%). Conclusion Hispanic CMML patients from PR had a significantly lower rate in cytogenetic abnormalities; relatively lower mutational rates in ASXL1, NRAS, RUNX1, and SETBP1; and a higher mutational rate in muTET2/wtASXL1. The findings raise a possibility of a better prognosis in Hispanic CMML patients and could be one of the explanations of a lower incidence rate of CMML in Hispanic population.
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Garcia-Gisbert, Nieves, Leonor Arenillas, David Roman-Bravo, Juan José Rodríguez-Sevilla, Brayan Merchan, Sara Garcia-Avila, Concepción Fernández-Rodríguez, et al. "Multiple TET2 Mutations As a New Biological Clue for Differentiating Oligomonocytic Chronic Myelomonocytic Leukemia from Myelodysplastic Syndromes." Blood 138, Supplement 1 (November 5, 2021): 1530. http://dx.doi.org/10.1182/blood-2021-152674.
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Abstract Introduction. Oligomonocytic chronic myelomonocytic leukemia (OM-CMML) is defined as those myelodysplastic syndromes (MDS) or MDS/MPN unclassifiable cases with relative monocytosis (≥ 10% monocytes) and a total monocyte count of 0.5-<1x10 9/L. These patients show similar clinical, genomic and immunophenotypic features than overt CMML, although the majority of them are currently classified as MDS following WHO 2017 classification. TET2 is the most prevalent mutated gene in CMML and it is frequent to find multiple TET2 mutations in the same patient. Objective. We investigated TET2 mutations in 42 OM-CMML, their diagnostic value and their correlation with immunophenotypic pattern, and compared them with that observed in 54 CMML and 86 MDS. Patients and methods. Samples were collected from 182 patients: 42 OM-CMML, 54 overt CMML, and 86 MDS. Molecular characterization was performed by next-generation sequencing (NGS) using a custom panel (QIAseq Custom DNA Panels, Qiagen) including the whole codifying region of 25 myeloid-associated genes and sequenced using Illumina technology. Multiparametric flow cytometry (FC) analysis of monocyte subsets was performed on whole PB collected on EDTA. Cell surface staining of 2 × 10 6 cells was performed and at least 500 000 total events were acquired per tube (FACS Canto II; BD Biosciences). The FC strategy analysis, the 5-tube experimental panel, and the NGS custom panel are described in Calvo & Garcia-Gisbert, Blood Adv 2020. Results. Patients with multiple TET2 (multi-TET2) mutations (2 or more) were identified with similar percentages in OM-CMML (17/42, 40.5%) and CMML (29/54, 53.7%) while they were infrequent in MDS (5/86, 5.8%) (P<0.001). In MDS patients, 4/5 with multi-TET2 showed a percentage of monocytes >10% though they were not considered OM-CMML since the monocyte count was below 500/microL. CMML and OM-CMML patients with multi-TET2 showed predominantly 2 TET2 mutations (CMML: 20/29, 69%; OM-CMML: 14/17, 82%;). The distribution of patients with >2 TET2 mutations was similar in CMML and OM-CMML. We did not observe differences among the frequency of nonsense, frameshift or missense TET2 mutations, nor between early or late-truncating (early: aa 1-1128, late: 1128-1936) TET2 mutations between OM-CMML and CMML.TET2 variant allele frequency (VAF) was significantly lower in MDS (median 11.83%) than in OM-CMML and CMML (P<0.001 in both comparisons). OM-CMML and CMML showed similar TET2 VAF (medians 41.4% and 40.3%). In those patients with TET2 VAF >55% or a sum of muti-TET2 mutations VAF above 55% (17 OM, 19 CMML, 2 MDS), we could infer a biallelic alteration in the same clone (Coltro, Leukemia 2020). We did not observe differences in the frequency of OM-CMML showing biallelic TET2 mutations when compared to CMML.The main clinical characteristics of CMML patients (overt and OM-CMML), grouped by TET2 mutational status (unmutated: TET2 WT; 1 TET mutation: TET2 single; ≥2 mutations: multi-TET2) are depicted in Table 1. As shown, we did not observed significant differences when comparing TET2 single to TET2 WT or multi-TET2 Of note, multi-TET2 patients showed a higher percentage of PB and BM monocytes, BM promonocytes and more dysgranulopoiesis than TET2 WT patients.Patients with TET2 WT presented a lower number of mutated genes than TET single and multi-TET2 patients (P=0.019 and P=0.029). In line with previous studies, IDH mutations and TET2 mutations where mutually exclusive (P=0.001). Co-mutation of SRSF2 and TET2, the well-accepted gene signature of CMML, was found in 25/96 patients (26.0%, 13 OM-CMML, 12 CMML) in 10 cases co-mutated with TET2 single and in 15 cases with multi-TET2.We assessed the proportion of OM-CMML patients with MO1>94% since this has been shown as very sensitive and specific feature of CMML. In TET2 mutated OM-CMML, we observed a higher proportion of patients with MO1>94% (90% mut. vs 40% WT; P=0.001) and CD56 expression on monocytes (70% mut. vs 30% WT; P=0.025). We observed a trend (non-significant) difference in the proportion of patients showing these features when comparing TET2 single vs multi-TET2 OM-CMML (single, CD56: 57.1%, MO1>94%: 85.7%; multi-TET2, CD56: 81.3%, MO1>94%: 93.8%). Conclusion. The high occurrence of multiple TET2 mutations in overt and OM-CMML and its infrequency in MDS is a new biological clue for supporting the consideration of OM-CMML in the continuum of CMML. Figure 1 Figure 1. Disclosures Salar: Celgene: Consultancy, Speakers Bureau; Gilead: Research Funding; Roche: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau. Bellosillo: Roche: Research Funding, Speakers Bureau; Qiagen: Consultancy, Speakers Bureau; Thermofisher Scientific: Consultancy, Speakers Bureau.
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Chen, Li Jun, Bo Sun, Jian Chao Diao, and Li Li Zhao. "Improved CMAC Neural Network Control for Superheated Steam Temperature." Advanced Materials Research 383-390 (November 2011): 111–17. http://dx.doi.org/10.4028/www.scientific.net/amr.383-390.111.
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Aiming at that superheated steam temperature system exists the large inertia and large time delay of the dynamic characteristics,and the converge speed of the conventional CMAC neural network is not fast enough to the real-time system, a credit assignment CMAC (CA-CMAC) neural network control is adopted in superheated steam temperature control system, which is proposed to speed up the learning process in CMAC. The simulation of the superheated steam temperature control system shows that CA-CMAC converges faster than the conventional CMAC. This result illustrates the effectiveness of this method.