Schwannomatosis is a late-onset tumor predisposition syndrome associated with the development of many different types of malignancies. A relevant genetic mechanism can be explained by three ...mutational events. The first-hit mutation is a germline mutation, and the SMARCB1 mutation on chromosome 22 is the most well-known genetic abnormality in patients with schwannomatosis. LZTR1 is another major predisposing gene in 22q-related schwannomatosis that lacks SMARCB1 variants. Although these two variants account for the occurrence of most familiar schwannomatoses, the genetic causes of sporadic schwannomatosis for the most part remain unknown. Therefore, current molecular diagnostic criteria cannot completely explain the basis of this disease. The common genetic background between schwannomatosis and other related malignant tumors is also unclear. Moreover, it is not easy to explain various clinical manifestations by only two known mutations. QUESTION/PURPOSES: (1) Are there important sequences outside the SMARCB1 or LZTR1 region on chromosome 22 that might carry a first-hit mutational predisposition to sporadic schwannomatosis? Or are there alternative evolutionarily conserved loci that might carry a first-hit mutational predisposition? (2) Is the age of disease onset associated to such genetic variants?
This study was a retrospective chart review and prospective genetic study on patients with schwannomatosis who were treated surgically. The clinical criteria to diagnose schwannomatosis were as follows: (1) histologically proven nonvestibular schwannomas; (2) no evidence of vestibular schwannomas on 3-mm brain MRI. A total of 21 patients were treated between March 2006 and June 2015. Since nine patients did not visit the outpatient clinic during the recruitment period, we obtained blood samples from 12 patients with schwannomatosis for a genetic analysis. After two patients were excluded because of their family history of schwannomatosis, genetic analyses were finally performed on 10 patients. Then, those with NF2, SMARCB1 or LZTR1 variants were screened by whole exome sequencing. All 10 patients passed our screening strategy. There were eight men and two women, with a median (range) age of 43 years (24 to 66) at the time of diagnosis. To select candidate genes, common ethnic variants and frequent mutations in in-house exome sequencing data were removed to exclude the population-specific polymorphisms not found in other population and to generalize the findings. Frameshift, nonsense, and splice-site variants were deemed pathogenic. Missense variants were classified as potentially pathogenic, variants of uncertain significance, or benign using in silico (via computer simulation) prediction algorithms, Sorting Intolerant From Tolerant (SIFT), Polymorphism Phenotyping v2 (PolyPhen-2), and Combined Annotation Dependent Depletion (CADD). A variant was considered potentially pathogenic if two or more algorithms predicted the variant to be damaging and benign if none considered it damaging. Then, potentially pathogenic variants only in the genes associated with cancer-predisposition or DNA damage repair were classified as the pathogenic candidate variants of sporadic schwannomatosis. The predictions for pathogenic candidate variants were checked again on Clinical Interpretation of Genetic Variants (InterVar) based on the American College of Medical Genetics guidelines and validated against Mendelian clinically applicable pathogenicity scores (M-CAP scores).
We detected 26 variants; 13 variants across 10 genes were predicted to be pathogenic and found in seven patients, two each in ARID1A, PTCH2, and NOTCH2 and one each in MSH6, ALPK2, MGMT, NOTCH1, CIC, TSC2, and CDKN2A. One frameshift deletion in PTCH2 met the criteria for pathogenic or likely pathogenic classification, as recommended by the American College of Medical Genetics guidelines. Six missense mutations were classified as possibly pathogenic variants based on M-CAP scores. Four predicted pathogenic missense variants were detected in DNA damage repair (DDR) genes. Three DDR genes were affected: ARID1A, MGMT, and MSH6. Among the nine predicted pathogenic mutations detected in known cancer-predisposing genes, one was a frameshift deletion and the others were missense mutations. Seven tumor suppressor genes were involved: PTCH2, ALPK2, CIC, NOTCH1, NOTCH2, TSC2, and CDKN2A. One patient with multiple pathogenic variants in two DDR genes, ARID1A and MSH6, received a schwannomatosis diagnosis at 33 years old. Each of the other patients who had single variants in the DDR gene received their diagnoses at 41 years of age. The age at diagnosis was 40 years or older in patients with variants in cancer-predisposing genes, except for one patient who had multiple variants in TSC2 and CDKN2A. The carrier of those variants received the diagnosis at 24 years old.
This study identified first-hit candidate mutations predisposing patients to schwannomatosis that were not related to SMARCB1 or LZTR1 variations in a cohort of patients with sporadic schwannomatosis. Patients with sporadic schwannomatosis without SMARCB1 or LZTR1 genetic variation may have developed the disease because of genomic variants related to cancer initiation in areas other than chromosome 22. Seven of 10 patients had predicted pathogenic germline mutations in DDR and cancer predisposition genes. We detected multiple cancer-related mutations in each patient. The age at the time schwannomatosis was diagnosed might be associated with a combination of variants and characteristics of the genes containing the variants; however, we did not have enough patients to confirm this association.
The germline mutations identified in this study and the ideas related to the age of disease onset may provide potential candidate variants for future research on sporadic schwannomatosis and help to revise the current clinical and molecular diagnostic criteria. Further in vivo and in vitro studies are needed for these variants.
In this work we analyze the global distribution and physical characteristics of nighttime midlatitude magnetic field fluctuations (MMFs) as observed by the CHAMP satellite from 2001 to 2002 (solar ...maximum) and from 2006 to 2007 (solar minimum). MMFs are defined as medium‐scale magnetic fluctuations perpendicular to the mean field, which are not accompanied by plasma density irregularities at the CHAMP altitude (∼400 km). MMFs occur at 15°–40° invariant latitude in the ionospheric F region. The occurrence is rare above the southern Atlantic ocean, and bears little connection to geomagnetic activity. The global MMF occurrence rate depends on season. The occurrence is generally low in equinox, maximizes around east Asia/Oceania and Europe/northern Atlantic Ocean in June solstice, and peaks above the American continents in December solstice. As the solar cycle declines, the detected MMF occurrence rate also decreases. The MMF occurrence peaks around 2100 LT and slowly decreases toward midnight. In the postmidnight sector, events are practically absent. The MMF occurrence is generally consistent with known features of nighttime medium‐scale traveling ionospheric disturbances (MSTIDs), such as the conjugate climatology, and premidnight occurrence peak in the east Asia/Oceania region. But differences in their distributions also exist, implying that factors other than MSTIDs, e.g., ionospheric conductivity, sporadic E layer or plasma instabilities, may play a nonnegligible role in generating MMFs. MMFs have a preferred direction of polarization, which is consistent with that of MSTIDs and again corroborates the close connection between these two phenomena. We interpret the observed magnetic deflections in terms of field‐aligned currents (FACs). The estimated wavelength range (∼200–500 km) of associated FAC pairs also agrees well with the size of MSTID density structures.
This paper presents studies on the self-interference level of a 28-GHz full-duplex phased-array system. The full-duplex system consists of two 64-element phased-arrays and a 28-GHz canceller. The ...phased-arrays are designed with 2×2 beamformer chips, and the arrays are used as a transmitter and a receiver with a cross-polarization set-up. The 28-GHz canceller is also based on the same 2×2 beamformer chip with multiple-delay taps. The full duplex front-end with a canceller results in 57-dB isolation between the transmitting and receiving arrays at 28.5-29.5 GHz without saturating any LNAs. The system requires only 16-dB additional digital cancellation to bring the self-interference down to the receiver noise floor of 1-GHz bandwidth while the transmit EIRP is maintained at 41 dBm.
To develop a clinically effective bone regeneration strategy, we compared bone regeneration using allogeneic cancellous bone granule scaffolds loaded with autologous bone marrow-derived mesenchymal ...stem cells (BM-MSC) with or without autologous platelet-rich plasma (PRP). Critical-sized segmental bone defects were made at the mid-shaft of both radiuses in 41 New Zealand White rabbits. Small-sized allogeneic cancellous bone granules (300-700 μm in diameter) loaded with BM-MSC were implanted on one side, and PRP was added. On the other side, autologous BM-MSC loaded onto allogeneic cancellous granules were grafted as a control. Bone regeneration was assessed by radiographic evaluation at 4, 8, and 16 weeks postimplantation and by micro-computed tomography (micro-CT) and histological evaluation of the retrieved specimens at 8 and 16 weeks. The experimental group did not show significantly higher bone quantity indices than the control group at any time point. Micro-CT analysis revealed that both groups had similar mean total volumes, surface areas, and other parameters at 8 and 16 weeks. Histological evaluation of 8- and 16-week specimens also showed a similar progression of new bone formation and maturation. In this experiment using a contralateral control group in the same individual, an initial single addition of PRP in allogeneic cancellous bone granules loaded with BM-MSC for critical-sized bone defects in the weight-bearing area did not induce a consequent difference in bone healing. Further research into the optimal preparation and application of PRP is necessary. Furthermore, studies involving a greater number of subjects and larger experimental animals could determine the clinical relevance of PRP treatment.
Dysphagia is a common clinical condition characterized by difficulty in swallowing. It is sub-classified into oropharyngeal dysphagia, which refers to problems in the mouth and pharynx, and ...esophageal dysphagia, which refers to problems in the esophageal body and esophagogastric junction. Dysphagia can have a significant negative impact one's physical health and quality of life as its severity increases. Therefore, proper assessment and management of dysphagia are critical for improving swallowing function and preventing complications. Thus a guideline was developed to provide evidence-based recommendations for assessment and management in patients with dysphagia.
Nineteen key questions on dysphagia were developed. These questions dealt with various aspects of problems related to dysphagia, including assessment, management, and complications. A literature search for relevant articles was conducted using Pubmed, Embase, the Cochrane Library, and one domestic database of KoreaMed, until April 2021. The level of evidence and recommendation grade were established according to the Grading of Recommendation Assessment, Development and Evaluation methodology.
Early screening and assessment of videofluoroscopic swallowing were recommended for assessing the presence of dysphagia. Therapeutic methods, such as tongue and pharyngeal muscle strengthening exercises and neuromuscular electrical stimulation with swallowing therapy, were effective in improving swallowing function and quality of life in patients with dysphagia. Nutritional intervention and an oral care program were also recommended.
This guideline presents recommendations for the assessment and management of patients with oropharyngeal dysphagia, including rehabilitative strategies.
Interleukin-34 (IL-34) is a recently defined cytokine, showing a functional overlap with macrophage colony stimulating factor (M-CSF). This study was undertaken to address the expression of IL-34 in ...rheumatoid arthritis (RA) patients and to investigate its regulation and pathogenic role in RA.
IL-34 levels were determined in the RA synovium, synovial fluid (SF) and fibroblast-like synovial cells (FLS) by immunohistochemistry, real-time PCR, enzyme-linked immunosorbent assay and immunoblotting. RA activity was assessed using Disease Activity Score 28 (DAS28) activity in the plasma collected at baseline and one year after treatment. Conditioned media (CM) were prepared from RA FLS culture with tumor necrosis factor alpha (TNFα) for 24 hours and used for functional assay.
IL-34 was expressed in the synovium, SF, and FLS from RA patients. The production of IL-34 in FLS was up-regulated by TNFα in RA samples compared with osteoarthritis (OA) patients. Importantly, the preferential induction of IL-34 rather than M-CSF by TNFα in RAFLS was mediated by the transcription factor nuclear factor kappa B (NF-κB) and activation of c-Jun N-terminal kinase (JNK). IL-34 elevation in plasma from RA patients was decreased after the administration of disease-modifying anti-rheumatic drugs (DMARDs) in accordance with a decrease in DAS28. CM from RAFLS cultured with TNFα promoted chemotactic migration of human peripheral blood mononuclear cells (PBMCs) and subsequent osteoclast (OC) formation, effects that were attenuated by an anti-IL-34 antibody.
These data provide novel information about the production of IL-34 in RA FLS and indicate that IL-34 is an additional osteoclastogenic factor regulated by TNFα in RA, suggesting a discrete role of IL-34 in inflammatory RA diseases.
N-doped carbon has been recognized as a promising electro-catalytic material for oxygen reduction reactions (ORRs). Herein, as a promoter of ORRs in acid media, sulfur and/or selenium atoms are ...additionally decorated onto the N-doped graphene-CNT self-assembly (NGCA) by heat-treatment with diphenyldisulfide and/or diphenyldiselenide. It is demonstrated that S and Se are successfully doped in the carbon lattice with dominant phases of -C-S-C- and -C-Se-C-, respectively. In the ORRs, the prepared materials exhibit similar onset potentials at similar to 0.85 V (vs.RHE) regardless of chalcogenation. However, the additional doping of S and/or Se in the NGCA increases the current from ORRs in acid media. Specifically, additional Se-doping demonstrates significantly improved ORR activity with a high methanol tolerance and long-term stability in acid media compared to Pt/C. It is suggested that the high ORR activity of the carbon materials is related to the asymmetric spin and charge densities of the carbon atoms, which are enhanced by the additional doping of S and/or Se.
Electrocatalytic conversion of CO
into value-added products offers a new paradigm for a sustainable carbon economy. For active CO
electrolysis, the single-atom Ni catalyst has been proposed as ...promising from experiments, but an idealized Ni-N
site shows an unfavorable energetics from theory, leading to many debates on the chemical nature responsible for high activity. To resolve this conundrum, here we investigated CO
electrolysis of Ni sites with well-defined coordination, tetraphenylporphyrin (N
-TPP) and 21-oxatetraphenylporphyrin (N
O-TPP). Advanced spectroscopic and computational studies revealed that the broken ligand-field symmetry is the key for active CO
electrolysis, which subordinates an increase in the Ni redox potential yielding Ni
. Along with their importance in activity, ligand-field symmetry and strength are directly related to the stability of the Ni center. This suggests the next quest for an activity-stability map in the domain of ligand-field strength, toward a rational ligand-field engineering of single-atom Ni catalysts for efficient CO
electrolysis.
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