TbMnO3 is an orthorhombic insulator where incommensurate spin order for temperature T(N)<41 K is accompanied by ferroelectric order for T<28 K. To understand this, we establish the magnetic structure ...above and below the ferroelectric transition using neutron diffraction. In the paraelectric phase, the spin structure is incommensurate and longitudinally modulated. In the ferroelectric phase, however, there is a transverse incommensurate spiral. We show that the spiral breaks spatial inversion symmetry and can account for magnetoelectricity in TbMnO3.
The genetics behind the progression of myelodysplasia to secondary acute myeloid leukemia (sAML) is poorly understood. In this study, we profiled somatic mutations and their dynamics using next ...generation sequencing on serial samples from a total of 124 patients, consisting of a 31 patient discovery cohort and 93 patients from two validation cohorts. Whole-exome analysis on the discovery cohort revealed that 29 of 31 patients carry mutations related to at least one of eight commonly mutated pathways in AML. Mutations in genes related to DNA methylation and splicing machinery were found in T-cell samples, which expand at the initial diagnosis of the myelodysplasia, suggesting their importance as early disease events. On the other hand, somatic variants associated with signaling pathways arise or their allelic burdens expand significantly during progression. Our results indicate a strong association between mutations in activated signaling pathways and sAML progression. Overall, we demonstrate that distinct categories of genetic lesions play roles at different stages of sAML in a generally fixed order.
Thoracic epidural analgesia is the standard postoperative pain management strategy in esophageal cancer surgery. However, paravertebral block analgesia may achieve comparable pain control while ...inducing less side effects, which may be beneficial for postoperative recovery. This study primarily aims to compare the postoperative quality of recovery between paravertebral catheter versus thoracic epidural analgesia in patients undergoing minimally invasive esophagectomy.
This study represents a randomized controlled superiority trial. A total of 192 patients will be randomized in 4 Dutch high-volume centers for esophageal cancer surgery. Patients are eligible for inclusion if they are at least 18 years old, able to provide written informed consent and complete questionnaires in Dutch, scheduled to undergo minimally invasive esophagectomy with two-field lymphadenectomy and an intrathoracic anastomosis, and have no contra-indications to either epidural or paravertebral analgesia. The primary outcome is the quality of postoperative recovery, as measured by the Quality of Recovery-40 (QoR-40) questionnaire on the morning of postoperative day 3. Secondary outcomes include the QoR-40 questionnaire score Area Under the Curve on postoperative days 1-3, the integrated pain and systemic opioid score and patient satisfaction and pain experience according to the International Pain Outcomes (IPO) questionnaire, and cost-effectiveness. Furthermore, the groups will be compared regarding the need for additional rescue medication on postoperative days 0-3, technical failure of the pain treatment, duration of anesthesia, duration of surgery, total postoperative fluid administration day 0-3, postoperative vasopressor and inotrope use, length of urinary catheter use, length of hospital stay, postoperative complications, chronic pain at six months after surgery, and other adverse effects.
In this study, it is hypothesized that paravertebral analgesia achieves comparable pain control while causing less side-effects such as hypotension when compared to epidural analgesia, leading to shorter postoperative length of stay on a monitored ward and superior quality of recovery. If this hypothesis is confirmed, the results of this study can be used to update the relevant guidelines on postoperative pain management for patients undergoing minimally invasive esophagectomy.
Netherlands Trial Registry, NL8037. Registered 19 September 2019.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Activation of the extensive cross-talk among the receptor tyrosine kinases (RTKs), particularly ErbB family-Met cross-talk, has emerged as a likely source of drug resistance. Notwithstanding ...brilliant successes were attained while using small-molecule inhibitors or antibody therapeutics against specific RTKs in multiple cancers over recent decades, a high recurrence rate remains unsolved in patients treated with these targeted inhibitors. It is well aligned with multifaceted properties of cancer and cross-talk and convergence of signaling pathways of RTKs. Thereby many therapeutic interventions have been actively developed to overcome inherent or acquired resistance. To date, no bispecific antibody (BsAb) showed complete depletion of dual RTKs from the plasma membrane and efficient dual degradation. In this manuscript, we report the first findings of a target-specific dual internalization and degradation of membrane RTKs induced by designed BsAbs based on the internalizing monoclonal antibodies and the therapeutic values of these BsAbs. Leveraging the anti-Met mAb able to internalize and degrade by a unique mechanism, we generated the BsAbs for Met/epidermal growth factor receptor (EGFR) and Met/HER2 to induce an efficient EGFR or HER2 internalization and degradation in the presence of Met that is frequently overexpressed in the invasive tumors and involved in the resistance against EGFR- or HER2-targeted therapies. We found that Met/EGFR BsAb ME22S induces dissociation of the Met-EGFR complex from Hsp90, followed by significant degradation of Met and EGFR. By employing patient-derived tumor models we demonstrate therapeutic potential of the BsAb-mediated dual degradation in various cancers.
Objectives
HIV‐associated neurocognitive disorder (HAND) is an independent predictor of early mortality and is associated with many difficulties in activities of daily living. We sought to determine ...the prevalence of and risk factors for HAND in HIV‐infected Koreans. In addition, we investigated the performance of screening tools and components of neuropsychological (NP) tests for diagnosing HAND.
Methods
HIV‐infected patients were enrolled consecutively from two different urban teaching hospitals in Seoul, South Korea between March 2012 and September 2012. Participants completed a detailed NP assessment of six cognitive domains commonly affected by HIV. The Frascati criteria were used for diagnosing HAND. Four key questions, the International HIV Dementia Scale (IHDS) and Montreal Cognitive Assessment (MoCA)‐K were also assessed as potential tools for screening for HAND.
Results
Among the 194 participants, the prevalence of HAND was 26.3%. Asymptomatic neurocognitive impairment and minor neurocognitive disorder accounted for 52.9 and 47.1% of the patients with HAND, respectively. In multivariate analysis, haemoglobin (Hb) level ≤ 13 g/dL (P = 0.046) and current use of a protease inhibitor‐based regimen (P = 0.031) were independent risk factors for HAND. The sensitivity and specificity of the IHDS were 72.6 and 60.8%, and those of MoCA‐K were 52.9 and 73.4%, respectively. The IHDS (P < 0.001) and MoCA‐K (P < 0.001) were both useful for screening for HAND. Among NP tests, the sensitivity and specificity of the Grooved Pegboard Test were 90.2 and 72.0%, and those of the Wisconsin Card Sorting Test were 61.2 and 84.4%, respectively.
Conclusions
HAND is a prevalent comorbidity in HIV‐infected Koreans. Active screening and diagnosis with effective tools, such as the IHDS, MoCA‐K and Grooved Pegboard Test, could be used to identify this important complication.
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A magnetized inductively coupled plasma ion beam etcher (MICP-IBE) was designed by employing electromagnets around the etcher (IBE). A magnetic field can be set up such that the magnitude of the ...magnetic flux density on the screen grid increases or decreases with the radial distance from the screen grid center. Four different types of magnetic field conditions were considered. The plasma densities and electron temperatures were measured as functions of radial distance from the screen grid center under each condition. In addition, ion flux was measured with respect to radial distance from the substrate center using ion energy analyzer (IEA), after which the uniformity characteristics of the ion flux in the substrate were investigated. The dry etching characteristics of CoFeB, a typical alloy being used in the magnetic memory device, were investigated. The uniformity characteristics of the ion flux and the etch rate can be improved with the proper design of magnetic field conditions; however, the improvement was confirmed to be limited. In this respect, a new screen and acceleration grid were designed that have different grid hole densities with radial distance from the grid center (hereafter referred to as the proposed grid). Using the proposed grid, the ion flux and etch rate of CoFeB were measured with respect to radial distance from the substrate center, to see if the radial etch rate uniformity can be improved further. The CoFeB etch rate non-uniformity in the proposed grid (11.65%) was lower than that for the conventional grid (17.5%).
Although a great deal is known biochemically about peroxiredoxins (Prxs), little is known about their real physiological function. We show here that two cytosolic yeast Prxs, cPrxI and II, which ...display diversity in structure and apparent molecular weights (MW), can act alternatively as peroxidases and molecular chaperones. The peroxidase function predominates in the lower MW forms, whereas the chaperone function predominates in the higher MW complexes. Oxidative stress and heat shock exposure of yeasts causes the protein structures of cPrxI and II to shift from low MW species to high MW complexes. This triggers a peroxidase-to-chaperone functional switch. These in vivo changes are primarily guided by the active peroxidase site residue, Cys
47, which serves as an efficient “H
2O
2-sensor” in the cells. The chaperone function of these proteins enhances yeast resistance to heat shock.
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