Genetic diagnosis of inborn errors of immunity using clinical exome sequencing

Inborn errors of immunity (IEI) include a variety of heterogeneous genetic disorders in which defects in the immune system lead to an increased susceptibility to infections and other complications. Accurate, prompt diagnosis of IEI is crucial for treatment plan and prognostication. In this study, clinical utility of clinical exome sequencing (CES) for diagnosis of IEI was evaluated. For 37 Korean patients with suspected symptoms, signs, or laboratory abnormalities associated with IEI, CES that covers 4,894 genes including genes related to IEI was performed. Their clinical diagnosis, clinical characteristics, family history of infection, and laboratory results, as well as detected variants, were reviewed. With CES, genetic diagnosis of IEI was made in 15 out of 37 patients (40.5%). Seventeen pathogenic variants were detected from IEI-related genes, BTK, UNC13D, STAT3, IL2RG, IL10RA, NRAS, SH2D1A, GATA2, TET2, PRF1, and UBA1, of which four variants were previously unreported. Among them, somatic causative variants were identified from GATA2, TET2, and UBA1. In addition, we identified two patients incidentally diagnosed IEI by CES, which was performed to diagnose other diseases of patients with unrecognized IEI. Taken together, these results demonstrate the utility of CES for the diagnosis of IEI, which contributes to accurate diagnosis and proper treatments

Comparison of treatment plans between IMRT with MR-linac and VMAT for lung SABR

Background The aim of this study was to compare the plan quality of magnetic-resonance image-based intensity modulated radiation therapy (MRI-based-IMRT) with the MRIdian Linac system to that of volumetric modulated arc therapy (VMAT) with the TrueBeam STx system for lung stereotactic ablative radiotherapy (SABR). Methods A total of 22 patients with tumors located in the lower lobe were retrospectively selected for the study. For each patient, both the MRI-based-IMRT and VMAT plans were generated using an identical CT image set and identical structures with the exception of the planning target volume (PTV). The PTVs of the MRI-based-IMRT were generated by adding an isotropic margin of 3 mm from the gross tumor volume, whereas those of VMAT were generated by adding an isotropic margin of 5 mm from the internal target volume. For both the MRI-based-IMRT and VMAT, the prescription doses to the PTVs were 60 Gy in four fractions. Results The average PTV volume of the MRI-based-IMRT was approximately 4-times smaller than that of VMAT (p <  0.001). The maximum dose to the bronchi for the MRI-based-IMRT was smaller than that for the VMAT (20.4 Gy versus 24.2 Gy, p <  0.001). In addition, V40Gy of the rib for the MRI-based-IMRT was smaller than that for the VMAT (1.8 cm3 versus 7.7 cm3, p = 0.008). However, the maximum doses to the skin and spinal cord for the MRI-based-IMRT (33.0 Gy and 14.5 Gy, respectively) were larger than those for the VMAT (27.8 Gy and 11.0 Gy, respectively) showing p values of less than 0.02. For the ipsilateral lung, the mean dose, V20Gy, V10Gy, and V5Gy for the MRI-based-IMRT were smaller than those for the VMAT (all with p <  0.05). For the contralateral lung, V5Gy, V10Gy, D1500cc, and D1000cc for the MRI-based-IMRT were larger than those for the VMAT (all with p <  0.05). The mean dose and V50% of the whole body for the MRI-based-IMRT were smaller than those for the VMAT (0.9 Gy versus 1.2 Gy, and 78.7 cm3 versus 103.5 cm3, respectively, all at p <  0.001). Conclusions The MRI-based-IMRT using the MRIdian Linac system could reduce doses to bronchi, rib, ipsilateral lung, and whole body compared to VMAT for lung SABR when the tumor was located in the lower lobe.This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (No. 2017M2A2A7A02020640, 2017M2A2A7A02020641, and 2017M2A2A7A02020643)

Effect of changes in monitor unit rate and energy on dose rate of total marrow irradiation based on Linac volumetric arc therapy

Background This study set out to evaluate the effect of dose rate on normal tissues (the lung, in particular) and the variation in the treatment efficiency as determined by the monitor unit (MU) and energy applied in Linac-based volumetric arc therapy (VMAT) total marrow irradiation (TMI). Methods Linac-based VMAT plans were generated for the TMI for six patients. The planning target volume (PTV) was divided into six sub-volumes, each of which had their own isocenter. To examine the effect of the dose rate and energy, a range of MU rates (40, 60, 80, 100, 300, and 600 MU/min) were selected for 6, 10, and 15 MV. All the plans were verified by portal dosimetry. Results The dosimetric parameters for the target and normal tissue were consistent in terms of the energy and MU rate. The beam-on time was changed from 59.6 to 6 min for 40 and 600 MU/min. When 40 MU/min was set for the lung, the dose rate delivered to the lung was less than 6 cGy/min (that is, 90%), while the beam-on time was approximately 10 min. The percentage volume of the lung receiving 20 cGy/min was 1.47, 3.94, and 6.22% at 6, 10, and 15 MV, respectively. However, for 600 MU/min, the total lung volume received over 6 cGy/min regardless of the energy, and over 20 cGy/min for 10 and 15 MV (i.e., 54.4% for 6 MV). Conclusions In TMI treatment, reducing the dose rate administered to the lung can decrease the incidence of pulmonary toxicity. To reduce the probability of normal tissue complications, the selection of the lowest MU rate is recommended for fields including the lung. To minimize the total treatment time, the maximum MU rate can be applied to other fields.This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (no. 2017M2A2A7A02020641) and the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (no. HA 16C0025)

Evaluation of effectiveness of fault-tolerant techniques in a digital instrumentation and control system with a fault injection experiment

Recently, instrumentation and control (I&amp;C) systems in nuclear power plants have undergone digitalization. Owing to the unique characteristics of digital I&amp;C systems, the reliability analysis of digital systems has become an important element of probabilistic safety assessment (PSA). In a reliability analysis of digital systems, fault-tolerant techniques and their effectiveness must be considered. A fault injection experiment was performed on a safety-critical digital I&amp;C system developed for nuclear power plants to evaluate the effectiveness of fault-tolerant techniques implemented in the target system. A software-implemented fault injection in which faults were injected into the memory area was used based on the assumption that all faults in the target system will be reflected in the faults in the memory. To reduce the number of required fault injection experiments, the memory assigned to the target software was analyzed. In addition, to observe the effect of the fault detection coverage of fault-tolerant techniques, a PSA model was developed. The analysis of the experimental result also can be used to identify weak points of fault-tolerant techniques for capability improvement of fault-tolerant techniques

Efficacy of tetracyclines and fluoroquinolones for the treatment of macrolide-refractory Mycoplasma pneumoniae pneumonia in children: a systematic review and meta-analysis

Abstract Background Mycoplasma pneumoniae is a common pathogen that causes community-acquired pneumonia in school-age children. Macrolides are considered a first-line treatment for M. pneumoniae infection in children, but macrolide-refractory M. pneumoniae (MRMP) strains have become more common. In this study, we assessed the efficacy of tetracyclines and fluoroquinolones in MRMP treatment in children through a systematic review and meta-analysis. Methods Two reviewers individually searched 10 electronic databases (Medline/Pubmed, Embase, the Cochrane Library, and core Korean, Chinese, and Japanese journals) for papers published from January 1, 1990 to March 8, 2018. The following data for each treatment group were extracted from the selected studies: intervention (tetracyclines and fluoroquinolones/comparator), patient characteristics (age and sex), and outcomes (fever duration, hospital stay length, treatment success rate, and defervescence rates 24, 48, and 72 h after starting treatment). Results Eight studies involving 537 participants were included. Fever duration and hospital stay length were shorter in the tetracycline group than in the macrolide group (weighted mean difference [WMD] = − 1.45, 95% confidence interval [CI]: − 2.55 to − 0.36, P = 0.009; and WMD = − 3.33, 95% CI: − 4.32 to − 2.35, P < 0.00001, respectively). The therapeutic efficacy was significantly higher in the tetracycline group than in the macrolide group (odds ratio [OR]: 8.80, 95% CI: 3.12–24.82). With regard to defervescence rate, patients in the tetracycline group showed significant improvement compared to those in the macrolide group (defervescence rate after 24 h, OR: 5.34, 95% CI: 1.81–15.75; after 48 h, OR 18.37, 95% CI: 8.87–38.03; and after 72 h, OR: 40.77, 95% CI: 6.15–270.12). There were no differences in fever improvement within 24 h in patients in the fluoroquinolone group compared to those in the macrolide group (OR: 1.11, 95% CI: 0.25–5.00), although the defervescence rate was higher after 48 h in the fluoroquinolone group (OR: 2.78, 95% CI: 1.41–5.51). Conclusion Tetracyclines may shorten fever duration and hospital stay length in patients with MRMP infection. Fluoroquinolones may achieve defervescence within 48 h in patients with MRMP infection. However, these results should be carefully interpreted as only a small number of studies were included, and they were heterogeneous.This study was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare, Republic of Korea (Grant number: HI16C2300)

Characteristics and outcomes of endoscopically resected colorectal cancers that arose from sessile serrated adenomas and traditional serrated adenomas

Background/AimsThe efficacy and safety of endoscopic resection of colorectal cancer derived from sessile serrated adenomas or traditional serrated adenomas are still unknown. The aims of this study were to verify the characteristics and outcomes of endoscopically resected early colorectal cancers developed from serrated polyps.MethodsAmong patients who received endoscopic resection of early colorectal cancers from 2008 to 2011, cancers with documented pre-existing lesions were included. They were classified as adenoma, sessile serrated adenoma, or traditional serrated adenoma according to the baseline lesions. Clinical characteristics, pathologic diagnosis, and outcomes were reviewed.ResultsOverall, 208 colorectal cancers detected from 198 patients were included: 198 with adenoma, five with sessile serrated adenoma, and five with traditional serrated adenoma. The sessile serrated adenoma group had a higher prevalence of high-grade dysplasia (40.0% vs. 25.8%, P<0.001) than the adenoma group. During follow-up, local recurrence did not occur after endoscopic resection of early colorectal cancers developed from serrated polyps. In contrast, two cases of metachronous recurrence were detected within a short follow-up period.ConclusionsCautious observation and early endoscopic resection are recommended when colorectal cancer from serrated polyp is suspected. Colorectal cancers from serrated polyp can be treated successfully with endoscopy

Radiosensitization with combined use of olaparib and PI-103 in triple-negative breast cancer

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.Abstract Background Triple-negative breast cancer (TNBC) shows aggressive clinical behavior, but the treatment options are limited due to lack of a specific target. TNBC shares many clinical and pathological similarities with BRCA-deficient breast cancer, for which poly(ADP-ribose) polymerase (PARP) inhibitor is effective, but PARP inhibitor alone failed to show clinical effects in patients with sporadic TNBC. Radiation induces DNA double-strand breaks, and the phosphoinositide 3-kinase (PI3K) signaling pathway has been known to regulate steady-state levels of homologous recombination. A recent preclinical study showed that PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA-proficient TNBC to PARP inhibition. Therefore, we assessed the radiosensitizing effect, and the underlying mechanism of combination treatment with PARP inhibitor olaparib and PI3K inhibitor PI-103 in BRCA-proficient TNBC cells. Methods MDA-MB-435S cells were divided into four treatment groups, irradiation (IR) alone, olaparib plus IR, PI-103 plus IR, and olaparib plus PI-103 plus IR. Cells were exposed to the drugs for 2 hours prior to irradiation, and the cell survival curve was obtained using a clonogenic assay. Western blotting and immunofluorescent detection of γH2AX foci were performed. Xenograft and bioluminescence imaging were carried out to assess in vivo radiosensitivity. Results Combined use of olaparib and PI-103 enhanced radiation-induced death of MDA-MB-435S (sensitizer enhancement ratio[SER]0.05,1.7) and MDA-MB-231-BR (SER0.05,2.1) cells and significantly reduced tumor volume in a xenograft models (P < 0.001). Treatment with PI-103 showed persistent γH2AX foci, indicating delayed repair of DNA strand breaks. PI-103 alone increased levels of poly(ADP-ribose) and phosphorylated extracellular signal-regulated kinase, and downregulated BRCA1. Conclusions Combined use of olaparib and PI-103 enhanced radiation-induced cell death in BRCA-proficient MDA-MB-435S and MDA-MB-231-BR cells and xenografts. TNBC patients have high incidences of locoregional relapse and distant metastasis, and radiation therapy targets both locoregional control and treatment of distant recurrences such as brain metastasis or other oligometastasis. Targeting of the PI3K signaling pathway combined with PARP inhibition maybe a feasible approach to enhance effects of radiation in BRCA-proficient TNBC

Toll-like receptor 2 downregulation and cytokine dysregulation predict mortality in patients with Staphylococcus aureus bacteremia

Background Staphylococcus aureus bacteremia (SAB) presents heterogeneously, owing to the differences in underlying host conditions and immune responses. Although Toll-like receptor 2 (TLR2) is important in recognizing S. aureus, its function during S. aureus infection remains controversial. We aimed to examine the association of TLR2 expression and associated cytokine responses with clinical SAB outcomes. Methods Patients from a prospective SAB cohort at two tertiary-care medical centers were enrolled. Blood was sampled at several timepoints (≤5 d, 6–9 d, 10–13 d, 14–19 d, and ≥ 20 d) after SAB onset. TLR2 mRNA levels were determined via real-time PCR and serum tumor necrosis factor [TNF]-α, interleukin [IL]-6, and IL-10 levels were analyzed with multiplex-high-sensitivity electrochemiluminescent ELISA. Results TLR2 levels varied among 59 SAB patients. On days 2–5, TLR2 levels were significantly higher in SAB survivors than in healthy controls (p = 0.040) and slightly but not significantly higher than non-survivors (p = 0.120), and SAB patients dying within 7 d had lower TLR2 levels than survivors (P = 0.077) although statistically insignificant. IL-6 and IL-10 levels were significantly higher in non-survivors than in survivors on days 2–5 post-bacteremia (P = 0.010 and P = 0.021, respectively), and those dying within 7 d of SAB (n = 3) displayed significantly higher IL-10/TNF-α ratios than the survivors did (P = 0.007). Conclusion TLR2 downregulation and IL-6 and IL-10 concentrations suggestive of immune dysregulation during early bacteremia may be associated with mortality from SAB. TLR2 expression levels and associated cytokine reactions during early-phase SAB may be potential prognostic factors in SAB, although larger studies are warranted.This study was supported by a research grant (13–2014-002) from Seoul National University Bundang Hospital (Seongnam, South Korea). The funder had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript

Neural Dynamics of Olfactory Perception: Low- and High-Frequency Modulations of Local Field Potential Spectra in Mice Revealed by an Oddball Stimulus

Recent brain connectome studies have evidenced distinct and overlapping brain regions involved in processing olfactory perception. However, neural correlates of hypo- or anosmia in olfactory disorder patients are poorly known. Furthermore, the bottom-up and top-down processing of olfactory perception have not been well-documented, resulting in difficulty in locating the disease foci of olfactory disorder patients. The primary aim of this study is to characterize the bottom-up process of the neural dynamics across peripheral and central brain regions in anesthetized mice. We particularly focused on the neural oscillations of local field potential (LFP) in olfactory epithelium (OE), olfactory blub (OB), prefrontal cortex (PFC), and hippocampus (HC) during an olfactory oddball paradigm in urethane anesthetized mice. Odorant presentations evoked neural oscillations across slow and fast frequency bands including delta (1–4 Hz), theta (6–10 Hz), beta (15–30 Hz), low gamma (30–50 Hz), and high gamma (70–100 Hz) in both peripheral and central nervous systems, and the increases were more prominent in the infrequently presented odorant. During 5 s odorant exposures, the oscillatory responses in power were persistent in OE, OB, and PFC, whereas neural oscillations of HC increased only for short time at stimulus onset. These oscillatory responses in power were insignificant in both peripheral and central regions of the ZnSO4-treated anosmia model. These results suggest that olfactory stimulation induce LFP oscillations both in the peripheral and central nervous systems and suggest the possibility of linkage of LFP oscillations in the brain to the oscillations in the peripheral olfactory system