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Identification of specific leukemia subtypes is a key to successful risk-directed therapy in childhood acute lymphoblastic leukemia (ALL). Although RNA sequencing (RNA-seq) is the best approach to identify virtually all specific leukemia subtypes, the routine use of this method is too costly for patients in resource-limited countries. This study enrolled 295 patients with pediatric ALL from 2010 to 2020. Routine screening could identify major cytogenetic alterations in approximately 69% of B-cell ALL (B-ALL) cases by RT-PCR, DNA index, and multiplex ligation-dependent probe amplification. STIL-TAL1 was present in 33% of T-cell ALL (T-ALL) cases. The remaining samples were submitted for RNA-seq. More than 96% of B-ALL cases and 74% of T-ALL cases could be identified based on the current molecular classification using this sequential approach. Patients with Philadelphia chromosome-like ALL constituted only 2.4% of the entire cohort, a rate even lower than those with ZNF384-rearranged (4.8%), DUX4-rearranged (6%), and Philadelphia chromosome-positive (4.4%) ALL. Patients with ETV6-RUNX1, high hyperdiploidy, PAX5 alteration, and DUX4 rearrangement had favorable prognosis, whereas those with hypodiploid and KMT2A and MEF2D rearrangement ALL had unfavorable outcomes. With the use of multiplex ligation-dependent probe amplification, DNA index, and RT-PCR in B-ALL and RT-PCR in T-ALL followed by RNA-seq, childhood ALL can be better classified to improve clinical assessments.

Background/purpose Antimicrobial resistance in Taiwan has been on the rise for two decades. The implementation of pneumococcal conjugate vaccination (PCV13) and enhanced antimicrobial control (2013–2015) by the government may have changed the antibiotic resistance. Methods Four respiratory pathogens (Streptococcus pneumoniae, Haemophilus influenzae, Streptococcus pyogenes, and Moraxella catarrhalis) isolated in a single medical center during 2008–2017 were studied. We defined three temporal stages: (a) the first era (2008–2012), prior to implementation of the national immunization program (PCV13 vaccination), (b) the second era (2013–2015), during which an enhanced antibiotic control strategy was implemented, and (c) the third era (2016–2017), after implementation. Antimicrobial drug sensitivities were collected from two other hospitals: one from east Taiwan, one from west-central Taiwan. Results S. pneumoniae was frequently isolated during the first era. It declined progressively during the second era of PCV13 vaccination. S. pyogenes and M. catarrhalis were not frequently isolated. The drug susceptibility of S. pneumoniae to ceftriaxone and vancomycin remained high. The antimicrobial susceptibility of H. influenzae to amoxillin/clavulante declined over the three temporal stages, from 91.9%-79.5%–58.5% (all p Conclusion Antimicrobial resistance of H. influenzae increased during the latter part of the study period. The PCV13 vaccination program reduced the invasive pneumococcal disease and reduced the stress on the emergent drug resistance. This enhanced antibiotic control strategy was effective in terms of nosocomial drug resistance but not for community-associated pathogens.

B-cell acute lymphoblastic lymphoma (B-ALL) is a disease found mainly in children and in young adults. B-ALL is characterized by the rapid proliferation of poorly differentiated lymphoid progenitor cells inside the bone marrow. In the United States, ~4,000 of these patients are diagnosed each year, accounting for ~30% of childhood cancer types. The tumorigenesis of the disease involves a number of abnormal gene expressions (including TEL-AML1, BCR-ABL-1, RAS and PI3K) leading to dysregulated cell cycle. Risk factors of B-ALL are the history of parvovirus B 19 infection, high birth weight and exposure to environmental toxins. These risk factors can induce abnormal DNA methylation and DNA damages. Treatment procedures are divided into three phases: Induction, consolidation and maintenance. The goal of treatment is complete remission without relapses. Apart from traditional treatments, newly developed approaches include gene targeting therapy, with the aim of wiping out leukemic cells through the inhibition of mitogen-activated protein kinases and via c-Myb inhibition enhancing sensitivity to chemotherapy. To evaluate the efficacy of ongoing treatments, several indicators are currently used. The indicators include the expression levels of microRNAs (miRs) miR-146a, miR-155, miR-181a and miR-195, and soluble interleukin 2 receptor. Multiple drug resistance and levels of glutathione reductase can affect treatment efficacy through the increased efflux of anti-cancer drugs and weakening the effect of chemotherapy through the reduction of intracellular reactive oxygen species. The present review appraised recent studies on B-ALL regarding its pathogenesis, risk factors, treatments, treatment evaluation and causes of disease relapse. Understanding the mechanisms of B-ALL initiation and causes of treatment failure can help physicians improve disease management and reduce relapses.

Background: Enterovirus-D68 (EV-D68) has been endemic in Taiwan for some years with a small number of positive cases. Detailed information about respiratory presentation is lacking. This study characterized the clinical course in children admitted to the medical center and regional hospital in Taichung during 2015. Methods: Retrospective chart review of patients with confirmed EV-D68 infection admitted to the medical center and regional hospital in Taichung with respiratory symptoms in the second half of 2015. Past medical history, clinical presentation, management, and course in hospital were collected and analyzed. Simple demographic data and clinical symptoms were also collected from patients confirmed with EV-D68 infection who visited clinics in Taichung. Results: Six children were included. Two patients had a prior history of asthma or recurrent dyspnea, and one had other preexisting medical comorbidities. One child was admitted to the pediatric intensive care unit. All the patients were cured. Cough, rhinorrhea, tachypnea and fever were the most common clinical symptoms among inpatients, while influenza-like illness (ILI) was prevalent in outpatients. Conclusion: EV-D68 infection resulted in respiratory presentations of asthma-like illness in the hospitalized pediatric population. Patients with a prior history of asthma or recurrent dyspnea appear to be more severely affected. Key Words: enterovirus D68, respiratory presentation, taiwan

Refractory/relapsed acute myeloid leukemia is an advanced hematological malignancy with a poor prognosis in pediatric. The therapeutic options are limited and has been slow development of therapies for this age group. A combination of Venetoclax and Azacitidine therapy in newly diagnosed elderly patients with acute myeloid leukemia and refractory/relapsed disease has achieved impressive results. Whether similar results can be attained in pediatric patients is unknown. We present a case of adolescent girl with acute myeloid leukemia secondary to myelodysplastic syndrome, who was deemed unfit to undergo conventional chemotherapy and, was treated instead with the Venetoclax and Azacitidine.

T-cell acute lymphoblastic leukemia (T-ALL) is a common pediatric malignancy, characterized by the abnormal presence of immature T-cell progenitors. Conventional treatments for T-ALL fail to prevent or cure the disease, with a high-risk of recurrence after the first remission. Thus, medical options are in demand to develop novel therapies for patients suffering with T-ALL. Niclosamide, a traditional oral anti-helminthic drug, has been reported to be a potential anticancer agent that regulates intracellular signaling pathways. Few studies have yet investigated the effects of niclosamide on the development of T-ALL. Here, the present study aimed to investigate the anti-leukemia effects of niclosamide on T-ALL. We first hypothesized that the suppressive effects of niclosamide on the tumor growth of T-ALL are exerted by regulating autophagy and apoptosis. Following niclosamide treatment, T-ALL cell viability was evaluated using MTT assay, and apoptosis with Annexin V/propidium iodide staining. In T-ALL cells treated with niclosamide, changes in apoptosis- and autophagy-related proteins were analyzed by western blotting. In addition, in an in vivo model, T-ALL xenograft mice were used to study the anti-leukemia effects of niclosamide. The results showed that niclosamide significantly reduced the viability of Jurkat and CCRF-CEM T-ALL cells in both a dose- and time-dependent manner. Niclosamide significantly activated the early and late phases of apoptosis in Jurkat (at 2 µM) and CCRF-CEM cells (at 1 µM). Furthermore, niclosamide upregulated protein expression of cleaved caspase-3 and LC3B, while downregulated those of Bcl-2 and p62, in a dose-dependent manner in both Jurkat and CCRF-CEM cells. The in vivo results showed that niclosamide treatment significantly suppressed tumor growth and the disease progression in T-ALL xenograft mice by activating cleaved caspase-3 and LC3B. We conclude that niclosamide plays an anti-leukemia role, and that it represents a novel approach for the treatment of T-ALL.

BACKGROUND The totally implanted vascular access device (TIVAD) is commonly used in patients with malignant tumors requiring chemotherapy or long-term intravenous infusion and those with difficulty placing peripheral venous catheters. It could also be used to draw blood in pediatric patients. Thus, how to maintain the patency and longevity of TIVAD is always emphasized. METHODS In this prospective study, TIVAD was randomly infused in patients under 18 years with three different concentrations of heparinized solutions: 10 mL with 100 U/ mL heparin, 20 mL with 10 U/mL heparin, and 30 mL with 10 U/mL heparin. RESULTS A total of 81 patients (46 males and 35 females) were enrolled in this study from Aug. 2, 2013, to Feb. 1, 2017. The mean age of those who received TIVAD implantation was 7.2 ± 5.3 years, and the mean duration of using TIVAD was 1027.6 ± 369.1 days. Patients without catheter occlusion events experienced significantly shorter hospitalizations, fewer admissions, and fewer punctures than those with catheter occlusion events (p < 0.05). The administration and frequency of blood transfusions, history of bacteremia, and medication history did not increase the risk of catheter occlusion, but puncture frequency increased this risk. In patients with catheter occlusion events (38/81, 46.9%), catheter patency was restored after instillation of urokinase solution. CONCLUSION In this study, the risk of TIVAD catheter occlusion was only related to puncture frequency regardless of the heparin flush composition or patient characteristics. A high puncture frequency of TIVAD during the 3.5-year study period significantly increased the risk of catheter occlusion. Besides, flushing and locking solutions for TIVAD using heparin at 10 U/mL was effective as using heparin at 100 U/mL regardless of the flushing volume of 10, 20 or 30 mL.

Background The factors that predict the progression of Mycoplasma pneumoniae infection remain inconclusive. Therefore, we investigated macrolide resistance prevalence, M pneumoniae genotype, and clinical characteristics of childhood M pneumoniae respiratory tract infections in Taiwan. Methods A total of 295 children hospitalized with respiratory tract infections with positive serological M pneumoniae immunoglobulin M test results were enrolled in this 3-year prospective study. Oropharyngeal swabs were obtained for M pneumoniae cultures and polymerase chain reaction tests. All M pneumoniae specimens were further characterized by P1 typing, multilocus variable-number tandem-repeat analysis (MLVA), and macrolide resistance genotyping. The clinical characteristics and blood cytokine profiles were analyzed accordingly. Results Of 138 M pneumoniae specimens, type I P1 was the predominant (136 of 138, 98.6%). The MLVA type P (4-4-5-7-2) was the leading strain (42 of 138, 30.4%), followed by type J, U, A, and X. The overall macrolide-resistant rate was 38.4% (53 of 138); the resistance rate increased dramatically yearly: 10.6% in 2017, 47.5% in 2018, and 62.5% in 2019 (P, We present a 3-year prospective study on the molecular epidemiology, clinical characteristics, and cytokine profiles of childhood M pneumoniae infection in Taiwan. An increased macrolide resistance rate associated with emergence of MLVA type U was noted.

Background/purpose: Staphylococcus aureus (S. aureus) causes diseases ranging from mild skin infections to invasive diseases. Carriage of S. aureus, including methicillin-resistant S. aureus (MRSA), is a significant risk factor for subsequent staphylococcal infection. Several studies discussed MRSA colonization in Taiwan, but mostly in northern Taiwan. This is the first study that estimates the prevalence of MRSA nasal colonization in healthy children and identifies the potential risk factors in central Taiwan. Methods: A total of 3144 healthy children aged 2–60 months who visited Taichung Veterans General Hospital (TCVGH) were screened for nasal S. aureus carriage from July 2005 to December 2010. Questionnaires included demographic information and potential risk factors for carriage of S. aureus were completed by parents/guardians. Results: Prevalence of MSSA and MRSA were 12.09% and 5.25%, respectively. The youngest group aged 2–6 months had the highest S. aureus carriage rate, and the carriage rate revealed a peak in summer. The nasal colonization of Streptococcus pneumoniae (S. pneumoniae) was a protective factor against S. aureus colonization. 85% of the MRSA colonizing isolates belonged to clonal complex 59/staphylococcal cassette chromosome type IV or VT, the local community clone in Taiwan. Conclusion: An increasing trend of MRSA nasal carriage rate in Taiwan had been brought forward, however, it was not observed in central Taiwan during the period of 2005–2010. We found a summer peak on both MRSA and MSSA carriages. Keywords: Central Taiwan, Children, Methicillin-resistant Staphylococcus aureus colonization

Background: Acute lymphoblastic leukemia (ALL) is a malignant disease characterized by an excessive number of immature lymphocytes, including immature precursors of both B- and T cells. ALL affects children more often than adults. Immature lymphocytes lead to arrested differentiation and proliferation of cells. Its conventional treatments involve medication with dexamethasone, vincristine, and other anticancer drugs. Although the current first-line drugs can achieve effective treatment, they still cannot prevent the recurrence of some patients with ALL. Treatments have high risk of recurrence especially after the first remission. Currently, novel therapies to treat ALL are in need. Autophagy and apoptosis play important roles in regulating cancer development. Autophagy involves degradation of proteins and organelles, and apoptosis leads to cell death. These phenomena are crucial in cancer progression. Past studies reported that many potential anticancer agents regulate intracellular signaling pathways. Methods: The authors discuss the recent research findings on the role of autophagy and apoptosis in ALL. Results: The autophagy and apoptosis are widely used in the treatment of ALL. Most studies showed that many agents regulate autophagy and apoptosis in ALL cell models, clinical trials, and ALL animal models. Conclusions: In summary, activating autophagy and apoptosis pathways are the main strategies for ALL treatments. For ALL, combining new drugs with traditional chemotherapy and glucocorticoids treatments can achieve the greatest therapeutic effect by activating autophagy and apoptosis.

Improvement in outcomes of children with acute myeloid leukemia (AML) is attributed to several refinements in clinical management. We evaluated treatment outcomes of Taiwanese pediatric AML patients in the past 20 years. Overall, 860 de novo AML patients aged 0–18 years and registered in the Childhood Cancer Foundation of R.O.C during January 1996–December 2019 were included. Survival analysis was performed to identify factors that improved treatment outcomes. Regardless of treatment modalities used, patients during 2008–2019 had better 5-year event-free survival (EFS) and overall survival (OS) rates than patients during 1996–2007. For patients received the TPOG-AML-97A treatment, only 5-year OS rates were significantly different between patients diagnosed before and after 2008. Patients with RUNX1–RUNX1T1 had similar relapse-free survival rates, but 5-year OS rates were better during 2008–2019. However, the survival of patients who received hematopoietic stem-cell transplantations (HSCT) did not differ significantly before and after 2008. For patients without relapse, the 5-year OS improved during 2008–2019. Non-relapse mortality decreased annually, and cumulative relapse rates were similar. In conclusion, 5-year EFS and OS rates improved during 2008–2019, though intensities of chemotherapy treatments were similar before and after 2008. Non-relapse mortality decreased gradually. Further treatment strategies including more intensive chemotherapy, novel agents’ use, identification of high-risk patients using genotyping and minimal residual disease, early intervention of HSCT, and antibiotic prophylaxis can be considered for future clinical protocol designs in Taiwan.

Background/purpose: Fever of unknown origin (FUO) can be caused by many clinical conditions and remains a diagnostic challenge in clinical practice. The etiology of FUO varies markedly among different age groups, geographic areas, and seasons. A four-stage investigative protocol for FUO is widely applied in clinical practice. The aim of this study was to evaluate the usefulness of this four-stage protocol for identifying the etiology of FUO in children. Methods: We enrolled children younger than 18 years of age who were admitted to the Taichung Veterans General Hospital during the period from January 2006 to December 2014 with FUO persisting for more than 3 weeks. The four-stage FUO investigative guideline was used to evaluate the etiology of fever in all patients enrolled in the study. Results: The etiology of FUO was identified in 79 (84.9%) of the 93 patients enrolled in the study. The most common cause of FUO was infectious disease (37.6%), followed by malignancy (17.2%), miscellaneous disease (16.1%), and collagen vascular disease (14.0%). With respect to the four-stage survey of FUO, 36 of the 79 patients (45.6%) were identified in Stage 3, 28 patients (35.4%) in Stage 2, 13 patients (16.5%) in Stage 4, and only two patients (2.5%) in Stage 1. Conclusion: A well-designed systemic review of the epidemiological information, medical history, physical examination, laboratory analysis, and adequate invasive procedures provide adequate data to identify the most common causes of FUO in children. Keywords: children, fever of unknown origin

Background Hospital-acquired infections are a leading cause of morbidity and mortality in neonatal intensive care units (NICU). The aim of the study was to investigate the change of nosocomial infection rate in a NICU during a 4-year surveillance period. Methods We investigated the changes in nosocomial infection rates, infection sites, and microorganism species in a NICU before and after the unit was moved to a new location, extending from November 2008 to October 2012.The new facility was opened on November 1, 2010 and the old NICU was closed on the same day. In the meantime, three catheter-based bundles were implemented in the new NICU and all intensive care units in our hospital due to the new policy. Data collection was performed by independent, experienced infection control nurses. Results A total of 512 neonates were admitted to the NICU and enrolled in this study. There were 242 infants who were admitted to the old NICU, and 270 infants in the new facility. During the study period, the rate of infection episodes decreased from 19.0% to 11.1% ( P = 0.01). Additionally, the average hospital-acquired infection rate decreased from 6.26 cases per 1000 patient-days to 4.09 cases per 1000 patient-days ( P = 0.03). The most common infection site was blood stream infection, which decreased from 8.3% to 3.7% ( P = 0.03). The total catheter-related infection rates of the blood stream, lower respiratory tract, and urinary tract decreased from 13.6% to 5.9% ( P = 0.003). Klebsiella pneumonia, E. coli , Methicillin-resistant Staphylococcus aureus (MRSA), and Coagulase-negative Staphylococci (CoNS) were the most frequently found pathogens in the old NICU, whereas MRSA, CoNS, E. faecalis, and A. baumannii were the most frequently found pathogens in the new NICU. Conclusion The change in the environment and implementation of device bundles in the NICU might be associated with the nosocomial infection rate.

Cavernous sinus thrombosis (CST) is a severe disease which can result from infection of any of the tissues drained by the cavernous sinus. We here review eight cases, including a 12-year-old girl, all secondary to sphenoid sinusitis. The clinical manifestations, laboratory data, imaging findings, pathogens, medications, surgical treatment and clinical outcomes were analyzed. All eight patients had headache and five of them fever. All cases were associated with one or more ophthalmic symptoms. In four cases, computed tomography/magnetic resonance imaging showed isolated sphenoid sinusitis. In three cases, streptococci were isolated from blood culture and two cases showed Staphylococcus aureus in blood and sinus cultures. In seven cases, surgery was undertaken. All eight subjects received antibiotics, and 5 were administered intravenous ceftriaxone and metronidazole. Six subjects received anticoagulation therapy and one received corticosteroids. No mortality was recorded. Three cases showed sequelae, including Lemierre syndrome, ophthalmic complaints, and cranial nerve paralysis. In conclusion, the management of CST should include intravenous antibiotic therapy, combined with endonasal sinus surgery.

Over the past few decades, allergic diseases have become increasingly prevalent worldwide. House dust mite (HDM) is the most important domestic source for allergic diseases such as allergic rhinitis, asthma and atopic dermatitis. Dermatophagoides pteronyssinus (Der p) is the major environmental allergen in southeast Asia because of the humid and warm environment is suitable for its growth. In the recent year, role of HDM allergen in allergic inflammation through innate immune system has been well studied. Toll-like receptors (TLRs), protease-activated receptors (PARs) and DC-SIGN could be activated by different HDM major allergens and proinflammatory cytokines also be upregulated. Treatment efficacy for HDM allergy is unsatisfied to the patients and the medication is limited. Immunotherapy provided an alternative option for treating HDM allergy through targeted to the mechanisms of allergic reaction and represented a long-term symptoms relief. Gene specific immunotherapy was currently being developed and it could decrease allergic inflammation and improve the efficacy of treatment. In this report, we reviewed recent studies about the role of HDM allergy in innate immune system and its immunotherapy. Understanding the HDM allergen induced signal transduction pathway and developed allergen specific immunotherapy could help physicians to create precise diagnosis and solve unmet need in HDM allergy.

Aims and objectives To explore the meaning of maternal caregiving in the Chinese culture for children newly diagnosed with acute lymphocytic leukemia (ALL). Background Recurrence of and death associated with ALL remain the main concerns for mothers. Mothers experience guilt and anxiety towards their child's cancer. Design Descriptive phenomenological study. Methods Twelve mothers were recruited from a medical centre in Central Taiwan. The mothers were primary caregivers for their child diagnosed as having ALL in the past 3 months to 1 year. Data were collected through semi-structured interviews and analysed using Colaizzi's method. Results Four main themes emerged: feeling this world crashing by knowing the diagnosis, feeling the double-edged sword of mothering, worrying about potential risks for their vulnerable child, and passing through difficulties with power of support. Conclusions Most mothers felt this world crashing due to potential loss of their child and seeing their child's suffering. The mother was blamed for her child's cancer but was also required to shoulder all caregiving for their child. The mothers needed to compromise their lives to protect their child from potential infection. Perceived power of support helped the mothers overcome difficulties. Relevance to clinical practice Findings support that nurses encouraging mothers to tell their stories, regardless of culture, will facilitate healing. Establishing trust and providing support from nurses, physicians, psychologists and social workers will lead mothers' readiness to deal with care of their sick child. Increasing visiting time for parental support for children hospitalized in the PICU is suggested as well.

Purpose: Hypercatecholaminemia-related heart failure has been proposed as the main cause of enterovirus A71-related (EV-A71) early mortality. The purpose of this study was to measure urine ...

The terminal is taken by the same quality standards in the process of receiving program source once it is determined in the traditional streaming media system. This is bound to reduce the Service Quality of the streaming media system caused by the difference in terminal performance, network bandwidth and others. In view of this, we propose a SVC solution based on Bit Plane Encoding which is integrated in the Android platform. The optimized strategy is formulated according to the different needs of the end customer, the heterogeneity of the terminal equipment and the change of the network bandwidth to realize the video quality of different stream can be transmitted in real time. Experimental results show that the network environment is automatically detected by the terminal equipment, which is accorded to encode the video so that the corresponding quality of the streaming media service is recommended for users.

Detailed mechanisms of W hi B - l ike (Wbl) proteins involved in antibiotic biosynthesis and morphological differentiation are poorly understood. Here, we characterize the role of WblA ch , a Streptomyces chattanoogensis L10 protein belonging to this superfamily. Based on DNA microarray data and verified by real-time quantitative PCR (qRT-PCR), the expression of wblA ch was shown to be positively regulated by AdpA ch . Gel retardation assays and DNase I footprinting experiments showed that AdpA ch has specific DNA-binding activity for the promoter region of wblA ch . Gene disruption and genetic complementation revealed that WblA ch acts in a positive manner to regulate natamycin production. When wblA ch was overexpressed in the wild-type strain, the natamycin yield was increased by ∼30%. This provides a strategy to generate improved strains for natamycin production. Moreover, transcriptional analysis showed that the expression levels of whi genes (including whiA , whiB , whiH , and whiI ) were severely depressed in the Δ wblA ch mutant, suggesting that WblA ch plays a part in morphological differentiation by influencing the expression of the whi genes.

Backgrounds and Purposes Minimal residual disease (MRD) monitoring has been proved to be the most important prognostic predictor in childhood acute lymphoblastic leukemia (ALL). The nationwide TPOG-ALL-2013 protocol (TPOG-2013), adapted from the St. Jude Total Therapy XV Study and Total Therapy XVI Study, was launched since January 2013. This is the first MRD-directed protocol for treatment of childhood ALL in Taiwan. Here, we report the improved treatment outcomes and the impacts of adherence to MRD time points. Patients and Methods Totally, 402 patients aged between 1-18 years and diagnosed before December 31, 2018, who had MRD monitoring at the major central laboratory (Chang Gung Memorial Hospital-Linkou), were enrolled with the last follow-up on June 30, 2019. According to TPOG-2013, two MRD measurements were scheduled on days 15-19 of induction (MRD1 time point, TP1) and days 35-42, end of induction (MRD2 time point, TP2) to make the definitive risk stratification to guide subsequent therapy. The methodologies of MRD measurement included multicolor flow cytometry for leukemia-associated immunophenotypes (LAIP) (82.3% of TPOG-2013 cohort), qPCR assay for clonally rearranged antigen-receptor genes (Ig/TCR) if no LAIP (12.5%). Since January 2018, reverse transcription real-time quantitative polymerase chain reaction (RT-qPCR) was applied to patients carrying fusion transcripts (5.2%) of TCF3-PBX1, ETV6-RUNX1, BCR-ABL1, KMT2A-AFF1 (AF4) and KMT2A-MLLT3. The clinical features and outcomes of patients treated with TPOG-2013 were compared with those of 1,300 patients treated with the previous TPOG-ALL-2002 protocol (TPOG-2002), which did not integrate the MRD monitoring. Results The median follow-up time of the 402 patients of TPOG-2013 cohort was 32.5 months (range, 1.0-79.2 months). There were no significant differences in gender, age, WBC counts, and lineage at diagnosis between the patients treated with TPOG-2002 and TPOG-2013. However, based on the MRD data, the percentages of patients assigned to each risk group of TPOG-2013 was statistically differed from those of TPOG-2002 (P< 0.0001). The 5-year event-free survival (EFS) (% ± SE) was significantly improved from 78.1 ± 1.2 of TPOG-2002 to 85.4 ± 2.5 of TPOG-2013 (P< 0.0001). Further, the cumulative incidences (% ± SE) of isolated CNS relapse and any CNS relapse significantly decreased from 4.0 ± 0.5 to 0.3 ± 0.3 (P= 0.001) and from 5.8 ± 0.7 to 1.2 ± 0.9 (P= 0.001), respectively. The issue of non-adherence to MRD monitoring emerged since the implementation of MRD-directed TPOG-2013. For further analysis, 321 (80%) patients with exact adherence (EA) to both TPs were assigned as MRD EA group; 80 (20%) patients who were non-adherence (NA) to either one of TPs as MRD NA group; and one patient died between the two TPs was excluded for the comparative outcome analysis. The rate of non-adherence decreased significantly from 26.5% in 2013 to 2.4% in 2018. The major causes of non-adherence for both TPs were delaying MRD monitoring due to neutropenic fever and documented infections. In MRD EA group, 12.5% of patients were upgraded to higher-risk treatment groups based on their MRD results. The MRD NA group had older age (≥ 10 years), lower standard-risk and lower incidence of ETV6-RUNX1 compared with MRD EA group. There were significant differences in outcomes between MRD EA and MRD NA groups: the 5-year EFS were 89.4 ± 2.4 and 71.9 ± 7.4, respectively (P= 0.0005), overall survival (OS) were 90.9 ± 2.1 and 75.6 ± 5.8, respectively (P= 0.0003), and the cumulative incidence of isolated CNS relapse were 0 and 1.4 ± 1.3, respectively (P= 0.048) (Figure 1). In multivariate analysis, older age (≥ 10 years), higher WBC count (≥ 50 × 109/L) at diagnosis and MRD non-adherence were independent predictors for inferior EFS. In addition to these three factors, a higher-risk classification also predicted an inferior OS (Figure 2). Conclusions Contemporary MRD-directed therapy has improved the treatment outcomes of childhood ALL in Taiwan. The adherence to MRD time points remains a significantly prognostic predictor in the era of MRD-guided treatment. Disclosures No relevant conflicts of interest to declare.

Aim To investigate the effects of 2-hydroxy-ethyl methacrylate (HEMA) on cytotoxicity and cyclooxygenase-2 (COX-2) protein expression in human osteoblasts. Methodology Cytotoxicity was judged using an Alamar Blue reduction assay on human osteoblast cell line U2OS. Western blot was used to evaluate the expression of COX-2 protein by HEMA. To determine whether glutathione (GSH) levels were important in cytotoxicity and COX-2 expression of HEMA, cells were pre-treated with the GSH precursor, 2-oxothiazolidine-4-carboxylic acid (OTZ), to boost thiol levels, or buthionine sulfoximine (BSO) to deplete GSH. Paired Student's t-tests were applied for the statistical analysis of the results. Results HEMA demonstrated a cytotoxic effect to U2OS cells in a dose-dependent manner (P

Here we report that in Streptomyces coelicolor, the protein stability of an ECF σ factor SigT, which is involved in the negative regulation of cell differentiation, was completely dependent on its cognate anti-σ factor RstA. The degradation of RstA caused a ClpP/SsrA-dependent degradation of SigT during cell differentiation. This was consistent with the delayed morphological development or secondary metabolism in the ΔclpP background after rstA deletion or sigT overexpression. Meanwhile, SigT negatively regulated clpP/ssrA expression by directly binding to the clpP promoter (clpPp). The SigT-clpPp interaction could be disrupted by secondary metabolites, giving rise to the stabilized SigT protein and retarded morphological development in a non-antibiotic-producing mutant. Thus a novel regulatory mechanism was revealed that the protein degradation of the ECF σ factor was initiated by the degradation of its anti-σ factor, and was accelerated in a dual positive feedback manner, through regulation by secondary metabolites, to promote rapid and irreversible development of the secondary metabolism. This ingenious cooperation of intracellular components can ensure economical and exquisite control of the ECF σ factor protein level for the proper cell differentiation in Streptomyces. Background: The appropriate protein levels of ECF (extra-cytoplasmic function) σ factors are essential for bacteria functions. Results: SigT degradation is dependent on ClpP protease and accelerated by secondary metabolites. Conclusion: SigT degradation is regulated in a dual positive feedback manner. Significance: This novel mechanism expands our understanding of ingenious cooperation of intracellular molecules for proper physiological functions of bacteria.

LysR-type transcriptional regulators (LTTRs) compose a large family and are responsible for various physiological functions in bacteria, while little is understood about their regulatory mechanism on secondary metabolism in Streptomyces . Here we reported that StgR, a typical LTTR in Streptomyces coelicolor , was a negative regulator of undecylprodigiosin (Red) and γ-actinorhodin (Act) production in the early developmental phase of secondary metabolism by suppressing the expression of two pathway-specific regulator genes, redD and actII-orf4 , respectively. Meanwhile, stgR expression was downregulated during secondary metabolism to remove its repressive effects on antibiotic production. Moreover, stgR expression was positively autoregulated by direct binding of StgR to its own promoter ( stgRp ), and the binding site adjacent to translation start codon was determined by a DNase I footprinting assay. Furthermore, the StgR- stgRp interaction could be destroyed by the antibiotic γ-actinorhodin produced from S. coelicolor . Thus, our results suggested a positive feedback regulatory mechanism of stgR expression and antibiotic production for the rapid and irreversible development of secondary metabolism in Streptomyces .

In childhood acute lymphoblastic leukemia (ALL), t(1;19)(q23;p13.3) with TCF3-PBX1 fusion is one of the most frequent translocations. Historically, it has been associated with poor prognosis. Intensive treatment, however, has improved its outcome. We determined the outcome of children with this genotype treated with contemporary intensive chemotherapy in Taiwan.In Taiwan Pediatric Oncology Group 2002 ALL studies, genotypes were determined by cytogenetic analysis and/or reverse transcriptase polymerase chain reaction assay. Based on presenting features, immunophenotype and genotype, patients were assigned to one of the three risk groups: standard risk (SR), high risk (HR), or very high risk (VHR). The patients with t(1;19)/TCF3-PBX1 were treated in the HR arm receiving more intensive chemotherapy. The outcomes of patients with t(1;19)/TCF3-PBX1 were compared to that of patients with other subtypes of B-precursor ALL (B-ALL).Of the 1,129 patients with B-ALL, 64 (5.7%) had t(1;19)/TCF3-PBX1; 51 of whom were treated in the HR arm, but 11 were treated in the VHR and 2 in the SR arm because of physician's preference. As a group, 64 patients with t(1;19)/TCF3-PBX1 had similar 5-year event-free survival (83.3 ± 4.8%) as those with TEL-AML1 (85.2 ± 3.4%, P = 0.984) or those with hyperdiploidy50 (84.0 ± 3.1%, P = 0.748). The cumulative risk of any (isolated plus combined) central nervous system relapse among patients with t(1;19)/TCF3-PBX1 (8.7 ± 3.8%) tended to be higher than that of patients with TEL-AML1 (5.8 ± 2.3%, P = 0.749) or those with hyperdiploidy (4.1 ± 1.8%, P = 0.135), albeit the differences did not reach statistical significance.With contemporary intensive chemotherapy, children with t(1;19)/TCF3-PBX1 fared as well as those with favorable genotypes (TEL-AML1 or hyperdiploidy).

Summary: The poor prognosis and rising incidence of esophageal cancer highlight the need for improved detection and prediction methods that are essential prior to treatment. Esophageal cancer is one of the most fatal malignancies worldwide, with a dramatic increase in incidence in the Western world occurring over the past few decades. Despite improvements in the management and treatment of esophageal cancer patients, the general outcome remains very poor for overall 5-year survival rates (∼10%) and 5-year postesophagectomy survival rates (∼15–40%). Esophageal cancer is often diagnosed during its advanced stages, the main reason being the lack of early clinical symptoms. In an attempt to improve the outcome of patients after surgery, such patients are often treated with neoadjuvent concurrent chemoradiotherapy (CCRT) in order to decrease tumor size. However, CCRT may enhance toxicity levels and possibly cause a delay in surgery for patients who respond poorly to CCRT. Thus, precise biomarkers that could predict or identify patients who may or may not respond well to CCRT can assist physicians in choosing the appropriate therapy for patients. Identifying susceptible gene and biomarkers can help in predicting the treatment response of patients while improving their survival rates. Keywords: esophageal cancer, genetic factors, risk factors

Kuan Y-H, Li Y-C, Huang F-M, Chang Y-C. The upregulation of tumour necrosis factor-α and surface antigens expression on macrophages by bisphenol A-glycidyl-methacrylate. International Endodontic Journal, 45, 619–626, 2012. Abstract Aim To evaluate the expression of tumour necrosis factor-α and surface antigens by bisphenol A-glycidyl-methacrylate (BisGMA) on murine macrophage cell line RAW264.7. Methodology Cytotoxicity was measured by tetrazolium bromide reduction assay. Tumour necrosis factor (TNF)-α was analysed by enzyme-linked immunosorbent assay. Cell surface antigens were investigated by flowcytometry. Statistical analyses were performed using anova followed by the Bonferroni’s t-test for multigroup comparisons. Results BisGMA exhibited cytotoxicity to RAW264.7 in a dose-dependent manner (P 0.05). Conclusions Taken together, the ability of macrophages to induce an appropriate immune response when exposed to BisGMA has the potential to upregulate TNF-α production and expression of surface antigens.

Background Empiric antibiotics are frequently given for children with acute exudative tonsillitis. A few studies have investigated the causative agent of acute "exudative" tonsillitis in children to evaluate the necessity of antibiotic therapy. This study tried to explore the common causative agent of acute exudative tonsillitis among children. Methods From April 2009 to March 2010, throat swabs were obtained and cultured for viruses and bacteria from children who visited the pediatric emergency rooms of two medical centers in central Taiwan with acute exudative tonsillitis. Demographic data and microbiological results were analyzed. Results A total of 294 children with acute exudative tonsillitis were enrolled during the 1-year prospective study, and 173 (58.8%) of them were younger than 7 years. Group A streptococci were isolated from only three (1.0%) children, and they were all older than 6 years. A total of 143 viruses were isolated from 140 (47.6%) children. Adenovirus (18.7%) and enterovirus (16.3%) were the most common viral etiologies, followed by influenza virus (5.4%), parainfluenza virus (5.1%), herpes simplex virus Type 1 (2.7%), and respiratory syncytial virus (0.3%). Group A streptococcus only contributed to a minimal portion of acute exudative tonsillitis. Conclusion Routine or immediate antibiotic therapy for acute exudative tonsillitis in children is not necessary.

Background Dysregulated T helper (Th) cells are considered important in the pathophysiology of chronic primary immune thrombocytopenia (ITP). The present study investigated whether levels of Th cytokines in pediatric patients with chronic ITP were different compared with healthy controls. Procedures Fifty-seven pediatric patients with chronic ITP and 28 healthy controls were enrolled. Patients were divided into three groups based on their platelet counts at the time of the study: (i) active disease 150 × 109/l (n = 11). Plasma concentration of Th1 [interferon gamma (INF-γ), interleukin 2 (IL-2)], Th2 (IL-4, IL-10), Th3 [transforming growth factor-β1 (TGF-β1)], and Th17 (IL-17) cytokines were investigated by enzyme-linked immunosorbent assay. Results IFN-γ was increased in patients with active (P

Background and Objective: Cigarette smoking is a major risk factor in the development and further progression of periodontal diseases. However, little is known about how nicotine influences the expression of osteolytic mediators in cigarette smoking-associated periodontal diseases. The aim of this study was to investigate the expression of interleukin-1, interleukin-8, receptor activator of nuclear factor-κB ligand (RANKL), gelatinases and tissue-type plasminogen activator in U2OS cells (from the human osteosarcoma cell line) stimulated with nicotine. Material and Methods: Differences in the expression of interleukin-1, interleukin-8 and RANKL mRNAs, in response to exposure to various concentrations of nicotine (0, 0.125, 0.25, 0.5 and 1 mm) were evaluated in U2OS cells using the reverse transcripttion–polymerase chain reaction.In addition, the levels of interleukin-1, interleukin-8 and RANKL proteins were determined using enzyme-linked immunosorbent assays. The gelatinolytic and caseinolytic activities in nicotine treated-U2OS cells were demonstrated using gelatin and casein zymography, respectively. Results: Nicotine was found to increase the expression of interleukin-1, interleukin-8 and RANKL mRNA and protein in U2OS cells (p

The Al2O3-SiO2 (sf) (volume fraction, 20%)/Al-12.6Si metal matrix composites (MMCs) with or without rare earth Pr addition were fabricated by infiltration squeeze method. Effect of Pr addition on microstructures and fractographs of Al-Si MMCs was investigated by SEM and TEM. Tensile properties at room temperature and 200℃ were tested. It is shown that the addition of Pr is favorable to produce uniform microstructures and modify the eutectic Si crystal effectively. Compounds/intermetallics with high content of Pr are formed at the interface between short fiber and matrix. Yield strength (σ0.2), ultimate tensile strength (σ(subscript b)) and fracture elongation of Al-Si MMCs are improved by adding suitable amount of Pr. Compared with those values of Al-Si based MMC at 200℃, σ0.2 and σ(subscript b) of MMC with 0.29% Pr are increased by 33% and 55%, respectively. The tensile fracture surface of Al-Si MMCs with Pr addition presents ductile fracture features.

Background and Objective: Cystatin C is a 13 kDa non-glycosylated, basic protein belonging to the cystatin family. It is consistently and dramatically upregulated in a variety of fibrotic diseases. However, little is known about the correlation between cystatin C and cyclosporine A-induced gingival overgrowth. The aim of this study was to compare cystatin C expression in normal, healthy gingival tissues and cyclosporine A-induced gingival overgrowth specimens and further explore the potential mechanism that may result in cystatin C expression. Material and Methods: Fifteen cyclosporine A-induced gingival overgrowth specimens and five normal gingival tissues were examined by immunohistochemistry. Three human gingival fibroblast (HGF) strains were established from crown-lengthening surgery. The reverse transcriptase-polymerase chain reaction was used to investigate the effects on HGFs exposed to cyclosporine A. In addition, predominant periodontal pathogens (Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis) and proinflammatory cytokines (interleukin-1α and tumor necrosis factor-α) were added to seek the possible regulatory mechanisms of cystatin C expression. Results: The cystatin C staining in gingival tissue was stronger in the cyclosporine A-induced gingival overgrowth group than in the normal gingival group (p

Aim To investigate the receptor activator of nuclear factor-kappa B (NF-κB) ligand (RANKL) in osteoblastic cells stimulated with inflammatory mediators. Methodology The expression of RANKL in human osteoblastic cell line U2OS stimulated by pro-inflammatory cytokine interleukin (IL)-1α and black-pigmented bacteria Porphyromonas endodontalis was investigated by Western blot and enzyme-linked immunosorbent assay (ELISA). The significance of the results obtained from control and treated groups was statistically analysed by the paired Student’s t-test. Results IL-1α was found to upregulate RANKL production in U2OS cells (P

BaTiO 3 films on Ti substrate were fabricated by alternative current(AC) and direct current(DC) micro arc oxidation (MAO). Microstructures of films were investigated by means of SEM, XRD and TEM. The results show that the amorphous phase and primitive cubic phase are the main phases in the films prepared by AC MAO. Even after being annealed at 1 200 °C for 8 h, only a few tetragonal phases can be observed in films prepared by AC MAO. However, tetragonal BaTiO 3 phase can be produced by DC MAO directly. In the films prepared by DC MAO, a mixture of cubic phase and tetragonal phase is formed. After sparking spacious distribution, sparking duration and temperature gradient near sparking sites were taken into account, and a mechanism of synthesis of tetragonal BaTiO 3 phase by DC MAO was proposed.

Background and Objective: Cyclosporin A is used as an immunosuppressive agent and its prominent side-effect is the induction of fibrous gingival overgrowth. The progression of fibrous gingival overgrowth results from the accumulation of extracellular matrix. Type I plasminogen activator inhibitor (PAI-1) acts as the inhibitor of extracellular matrix degradation and is involved in some fibrotic diseases. However, little is known about the correlation between PAI-1 and cyclosporin A-induced gingival overgrowth. The aim of this study was to investigate the effects of cyclosporin A on the expression of PAI-1 mRNA and protein in human gingival fibroblasts human gingival fibroblasts in vitro and to compare PAI-1 expression in normal healthy gingival tissues and cyclosporin A-induced gingival overgrowth specimens in vivo. Material and Methods: Quantitative reverse transcription–polymerase chain reaction and western blot assay were used to investigate the effects on human gingival fibroblasts exposed to cyclosporin A. In addition, 10 cyclosporin A-induced gingival overgrowth specimens and five normal gingival tissues were examined by immunohistochemistry. Results: Investigations of the time dependence of PAI-1 mRNA expression in human gingival fibroblasts treated with 200 ng/ml of cyclosporin A revealed a rapid accumulation of the transcript: a significant signal was first detectable after 1 h of exposure and the signal remained elevated throughout the 24-h incubation period (p