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Jejunal feeding is increasingly utilized in the pediatric population to reduce gastroesophageal reflux or aspiration pneumonia. We describe a pediatric patient who developed persistent neutropenia and anemia secondary to copper deficiency after more than one year of exclusive jejunal feeding. Bone marrow aspiration and trephine biopsy showed vacuolated myeloid and erythroid precursors compatible with copper deficiency. Short term treatment with mineral mixture powder including copper reversed the hematological abnormalities. This report highlights the risk of micronutrient deficiency and the haematological manifestations as a result of acquired copper deficiency in pediatric patients receiving long term jejunal feeding.

We evaluated the feasibility of existing risk assessment tools for chronic myeloid leukemia (CML) in children. Fifty-five patients with newly diagnosed CML between 1996 and 2019 were included. Forty-nine patients presented in chronic phase, thirty-six of whom were treated with upfront tyrosine kinase inhibitor (CP-TKI group); one presented in accelerated phase and four in blastic phase. Treatment, survival, responses, and tolerance were evaluated. All patients in the CP-TKI group received imatinib as their first TKI treatment. The 10-year overall survival (OS), progression-free survival (PFS), and event-free survival (EFS) of TKI-treated group was 97%, 91.4%, and 72.3%, respectively. At 60 months, the rates of major molecular response were 81.2% and deep molecular response was 67.5%. The EUTOS long-term survival (ELTS) risk grouping did not predict OS, PFS, or EFS. The IMAFAIL risk groups were correlated with the risk of imatinib failure. Further studies are required to modify the existing risk assessment tools for children.

Colorectal cancer (CRC) is the third most deadly cancer worldwide, and inflammatory bowel disease (IBD) is one of the critical factors in CRC carcinogenesis. IBD is responsible for an unphysiological and sustained chronic inflammation environment favoring the transformation. MicroRNAs (miRNAs) belong to a class of highly conserved short single-stranded segments (18–25 nucleotides) non-coding RNA and have been extensively discussed in both CRC and IBD. However, the role of miRNAs in the development of colitis-associated CRC (CAC) is less clear. The aim of this review is to summarize the major upregulated (miR-18a, miR-19a, miR-21, miR-31, miR-155 and miR-214) and downregulated (miR-124, miR-193a-3p and miR-139-5p) miRNAs in CAC, and their roles in genes’ expression modulation in chronic colonic-inflammation-induced carcinogenesis, including programmed cell-death pathways. These miRNAs dysregulation could be applied for early CAC diagnosis, to predict therapy efficacy and for precision treatment.

C-X-C motif chemokine 10 (CXCL10) is a crucial pro-inflammatory factor in chronic hepatitis. Autophagy dysregulation is known to contribute to hepatic inflammatory injury. Hence, we investigated the regulatory effect of CXCL10 on the autophagosome-lysosome system during non-alcoholic fatty liver disease (NAFLD) development. The effect of CXCL10 ablation by neutralizing monoclonal antibody (mAb) or genetic knockout on autophagic flux was evaluated in cultured hepatocytes and animal models of NAFLD. Results demonstrated that CXCL10 ablation protected against hepatocyte injury in vitro and steatohepatitis development in mice. Autophagic flux impairment was rectified by CXCL10 inhibition using anti-CXCL10 mAb in AML-12 and HepG2 liver cell lines and primary hepatocytes as evidenced by the attenuated accumulation of p62/SQSTM1 and LC3-II proteins and increased autophagic protein degradation. Impaired autophagic flux was significantly restored by CXCL10 knockout or anti-CXCL10 mAb in mice. Bafilomycin A1, an inhibitor of autolysosome formation, abolished the rectifying effect of anti-CXCL10 mAb or CXCL10 knockdown in AML-12 and primary hepatocytes, indicating CXCL10 impaired late-stage autophagy in NAFLD. Anti-CXCL10 mAb treatment also increased the fusion of LC3-positive autophagosomes with lysosomes in HepG2 cells challenged with palmitic acid, suggesting that CXCL10 ablation restored autolysosome formation. Consistently, the number of autolysosomes was significantly increased by CXCL10 knockout in mice as shown by electron microscopy. In conclusion, upregulated CXCL10 in steatohepatitis impairs autophagic flux by reducing autolysosome formation, thereby inhibiting autophagic protein degradation and the accumulation of ubiquitinated proteins, leading to the development of steatohepatitis.

A new constitutive equation is developed to model the flow stress on a metal surface undergone high speed impacts that result in strain hardening. The new equation is based on the Johnson-Cook model and has considered the effects of strain, strain rate, grain refinement, twin formation and twin spacing. Two mechanisms for the strain hardening are proposed: Grain refinement or twin formation, depending on the strain rate. At low strain rate, the Hall-Petch relation is obeyed, while at high strain rate, the flow stress is controlled by the formation of deformation twins. The theoretical estimation of flow stress agrees well with experimental data for stainless steel 304. According to the new model, the flow stress can be as high as 1.46 GPa at a strain rate of 105 /s. Keywords: SMAT, flow stress, grain refinement, twin spacing, metal plasticity.

Background & Aims p38 mitogen-activated protein kinases are important inflammatory factors. p38α alteration has been implicated in both human and mouse inflammatory disease models. Therefore, we aimed to characterize the cell type-specific role of p38α in non-alcoholic steatohepatitis (NASH). Methods Human liver tissues were obtained from 27 patients with non-alcoholic fatty liver disease (NAFLD) and 20 control individuals. NASH was established and compared between hepatocyte-specific p38α knockout (p38αΔHep), macrophage-specific p38α knockout (p38αΔMΦ) and wild-type (p38αfl/fl) mice fed with high-fat diet (HFD), high-fat/high-cholesterol diet (HFHC), or methionine-and choline-deficient diet (MCD). p38 inhibitors were administered to HFHC-fed wild-type mice for disease treatment. Results p38α was significantly upregulated in the liver tissues of patients with NAFLD. Compared to p38αfl/fl littermates, p38αΔHep mice developed significant nutritional steatohepatitis induced by HFD, HFHC or MCD. Meanwhile, p38αΔMΦ mice exhibited less severe steatohepatitis and insulin resistance than p38αfl/fl mice in response to a HFHC or MCD. The effect of macrophage p38α in promoting steatohepatitis was mediated by the induction of pro-inflammatory factors (CXCL2, IL-1β, CXCL10 and IL-6) secreted by M1 macrophages and associated signaling pathways. p38αΔMΦ mice exhibited M2 anti-inflammatory polarization as demonstrated by increased CD45+F4/80+CD11b+CD206+ M2 macrophages and enhanced arginase activity in liver tissues. Primary hepatocytes from p38αΔMΦ mice showed decreased steatosis and inflammatory damage. In a co-culture system, p38α deleted macrophages attenuated steatohepatitic changes in hepatocytes through decreased secretion of pro-inflammatory cytokines (TNF-α, CXCL10 and IL-6), which mediate M1 macrophage polarization in p38αΔMΦ mice. Restoration of TNF-α, CXCL10 or IL‐6 induced lipid accumulation and inflammatory responses in p38αfl/fl hepatocytes co-cultured with p38αΔMΦ macrophages. Moreover, pharmacological p38 inhibitors suppressed HFHC-induced steatohepatitis. Conclusions Macrophage p38α promotes the progression of steatohepatitis by inducing pro-inflammatory cytokine secretion and M1 polarization. p38 inhibition protects against steatohepatitis. Lay summary p38 mitogen-activated protein kinases are important inflammatory factors. In the present study, we demonstrated that p38α is upregulated in liver tissues of patients with non-alcoholic fatty liver diseases. Genetic deletion of p38α in macrophages led to ameliorated nutritional steatohepatitis in mice through decreased pro-inflammatory cytokine secretion and increased M2 macrophage polarization.

Objective Internal tandem duplication (ITD) of fms-like tyrosine kinase 3 (FLT3) is one of the most common mutations in acute myeloid leukemia (AML), occurring in nearly 30% of cases. FLT3-ITD involves in-frame duplication of 3-400 base-pairs at the juxta-membrane domain, resulting in ligand-independent activation of FLT3 signaling. Downstream effectors include activation of ERK/STAT5 via SRC kinase, activation of PI3K/AKT, phosphorylation of FOXO3A, down-regulation of equilibrative nucleoside transporter 1 (ENT1) for cytarabine, and induction of reactive oxygen species (ROS) that may lead to increased DNA damage and defective repair. The present study investigated if the latter can be effectively targeted for the treatment of this AML subtype. Methods Primary samples from patients with FLT3-ITD AML, human cell line carrying FLT3-ITD (MOLM-13) as well as mouse B-lymphoid Ba/F3 cells transduced with human FLT3-ITD were used in this study. Traffic Light Reporter (TLR) assay was used to measure fidelity of double-strand breaks (DSB) repair, either via error-free homologous recombination (HR) or error-prone non-homologous end joining (NHEJ). Percentage of repair events by HR or NHEJ were quantified by flow cytometry. DNA DSB were examined by γ-H2AX foci staining using confocal microscopy. Single-cell DSB were quantified by neutral comet assay and analysed by OpenComet software. The tail moment was calculated as the length of comet tail multiplied by the tail DNA %. MOLM-13 was transplanted into NOD/SCID/IL2Rg-/- (NSG) mice by tail vein injection. Treatment comprised cytarabine (25mg/kg, i.p., day 1-5) and doxorubicin (1.5mg/kg, i.v., day 1-3), with or without olaparib (25mg/kg, i.p., day 1-5). Comparisons between groups of numerical data were evaluated using Student's t-test. P-values less than 0.05 were considered statistically significant. Results To investigate the link between FLT3-ITD AML and DNA damage response (DDR), expression of critical DDR genes in primary AML samples was examined by real-time quantitative PCR. The panel of genes included apical kinase ATM, ATR and DNA-PKcs; DNA damage mediators BRCA1,BRCA2 and PARP1; downstream response kinase CHEK1 and CHEK2 and effectors TP53. Among them, BRCA2 was significantly down-regulated in FLT3-ITD AML(Wild-type FLT3=18 samples; FLT3-ITD=13 samples; Average dCt 9.7 in WT vs. 10.6 in ITD; p Conclusion Results from the present study supported the use of PARPi in the treatment of FLT3-ITD AML. Its therapeutic benefits in combination with chemotherapy would have to be further evaluated. Acknowledgements: Health and Medical Research Fund (Project number: 04152326) and Li Shu Fan Medical Foundation, LKS Faculty of Medicine, University of Hong Kong. Disclosures No relevant conflicts of interest to declare.

Objectives: Acute myeloid leukemia (AML) carrying internal tandem duplication (ITD) of Fms-Like Tyrosine Kinase 3 (FLT3) is associated with high relapse risk and adverse outcome. This single-arm, phase 2 study evaluated efficacy and safety of combination treatment with FLT3 inhibitor quizartinib and protein translation inhibitor omacetaxine mepesuccinate (OME), referred herein QUIZOM - in elderly patients with newly diagnosed FLT3-ITD AML or young patients with relapsed/refractory (R/R) diseases, whose outcome is hitherto dismal. Methods: R/R FLT3-ITD AML patients ≥ 18 years old or newly diagnosed patients ≥ 65 years old were recruited. Treatment comprised quizartinib 30 mg daily and OME [2 mg daily for 7 (first course) or 5 days (second course onwards) every 21-28 days] until disease progression or allogeneic hematopoietic stem cell transplantation (HSCT). Quizartinib was given as post HSCT maintenance after engraftment at doses ranging from 30 mg twice weekly to 30 mg daily, depending on blood counts. Primary endpoint was composite complete remission (CRc) defined by CR+CRi (CR with incomplete haematological recovery). Secondary endpoints were leukaemia-free (LFS) and overall survival (OS). Molecular responses were evaluated by FLT3-ITD based on PCR and NPM1 variant allele frequency (VAF) based on digital PCR (ddPCR). Mutation profiling was performed by MiSeq Next Generation Sequencing (NGS) based on IDT xGen Lockdown probes custom panel of 67 genes or TruSight myeloid panel of 54 genes. Results: Twenty-nine patients (R/R case=22; newly diagnosed case=7) were recruited between November 2017 and July 2019. Their clinicopathologic characteristics were shown in Table 1. Twenty-seven patients completed at least one course of QUIZOM (median= 2 courses, range: 1-20 courses) of whom 22 (R/R=19; newly diagnosed=3) achieved CR/CRi [CR=2 (7%); CRi=20 (74%), CRc=22 (81%)], 3 patients showed partial remission (PR) and 2 patients did not respond. All 6 patients who had prior FLT3 inhibitors (sorafenib or midostaurin) achieved CR/CRi. Median LFS and OS of CR/CRi group were 5.2 and 11.07 months (Figure 1). Seven patients received allogeneic HSCT of whom all have remained in remission post HSCT as of 31 July 2019 (OS 6.43 to 19.8 months) (Figure 1). Deep molecular responses (DMR) as defined by FLT3-ITD VAF ≤0.1% and NPM1 VAF ≤ 0.001% could be accomplished in 78% and 27% patients. Adverse effects associated with QUIZOM were primarily haematological and non-haematologic adverse effects were scarce. Two patients succumbed before commencement and on day 1 of QUIZOM due to pneumonia and intracranial haemorrhage. None of recurrently mutated genes was significantly associated with treatment responses in this cohort. Conclusion: QUIZOM is effective and safe for newly diagnosed and R/R FLT3-ITD AML. Acknowledgements: Li Shu Fan Medical Foundation, S.K. Yee Medical Foundation, Croucher Foundation, LKS Faculty of Medicine, University of Hong Kong, Daiichi Sankyo Inc. Disclosures No relevant conflicts of interest to declare.

Docking protein-1 (DOK1) is a tumor suppressor frequently lost in malignant cells, however, it retains the ability to control activities of immune receptors in adjacent stroma cells of the tumor microenvironment. We therefore hypothesized that addressing DOK1 may be useful for cancer immunotherapy. DOK1 mRNA and DOK1 protein expression were downregulated in tumor cells of gastric cancer patients (n = 249). Conversely, its expression was up-regulated in cases positive for Epstein Barr Virus (EBV+) together with genes related to macrophage biology and targets of clinical immunotherapy such as programmed-cell-death-ligand-1 (PD-L1). Notably, high DOK1 positivity in stroma cells conferred poor prognosis in patients and correlated with high levels of inducible nitric oxide synthase in CD68+ tumor-associated macrophages. In macrophages derived from human monocytic leukemia cell lines, DOK1 (i) was inducible by agonists of the anti-diabetic transcription factor peroxisome proliferator-activated receptor-gamma (PPARγ), (ii) increased polarization towards an inflammatory phenotype, (iii) augmented nuclear factor-κB-dependent transcription of pro-inflammatory cytokines and (iv) reduced PD-L1 expression. These properties empowered DOK1+ macrophages to decrease the viability of human gastric cancer cells in contact-dependent co-cultures. DOK1 also reduced PD-L1 expression in human primary blood monocytes. Our data propose that the drugability of DOK1 may be exploited to reprogram myeloid cells and enforce the innate immune response against EBV+ human gastric cancer.

A high power buck-boost switch-mode LED driver delivering a constant 350 mA with a power efficient current sensing scheme is presented in this paper. The LED current is extracted by differentiating the output capacitor voltage and maintained by a feedback. The circuit has been fabricated in a standard 0.35 μm AMS CMOS process. Measurement results demonstrated a power-conversion efficiency over 90% with a line regulation of 8%/V for input voltage of 3.3 V and current output between 200 mA and 350 mA.

The aza-Henry reaction of 3,4-dihydroisoquinoline is reported. The reaction is favourable in excess nitromethane under ambient conditions. Isolation of the unstable reaction product is achieved by acylation or alkylation, allowing the synthesis of Reissert-like compounds in good yields from a one-pot, three-component coupling. The rates of reaction for dihydroisoquinoline and the corresponding benzylisoquinolinium ion have been investigated in the presence and absence of base. The reaction with dihydroisoquinoline probably proceeds via an azinic acid tautomer of nitromethane, a reaction pathway unavailable to the isoquinolinium ion. The traditionally problematic reduction of two of the resulting β-nitroamine derivatives was achieved, providing access to a number of new chiral vicinal diamines.

The authors present an outbreak of disease associated with exposure to Stachybotrys chartarum and Aspergillus species. A courthouse and two associated office buildings had generated discomfort among employees for two years since initial occupancy. Multiple interventions had been unsuccessful An initial evaluation of 14 individuals identified three with potential asthma and three with symptoms consistent with interstitial lung disease. A clinical screening protocol to identify individuals who should be removed from work identified three likely and seven possible cases of building-related asthma. Detailed environmental and engineering assessments of the building identified major problems in mechanical system design, building construction, and operational strategies leading to excess moisture and elevated relative humidities. Moisture-damaged interior surfaces in both buildings were contaminated with S. chartarum, A. versicolor, and Penicillium species. Aspergillus species, especially A. versicolor, at concentrations of 10(1) to 10(4)/m3 dominated the indoor air under normal operating conditions. Bulk samples also revealed large quantities of Stachybotrys. A questionnaire survey of the three case and two control buildings documented between three- and 15-fold increases in symptoms. A nested case-control study suggested emphysematous-like disease in individuals meeting questionnaire definitions for cases. Replication of analysis strategies used in similar previous investigations suggested an association between worsening symptoms and decreased diffusing capacity of the lung. Performance on neuropsychological measures was similar for both cases and controls, although workers with symptoms reported increased levels of current but not past psychiatric symptomatology. Chemical analyses demonstrated the presence of satratoxins G and H. Cytotoxic laboratory analyses demonstrated the presence of agents with biological effectiveness in bulk materials. No association was seen between IgE or IgG antibodies and the presence of disease. This outbreak represents a likely human response to inhaled fungal toxins in indoor environments. Moisture indoors represents a public health issue currently inadequately addressed by building, health, or housing codes.

Lumped-element bandpass filter structures with enhanced stopband rejection targeted for low temperature co-fired ceramic (LTCC) implementation are proposed. Design equation formulations that take into account the effect of the transmission zeros are presented. For demonstration, RF filters operating at 2.4 GHz are fabricated and characterized. Both simulation and measurement results are shown for comparison.

An output-capacitor-free multi-stage low-dropout regulator (LDO) with new compensation scheme is presented. This scheme relieves the requirement of compensation capacitor to be 1.2 pF by making use of the large gate capacitance of pass transistor as a large on-chip compensation capacitor. With this compensation scheme, the LDO can employ a multi-stage error amplifier for precise line and load regulation (total line and load error < 0.04%) without sacrificing chip area and its bandwidth. Thus, recovery time of LDO is 1 mus upon a step-load change in between 1 mA and 100 mA. Its output-capacitor-free nature and high area-efficiency make it particularly attractive for system-on-chip (SoC) designs. Proposed LDO is fabricated in a 0.35 mum standard CMOS technology and measurement results confirm with analysis and simulation results.

Various band-pass filter configurations with improved stop-band characteristics are analyzed and implemented based upon the Low Temperature Co-Fired Ceramic (LTCC) technology. Design equations that take into account the effect of the transmission zeros are formulated. For illustration, a 2.4 GHz RF filter with transmission zeros located at 2.2 GHz is fabricated and characterized. Both EM simulation and experimental results are presented.