Variability in emergency department management of hypothermic infants ≤90 days of age.

OBJECTIVES: Hypothermic infants are at risk for serious bacterial and herpes simplex virus infections, but there are no evidence-based guidelines for managing these patients. We sought to characterize variations and trends in care for these infants in the emergency department (ED). METHODS: We conducted a retrospective cross-sectional study of infants under 90 days old presenting to 32 pediatric EDs from 2009 through 2019 with an International Classification of Diseases diagnosis code for hypothermia. We characterized variation in diagnostic testing, antimicrobial treatment, and disposition of children in three age groups (≤30 days, 31-60 days, and 61-90 days old) and analyzed care trends. RESULTS: Of 7828 ED encounters meeting inclusion criteria, most (81%) were ≤ 30 days of age. Infants in the 0-30 days old age group, compared to 61-90 days old age group, had a higher proportion of blood (75% vs. 68%), urine (72% vs. 64%), and cerebrospinal fluid (CSF; 35% vs. 22%) cultures obtained (p < 0.01) and greater antimicrobial use (81% vs. 68%; p < 0.01) in the ED. From 2009 to 2019, C-reactive protein (CRP), and procalcitonin usage steadily increased, from 25% to 40% and 0% to 30% respectively, while antibiotic use (83% to 77%), CSF testing (53% to 44%), and chest radiography (47% to 34%) decreased. Considerable interhospital variation was noted in testing and treatment, including CSF testing (14-70%), inflammatory markers (CRP and procalcitonin; 8-88%), and antibiotics (56-92%). CONCLUSION: Substantial hospital-level variation exists for managing hypothermic infants in the ED. Long-term trends are notable for changing practice over time, particularly with increased use of inflammatory markers. Prospective studies are needed to risk stratify and optimize care for this population.

High-Powered Magnet Exposures in Children: A Multi-Center Cohort Study.

BACKGROUND AND OBJECTIVES: High-powered magnets were effectively removed from the US market by the Consumer Product Safety Commission (CPSC) in 2012 but returned in 2016 after federal court decisions. The United States Court of Appeals for the 10th Circuit cited imprecise data among other reasons as justification for overturning CPSC protections. Since then, incidence of high-powered magnet exposure has increased markedly, but outcome data are limited. In this study, we aim to describe the epidemiology and outcomes in children seeking medical care for high-powered magnets after reintroduction to market. METHODS: This is a multicenter, retrospective cohort study of patients aged 0 to 21 years with a confirmed high-powered magnet exposure (ie, ingestion or insertion) at 25 children's hospitals in the United States between 2017 and 2019. RESULTS: Of 596 patients with high-powered magnet exposures identified, 362 (60.7%) were male and 566 (95%) were <14 years of age. Nearly all sought care for magnet ingestion (n = 574, 96.3%), whereas 17 patients (2.9%) presented for management of nasal or aural magnet foreign bodies, 4 (0.7%) for magnets in their genitourinary tract, and 1 patient (0.2%) had magnets in their respiratory tract. A total of 57 children (9.6%) had a life-threatening morbidity; 276 (46.3%) required an endoscopy, surgery, or both; and 332 (55.7%) required hospitalization. There was no reported mortality. CONCLUSIONS: Despite being intended for use by those >14 years of age, high-powered magnets frequently cause morbidity and lead to high need for invasive intervention and hospitalization in children of all ages.

Curcumin suppresses cell proliferation and triggers apoptosis in vemurafenib-resistant melanoma cells by downregulating the EGFR signaling pathway.

Melanoma is a malignant tumor with aggressive behavior. Vemurafenib, a BRAF inhibitor, is clinically used in melanoma, but resistance to melanoma cytotoxic therapies is associated with BRAF mutations. Curcumin can effectively inhibit numerous types of cancers. However, there are no reports regarding the correlation between curcumin and vemurafenib-resistant melanoma cells. In this study, vemurafenib-resistant A375.S2 (A375.S2/VR) cells were established, and the functional mechanism of the epidermal growth factor receptor (EGFR), serine-threonine kinase (AKT), and the extracellular signal-regulated kinase (ERK) signaling induced by curcumin was investigated in A375.S2/VR cells in vitro. Our results indicated that A375.S2/VR cells had a higher IC50 concentration of vemurafenib than the parental A375.S2 cells. Moreover, curcumin reduced the viability and confluence of A375.S2/VR cells. Curcumin triggered apoptosis via reactive oxygen species (ROS) production, disruption of mitochondrial membrane potential (ΔΨm), and intrinsic signaling (caspase-9/-3-dependent) pathways in A375.S2/VR cells. Curcumin-induced apoptosis was also mediated by the EGFR signaling pathway. Combination treatment with curcumin and gefitinib (an EGFR inhibitor) synergistically potentiated the inhibitory effect of cell viability in A375.S2/VR cells. The present study provides new insights into the therapy of vemurafenib-resistant melanoma and suggests that curcumin might be an encouraging therapeutic candidate for its drug-resistant treatment.

Curcumin Derivative MTH-3 Regulates Palmitate-induced Insulin Resistance in Mouse Myoblast C2C12 Cells.

BACKGROUND/AIM: At present, there are no effective drugs for the treatment of insulin resistance. MTH-3, a curcumin derivative, exerts potent anti-cancer effects. The aim of the present study was to explore whether MTH-3 is capable of regulating palmitic acid (PA)-induced insulin resistance in C2C12 cells. MATERIALS AND METHODS: Cell viability was examined using the MTT assay. C2C12 cells were treated with PA and evaluated for the production of oil droplets using an Oil Red O assay. Glucose uptake was analysed by the 2-NBDG assay. RESULTS: Treatment of cells with up to 500 µM PA for 24 h or with 5 or 10 µM MTH-3 had no effect on cell viability. PA induced production of oil droplets in C2C12 cells. After adding MTH-3, the quantity of oil droplets decreased significantly and glucose uptake recovered. CONCLUSION: MTH-3 may become an efficient drug for the treatment of insulin resistance and associated diseases.

Novel quinazolinone MJ­33 induces AKT/mTOR­mediated autophagy­associated apoptosis in 5FU­resistant colorectal cancer cells.

Novel quinazolinone compounds have been studied in the field of drug discovery for a long time. Among their broad range of pharmacological effects, certain compounds effectively inhibit cancer cell proliferation. MJ­33 is a quinazolinone derivative with proposed anticancer activities that was synthesized in our laboratory. The present study aimed to evaluate the anticancer activity of MJ­33 in fluorouracil (5FU)­resistant colorectal cancer cells (HT­29/5FUR) and to investigate the underlying molecular mechanisms. The cell viability assay results indicated that HT­29/5FUR cell viability was inhibited by MJ­33 treatment in a concentration­dependent manner compared with the control group. The cellular morphological alterations observed following MJ­33 treatment indicated the occurrence of apoptosis and autophagy, as well as inhibition of cell proliferation in a time­dependent manner compared with the control group. The acridine orange, LysoTracker Red and LC3­green fluorescent protein staining results indicated that MJ­33 treatment significantly induced autophagy compared with the control group. The DAPI/TUNEL dual staining results demonstrated increased nuclear fragmentation and condensation following MJ­33 treatment compared with the control group. The Annexin V apoptosis assay and image cytometry analysis results demonstrated a significant increase in apoptotic cells following MJ­33 treatment compared with the control group. The western blotting results demonstrated markedly decreased Bcl­2, phosphorylated (p)­BAD, pro­caspase­9 and pro­caspase­3 expression levels, and notably increased cytochrome c and apoptotic peptidase activating factor 1 expression levels following MJ­33 treatment compared with the control group. Moreover, the expression levels of autophagy­related proteins, including autophagy related (ATG)­5, ATG­7, ATG­12, ATG­16, p62 and LC3­II, were increased following MJ­33 treatment compared with the control group. Furthermore, MJ­33­treated HT­29/5FUR cells displayed decreased expression levels of p­AKT and p­mTOR compared with control cells. The results suggested that MJ­33­induced apoptosis was mediated by AKT signaling, and subsequently modulated via the mitochondria­dependent signaling pathway. Therefore, the results suggested that suppression of AKT/mTOR activity triggered autophagy in the HT­29/5FUR cell line. In summary, the results indicated that MJ­33 inhibited HT­29/5FUR cell viability, and induced apoptosis and autophagy via the AKT/mTOR signaling pathway. The present study may provide novel insight into the anticancer effects and mechanisms underlying MJ­33 in 5FU­resistant colorectal cancer cells.

Bioinspired Diatomite Membrane with Selective Superwettability for Oil/Water Separation.

Membranes with selective superwettability for oil/water separation have received significant attention during the past decades. Hierarchical structures and surface roughness are believed to improve the oil repellency and the stability of Cassie-Baxter state. Diatoms, unicellular photosynthetic algae, possess sophisticated skeletal shells (called frustules) which are made of hydrated silica. Motivated by the hierarchical micro- and nanoscale features of diatom, we fabricate a hierarchical diatomite membrane which consists of aligned micro-sized channels by the freeze casting process. The fine nano-porous structures of frustules are well preserved after the post sintering process. The bioinspired diatomite membrane performs both underwater superoleophobicity and superhydrophobicity under various oils. Additionally, we demonstrate the highly efficient oil/water separation capabililty of the membranes in various harsh environments. The water flux can be further adjusted by tuning the cooling rates. The eco-friendly and robust bioinspired membranes produced by the simple, cost-effective freeze casting method can be potentially applied for large scale and efficient oil/water separation.

Design, synthesis, biological evaluation and molecular modeling studies of 1-aryl-6-(3,4,5-trimethoxyphenyl)-3(Z)-hexen-1,5-diynes as a new class of potent antitumor agents.

A series of novel enediyne-containing molecules, 1-aryl-6-(3,4,5-trimethoxyphenyl)-3(Z)-hexen-1,5-diynes, were synthesized and displayed significant IC50 values of 10(-7) to 10(-6) M against various cancer cell lines. Of these compounds, 1-(2-pyridinyl)-6-(3,4,5-trimethoxyphenyl)-3(Z)-hexen-1,5-diyne (8) demonstrated the greatest growth inhibition activity. Compound 8 also arrested cancer cells in the G2/M phase and induced apoptosis via activation of Caspase-3. In addition to the G2/M block, compound 8 caused microtubule depolymerization at low concentrations and markedly decreased tumor size in xenographic studies.

1-(2-((Z)-6-(2-(Trifluoromethyl)phenyl)hexa-3-en-1,5-diynyl)phenyl)piperidin-2-one as a new potent apoptosis agent.

Compounds 4a-f, 5a-f and 6-9, showed significant growth inhibition activity against human tumor cell lines. Of these compounds, 1-(2-((Z)-6-(2-(trifluoromethyl)phenyl)hexa-3-en-1,5-diynyl)phenyl)piperidin-2-one (8) displayed the most potent growth inhibition activity. Compound 8 also arrested cancer cells in G2/M phase and induced apoptosis via activation of caspase-3 and -9. According to western-blotting analysis, compound 8 can up-regulate Bax, down-regulate Bcl-2 and XIAP, as well as promote cytochrome c release.

Synthesis and biological evaluation of novel symmetry bis-enediynes.

A series of acyclic symmetry bis-enediynes have been synthesized successfully and their bioactivities were evaluated. Among them, 1,6-bis(4-((2-(pyridin-2-ylethynyl)phenyl)ethynyl)phenoxy)hexane 8g showed good inhibition activity against the CCRF-CEM (GI(50)=0.04 microM) and HL-60 (GI(50)=0.09 microM) cell lines of human leukemia. The cell cycle analysis shows that compound 8g arrests cell cycle via inhibiting Cyclin A and Cyclin B expressions in low concentration and induces a significant apoptosis progress in high concentration.

2-(6-aryl-3(Z)-hexen-1,5-diynyl)anilines as a new class of potent antitubulin agents.

Compounds 2a- h and 6 displayed significant GI 50 values of 10(-7)-10(-6) M against various cancer cell lines. Of these compounds, 2-(6-(2-trifluoromethylphenyl))-3(Z)-hexen-1,5-diynyl)aniline (2c) showed the most potent growth inhibition activity. Compound 2c also arrested cancer cells in the G2/M phase and in low concentration reduced a significant percentage of MDA-MB-231/ATCC breast cancer tetraploid cells. In addition to the G2/M block, compound 2c caused microtubule depolymerization and induced apoptosis via activation of the caspase family.

JNK and ERK mitogen-activated protein kinases mediate THDA-induced apoptosis in K562 cells.

2-(6-(2-thieanisyl)-3(Z)-hexen-1, 5-diynyl) aniline (THDA), an enediyne compound, was identified in our laboratory as a novel antineoplastic agent against human leukemia K562 cells. THDA-induced apoptosis was associated with the upregulation of Bax, downregulation of X-linked inhibitor of apoptosis (XIAP), as well as the activation of caspase-3 and caspase-9. In addition, the mitogen-activated protein family kinases, including c-Jun N-terminal kinase (JNK) and extracellular signal-regulated protein kinase (ERK) kinases, and the transcription factor c-Jun were all activated by phosphorylation after 6 h exposure to THDA. Phosphorylation (activation) of JNK and ERK kinases by THDA was blocked by an ERK inhibitor, PD98059, or a JNK inhibitor, JNK-1, respectively, suggesting that THDA-induced apoptosis in K562 cells is ERK and JNK dependent. Moreover, the blockade of ERK and JNK also attenuated the modulation of Bax and XIAP, as well as the activation of caspase-3 and caspase-9 induced by THDA. These findings suggest that the activation of JNK and ERK is involved in the THDA-induced apoptosis of K562 cells. Therefore, this investigation, for the first time, uncovered the biological properties of this novel antitumor enediyne.

Novel acyclic enediynes inhibit Cyclin A and Cdc25C expression and induce apoptosis phenomenon to show potent antitumor proliferation.

A series of acyclic enediynes showing significant inhibition on the growth of tumor cancer is disclosed. To investigate the structure-activity relationship, compounds 12-33 were synthesized. Among them, compound 17 showed most potent growth inhibition activity against all tumor cell lines at low concentration, such as SR (0.4microM) and MDA-MB-435 (0.8microM), and almost completely blocked cell cycle in G2/M phase via controlling Cyclin A and Cdc25C expression. On the other hand, compound 29 showed potent induced apoptosis activity by inducing activation of caspase-3, -8, and -9. Thus, this article disclosed a new multiple-protein regulator in cell cycle regulation and induced apoptosis to achieve the goal of anticancer drug.

Cytotoxicities, cell cycle and caspase evaluations of 1,6-diaryl-3(Z)-hexen-1,5-diynes, 2-(6-aryl-3(Z)-hexen-1,5-diynyl)anilines and their derivatives.

Compounds 3, 6-7, 9-10, 15-17, and 20-21 showed growth inhibition effects on a full panel of 60 human cancer cell lines, and most of the average IC50 values of the indicated analogues were from < 0.01 to 96.6 microM, in which analogues 16 and 17 revealed the highest cytotoxic activity with the cancer cell lines at 10(-7) M concentration range. During the cell cycle analysis, a moderate to high apoptotic progress induction was shown by 3, 9, 16-17, and 20 compared with the control, which 2-(6-(2-thienyl)-3(Z)-hexen-1,5-diynyl)aniline 16 showed the highest apoptotic effect. Structures 16-17 displayed a significant G2/M phase arrest in the cell growth cycle compared with other derivatives, which the proportions of the G2/M phase cells were accumulated to 71.5% and 82.6%, respectively. Moreover, the colorimetric assay of 16-17 also provided advanced evidence to the relationship between the compounds and the caspase-3 enzyme, which was one of the major promoters of apoptotic effect.

Remarkable G2/M phase arrest and apoptotic effect performed by 2-(6-aryl-3-hexen-1,5-diynyl) benzonitrile antitumor agents.

2-(6-aryl-3-hexen-1,5-diynyl)benzonitriles 3a-j showed growth inhibition effects on a full panel of 60 human cancer cell lines in low micro-concentrations, in which compounds 3c,d displayed a significant G2/M arrest in the cell growth cycle compared with other derivatives and an apoptotic progress induction were also shown by 3a-d.