A thermally responsive biopolymer conjugated to an acid-sensitive derivative of paclitaxel stabilizes microtubules, arrests cell cycle, and induces apoptosis

Poor aqueous solubility limits the therapeutic index of paclitaxel as an anti-cancer drug. Synthesis of soluble prodrugs of paclitaxel, or conjugation of the drug to macromolecular carriers have been reported to increase its water-solubility. Macromolecular drug carriers have an added advantage of targeting the drug to the tumor site due to the abnormal tumor blood and lymphatic vasculature. This study describes a thermally responsive macromolecular carrier, elastin-like polypeptide (ELP) for the delivery of paclitaxel. Paclitaxel was bound to ELP by conjugation with the 6-maleimidocaproyl hydrazone derivative of paclitaxel, an acid-sensitive paclitaxel prodrug, for the potential treatment of breast cancer. Focused hyperthermia above a specific transition temperature at the site of a tumor causes ELP to aggregate and accumulate, thereby increasing the local concentration of the drug cargo. The paclitaxel prodrug described here bears an acid-sensitive linker that is cleavable at the lysosomal/endosomal pH, which allows a controlled intracellular release of the drug. The ELP-delivered paclitaxel in the presence of hyperthermia inhibits MCF-7 cell proliferation by stabilizing the microtubule structures, arresting the cells at the G2/M stage, and inducing apoptosis in a manner similar to conventional paclitaxel. It also inhibits proliferation of a paclitaxel resistant MCF-7 cell line. These data provide an in vitro proof of concept for the use of ELP as a delivery vehicle of paclitaxel.     

Risk assessments for the insect repellents DEET and picaridin

For the use of topical insect repellents, DEET and picaridin, human health risk assessments were conducted for various population subgroups. Acute, subchronic, and chronic dermal exposures were examined. No-observed-effect-levels (NOELs) of 200, 300, and 100mg/kg body weight (BW) were used as endpoints for DEET for acute, subchronic, and chronic exposures, respectively. For picaridin, a NOEL of 2000 mg/kg BW/day for acute exposure and a NOEL of 200 mg/kg BW/day for subchronic and chronic exposures were used. Daily exposures to several population subgroups were estimated. Risks were characterized using the Margin of Exposure (MOE) method (NOEL divided by the estimated exposure), whereby estimated MOEs were compared to an MOE of 100. Estimates of daily exposures ranged from 2 to 59 mg/kg BW/day for DEET and 2 to 22 mg/kg BW/day for picaridin. Children had the lowest MOEs. However, none of the estimated exposures exceeded NOELs for either repellent. At 40% DEET for acute exposure, children < or = 12 years had MOEs below 100. For subchronic and chronic exposures children at > or = 25% DEET and at 15% picaridin had MOEs below 100. Therefore, we found no significant toxicological risks from typical usage of these topical insect repellents.     

Flavonoids from Iris songarica and their antioxidant and estrogenic activity

A new dihydroflavonol, songaricol ( 1) and seven known flavonoids, ayamenin A ( 2), irisflavone A ( 3), 5,7-dihydroxy-2',6-dimethoxyisoflavone ( 4), irilin B ( 5), 5,3'-dihydroxy-7,8,2'-trimethoxyisoflavone ( 6) and irisoid A ( 7) were isolated from rhizome and roots of IRIS SONGARICA. Structure elucidation of 1 was achieved through extensive NMR and circular dichroism techniques. Compounds 1, 5 and 7 showed antioxidant activity in HL-60 cells (IC50 values of 21, 11 and 3.8 microg/mL), whereas 2, 5 and the previously isolated irisone B were able to show estrogenic response (EC50 values of 305.5, 159.7 and 322.0 microg/mL) in yeast cells expressing human estrogen receptor (ER-alpha).     

Antibody Profiles According to Mild or Severe SARS-CoV-2 Infection,Atlanta, Georgia,USA, 2020

Among patients with coronavirus disease (COVID-19), IgM levels increased early after symptom onset for those with mild and severe disease, but IgG levels increased early only in those with severe disease. A similar pattern was observed in a separate serosurveillance cohort. Mild COVID-19 should be investigated separately from severe COVID-19.     

Oxidized phospholipids derived from ozone-treated lung surfactant extract reduce macrophage and epithelial cell viability

Ozone is known to be a highly toxic gas present in the urban air which exerts its effect on pulmonary tissue through its facile chemical reactions with target molecules in the airway. One of the first barriers encountered by ozone is epithelial lining fluid which contains pulmonary surfactant rich in glycerophosphocholine lipids. The reaction of ozone with calf lung surfactant extract was found to result in the production of 1-palmitoyl-2-(9'-oxo-nonanoyl)-glycerophosphocholine (16:0a/9-al-GPCho) as an expected product of the ozonolysis of abundant unsaturated phospholipids containing unsaturated fatty acyl groups with a double bond at carbon-9. This oxidized phospholipid was identified as a biologically active product in that it reduced elicited macrophage viability by necrosis with an ED(50) of 6 microM. Further studies of the biological activity of 16:0a/9-al-GPCho revealed that concentrations from 100 to 200 nM initiated apoptosis in pulmonary epithelial-like A549 cells as assessed by TUNEL staining, nuclear size, and caspase-3 activation with loss of viability indicated by reduction of mitochondrial dehydrogenase activity. The release of IL-8, a neutrophil chemokine, from A549 cells was also stimulated by 50-100 nM 16:0a/9-al-GPCho. Exposure of calf lung surfactant to low levels of ozone (62.5, 125, and 250 ppb) for various time periods from 2 to 48 h in a feedback-regulated ozone exposure chamber resulted in a dose- and time-dependent increase in the formation of 16:0a/9-al-GPCho as measured by a specific and sensitive LC/MS/MS assay. The quantity of this biologically active chain-shortened glycerophosphocholine lipid generated even at 125 ppb ozone for 2-4 h (50-100 nM) was consistent with this product mediating the toxic effects of ozone on cells in contact with surfactant.     

True knot in Ryles tube: a case report

Insertion of Ryles tube is a simple routine procedure. During its insertion, minor complications like trauma to nose, nasopharynx and oral cavity do happen from time to time. But as the Ryles tube is usually inserted blindly, potentially life threatening complications like inadvertent entry into trachea, cranial cavity and intravascular penetration have been reported. Folds and kinks may occur, but true knot of the Ryles tube, which we now report, is very rare.     

Innate Immune Response and Inflammasome Activation During SARS-CoV-2 Infection

Inflammation - The novel coronavirus SARS-CoV-2, responsible for the COVID-19 outbreak, has become a pandemic threatening millions of lives worldwide. Recently, several vaccine candidates and drugs...     

DNA methylation patterns in luminal breast cancers differ from non-luminal subtypes and can identify relapse risk independent of other clinical variables

The diversity of breast cancers reflects variations in underlying biology and affects the clinical implications for patients. Gene expression studies have identified five major subtypes- Luminal A, Luminal B, basal-like, ErbB2+ and Normal-Like. We set out to determine the role of DNA methylation in subtypes by performing genome-wide scans of CpG methylation in breast cancer samples with known expression-based subtypes. Unsupervised hierarchical clustering using a set of most varying loci clustered the tumors into a Luminal A majority (82%) cluster, Basal-like/ErbB2+ majority (86%) cluster and a non-specific cluster with samples that were also inconclusive in their expression-based subtype correlations. Contributing methylation loci were both gene associated loci (30%) and non-gene associated (70%), suggesting subtype dependant genome-wide alterations in the methylation landscape. The methylation patterns of significant differentially methylated genes in luminal A tumors are similar to those identified in CD24?+?luminal epithelial cells and the patterns in basal-like tumors similar to CD44?+?breast progenitor cells. CpG islands in the HOXA cluster and other homeobox (IRX2, DLX2, NKX2-2) genes were significantly more methylated in Luminal A tumors. A significant number of genes (2853, p?相似文献