Detection ofrat gene alterations andras proteins in colorectal cancer

DNA extracted from 31 primary colorectal carcinomas was analyzed for the presence ofras gene amplification and mutations. Nine carcinomas had Ha-ras amplification and seven Ki-ras amplification. Nine carcinomas had codon 12 Ki-ras mutations. Immunohistochemical staining forras proteins revealed a normal membrane association in normal mucosa and benign polyps but an abnormal cytoplasmic distribution in carcinomas. Amplification, mutations, and immunohistochemical staining were independent of histologic differentiation, Duke's stage, or DNA ploidy status. This study demonstrates that abnormalities ofras genes are a common finding in colorectal carcinomas. They are potentially important biologic changes associated with malignancy, although they do not appear to be related to clinical behavior. Supported by The Cancer Research Campaign and the North West Regional Health Authority.     

Intramuscular gold decreases cytokine expression and macrophage numbers in the rheumatoid synovial membrane.

OBJECTIVES--Cytokines, released from mononuclear cells (MNC) are mediators of joint destruction in rheumatoid arthritis (RA). The mechanisms of action of gold salts used in the treatment of RA are unknown. The aim of this study was to investigate cytokine expression and intensity of MNC infiltrate in the RA synovial membrane (SM) following treatment with sodium aurothiomalate (SAT). METHODS--Sequential blind needle biopsies were obtained at entry into the study and at two and 12 weeks after the start of SAT therapy in 10 patients with active RA. SMs were stained with a panel of monoclonal antibodies to assess cytokine expression (IL-1 alpha, IL-1 beta, TNF-alpha, IL-6, and GM-CSF). RESULTS--There was a significant decrease in IL-1 alpha, IL-1 beta, IL-6 and TNF-alpha expression 12 weeks after treatment (p < 0.004, p < 0.002, p < 0.009 and p < 0.004 respectively). This was noted in the lining layer, the perivascular aggregates and the connective tissue areas. Detailed examination of the MNC infiltrate showed a significant reduction in inflammatory monocytes (MONO) in the lining layer at two weeks (p < 0.03). A decrease in the number of CD68+ macrophages (MAC) was noted in the perivascular and connective tissue areas at 12 weeks. No significant changes were observed in the number of T and B cells and blood vessels. CONCLUSION--The results suggest that gold may suppress RA disease activity by diminishing MONO and MAC numbers and consequently monokine production in the SM.     

The loss-of-function PCSK9Q152H variant increases ER chaperones GRP78 and GRP94 and protects against liver injury

Individuals harboring the loss-of-function (LOF) proprotein convertase subtilisin/kexin type 9 Gln152His variation (PCSK9^Q152H) have low circulating low-density lipoprotein cholesterol levels and are therefore protected against cardiovascular disease (CVD). This uncleavable form of proPCSK9, however, is retained in the endoplasmic reticulum (ER) of liver hepatocytes, where it would be expected to contribute to ER storage disease (ERSD), a heritable condition known to cause systemic ER stress and liver injury. Here, we examined liver function in members of several French-Canadian families known to carry the PCSK9^Q152H variation. We report that PCSK9^Q152H carriers exhibited marked hypocholesterolemia and normal liver function despite their lifelong state of ER PCSK9 retention. Mechanistically, hepatic overexpression of PCSK9^Q152H using adeno-associated viruses in male mice greatly increased the stability of key ER stress-response chaperones in liver hepatocytes and unexpectedly protected against ER stress and liver injury rather than inducing them. Our findings show that ER retention of PCSK9 not only reduced CVD risk in patients but may also protect against ERSD and other ER stress–driven conditions of the liver. In summary, we have uncovered a cochaperone function for PCSK9^Q152H that explains its hepatoprotective effects and generated a translational mouse model for further mechanistic insights into this clinically relevant LOF PCSK9 variant.     

Chemical composition and larvicidal activity of several essential oils from Hypericum species from Tunisia

The chemical composition of the essential oils extracted from some Tunisian Hypericum species and their larvicidal activity against Culex pipiens larvae were evaluated. The chemical compositions of the essential oils from the aerial plant parts were analyzed using gas chromatography–mass spectrometry. One hundred and thirty-four compounds were identified, ranging between 85.1 and 95.4 % of the oil's composition. The components were monoterpene hydrocarbons, oxygenated monoterpenes, sesquiterpene hydrocarbons, oxygenated sesquiterpenes, non-terpenic hydrocarbons, and others. The larvicidal activity of the essential oils was evaluated using a method recommended by WHO. Larvicidal tests revealed that essential oils from the Hypericum species have a significant larvicidal activity against C. pipiens, with LC₅₀ ranging between 102.82 and 194.70 ppm. The most powerful essential oils against these larvae were Hypericum tomentosum and Hypericum humifusum samples, followed by the essential oil of Hypericum perforatum.     

Trimethoprim-sulfamethoxazole as de-escalation in ventilator-associated pneumonia: a cohort study subanalysis

European Journal of Clinical Microbiology & Infectious Diseases - This is a subanalysis of a previous study which compared the effectiveness of trimetoprim-sulfametoxazole (TMP-SMX) with all...     

Marine natural products from sponges (Porifera) of the order Dictyoceratida (2013 to 2019); a promising source for drug discovery

Marine organisms have been considered an interesting target for the discovery of different classes of secondary natural products with wide-ranging biological activities. Sponges which belong to the order Dictyoceratida are distinctly classified into 5 families: Dysideidae, Irciniidae, Spongiidae, Thorectidae, and Verticilliitidae. In this review, compounds isolated from Dictyoceratida sponges were discussed with their biological potential within the period 2013 to December 2019. Moreover, analysis of the physicochemical properties of these marine natural products was investigated and the results showed that 78% of the compounds have oral bioavailability potential. This review highlights sponges of the order Dictyoceratida as exciting source for discovery of new drug leads.

Marine organisms have been considered an interesting target for the discovery of different classes of secondary natural products with wide-ranging biological activities.     

Instant and quantitative epoxidation of styrene under ambient conditions over a nickel(ii)dibenzotetramethyltetraaza[14]annulene complex immobilized on amino-functionalized SBA-15

Nickel(ii)dibenzotetramethyltetraaza[14]annulene complex (Nitmtaa) was synthetized and immobilized on post amino-functionalized SBA-15 (N-SBA-15) to obtain a stable and reusable nanocatalyst named as Nitmtaa@N-SBA-15. Here (3-aminopropyl)triethoxysilane (APTES) was first grafted on the surface SBA-15, then Nitmtaa was added and coordinated on the silica surface via APTES amine groups. The structure and morphology, and thermal stability of the prepared nanocatalyst was investigated using SEM, HR-TEM, BET, FT-IR, powder XRD, and TGA. HR-TEM and XRD results revealed a high dispersion of Nitmtaa on the SBA-15 surface. The catalytic activity of this nanocatalyst was evaluated in the epoxidation of styrene, under ambient conditions, using meta-chloroperoxybenzoic acid (m-CPBA) as the oxygen donor. This nanocatalyst showed an immediate and quantitative epoxidation of styrene with high turn-over-frequency ∼31.58 s⁻¹. Moreover, the superior catalytic activity and high stability of Nitmtaa@N-SBA-15 could be maintained after four successive cycles. A possible reaction mechanism is also proposed.

Immediate and quantitative epoxidation of styrene under ambient conditions catalyzed by new nanocatalyst obtained by immobilizing nickel(ii)dibenzotetramethyltetraaza[14]annulene in amino-functionalized SBA-15.