Healthcare Worker Seroconversion in SARS Outbreak

Serum samples were obtained from healthcare workers 5 weeks after exposure to an outbreak of severe acute respiratory syndrome (SARS). A sensitive dot blot enzyme-linked immunosorbent assay, complemented by a specific neutralization test, shows that only persons in whom probable SARS was diagnosed had specific antibodies and suggests that subclinical SARS is not an important feature of the disease

Effects of acutely inhibiting PI3K isoforms and mTOR on regulation of glucose metabolism in vivo

In in vitro studies class-I PI3Ks (phosphoinositide 3-kinases), class-II PI3Ks and mTOR (mammalian target of rapamycin) have all been described as having roles in the regulation of glucose metabolism. The relative role each plays in the normal signalling processes regulating glucose metabolism in vivo is less clear. Knockout and knockin mouse models have provided some evidence that the class-I PI3K isoforms p110α, p110β, and to a lesser extent p110γ, are necessary for processes regulating glucose metabolism and appetite. However, in these models the PI3K activity is chronically reduced. Therefore we analysed the effects of acutely inhibiting PI3K isoforms alone, or PI3K and mTOR, on glucose metabolism and food intake. In the present study impairments in glucose tolerance, insulin tolerance and increased hepatic glucose output were observed in mice treated with the pan-PI3K/mTOR inhibitors PI-103 and NVP-BEZ235. The finding that ZSTK474 has similar effects indicates that these effects are due to inhibition of PI3K rather than mTOR. The p110α-selective inhibitors PIK75 and A66 also induced these phenotypes, but inhibitors of p110β, p110δ or p110γ induced only minor effects. These drugs caused no significant effects on BMR (basal metabolic rate), O2 consumption or water intake, but BEZ235, PI-103 and PIK75 did cause a small reduction in food consumption. Surprisingly, pan-PI3K inhibitors or p110α inhibitors caused reductions in animal movement, although the cause of this is not clear. Taken together these studies provide pharmacological evidence to support a pre-eminent role for the p110α isoform of PI3K in pathways acutely regulating glucose metabolism

Targeting codon 158 p53-mutant cancers via the induction of p53 acetylation

Abstract: Gain of function (GOF) DNA binding domain (DBD) mutations of TP53 upregulate chromatin regulatory genes that promote genome-wide histone methylation and acetylation. Here, we therapeutically exploit the oncogenic GOF mechanisms of p53 codon 158 (Arg158) mutation, a DBD mutant found to be prevalent in lung carcinomas. Using high throughput compound screening and combination analyses, we uncover that acetylating mutp53R158G could render cancers susceptible to cisplatin-induced DNA stress. Acetylation of mutp53R158G alters DNA binding motifs and upregulates TRAIP, a RING domain-containing E3 ubiquitin ligase which dephosphorylates IĸB and impedes nuclear translocation of RelA (p65), thus repressing oncogenic nuclear factor kappa-B (NF-ĸB) signaling and inducing apoptosis. Given that this mechanism of cytotoxic vulnerability appears inapt in p53 wild-type (WT) or other hotspot GOF mutp53 cells, our work provides a therapeutic opportunity specific to Arg158-mutp53 tumors utilizing a regimen consisting of DNA-damaging agents and mutp53 acetylators, which is currently being pursued clinically

Consensus Recommendations by the Asian Pacific Society of Cardiology: Optimising Cardiovascular Outcomes in Patients with Type 2 Diabetes

The Asian Pacific Society of Cardiology convened a consensus statement panel for optimising cardiovascular (CV) outcomes in type 2 diabetes, and reviewed the current literature. Relevant articles were appraised using the Grading of Recommendations, Assessment, Development and Evaluation system, and consensus statements were developed in two meetings and were confirmed through online voting. The consensus statements indicated that lifestyle interventions must be emphasised for patients with prediabetes, and optimal glucose control should be encouraged when possible. Sodium–glucose cotransporter 2 inhibitors (SGLT2i) are recommended for patients with chronic kidney disease with adequate renal function, and for patients with heart failure with reduced ejection fraction. In addition to SGLT2i, glucagon-like peptide-1 receptor agonists are recommended for patients at high risk of CV events. A blood pressure target below 140/90 mmHg is generally recommended for patients with type 2 diabetes. Antiplatelet therapy is recommended for secondary prevention in patients with atherosclerotic CV disease

Reactive oxygen species-mediated cancer therapy with silica-based nanoparticles

Reactive oxygen species (ROS) is important for the well-being of cells since they served as messengers. However, too much ROS will kill them because of their high reactivity with DNA and surrounding organelles. Nanoparticles made from silica and ROS-producing agents have been successfully synthesized. They can manipulate the ROS within cancer cells by raising it to apoptotic or necrosis levels. The first project talks about the use of a nanoreactor that produces ·OH radicals independently. A photosensitizer was loaded into it as well to generate even more radicals for enhanced therapy. This was subsequently subjected to both in-vitro and in vivo testing. The second project explores the use of a new ligand to fabricate an organically modified silica nanocomposite capable of not only generating the ROS H2O2, but reducing the antioxidant capabilities of cancer cells to enhance the effectiveness of the produced ROS. The third project combined the use of the nanoreactor in the first project with a silane conjugated glucose oxidase for increased ·OH radicals production. In summary, this thesis showed that ROS can be effectively exploited to treat cancer.Doctor of Philosoph

Aesthetic Design of Skin-Sparing Mastectomy Incisions for Immediate Autologous Tissue Breast Reconstruction in Asian Women

Background The advent of skin-sparing mastectomy has allowed for the reconstruction of the breast and nipple with improved cosmesis. However, the nipple-areolar complex (NAC) in Asian patients is more pigmented and scars easily. Therefore, commonly described incisions tend to result in poor aesthetic outcomes in Asian patients with breast cancer. Methods We describe an algorithmic approach to skin-sparing mastectomy incisions in Asian patients on the basis of the location of the biopsy scar and the tumor site and size. Four incision types are described: peri-areolar, a peri-areolar incision with a second distant skin paddle, "racquet handle," and peri-areolar with adjacent skin excision. Results 281 immediate breast reconstructions were performed between May 2001 and February 2012 after skin-sparing mastectomy. The mastectomy incisions used included the peri-areolar design (n=124, 44%), peri-areolar design with a second distant skin paddle (n=39, 14%), "racquet handle" (n=21, 7.5%), and peri-areolar design with adjacent skin excision (n=42, 14%). The traditional elliptical incision and other variants where the NAC outline was not preserved were performed in the remaining 55 patients. The average follow-up was 44.7 months during which there was 1 case of total flap loss and 7 cases of partial flap necrosis; all remaining flaps survived. 24% of the patients (68/281) underwent subsequent nipple reconstruction. Conclusions Our algorithm avoids breast incisions that are randomly placed or excessively long and prevents the unnecessary sacrifice of normal breast skin. This allows skin-sparing mastectomy and immediate breast reconstruction to be performed with a consistently achievable aesthetic result in Asian women without neglecting oncological safety

An unusual case of recurrent obstructive jaundice

10.1053/j.gastro.2010.07.064Gastroenterology14051401-GAST

Expression of EBV Latent Antigens, Mammalian Target of Rapamycin, and Tumor Suppression Genes in EBV-Positive Smooth Muscle Tumors: Clinical and Therapeutic Implications

10.1158/1078-0432.CCR-08-2979CLINICAL CANCER RESEARCH15175350-5358United State