Stephania delavayi Diels. inhibits breast carcinoma proliferation through the p38 MAPK/NF-κB/COX-2 pathway

The nuclear factor κB (NF-κB)/inhibitor of κ kinase-β (IKKβ) signaling pathway is important in tumor promotion and progression. MDA-MB-231 human breast carcinoma cells express COX-2 and show a constitutive phosphorylation of NF-κB. Many non-specific inhibitors of IKKβ and NF-κB are used to inhibit tumor promotion and progression. The Stephania delavayi Diels. (S. delavayi Diels.) extract has been reported to safely activate B cell immunity and there is evidence suggesting that it may be a promising new anticancer therapeutic agent. S. delavayi Diels. extract suppressed proliferation of the breast cancer cell lines MDA-MB-231 and MCF-7 by inducing cell death. To aid in the development of the S. delavayi Diels. extract as a therapeutic agent, its mechanisms of action were investigated, in particular its effects on p38 MAPK, NF-κB and COX-2, which play important roles in inflammation and cancer. S. delavayi Diels. stimulated p38 MAPK phosphorylation but reduced NF-κB phosphorylation and COX-2 expression in a dose- and time-dependent manner. Thus, S. delavayi Diels., which appears to act primarily through p38 MAPK/NF-κB/COX-2 signaling in breast carcinomas, may be a potent anticancer agent with target specificity and low toxicity.     

(3-Chloroacetyl)-indole, a novel allosteric AKT inhibitor, suppresses colon cancer growth in vitro and in vivo

Indole-3-carbinol (I3C) is produced in Brassica vegetables such as broccoli and cabbage and has been shown to inhibit proliferation and induce apoptosis in various cancer cells, including breast, prostate, colon, and leukemia. However, only high doses of I3C were shown to inhibit cell proliferation (IC(50) = 200-300 μmol/L). Our goal here was to develop a more potent antitumor agent by modifying the structure of I3C. We created I3C derivatives and found that (3-chloroacetyl)-indole (3CAI) more strongly inhibited colon cancer cell growth than I3C. In addition, by screening 85 kinases in a competitive kinase assay, we found that 3CAI was a specific AKT inhibitor. AKT is a serine/threonine kinase that plays a pivotal role in promoting transformation and chemoresistance by inducing proliferation and inhibiting apoptosis. Therefore, AKT is regarded as a critical target for cancer therapy. 3ICA, a derivative of I3C, is a potent and specific AKT inhibitor. This compound showed significant inhibition of AKT in an in vitro kinase assay and suppressed expression of AKT direct downstream targets such as mTOR and GSK3β as well as induced growth inhibition and apoptosis in colon cancer cells. In addition, oral administration of this potent AKT inhibitor suppressed cancer cell growth in an in vivo xenograft mouse model.     

A novel two-stage, transdisciplinary study identifies digoxin as a possible drug for prostate cancer treatment

Identification of novel indications for commonly prescribed drugs could accelerate translation of therapies. We investigated whether any clinically-used drugs might have utility for treating prostate cancer by coupling an efficient, high-throughput laboratory-based screen and a large, prospective cohort study. In stage 1, we conducted an in vitro prostate cancer cell cytotoxicity screen of 3,187 compounds. Digoxin emerged as the leading candidate given its potency in inhibiting proliferation in vitro (mean IC??=163 nM) and common use. In stage 2, we evaluated the association between the leading candidate drug from stage 1 and prostate cancer risk in 47,884 men followed 1986-2006. Regular digoxin users (versus nonusers: RR=0.76, 95% CI 0.61-0.95), especially users for ≥ 10 years (RR=0.54, 95% CI 0.37-0.79, P-trend<0.001), had a lower prostate cancer risk. Digoxin was highly potent in inhibiting prostate cancer cell growth in vitro and its use was associated with a 25% lower prostate cancer risk. SIGNIFICANCE: Our two-stage transdisciplinary approach for drug repositioning provides compelling justification for further mechanistic and possibly clinical testing of the leading nonchemotherapy candidate, digoxin, a cardiac glycoside, as a drug for prostate cancer treatment. Perhaps of equal importance, our study illustrates the power of the transdisciplinary approach in translational cancer research. By coupling laboratory and epidemiologic methods and thinking, we reduced the probability of identifying false-positive candidate drugs for the next steps in testing.     

Perioperative administration of pregabalin for pain after robot-assisted endoscopic thyroidectomy: a randomized clinical trial

Background  

Perioperative administration of pregabalin, which is effective for neuropathic pain, might reduce early postoperative and chronic pain. This randomized, double-blinded, placebo-controlled trial (Clinical Trials.gov ID NCT00905580) was designed to investigate the efficacy and safety of pregabalin for reducing both acute postoperative pain and the development of chronic pain in patients after robot-assisted endoscopic thyroidectomy.     

Tufting Enteropathy with EpCAM Mutations in Two Siblings

Tufting enteropathy is a rare autosomal recessive disorder presenting with early-onset severe intractable diarrhea. The epithelial cell adhesion molecule gene (EpCAM) has recently been identified as the gene responsible for tufting enteropathy. Based on histology, a diagnosis of tufting enteropathy was made in two Korean siblings. They developed chronic diarrhea and failure to thrive. They had a broad nasal bridge and micrognathia. Duodenal and colonic biopsies showed villous atrophy, disorganization of surface enterocytes, and focal crowding resembling tufts. Protracted diarrhea continued and so cyclic parenteral nutrition was supplied. The sister had juvenile rheumatoid arthritis. Mutation analysis of EpCAM identified two compound heterozygous mutations in these siblings: 1) a donor splicing site mutation in intron 5 (c.491+1G>A) and 2) a novel nonsense mutation in exon 3 (c.316A>T, Lys106X). Analysis of EpCAM will be useful for genetic counseling and prenatal diagnosis of tufting enteropathy.     

Complete endoscopic resection of very early stage gastric plasmacytoma

Gastric plasmacytomas are very rare, and most are not detected until the disease has progressed to an advanced stage. However, there have been recent reports of cases of early-stage gastric plasmacytoma, in which neoplastic cells are confined to the mucosa or submucosa. Here we report a case of a very early stage gastric plasmacytoma that was confined to the lamina propria of the gastric mucosa. The lesion was successfully and completely removed by endoscopic submucosal dissection, and the surveillance endoscopy showed no recurrence during the follow-up of 40 months. This report appears to be the first documented case of complete endoscopic removal of a primary gastric plasmacytoma.     

Intradural Extramedullary Tuberculoma Mimicking En Plaque Meningioma

A 24-year-old man with tuberculosis meningitis developed acute paraplegia and sensory disturbances 5 weeks after receiving conventional antituberculous therapy. Magnetic resonance imaging revealed an intradural extramedullary long segmental mass mimicking en plaque meningioma at the T2-T6 vertebrae levels. Prompt surgical decompression was performed. A histology examination of the mass revealed a tuberculoma. After surgery, the patient showed improved motor power and a normal bladder function. Intradural extramedullary tuberculoma of the spinal cord is rare complication of tuberculosis meningitis, which can occur as a response to conventional antituberculous therapy.