A rare case of infected urachal cyst leading to intestinal obstruction in a 3-month-old boy with febrile urinary tract infection: Case report.

RATIONALE: Urachal anomalies are rare and can present with various clinical manifestations. Urachal remnants, in particular, can be difficult to diagnose because of atypical symptoms at presentation. This study reports a case of intestinal obstruction in an infant secondary to an infected urachal cyst. PATIENTS CONCERNS: A 3-month-old boy with a known febrile urinary tract infection developed acute abdominal distension. DIAGNOSES: Abdominal ultrasound (US) and computed tomography (CT) revealed a nonspecific, ill-defined soft tissue density at the mid-abdomen, associated with intestinal obstruction. INTERVENTIONS: Emergency exploratory laparotomy was performed. The site of the obstruction was found to be at the mid-small bowel; the proximal small bowel was markedly distended, and the small bowel and sigmoid colon were adherent to urachal remnant. The urachal remnant was excised, and the peritoneal adhesions were lysed. OUTCOMES: The day after surgery, the patient was discharged without any complications. LESSONS: Intestinal obstruction is an exceedingly rare presentation of urachal remnants. This case highlights that urachal anomalies should be considered in the differential diagnosis in patients with intestinal obstruction and a concurrent febrile urinary tract infection.

Long-term outcomes and associated prognostic risk factors of childhood-onset lupus nephritis.

Background: This study investigated the clinical characteristics and kidney outcomes of childhood-onset lupus nephritis (LN), and risk factors associated with prognosis. Methods: We enrolled 216 patients with histologically diagnosed LN during childhood. The Korean Society of Pediatric Nephrology organized a retrospective cohort study of childhood-onset LN in 13 major pediatric nephrology centers in South Korea. Results: The mean age at kidney biopsy was 13.2 ± 3.22 years. The main forms of presentation were nephrotic syndrome and/or hematuria in 152 patients (70.4%), and the most common histological finding was World Health Organization (WHO) class IV in 138 patients (63.9%), followed by WHO class III in 34 patients (15.7%). In the outcome analysis, the mean follow-up period of the patients was 7.8 ± 5.11 years. At last follow-up, 32 patients (14.8%) developed advanced chronic kidney disease (CKD). Male sex and failure to achieve remission at 12 months of treatment were significant risk factors for developing advanced CKD (hazard ratio of 2.57 and 2.29, respectively). Conclusion: Our study demonstrated the clinical characteristics and long-term outcomes of patients with childhood-onset LN. Male sex and failure to achieve remission in the first year of treatment were predictive of advanced CKD. Therefore, prompt awareness and close monitoring of these high-risk patients are needed, which may further improve the prognosis of children with LN.

Levosimendan inhibits disulfide tau oligomerization and ameliorates tau pathology in TauP301L-BiFC mice.

Tau oligomers play critical roles in tau pathology and are responsible for neuronal cell death and transmitting the disease in the brain. Accordingly, preventing tau oligomerization has become an important therapeutic strategy to treat tauopathies, including Alzheimer's disease. However, progress has been slow because detecting tau oligomers in the cellular context is difficult. Working toward tau-targeted drug discovery, our group has developed a tau-BiFC platform to monitor and quantify tau oligomerization. By using the tau-BiFC platform, we screened libraries with FDA-approved and passed phase I drugs and identified levosimendan as a potent anti-tau agent that inhibits tau oligomerization. 14C-isotope labeling of levosimendan revealed that levosimendan covalently bound to tau cysteines, directly inhibiting disulfide-linked tau oligomerization. In addition, levosimendan disassembles tau oligomers into monomers, rescuing neurons from aggregation states. In comparison, the well-known anti-tau agents methylene blue and LMTM failed to protect neurons from tau-mediated toxicity, generating high-molecular-weight tau oligomers. Levosimendan displayed robust potency against tau oligomerization and rescued cognitive declines induced by tauopathy in the TauP301L-BiFC mouse model. Our data present the potential of levosimendan as a disease-modifying drug for tauopathies.

The First Case of an Infant with Familial A20 Haploinsufficiency in Korea.

Haploinsufficiency of A20 (HA20) is a newly described autoinflammatory disease caused by loss-of-function mutations in the TNFAIP3 gene. Clinical phenotypes are heterogenous and resemble Behçet's disease, juvenile idiopathic arthritis, inflammatory bowel disease, or periodic fever syndrome, with symptoms developing at an early age. Here, we report the first case of infantile familial HA20 in Korea, which mimics neonatal lupus erythematosus (NLE). A 2-month-old infant exhibited symptoms including recurrent fever, erythematous rashes, and oral ulcers, with elevated liver enzymes, and tested positive for several autoantibodies, similar to systemic lupus erythematosus (SLE); therefore, she was suspected to have NLE. However, six months after birth, symptoms and autoantibodies persisted. Then, we considered the possibility of other diseases that could cause early onset rashes and abnormal autoantibodies, including autoinflammatory syndrome, monogenic SLE, or complement deficiency, all of which are rare. The detailed family history revealed that her father had recurrent symptoms, including oral and genital ulcers, knee arthralgia, abdominal pain, and diarrhea. These Behcet-like symptoms last for many years since he was a teenager, and he takes medications irregularly only when those are severe, but doesn't want the full-scale treatment. Whole-exome sequencing was conducted to identify a possible genetic disorder, which manifested as pathogenic variant nonsense mutation in the TNFAIP3 gene, leading to HA20. In conclusion, HA20 should be considered in the differential diagnosis of an infant with an early-onset dominantly inherited inflammatory disease that presents with recurrent oral and genital ulcerations and fluctuating autoantibodies. Additionally, it also should be considered in an infant with suspected NLE, whose symptoms and abnormal autoantibodies persist.

Development of an Aryloxazole Derivative as a Brain-Permeable Anti-Glioblastoma Agent.

Glioblastoma drug development has been difficult due to the extremely low blood brain barrier (BBB) penetration of conventional anti-cancer agents. P-glycoprotein, an efflux membrane transporter, is responsible for the poor brain uptake of small and hydrophobic drug substances. To develop brain-penetrable anti-tumor agents, we designed colchicine derivatives containing an aryloxazole moiety, which is known to inhibit P-glycoprotein. Among those tested, an aryloxazole derivative named KIST-G1 showed the strongest anti-glioblastoma cell proliferation activity (IC50 = 3.2 ± 0.8 nM). Compared to colchicine, KIST-G1 showed dramatically increased BBB-permeable properties presenting 51.7 ± 0.5 (10-6 cm/s) parallel artificial membrane permeability assay (PAMPA) permeability and 45.0 ± 6.0% of P-gp inhibition. Aid by the BBB-permeable properties, KIST-G1 (5 mg/kg) suppressed glioblastoma cell growth and migration almost completely in the brain of glioblastoma xenograft models by showing 98.2 ± 0.1% reduced tumor area compared with phosphate buffered saline (PBS)-injected control. In comparison, temozolomide, which is the most widely used drug for glioblastoma, showed only moderate effects. Our results demonstrate the effectiveness of an aryloxazole moiety in targeting brain tumors and suggest KIST-G1 as a potent anti-glioblastoma agent.

A rare case of multiple pituitary adenomas in an adolescent Cushing disease presenting as a vertebral compression fracture.

Cushing disease in children and adolescents, especially with multiple pituitary adenomas (MPAs), is very rare. We report 17-year-old boy with MPAs. He presented with a vertebral compression fracture, weight gain, short stature, headache, and hypertension. On magnetic resonance imaging (MRI), only a left pituitary microadenoma was found. After surgery, transient clinical improvement was observed but headache and hypertension were observed again after 3 months later. Follow-up MRI showed a newly developed right pituitary microadenoma 6 months after the surgery. The need for careful clinical and radiographic follow-up should be emphasized in the search for potential MPAs in patients with persistent Cushing disease.

Synthesis and biological evaluation of pyrimidine-based dual inhibitors of human epidermal growth factor receptor 1 (HER-1) and HER-2 tyrosine kinases.

A novel series of N(4)-(3-chlorophenyl)-5-(oxazol-2-yl)pyrimidine-4,6-diamines were synthesized and evaluated as dual inhibitors of HER-1/HER-2 tyrosine kinases. In contrast to the currently approved HER-2-targeted agent (lapatinib, 1), our irreversible HER-1/HER-2 inhibitors have the potential to overcome the clinically relevant and mutation-induced drug resistance. The selected compound (19a) showed excellent inhibitory activity toward HER-1/HER-2 tyrosine kinases with selectivity over 20 other kinases and inhibited the proliferation of both cancer cell types: lapatinib-sensitive cell lines (SK-Br3, MDA-MB-175, and N87) and lapatinib-resistant cell lines (MDA-MB-453, H1781, and H1975). The excellent pharmacokinetic profiles of 19a in mice and rats led us to further investigation of a novel therapeutic agent for HER-2-targeting treatment of solid tumors, especially HER-2-positive breast/gastric cancer and HER-2-mutated lung cancer.

Antitumor activity of HM781-36B, a highly effective pan-HER inhibitor in erlotinib-resistant NSCLC and other EGFR-dependent cancer models.

The epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases has been implicated in a variety of cancers. In particular, activating mutations such as the L858R point mutation in exon 21 and the small in-frame deletions in exon 19 of the EGFR tyrosine kinase domain are correlated with sensitivity to EGFR tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC) patients. Clinical treatment of patients is limited by the development of drug resistance resulting mainly from a gatekeeper mutation (T790M). In this study, we evaluated the therapeutic potential of a novel, irreversible pan-HER inhibitor, HM781-36B. The results from this study show that HM781-36B is a potent inhibitor of EGFR in vitro, including the EGFR-acquired resistance mutation (T790M), as well as HER-2 and HER-4, compared with other EGFR tyrosine kinases inhibitors (erlotinib, lapatinib and BIBW2992). HM781-36B treatment of EGFR DelE746_A750-harboring erlotinib-sensitive HCC827 and EGFR L858R/T790M-harboring erlotinib-resistant NCI-H1975 NSCLC cells results in the inhibition of EGFR phosphorylation and the subsequent deactivation of downstream signaling proteins. Additionally, HM781-36B shows an excellent efficacy in a variety of EGFR- and HER-2-dependent tumor xenograft models, including erlotinib-sensitive HCC827 NSCLC cells, erlotinib-resistant NCI-H1975 NSCLC cells, HER-2 overexpressing Calu-3 NSCLC cells, NCI-N87 gastric cancer cells, SK-Ov3 ovarian cancer cells and EGFR-overexpressing A431 epidermoid carcinoma cancer cells. On the basis of these preclinical results, HM781-36B is the most potent pan-HER inhibitor, which will be advantageous for the treatment of patients with NSCLC including clinical limitation caused by acquired mutation (EGFR T790M), breast cancer and gastric cancer.

Role of surgical resection for pulmonary metastasis of hepatocellular carcinoma.

INTRODUCTION: The lung is one of the most important organs affected by metastasis of hepatocellular carcinoma. However, pulmonary metastasectomy for hepatocellular carcinoma has not been well documented. The aim of this study was to evaluate long-term outcome after pulmonary metastasectomy due to metastasis of hepatocellular carcinoma. METHODS: Between January 1998 and December 2008, 41 patients underwent pulmonary metastasectomy. Retrospective reviews of medical records and telephone surveys were conducted to identify risk factors of long-term survival. RESULTS: Median time between a complete remission of hepatocellular carcinoma and pulmonary metastasectomy was 11 (4-105) months. During median 25-month follow-up time after metastasectomy, hepatocellular carcinoma recurred in 33 patients. Overall survival rate was 66.9±10% in all 41 patients and disease free survival was 24.5±10% in 24 patients who had no viable hepatocellular carcinoma in the liver preoperatively. An analysis of recurrence revealed that survival was better in patients whose recurrence was limited to either in the liver or lungs compared to that in patients whose recurrence took place in the distant organ other than the liver or lungs (extrahepatic/extrapulmonary metastasis) (p=0.004, log-rank). CONCLUSIONS: Pulmonary metastasectomy for hepatocellular carcinoma can be performed safely without major morbidity. Recurrence at organs other than the liver or lung was found to result in poor survival, which suggests that a careful search for distant metastasis at other locations is mandatory for patient selection. This study demonstrated that pulmonary metastasectomy can play an important role in selected patients with pulmonary metastasis of hepatocellular carcinoma.

Discovery of a novel Her-1/Her-2 dual tyrosine kinase inhibitor for the treatment of Her-1 selective inhibitor-resistant non-small cell lung cancer.

A novel series of (S)-1-acryloyl-N-[4-(arylamino)-7-(alkoxy)quinazolin-6-yl]pyrrolidine-2-carboxamides were synthesized and evaluated as Her-1/Her-2 dual inhibitors. In contrast to the Her-1 selective inhibitors, our novel compounds are irreversible inhibitors of Her-1 and Her-2 tyrosine kinases with the potential to overcome clinically relevant, mutation-induced drug resistance. The selected compounds (19c, 19d) showed excellent EGFR inhibition activity even toward the T790M mutation of Her-1 tyrosine kinase with excellent selectivity. The excellent pharmacokinetic profiles of these compounds in rats and their robust in vivo efficacy in an A431 xenograft model clearly demonstrate that they merit further investigation as novel therapeutic agents for EGFR-targeting treatment of solid tumors, especially Her-1 selective inhibitor-resistant non-small cell lung cancer.

Role of pancreatitis-associated protein 1 on oxidative stress-induced cell death of pancreatic acinar cells.

Previously we showed that oxidative stress induces apoptosis of pancreatic acinar cells with nuclear loss of DNA repair proteins. Oxidative stress has an important role in the pathogenesis of pancreatitis. Pancreatitis-associated protein 1 (PAP-1) is a protein secreted upon induction of acute pancreatitis. In this study, we investigated the role of PAP-1 on oxidative stress-induced cell death of pancreatic acinar AR42J cells. AR42J cells were transfected with or without full-length sense cDNA of PAP-1 (PAP-1 S cDNA) or antisense cDNA of PAP-1 (PAP-1 AS cDNA) and received oxidative stress caused by glucose oxidase acting on beta-D-glucose, glucose/glucose oxidase. PAP-1 mRNA expression and cell viability were determined. As a result, oxidative stress induced PAP-1 mRNA expression in AR42J cells in a time-dependent manner. Cell viability decreased with the concentration of glucose oxides delivered to the cells that had received glucose. Oxidative stress-induced PAP-1 expression was augmented in the cells transfected with PAP-1 S cDNA compared with wild-type cells or cells transfected with control vector pcDNA. PAP-1 induction by oxidative stress decreased in the cells transfected with PAP-1 AS cDNA. Cell death caused by oxidative stress was inhibited in the cells transfected with PAP-1 S cDNA, but it increased in the cells transfected with PAP-1 AS cDNA. These results indicate that PAP-1 may be a defensive gene for oxidative stress-induced cell death of pancreatic acinar cells.

Structure-based virtual screening of Src kinase inhibitors.

Src is an important target in multiple processes associated with tumor growth and development, including proliferation, neovascularization, and metastasis. In this study, hit identification was performed by virtual screening of commercial and in-house compound libraries. Docking studies for the hits were performed, and scoring functions were used to evaluate the docking results and to rank ligand-binding affinities. Subsequently, hit optimization for potent and selective candidate Src inhibitors was performed through focused library design and docking analyses. Consequently, we report that a novel compound '43' with an IC(50) value of 89 nM, representing (S)-N-(4-(5-chlorobenzo[d][1,3]dioxol-4-ylamino)-7-(2-methoxyethoxy)quinazolin-6-yl)pyrrolidine-2-carboxamide, is highly selective for Src in comparison to EGFR (IC(50) ratio>80-fold) and VEGFR-2 (IC(50) ratio>110-fold). Compound 43 exerted anti-proliferative effects on Src-expressing PC3 human prostate cancer and A431 human epidermoid carcinoma cells, with calculated IC(50) values of 1.52 and 0.78 microM, respectively. Moreover, compound 43 (0.1 microM) suppressed the phosphorylation of extracellular signal-regulated kinases and p90 ribosomal S6 kinase, downstream molecules of Src, in a time-dependent manner, in both PC3 and A431 cell lines. The docking structure of compound 43 with Src disclosed that the chlorobenzodioxole moiety and pyrrolidine ring of C-6 quinazoline appeared to fit tightly into the hydrophobic pocket of Src. Additionally, the pyrrolidine NH forms a hydrogen bond with the carboxyl group of Asp348. These results confirm the successful application of virtual screening studies in the lead discovery process, and suggest that our novel compound 43 can be an effective Src inhibitor candidate for further lead optimization.

Oxidative stress induces nuclear loss of DNA repair proteins Ku70 and Ku80 and apoptosis in pancreatic acinar AR42J cells.

Cell death linked to oxidative DNA damage has been implicated in acute pancreatitis. The severe DNA damage, which is beyond the capacity of the DNA repair proteins, triggers apoptosis. It has been hypothesized that oxidative stress may induce a decrease in the Ku70 and Ku80 levels and apoptosis in pancreatic acinar cells. In this study, it was found that oxidative stress caused by glucose oxidase (GO) acting on beta-d-glucose, glucose/glucose oxidase (G/GO), induced slight changes in cytoplasmic Ku70 and Ku80 but drastically induced a decrease in nuclear Ku70 and Ku80 both time- and concentration-dependently in AR42J cells. G/GO induced apoptosis determined by poly(ADP-ribose) polymerase cleavage, an increase in expression of p53 and Bax, and a decrease in Bcl-2 expression. G/GO-induced apoptosis was in parallel with the loss of nuclear Ku proteins in AR42J cells. Caspase-3 inhibitor prevented G/GO-induced nuclear Ku loss and cell death. G/GO did not induce apoptosis in the cells transfected with either the Ku70 or Ku80 expression gene but increased apoptosis in those transfected with the Ku dominant negative mutant. Pulse and pulse-chase results show that G/GO induced Ku70 and Ku80 syntheses, even though Ku70 and Ku80 were degraded both in cytoplasm and nucleus. G/GO-induced decrease in Ku binding to importin alpha and importin beta reflects possible modification of nuclear import of Ku proteins. The importin beta level was not changed by G/GO. These results demonstrate that nuclear decrease in Ku70 and Ku80 may result from the decrease in Ku binding to nuclear transporter importins and the degradation of Ku proteins. The nuclear loss of Ku proteins may underlie the mechanism of apoptosis in pancreatic acinar cells after oxidative stress.