Citations

Significance We have identified a lethal subtype of gastric cancer (GC) that is characterized by high levels of clonal heterogeneity and TP53 (tumor protein P53) mutation. We have also uncovered key novel mutations in the targetable NRG1 (neuregulin-1) and ERBB4 (V-Erb-B2 avian erythroblastic leukemia viral oncogene homolog 4) ligand-receptor pair and identified BRCA2 (breast cancer 2, early onset) mutations as new genetic markers to predict better survival for GC. Our study represents a novel approach for GC personalized medicine and identified novel clinical actionable therapies for GC therapy.

We treated 26 eyes of 25 young patients having a mean age of 30 years with intravitreal vascular endothelial growth factor (VEGF) inhibitor for choroidal new vessel (CNV) formation overlying choroidal osteoma over a mean follow-up of 26 months. Mean number of injections was 2.4 at 6 months, 3.2 at 12 months, and 5.5 at 24 months. CNV was subfoveal in 14 eyes, juxtafoveal in 5, extrafoveal in 5, and peripapillary in 2. By paired comparison, mean decrease from baseline was 119.7 microns at 6 months (n=15;P=0.001), 105.3 microns at 1 year (n=10;P=0.03), and 157.6 microns at 2 years (n=7;P=0.08). BCVA improved by 3.3 lines at 6 months after therapy (n=26;P<0.001), 2.8 lines (n=20;P=0.01) at 1 year, and 3.1 lines (n=13;P=0.049) at 2 years. We conclude that intravitreal anti-VEGF injections improve vision in majority of eyes with CNV from choroidal osteoma.

Significance Tumor cells adapt to hypoxia by modulating energy production and utilization. Endocytosis is an energy-consuming process that is suppressed during hypoxia. Our studies show that Dynamin 2 (DNM2), a key component of endocytic machinery, is transcriptionally suppressed by HIF-1. Genetic and pharmacological inactivation of DNM2 stabilized HIF-1α and HIF-2α. Furthermore, miR-199a, which is encoded from the opposite strand of DNM2 , exerts reciprocal negative regulation upon HIF-1α and HIF-2α. Overexpression of miR-199a decreased HIF-1α and HIF-2α, cell migration, and metastasis. These findings establish a regulatory loop between endocytic pathway and hypoxic response in tumor cells.

AbstractObjectivesCompare healthcare resource utilization (HCRU) and costs between patients prescribed opioids (RxOP) and those who were not (NoRxOP) during an emergency department (ED) or inpatient visit.MethodsRetrospective cohort analysis was performed (January 2006 to September 2010). Continuously eligible RxOP patients in ED/inpatient settings (January 2007 to September 2009) were included if age was ≥ 12 years by initial prescription date (or random date between first ED/inpatient admission and September 30, 2009 [NoRxOP patients]).Healthcare resource utilization and costs for 12 months after initial prescription were compared. Univariate descriptive analyses were performed for baseline and outcome variables and compared using appropriate tests. Risk adjustment compared HCRU between RxOP and NoRxOP cohorts for the postindex period.ResultsOf 27,599 eligible patients, RxOP patients (n = 18,819) were younger, less likely to be male, more likely to reside in southern United States and to have Preferred Provider Organization health plans, and had lower comorbidity index scores, compared with NoRxOP patients (n = 8,780). RxOP patients were less likely to have nonpain‐related comorbidities and more frequently diagnosed with pain‐related comorbidities.Unmatched and propensity‐matched RxOP patients experienced higher HCRU and costs in all subcategories (total, inpatient, outpatient ED, physician, pharmacy, other outpatient settings). Opioid abuse frequency was low in patients with common diagnoses/procedures within 3 months before initial prescription (0.48%). Average time to abuse was < 1 year (201 days).ConclusionMost patients were prescribed opioids initially during ED/inpatient visits and incurred higher HCRU than those not prescribed opioids. Among those with diagnosed opioid abuse after initiating opioids, time to diagnosis was rapid (range: 14 to 260 days) for patients with common diseases and procedures.

Genetic College Many genomic elements in humans are associated with behavior, including educational attainment. In a genome-wide association study including more than 100,000 samples, Rietveld et al. (p. 1467 , published online 30 May; see the Perspective by Flint and Munafò ) looked for genes related to educational attainment in Caucasians. Small genetic effects at three loci appeared to impact educational attainment.

Abstract Purpose: Glioblastoma multiforme (GBM) is a devastating disease. Recent studies suggest that the stem cell properties of GBM contribute to the development of therapy resistance. Experimental Design: The expression of Survivin and Ran was evaluated by immunohistochemistry with GBM tissues, and quantitative reverse transcriptase (qRT)-PCR and immunocytochemistry with patient-derived GBM sphere cultures. With a computational structure-based drug design, 11 small-molecule compounds were designed, synthesized, and evaluated as inhibitor candidates for the molecular interaction of Survivin protein. The molecular mechanism of the lead compound, LLP-3, was determined by Western blot, ELISA, in situ proximity ligation assay, and immunocytochemistry. The effects of LLP-3 treatment on GSCs were evaluated both in vitro and in vivo. Quantitative immunohistochemistry was carried out to compare Survivin expression in tissues from 44 newly diagnosed and 31 recurrent post-chemoradiation GBM patients. Lastly, the sensitivities of temozolomide-resistant GBM spheres to LLP-3 were evaluated in vitro. Results: Survivin and Ran were strongly expressed in GBM tissues, particularly in the perivasculature, and also in patient-derived GSC cultures. LLP-3 treatment disrupted the Survivin–Ran protein complex in cancer cells and abolished the growth of patient-derived GBM spheres in vitro and in vivo. This inhibition was dependent on caspase activity and associated with p53 status of cells. Immunohistochemistry showed that Survivin expression is significantly increased in recurrent GBM compared with newly diagnosed tumors, and temozolomide-resistant GBM spheres exhibited high sensitivities to LLP-3 treatment. Conclusions: Disruption of the Survivin–Ran complex by LLP-3 abolishes survival and growth of GSCs both in vitro and in vivo, indicating an attractive novel therapeutic approach for GBM. Clin Cancer Res; 19(3); 631–42. ©2012 AACR.

We present here a novel case of an atypical Omenn syndrome (OS) phenotype due to mutations in theADAgene encoding adenosine deaminase. This case is noteworthy for a significant increase in circulating CD56brightCD16- cytokine-producing NK cells after treatment with steroids for skin rash.