Citations

BackgroundBalloon sinus dilation (BSD) is a commonly performed sinus procedure in the United States. Several cadaveric studies have evaluated BSD accuracy and the maxillary sinus has consistently been shown to be the most challenging to cannulate. We designed an independent study to evaluate the intraoperative accuracy of maxillary sinus BSD.MethodsA prospective, single‐blinded trial evaluating the accuracy of maxillary sinus BSD was performed using 2 commercially available BSD systems (guidewire‐ and probe‐based systems) randomly assigned to patients undergoing endoscopic surgery for chronic rhinosinusitus without nasal polyps (CRSsNP) or a skullbase approach in patients without sinus disease. All patients underwent maxillary BSD followed by uncinectomy to reveal dilation of the natural maxillary sinus ostia. The recorded procedures were reviewed by 3 fellowship‐trained rhinologists from different institutions blinded to the BSD system utilized. The primary endpoint compared accuracy of maxillary BSD attempts. The secondary endpoint compared accuracy between the 2 systems.ResultsTwenty‐nine maxillary BSD procedures were performed in 18 patients (age range, 20‐79 years; mean, 51 years) without nasal polyposis undergoing maxillary antrostomy as part of a more extensive procedure. BSD was successful in 18 of 29 (62%) attempts and unsuccessful in 9 of 29 (31%) attempts, with statistically “almost perfect” interrater agreement (kappa = 0.86). There was no statistical difference between the 2 BSD systems (p = 0.81).ConclusionMaxillary BSD appeared to be less accurate in living patients when compared with findings from previously published cadaver studies. There were no differences in accuracy between the probe‐ and guidewire‐based systems. This is the first non‒industry‐sponsored study evaluating maxillary sinus BSD in living patients. Further studies are needed to investigate the clinical implications of our findings.

102 Background: This phase II study aimed to investigate the safety and efficacy of XP compared to SP in the first-line treatment of HER2 negative AGC. Methods: Patients were randomly assigned to receive either SP (S-1 at 40–60 mg twice daily for 21 days plus cisplatin at 60 mg/ m2 on day 8, every 5 weeks) or XP (capecitabine 1,000 mg/m2 twice daily for 14 days plus cisplatin 80 mg/m2 on day 1, every 3 weeks). Primary endpoint was response rate (RR), and secondary endpoints were progression-free survival (PFS), overall survival (OS), time to treatment failure (TTF), and adverse events. Results: 84 eligible patients were randomly assigned to receive SP ( N = 41) or XP ( N = 43). No statistical difference was observed in overall RR between the SP and XP groups [51.2% (95% CI, 35.1% to 67.1%) vs. 53.5% (95% CI, 37.7% to 68.8%), P = 1.000]. Despite not significant, however, SP vs. XP showed a trend toward better PFS [median, 5.9 months vs. 4.1 months; hazard ratio (HR), 0.763; 95% CI, 0.462 to 1.259; P = .284] and OS (median, 13.5 months vs. 10.0 months; HR, 0.776; 95% CI, 0.485 to 1.244; P = .290). This trend in the SP vs. XP comparison was more pronounced in TTF (median, 4.5 months vs. 3.1 months; HR, 0.651; 95% CI, 0.421 to 1.006; P = .052). Common grade 3 to 4 hematological toxicities were neutropenia and anemia (SP group, 23% and 23%; XP group, 35% and 28%). Grade 3-4 anorexia and hyponatremia were more frequently seen in the XP group (31% and 16%) compared to the SP group (13% and 5%). Treatment-related deaths occurred in one patient (2.3%) in the XP group. Conclusions: XP failed to demonstrate the superior efficacy over SP. Higher incidence of severe toxicities by XP suggests SP as the standard 1st line chemotherapy for HER2 negative AGC in Japan. Clinical trial information: UMIN000006755.

Abstract Background: Retinoblastoma (RB) is the most frequent pediatric retinal tumor. In the present study, to elucidate chemoresistance mechanisms and identify potential biomarkers in RB, we utilized RNA sequencing (RNAseq) technological platforms to reveal transcriptome profiles and identify any differentially expressed genes (DEGs) between an etoposide drug-resistant subline (Y79/EDR) and parental Y79 cells. Methods: To test whether Y79/EDR cells showed resistance to antineoplastic agents for RB, we treated the cells with etoposide, carboplatin and vincristine and analyzed them with a Cell Counting Kit-8 (CCK-8). Y79/EDR and parental Y79 cells were used for RNAseq and bioinformatics analysis to enable a genome-wide review of DEGs between the two lines using the DESeq R package (1.10.1). Then, DEG enrichment in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways was analyzed with KOBAS software. Next, real-time quantitative polymerase chain reaction (QRT-PCR) and cytotoxicity assays were performed to experimentally and functionally validate the identified candidate biomarkers. Results: Y79/EDR cells showed resistance to etoposide, carboplatin and vincristine at different concentrations. In total, 524 transcripts were differentially expressed in Y79/EDR cells based on analysis of fragments per kilobase of transcript per million fragments mapped (FPKM); among these, 57 genes were downregulated and 467 genes were upregulated in Y79/EDR cells compared to parental Y79 cells. We selected candidate DEGs, including ARHGAP9, HIST1H4H, RELN, DDIT4, HK2, STC1 and PFKFB4, for mRNA expression validation with QRT-PCR assays and found that the expression levels determined by QRT-PCR were consistent with the RNAseq data. Further studies involving downregulation of ARHGAP9 with a specific siRNA pool showed that ARHGAP9 altered the cellular sensitivity of Y79 cells to etoposide and carboplatin. Conclusion: Our initial findings provided a genomic view of the transcription profiles of etoposide-induced acquired resistance in RB. Follow-up studies indicated that ARHGAP9 might be a chemoresistance biomarker in RB, providing insight into potential therapeutic targets for overcoming acquired chemoresistance in RB. These findings can aid in understanding and overcoming chemoresistance during treatment of RB in the clinic.

Data on disease burden are often used for assessing population health, evaluating the effectiveness of interventions, formulating health policies, and planning future resource allocation. We investigated whether Internet usage and social media data, specifically the search volume on Google, page view count on Wikipedia, and disease mentioning frequency on Twitter, correlated with the disease burden, measured by prevalence and treatment cost, for 1633 diseases over an 11-year period. We also applied least absolute shrinkage and selection operator to predict the burden of diseases. We found that Google search volume is relatively strongly correlated with the burdens for 39 of 1633 diseases, including viral hepatitis, diabetes mellitus, multiple sclerosis, and hemorrhoids. Wikipedia and Twitter data strongly correlated with the burdens of 15 and 7 diseases, respectively. However, an accurate analysis must consider each condition’s characteristics, including acute/chronic nature, severity, familiarity to the public, and the presence of stigma.

Intracellular delivery is a critical step in biological discoveries and has been widely utilized in biomedical research. A variety of molecular tools have been developed for cell-based gene therapies, including FDA approved CAR-T immunotherapy, iPSC, cell reprogramming and gene editing. Despite the inspiring results of these applications, intracellular delivery of foreign molecules including nucleic acids and proteins remains challenging. Efficient yet non-invasive delivery of biomolecules in a high-throughput manner has thus long fascinates the scientific community. As one of the most popular non-viral technologies for cell transfection, electroporation has gone through enormous development with the assist of nanotechnology and microfabrication. Emergence of miniatured electroporation system brought up many merits over the weakness of traditional electroporation system, including precise dose control and high cell viability. These new generation of electroporation systems are of considerable importance to expand the biological applications of intracellular delivery, bypassing the potential safety issue of viral vectors. In this review, we will go over the recent progresses in the electroporation-based intracellular delivery and several potential applications of cutting-edge research on the miniatured electroporation, including gene therapy, cellular reprogramming and intracellular probe.

The interaction of death-associated protein kinase 1 (DAPK1) with the 2B subunit (GluN2B) C-terminus of N-methyl-D-aspartate receptor (NMDAR) plays a critical role in the pathophysiology of depression and is considered a potential target for the structure-based discovery of new antidepressants. However, the 3D structures of C-terminus residues 1290–1310 of GluN2B (GluN2B-CT1290-1310) remain elusive and the interaction between GluN2B-CT1290-1310 and DAPK1 is unknown. In this study, the mechanism of interaction between DAPK1 and GluN2B-CT1290-1310 was predicted by computational simulation methods including protein–peptide docking and molecular dynamics (MD) simulation. Based on the equilibrated MD trajectory, the total binding free energy between GluN2B-CT1290-1310 and DAPK1 was computed by the mechanics generalized born surface area (MM/GBSA) approach. The simulation results showed that hydrophobic, van der Waals, and electrostatic interactions are responsible for the binding of GluN2B-CT1290–1310/DAPK1. Moreover, through per-residue free energy decomposition and in silico alanine scanning analysis, hotspot residues between GluN2B-CT1290-1310 and DAPK1 interface were identified. In conclusion, this work predicted the binding mode and quantitatively characterized the protein–peptide interface, which will aid in the discovery of novel drugs targeting the GluN2B-CT1290-1310 and DAPK1 interface.

Replacement of the exocrine parenchyma by fibrous tissue is a main characteristic of chronic pancreatitis. Understanding the mechanisms of pancreatic fibrogenesis is critical for the development of preventive and therapeutic interventions. Cyclooxygenase-2 (COX-2), a rate-limiting enzyme for prostaglandin synthesis, is expressed in patients with chronic pancreatitis. However, it is unknown whether COX-2 can cause chronic pancreatitis. To investigate the roles of pancreatic acinar COX-2 in fibrogenesis and the development of chronic pancreatitis, COX-2 was ectopically expressed specifically in pancreatic acinar cells in transgenic mice. Histopathological changes and expression levels of several profibrogenic factors related to chronic pancreatitis were evaluated. COX-2 was expressed in the pancreas of the transgenic mice, as detected by Western blot analysis. Immunohistochemical staining showed COX-2 was specifically expressed in pancreatic acinar cells. COX-2 expression led to progressive changes in the pancreas, including pancreas megaly, persistent inflammation, collagen deposition, and acinar-to-ductal metaplasia. Quantitative RT-PCR and immunostaining showed that profibrogenic factors were upregulated and pancreatic stellate cells were activated in the COX-2 transgenic mice. Expression of COX-2 in pancreatic acinar cells is sufficient to induce chronic pancreatitis. Targeting this pathway may be valuable in the prevention of chronic pancreatitis. NEW & NOTEWORTHY COX-2 expression is observed in pancreatic tissues of human chronic pancreatitis. In this study, we showed that COX-2 expression caused the development of chronic pancreatitis in transgenic mice, supporting the idea that COX-2 inhibition may be an effective preventive and therapeutic strategy.