Understanding surgical attrition for "resectable" pancreatic cancer.

OBJECTIVES: We used a novel combined analysis to evaluate various factors associated with failure to undergo surgery in non-metastatic pancreatic cancer. METHODS: We identified rates of surgery and reasons for surgical attrition from clinical trials, which studied neoadjuvant therapy in resectable pancreatic cancer. Next, we queried the National Cancer Database (NCDB) for Stage I-III, T1-3 pancreatic adenocarcinoma patients. We investigated the rates and factors associated with the receipt of surgery. Finally, we evaluated variable importance predicting the receipt of surgery. RESULTS: In clinical trials, 25-30 % of patients did not undergo surgery, mostly due to disease progression. In the NCDB, the overall surgical rate was only 49 %, but increased to 67 % in a curated cohort meant to mirror clinical trial patients. Patients treated at low-volume institutions (OR = 0.64, 95 % CI: 0.61-0.67) and who were uninsured (OR = 0.56, 95 % CI: 0.52-0.62) and Medicaid-insured (OR = 0.67, 95 % CI: 0.64-0.71) were less likely to receive potentially curative surgery. CONCLUSION: We have identified a realistic target surgery rate of 70%-75 % in potentially-resectable pancreatic cancer. While attrition to pancreatic cancer surgery is mostly due to tumor biology, our study identified the most important non-medical barriers, such as facility volume and insurance, affecting pancreatic cancer surgery.

Identification of Clinically Significant Cytokine Signature Clusters in Patients With Septic Shock.

OBJECTIVES: To identify cytokine signature clusters in patients with septic shock. DESIGN: Prospective observational cohort study. SETTING: Single academic center in the United States. PATIENTS: Adult (≥ 18 yr old) patients admitted to the medical ICU with septic shock requiring vasoactive medication support. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One hundred fourteen patients with septic shock completed cytokine measurement at time of enrollment (t 1 ) and 24 hours later (t 2 ). Unsupervised random forest analysis of the change in cytokines over time, defined as delta (t 2 -t 1 ), identified three clusters with distinct cytokine profiles. Patients in cluster 1 had the lowest initial levels of circulating cytokines that decreased over time. Patients in cluster 2 and cluster 3 had higher initial levels that decreased over time in cluster 2 and increased in cluster 3. Patients in clusters 2 and 3 had higher mortality compared with cluster 1 (clusters 1-3: 11% vs 31%; odds ratio [OR], 3.56 [1.10-14.23] vs 54% OR, 9.23 [2.89-37.22]). Cluster 3 was independently associated with in-hospital mortality (hazard ratio, 5.24; p = 0.005) in multivariable analysis. There were no significant differences in initial clinical severity scoring or steroid use between the clusters. Analysis of either t 1 or t 2 cytokine measurements alone or in combination did not reveal clusters with clear clinical significance. CONCLUSIONS: Longitudinal measurement of cytokine profiles at initiation of vasoactive medications and 24 hours later revealed three distinct cytokine signature clusters that correlated with clinical outcomes.

Induction of retinal progenitors and neurons from mammalian Müller glia under defined conditions.

Vision impairment caused by loss of retinal neurons affects millions of people worldwide, and currently, there is no effective treatment. Müller glia of mammalian retina may represent an under-recognized and potential source for regeneration of a wide range of retinal cell types, including retinal ganglion cells and photoreceptors. Here, we demonstrated that mouse Müller glia cells have the capacity to be reprogrammed into the retinal neuronal cell fate and are competent to give rise to photoreceptors under a defined culture condition. Inactivation of p53 released proliferation restriction of Müller glia and significantly enhanced the induction of retinal progenitor from Müller glia in culture. Moreover, following the ocular transplantation, the Müller glia-derived progenitors were differentiated toward the fates of photoreceptors and retinal ganglion cells. Together, these results demonstrate the feasibility of using Müller glia as a potential source for retinal repair and regeneration.

The tumor suppressor microRNA, miR-124a, is regulated by epigenetic silencing and by the transcriptional factor, REST in glioblastoma.

Reduced levels of specific microRNA in cancer are frequently reported and associated with attenuated cancer genes and associated pathways. We previously reported a loss of miR-124a in glioblastoma (GBM) patient specimens; however, the upstream causes of this loss are largely unknown. Loss of miR-124a has been attributed to hypermethylation while other studies have shown miR-124a to be regulated by the repressor-element-1-silencing transcription factor (REST, also known as neuron-restrictive silencing factor). This current study looked at both epigenetic and transcription factor regulation as potential mechanisms resulting in the loss of miR-124a expression in GBM patient specimens and cell lines. Hypermethylation of miR-124a was observed in 82 % of GBM patient specimens (n = 56). In vitro miR-124a expression levels also increased after treatment of several patient-derived cell lines with 5-aza-2'-deoxycytidine. Additionally, we also demonstrated a positive interaction between REST activity and miR-124a using a luciferase-binding assay and we correlated the reciprocal expression of REST and miR-124a in our clinical cohort. This result indicates that miR-124a expression may also be modulated through the upstream targeting of REST. Preclinical studies involving inhibitors of REST and treatment with demethylating agents with the intent to increase miR-124a levels could be interesting.

Three-Dimensional Bioprinting in Cardiovascular Disease: Current Status and Future Directions.

Three-dimensional (3D) printing plays an important role in cardiovascular disease through the use of personalised models that replicate the normal anatomy and its pathology with high accuracy and reliability. While 3D printed heart and vascular models have been shown to improve medical education, preoperative planning and simulation of cardiac procedures, as well as to enhance communication with patients, 3D bioprinting represents a potential advancement of 3D printing technology by allowing the printing of cellular or biological components, functional tissues and organs that can be used in a variety of applications in cardiovascular disease. Recent advances in bioprinting technology have shown the ability to support vascularisation of large-scale constructs with enhanced biocompatibility and structural stability, thus creating opportunities to replace damaged tissues or organs. In this review, we provide an overview of the use of 3D bioprinting in cardiovascular disease with a focus on technologies and applications in cardiac tissues, vascular constructs and grafts, heart valves and myocardium. Limitations and future research directions are highlighted.

Binding Characterization of GPCRs-Modulator by Molecular Complex Characterizing System (MCCS).

Increasing attention has been devoted to allosteric modulators as the preferred therapeutic agents for their colossal advantages such as higher selectivity, fewer side effects, and lower toxicity since they bind at allosteric sites that are topographically distinct from the classic orthosteric sites. However, the allosteric binding pockets are not conserved and there are no cogent methods to comprehensively characterize the features of allosteric sites with the binding of modulators. To overcome this limitation, our lab has developed a novel algorithm that can quantitatively characterize the receptor-ligand binding feature named Molecular Complex Characterizing System (MCCS). To illustrate the methodology and application of MCCS, we take G protein coupled receptors (GPCRs) as an example. First, we summarized and analyzed the reported allosteric binding pockets of class A GPCRs using MCCS. Sequentially, a systematic study was conducted between cannabinoid receptor type 1 (CB1) and its allosteric modulators, where we used MCCS to analyze the residue energy contribution and the interaction pattern. Finally, we validated the predicted allosteric binding site in CB2 via MCCS in combination with molecular dynamics (MD) simulation. Our results demonstrate that the MCCS program is advantageous in recapitulating the allosteric regulation pattern of class A GPCRs of the reported pockets as well as in predicting potential allosteric binding pockets. This MCCS program can serve as a valuable tool for the discovery of small-molecule allosteric modulators for class A GPCRs.

Structure and expression patterns of Drosophila TULP and TUSP, members of the tubby-like gene family.

Tubby is a mouse gene that may provide a model for adult-onset obesity in humans. It is a member of a four gene family in mammals that collectively encode the Tubby-like proteins (TULPs), putative transcription factors which share similar 260 amino acid 'tubby domains' at their C-termini. The mammalian genome also encodes distant relatives of TULPs, which have been called TUSPs (tubby domain superfamily proteins). We have characterized the transcription unit of the single Drosophila TULP homolog, analyzed the expression pattern of the Drosophila TULP and TUSP genes, and determined the evolutionary relationships between the Drosophila proteins and members of the tubby domain superfamily in other organisms. Interestingly, like its mammalian homologs, Drosophila TULP is principally expressed in the embryonic central and peripheral nervous systems. This suggests that mammalian and Drosophila TULPs may possess some conserved functional properties in the nervous system. The Drosophila TUSP gene is also expressed in the central nervous system and olfactory organ but in few other peripheral sensory organs.