Thomas J. Quinn

Extracellular signal-regulated kinase is involved in alpha-synuclein-induced mitochondrial dynamic disorders by regulating dynamin-like protein 1.

Compounding evidence suggests that alpha-synuclein (SNCA) plays an important role in the pathogenesis of Parkinsons disease (PD) by inducing neurotoxicity. Mitochondria are highly dynamic organelles that undergo fusion and fission processes, the imbalance of which has been viewed as a key trigger for PD. However, the underlying relationship between SNCA and mitochondrial dynamics remains unclear. This study demonstrated that SNCA overexpression not only altered mitochondrial morphology, but also significantly increased the translocation of mitochondrial fission protein dynamin-like protein 1 (DLP1). To further investigate the mechanism of SNCAs effect on mitochondrial dynamics, the proteomic technique, stable isotope labeling of amino acid in cell cultures (SILAC), was used. The extracellular signal-regulated kinase (ERK) was confirmed to be involved in the regulation of DLP1 and SNCA-mediated neurotoxicity. Finally, additional results demonstrated that SNCA inducing both mitochondrial dynamic disorders and neurotoxicity could be ameliorated by curcumin through ERK inhibition, which implied that the agent could be used to prevent and treat PD in the future.

Pasireotide (SOM230) is effective for the treatment of pancreatic neuroendocrine tumors (PNETs) in a multiple endocrine neoplasia type 1 (MEN1) conditional knockout mouse model

BACKGROUND Pasireotide (SOM230), a long-acting somatostatin analogue (LAR), has improved agonist activity at somatostatin receptors. We tested the effect of SOM230 on insulin secretion, serum glucose concentrations, tumor growth, and survival using an MEN1 transgenic mouse model. METHODS Eight 12-month-old conditional Men1 knockout mice with insulinoma were assessed. The treatment (n = 4) and control groups (n = 4) received monthly subcutaneous injections of SOM230 or PBS. Serum insulin and glucose levels were determined by enzyme-linked immunosorbent assay and enzymatic colorimetric assay, respectively. Tumor activity, growth, and apoptosis were determined by microPET/CT scan and histologic analysis. RESULTS On day 7, there was a decrease in serum insulin levels from 1.06 ± 0.28 μg/L to 0.37 ± 0.17 μg/L (P = .0128) and a significant increase in serum glucose from 4.2 ± 0.45 mmol/L to 7.12 ± 1.06 mmol/L (P = .0075) in the treatment group but no change in the control group. Tumor size was less in the treatment group (2,098 ± 388 μm(2)) compared with the control group (7,067 ± 955 μm(2); P = .0024). Furthermore, apoptosis was increased in the treatment group (6.9 ± 1.23%) compared with the control group (0.29 ± 0.103%; P = .002). CONCLUSION SOM230 demonstrates antisecretory, antiproliferative, and proapoptotic activity in our MEN1 model of insulinoma. Further studies of the effects of SOM230 in PNET patients with MEN1 mutations are warranted.

Salivary DJ-1 could be an indicator of Parkinson's disease progression.

Objective: The goal of the current investigation was to explore whether salivary DJ-1 could be a potential biomarker for monitoring disease progression in Parkinsons disease (PD) by evaluating the association between salivary DJ-1 concentrations and nigrostriatal dopaminergic function. Methods: First, in 74 patients with PD and 12 age-matched normal controls, single photon emission computed tomography (SPECT) imaging with labeled dopamine transporters (DAT) (99mTc-TRODAT-1), which has been used for measuring DAT density in PD was prformed. Then, the DJ-1 level in their saliva was analyzed by quantitative and sensitive Luminex assay and compared to caudate or putamen DAT density. Finally, based on the above, our cross-section study was carried out in 376 research volunteers (285 patients with PD and 91 healthy controls) to measure salivary DJ-1 level. Results: From our analysis, we found a correlation between salivary concentration of DJ-1 and putamen nucleus uptake of 99mTc-TRODAT-1 in the PD group. Although salivary DJ-1 levels were not affected by UPDRS scores, gender, age, and pharmacotherapy, DJ-1 levels in H&Y 4 stage of PD were higher than those in H&Y 1-3 stage as well as those in healthy controls. Salivary DJ-1 also decreased significantly in mixed type PD patients compared to the tremor-dominant type (TDT) and akinetic-rigid dominant type (ARDT) PD patients. Conclusions: According to the investigation in a large cohort, we reported for the first time the prognostic potential of the salivary DJ-1 as a biomarker for evaluating nigrostriatal dopaminergic function in PD.

Structure-guided development of a high-affinity human Programmed Cell Death-1: Implications for tumor immunotherapy

Programmed Cell Death-1 (PD-1) is an inhibitory immune receptor, which plays critical roles in T cell co-inhibition and exhaustion upon binding to its ligands PD-L1 and PD-L2. We report the crystal structure of the human PD-1 ectodomain and the mapping of the PD-1 binding interface. Mutagenesis studies confirmed the crystallographic interface, and resulted in mutant PD-1 receptors with altered affinity and ligand-specificity. In particular, a high-affinity mutant PD-1 (HA PD-1) exhibited 45 and 30-fold increase in binding to PD-L1 and PD-L2, respectively, due to slower dissociation rates. This mutant (A132L) was used to engineer a soluble chimeric Ig fusion protein for cell-based and in vivo studies. HA PD-1 Ig showed enhanced binding to human dendritic cells, and increased T cell proliferation and cytokine production in a mixed lymphocyte reaction (MLR) assay. Moreover, in an experimental model of murine Lewis lung carcinoma, HA PD-1 Ig treatment synergized with radiation therapy to decrease local and metastatic tumor burden, as well as in the establishment of immunological memory responses. Our studies highlight the value of structural considerations in guiding the design of a high-affinity chimeric PD-1 Ig fusion protein with robust immune modulatory properties, and underscore the power of combination therapies to selectively manipulate the PD-1 pathway for tumor immunotherapy.

Low-Intensity Focused Ultrasound Induces Reversal of Tumor-Induced T Cell Tolerance and Prevents Immune Escape

Immune responses against cancer cells are often hindered by immunosuppressive mechanisms that are developed in the tumor microenvironment. Induction of a hyporesponsive state in tumor Ag-specific T cells is one of the major events responsible for the inability of the adaptive immune system to mount an efficient antitumor response and frequently contributes to lessen the efficacy of immunotherapeutic approaches. Treatment of localized tumors by focused ultrasound (FUS) is a minimally invasive therapy that uses a range of input energy for in situ tumor ablation through the generation of thermal and cavitation effect. Using a murine B16 melanoma tumor model, we show that a variant of FUS that delivers a reduced level of energy at the focal point and generates mild mechanical and thermal stress in target cells has the ability to increase immunogenic presentation of tumor Ags, which results in reversal of tumor-induced T cell tolerance. Furthermore, we show that the combination of nonablative low-energy FUS with an ablative hypofractionated radiation therapy results in synergistic control of primary tumors and leads to a dramatic reduction in spontaneous pulmonary metastases while prolonging recurrence-free survival only in immunocompetent mice.

Salivary total α-synuclein, oligomeric α-synuclein and SNCA variants in Parkinson’s disease patients

The present study was to evaluate the diagnostic value of salivary total and oligomeric α-synuclein levels in PD. Furthermore, we sought to explore the relationship between salivary total α-synuclein and α-synuclein SNP variants levels. 201 PD patients and 67 controls were recruited, of which there also had the genetic information of two positive α-synuclein (SNCA) loci. Salivary total α-synuclein was assayed using a highly sensitive Luminex assay and oligomeric α-synuclein was quantified by the combination of Gel filtration chromatography and Western blot, respectively. From our analysis,No difference in salivary total α-synuclein levels was found between PD patients and healthy controls, it decreased with age in PD patients, and was closely associated with genotypic distribution of rs11931074 and rs894278 in PD, respectively. After controlled for age and genders, G allele of rs11931074 was correlated with lower salivary total α-synuclein levels, while G allele of rs894278 was also correlated with the higher levels. Simultaneously, the further study was shown that salivary oligomeric α-synuclein in PD patients significantly increased comparing to healthy controls. In conclusions,our study firstly demonstrated that salivary total α-synuclein levels could be manipulated by different α-synuclein SNPs and salivary oligomeric α-synuclein could be a potential diagnostic indicator of PD.

In vivo proton MR spectroscopy of pancreatic neuroendocrine tumors in a multiple endocrine neoplasia type 1 conditional knockout mouse model

MR spectroscopy (MRS) can improve diagnosis and follow treatment in cancer. However, no study has yet reported application of in vivo 1H‐MRS in malignant pancreatic lesions. This study quantitatively determined whether in vivo 1H‐MRS on multiple endocrine neoplasia type 1 (Men1) conditional knockout (KO) mice and their wild type (WT) littermates could detect differences in total choline (tCho) levels between tumor and control pancreas.

Angiogenin variants are not associated with Parkinson's disease in the ethnic Chinese population

Recently, the angiogenin gene has been reported to be significantly associated with Parkinsons disease and amyotrophic lateral sclerosis in populations of European and American ancestry. But there have been no studies investigating the association between angiogenin and Parkinsons disease in the ethnic Chinese population. We conducted a case-control study to evaluate the association between angiogenin and Parkinsons disease in a Chinese population from mainland China. We sequenced the exons of angiogenin in 532 Parkinsons disease patients and 480 controls. We did not detect an angiogenin coding region mutation in either the patients or the controls. Our data do not support the association of angiogenin variants with PD in Han Chinese of mainland China.

Targeting Tumor Vasculature Using Adeno-Associated Virus Phage Vectors Coding Tumor Necrosis Factor-α

An advantage of targeted gene therapy is the potential for effectively delivering anti-vascular and antitumor therapy directly to the site of the tumor, thus maximizing therapeutic efficacy and minimizing toxicity. The use of a vector capable of directed cell transduction can result in the sustained expression of the therapeutic agent. This chapter reviews the current status of vector strategies, targeted gene therapy with tumor-specific promoter and antibody and peptide conjugation, and outlines the challenges faced for the next-generation of gene transfer technology. Furthermore, it summarizes the results of preclinical anti-angiogenic gene therapy investigations, which utilize novel targeted tumor necrosis factor-α treatment, and discusses potential clinical applications of this treatment strategy.

Neoadjuvant radiation therapy for the management of myoepithelial carcinoma of the upper extremity: Neoadjuvant radiation therapy

Myoepithelial tumors of the soft tissue are a rare tumor displaying myoepithelial elements and lacking obvious ductal differentiation. The rarity of these precludes any evidence‐based consensus regarding optimal management. Nevertheless, the current approach to these lesions begins with amputation or complete excision. The efficacy of neoadjuvant or adjuvant radiation therapy or chemotherapy has not been established. Here, we present the first report to the authors’ knowledge of neoadjuvant radiation therapy for the treatment of this rare soft tissue neoplasm and review the management and outcomes of published cases of myoepithelial carcinoma. A patient with a soft tissue myoepithelial carcinoma that declined both amputation and chemotherapy was treated with neoadjuvant radiation therapy and wide surgical excision followed by a brachytherapy boost to the resected tumor bed. Neoadjuvant radiation therapy resulted in an excellent response with extensive treatment‐related changes consisting predominantly of fibrosis, hyalinization and hemorrhage and only 10% residual viable myoepithelial carcinoma present in the surgical specimen.