A novel small-molecule binds to the influenza A virus RNA promoter and inhibits viral replication.

Through screening by NMR spectroscopy, we discovered a novel scaffold (DPQ: 6,7-dimethoxy-2-(1-piperazinyl)-4-quinazolinamine) that binds specifically to the influenza A virus RNA promoter. The solution structure of the RNA-DPQ complex reported here demonstrates that the internal loop is the binding site of DPQ. The scaffold exhibits antiviral activity against influenza viruses.

Segmental progression of cardinal motor symptoms in Parkinson's disease: a pilot study suggesting a practical approach to rate disease course in the early stages.

Little is known about the anatomical progression over the body segments of extrapyramidal signs in Parkinson's disease (PD); furthermore a great unmet need is the availability of instruments able to detect disease progression, even in the early phase. The purpose of this study is to demonstrate that assessing topographical distribution of the cardinal motor features of PD may significantly improve the evaluation of disease progression in the early stages. Forty-four drug-naïve PD patients were included in the study.

Genetic inactivation or pharmacological inhibition of Pdk1 delays development and inhibits metastasis of Braf(V600E)::Pten(-/-) melanoma.

Phosphoinositide-dependent kinase-1 (PDK1) is a serine/threonine protein kinase that phosphorylates members of the conserved AGC kinase superfamily, including AKT and protein kinase C (PKC), and is implicated in important cellular processes including survival, metabolism and tumorigenesis. In large cohorts of nevi and melanoma samples, PDK1 expression was significantly higher in primary melanoma, compared with nevi, and was further increased in metastatic melanoma. PDK1 expression suffices for its activity, owing to auto-activation, or elevated phosphorylation by phosphoinositide 3'-OH-kinase (PI3K).

Gender differences in non-motor symptoms in early, drug naïve Parkinson's disease.

Gender differences in brain structure and function may lead to differences in the clinical expression of neurological diseases, including Parkinson's disease (PD). Few studies reported gender-related differences in the burden of non-motor symptoms (NMS) in treated PD patients, but this matter has not been previously explored in drug-naïve PD patients. This study is to assess gender differences in the prevalence of NMS in a large sample of early, drug-naïve PD patients compared with age and sex-matched healthy controls.

The use of University of Pennsylvania Smell Identification Test in the diagnosis of Parkinson's disease in Italy.

Hyposmia is a common finding in Parkinson's disease (PD). The 40-item University of Pennsylvania Smell Identification Test (UPSIT-40) has been adapted and administered in several countries as a diagnostic tool in the diagnosis of PD. We have developed a culturally adapted version of the UPSIT-40 and applied it to 61 nondemented Italian controls and to 68 PD patients.

The heterogeneity of early Parkinson's disease: a cluster analysis on newly diagnosed untreated patients.

Background: The variability in the clinical phenotype of Parkinson's disease seems to suggest the existence of several subtypes of the disease. To test this hypothesis we performed a cluster analysis using data assessing both motor and non-motor symptoms in a large cohort of newly diagnosed untreated PD patients.

Methods: We collected data on demographic, motor, and the whole complex of non-motor symptoms from 100 consecutive newly diagnosed untreated outpatients.

Dopaminergic neuronal imaging in genetic Parkinson's disease: insights into pathogenesis.

Objectives: To compare the dopaminergic neuronal imaging features of different subtypes of genetic Parkinson's Disease.

Methods: A retrospective study of genetic Parkinson's diseases cases in which DaTSCAN (123I-FP-CIT) had been performed. Specific non-displaceable binding was calculated for bilateral caudate and putamen for each case.

Structure-based design of covalent Siah inhibitors.

The E3 ubiquitin ligase Siah regulates key cellular events that are central to cancer development and progression. A promising route to Siah inhibition is disrupting its interactions with adaptor proteins. However, typical of protein-protein interactions, traditional unbiased approaches to ligand discovery did not produce viable hits against this target, despite considerable effort and a multitude of approaches.

Enhanced prostate cancer gene transfer and therapy using a novel serotype chimera cancer terminator virus (Ad.5/3-CTV).

Few options are available for treating patients with advanced prostate cancer (PC). As PC is a slow growing disease and accessible by ultrasound, gene therapy could provide a viable option for this neoplasm. Conditionally replication-competent adenoviruses (CRCAs) represent potentially useful reagents for treating PC.

Synthesis and SAR studies of dual AKT/NF-κB inhibitors against melanoma.

The protein Kinase B alpha (AKT) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways are central regulators of cellular signaling events at the basis of tumor development and progression. Both pathways are often up-regulated in different tumor types including melanoma. We recently reported the identification of compound 1 (BI-69A11) as inhibitor of the AKT and the NF-κB pathways.

Sabutoclax (BI97C1) and BI112D1, putative inhibitors of MCL-1, induce mitochondrial fragmentation either upstream of or independent of apoptosis.

Owing to the high levels of antiapoptotic B-cell lymphoma 2 (BCL-2) family members observed in several cancers, there has been a major effort to develop inhibitors of the BCL2-family as chemotherapeutic agents. Of the different members in the BCL-2 family, myeloid cell leukemia sequence 1 (MCL-1) is commonly amplified in human tumors and is associated with their relapse and chemoresistance. As a result, specific inhibitors of MCL-1 are being designed to treat resistant tumors.

Insulin-like growth factor-1 predicts cognitive functions at 2-year follow-up in early, drug-naïve Parkinson's disease.

Background And Purpose: Cognitive impairment is common in Parkinson's disease (PD), even in the early stages. We aimed to assess the relationship between insulin-like growth factor-1 (IGF-1) and cognitive functions in early, drug-naïve patients with PD.

Methods: Serum IGF-1 was measured in 65 early, drug-naïve patients with PD that underwent a complete neuropsychological battery at baseline and after 2 years.

Endoplasmic reticulum membrane reorganization is regulated by ionic homeostasis.

Recently we described a new, evolutionarily conserved cellular stress response characterized by a reversible reorganization of endoplasmic reticulum (ER) membranes that is distinct from canonical ER stress and the unfolded protein response (UPR). Apogossypol, a putative broad spectrum BCL-2 family antagonist, was the prototype compound used to induce this ER membrane reorganization. Following microarray analysis of cells treated with apogossypol, we used connectivity mapping to identify a wide range of structurally diverse chemicals from different pharmacological classes and established their ability to induce ER membrane reorganization.

Insulin-like growth factor-1 and progression of motor symptoms in early, drug-naïve Parkinson's disease.

Much pre-clinical evidence show that insulin-like growth factor 1 (IGF-1) provides protection against loss of dopaminergic neurons. Recently, IGF-1 has been proposed as a possible biomarker for early diagnosis of Parkinson's disease (PD). We aimed to assess the relationship between serum IGF-1 levels and progression of motor symptoms in a cohort of drug-naïve PD patients.

The natural history of multiple system atrophy: a prospective European cohort study.

Background: Multiple system atrophy (MSA) is a fatal and still poorly understood degenerative movement disorder that is characterised by autonomic failure, cerebellar ataxia, and parkinsonism in various combinations. Here we present the final analysis of a prospective multicentre study by the European MSA Study Group to investigate the natural history of MSA.

Methods: Patients with a clinical diagnosis of MSA were recruited and followed up clinically for 2 years.

HTS by NMR of combinatorial libraries: a fragment-based approach to ligand discovery.

Fragment-based ligand design (FBLD) approaches have become more widely used in drug discovery projects from both academia and industry, and are even often preferred to traditional high-throughput screening (HTS) of large collection of compounds (>10(5)). A key advantage of FBLD approaches is that these often rely on robust biophysical methods such as NMR spectroscopy for detection of ligand binding, hence are less prone to artifacts that too often plague the results from HTS campaigns. In this article, we introduce a screening strategy that takes advantage of both the robustness of protein NMR spectroscopy as the detection method, and the basic principles of combinatorial chemistry to enable the screening of large libraries of fragments (>10(5) compounds) preassembled on a common backbone.

A Pan-BCL2 inhibitor renders bone-marrow-resident human leukemia stem cells sensitive to tyrosine kinase inhibition.

Leukemia stem cells (LSCs) play a pivotal role in the resistance of chronic myeloid leukemia (CML) to tyrosine kinase inhibitors (TKIs) and its progression to blast crisis (BC), in part, through the alternative splicing of self-renewal and survival genes. To elucidate splice-isoform regulators of human BC LSC maintenance, we performed whole-transcriptome RNA sequencing, splice-isoform-specific quantitative RT-PCR (qRT-PCR), nanoproteomics, stromal coculture, and BC LSC xenotransplantation analyses. Cumulatively, these studies show that the alternative splicing of multiple prosurvival BCL2 family genes promotes malignant transformation of myeloid progenitors into BC LSCS that are quiescent in the marrow niche and that contribute to therapeutic resistance.

Heterotypic Sam-Sam association between Odin-Sam1 and Arap3-Sam: binding affinity and structural insights.

Arap3 is a phosphatidylinositol 3 kinase effector protein that plays a role as GTPase activator (GAP) for Arf6 and RhoA. Arap3 contains a sterile alpha motif (Sam) domain that has high sequence homology with the Sam domain of the EphA2-receptor (EphA2-Sam). Both Arap3-Sam and EphA2-Sam are able to associate with the Sam domain of the lipid phosphatase Ship2 (Ship2-Sam).

MDA-9/syntenin and IGFBP-2 promote angiogenesis in human melanoma.

Melanoma differentiation-associated gene-9 (mda-9/syntenin) encodes an adapter scaffold protein whose expression correlates with and mediates melanoma progression and metastasis. Tumor angiogenesis represents an integral component of cancer metastasis prompting us to investigate a possible role of mda-9/syntenin in inducing angiogenesis. Genetic (gain-of-function and loss-of-function) and pharmacologic approaches were used to modify mda-9/syntenin expression in normal immortal melanocytes, early radial growth phase melanoma, and metastatic melanoma cells.

Side of onset does not influence cognition in newly diagnosed untreated Parkinson's disease patients.

Background: A relation between the side of motor onset and cognitive impairment in early PD has been reported, suggesting that the asymmetric degeneration affecting subcortical regions may play a pivotal role in lateralized cognitive function. However, evidences are controversial and all previous studies were performed on treated patients, though it is known that dopaminergic therapy can affect cognition in PD.

Methods: Sixty-nine early untreated PD patients underwent an extensive neuropsychological battery exploring memory, visuospatial and attention/executive functions.

Targeting the Bcl-2 family for cancer therapy.

Introduction: Programmed cell death is well-orchestrated process regulated by multiple pro-apoptotic and anti-apoptotic genes, particularly those of the Bcl-2 gene family. These genes are well documented in cancer with aberrant expression being strongly associated with resistance to chemotherapy and radiation.

Areas Covered: This review focuses on the resistance induced by the Bcl-2 family of anti-apoptotic proteins and current therapeutic interventions currently in preclinical or clinical trials that target this pathway.

Targeted delivery of paclitaxel to EphA2-expressing cancer cells.

Purpose: YSA is an EphA2-targeting peptide that effectively delivers anticancer agents to prostate cancer tumors. Here, we report on how we increased the drug-like properties of this delivery system.

Experimental Design: By introducing non-natural amino acids, we have designed two new EphA2 targeting peptides: YNH, where norleucine and homoserine replace the two methionine residues of YSA, and dYNH, where a D-tyrosine replaces the L-tyrosine at the first position of the YNH peptide.