Abstract: The majority of deaths due to thyroid cancer occur in patients with advanced DTC refractory to radioactive iodine. The spectacular advances in molecular medicine of recent years have opened new therapeutic possibilities. Currently, there is general agreement that treatment with Tyrosine Kinase Inhibitors (TKI) should only be considered in patients with differentiated thyroid carcinoma refractory to radioactive iodine, with progressive and / or symptomatic metastatic disease that can not otherwise be treated locally. Most of these "new molecules" are multichannel inhibitors with varied action, which interact on different proteins such as RET, BRAF, cKIT, MET, EGFR, MAPK, PDGFR, etc. In addition, they have the additional advantage that they markedly prevent angiogenesis by acting on VEGFR 1, 2, and 3. TKI are associated with progression-free survival but not curative. Also, causes adverse effects that can affect the quality of life.The prolongation of progression-free survival has been demonstrated with sorafenib and lenvatinib compared with placebo in two phase III trials. These two drugs have been approved by the FDA and the European Medicines Agency for use in patients refractory to radioactive iodine with metastatic disease. Based on the Phase II Trials there are other Tyrosine Kinase Inhibitors (TKI) available such as sunitinib, axitinib or pazopanib that can produce some kind of clinical benefit and therefore need further investigation.
Abstract: Statins provide a very effective approach in reducing plasma cholesterol levels and cardiovascular risk. However, the proportion of patients who fail to achieve desirable plasma lipid levels ranges from 16%–53%, worldwide. This percentage reaches up to 80% in patients with familial hypercholesterolemia. Additionally, many patients are unable to tolerate statins, particularly at the highest approved dose level. New treatments that aggressively reduce lipid levels in patients with severe hypercholesterolemia, or those unable to reach their lipid targets, are therefore required. The most promising approaches in this context, such as inhibitors of the synthesis of apolipoprotein B (apoB) containing lipoproteins (apoB silencing or microsomal triglyceride transfer protein [MTP] inhibition) or proprotein convertase subtilisin/kexin type 9 (PCSK9) blockers, all decrease low-density lipoprotein (LDL) extensively. Increasing low levels of high-density lipoprotein (HDL) cholesterol via cholesteryl ester transfer protein inhibitors or apolipoprotein A-1 (ApoA-1) inducers and improving their quality with HDL or ApoA-1 mimetics represent also important options. Drugs affecting HDL, however, may not be all alike and require adequate scrutiny of the mechanisms involved. Until we have a better understanding of these issues, further LDL lowering in high-risk patients represents the soundest approach.
mammals have at least two other MAP Kinase pathways, the JNK ( c -ju n N - te r m in a l K in a s e ) /S A P K (S tre s s a c tiv a te d p r o te in kinase) and p38/RK (Reactivating Kinase) pathw ays, also known as stress response kinases (review ed by K yriakis and Avruch, 1996). G row th facto rs th at stim u late the E R K p a th w a y are m ostly p oor activators o f the stress response kinases, though EOF has been reported to give a 15-fold activation of JN K in HeLa cells (Minden et al., 1995). In contrast, JN K and p38 are both comm only activated in response to cellular stresses such as ultraviolet irradiation or heat and inflam m atory cytokines such as T N F a and in te rle u k in -1 (IL-1). These kinase pathw ays are, therefore, th ought to play a role in inflam m ation. Figure 1.6 sum m arises the kinases involved that have been cloned so far and their know n transcription factor targets. (T reism an, 1995, Treisman, 1996, Hill and Treism an, 1995). It can be seen that, for the JN K and p38 pathways, a large num ber o f isoform s of each kinase have been found and the overall p ictu re is m ade more com plex by functional redundancy and crosstalk betw een the d ifferen t pathw ays.
188 Read more
Current systemic therapies for breast cancer are often limited by their nonspecific mechanism of action, unwanted toxicities on normal tissues, and short-term efficacy due to the emergence of drug resistance. However, identification of the molecular abnormalities in cancer, in particular the key proteins involved in abnormal cell growth, has resulted in development of various signal transduction inhibitor drugs as new treatment strategies against the disease. Protein farnesyltransferase inhibitors (FTIs) were originally designed to target the Ras signal transduction pathway, although it is now clear that several other intracellular proteins are dependent on post-translational farnesylation for their function. Preclinical data revealed that although FTIs inhibit the growth of ras-transformed cells, they are also potent inhibitors of a wide range of cancer cell lines that contain wild-type ras, including breast cancer cells. Additive or synergistic effects were observed when FTIs were combined with cytotoxic agents (in particular the taxanes) or endocrine therapies (tamoxifen). Phase I trials with FTIs have explored different schedules for prolonged administration, and dose-limiting toxicities included myelosuppression, gastrointestinal toxicity and neuropathy. Clinical efficacy against breast cancer was seen for the FTI tipifarnib in a phase II study. Based on promising preclinical data that suggest synergy with taxanes or endocrine therapy, combination clinical studies are now in progress to determine whether FTIs can add further to the efficacy of conventional breast cancer therapies.
Intracellular signaling pathways transmit environmental infor- mation to the cytoplasm and the nucleus, where they regulate cellular responses and gene transcription. Understanding the hierarchy and pathogenic significance of these pathways in autoimmunity has led to the development of compounds that block several promising targets [37,38]. Orally bioavailable small-molecule inhibitors are currently the most likely approach, although biologics like small interfering RNA and genes that express dominant negative kinases are also possible. It is likely that the small-molecule approach, though still in its infancy, will advance rapidly over the next decade. If successful, these small compounds could augment or replace more expensive parenteral biologics that are currently the mainstay of treatment. Several hurdles still need to be overcome, including improved compound specificity and the importance of many key pathways for homeostasis and host defense .
11 Read more
more hope for the disease-free survival time, there is still a substantial room for improving treatment. Tumor trans- formation into a more aggressive phenotype and develop- ment of resistance to standard chemotherapy regimens in the course of FL remain the main causes of deaths in patients with this type of lymphoma. A large number of novel agents potentially useful in FL patients are in the clinical trial pipeline which includes new chemotherapeu- tics, bcl2 SMIs, monoclonal antibodies, apoptosis-induc- ing agents, and immunomodulators. These therapies could help to extend the duration of remission without adding any further burden of toxicity. It is also becoming clear that the therapy for FL also needs to be adapted to the patient's individual status, depending on the aggres- siveness of the disease, gene-signatures and tumor micro- environment while relying on a continuously growing repertoire of salvage therapies.
14 Read more
exists a clinical need for the identification of more inhib- itory receptors, which might contribute to and increase the activity of the up to now identified immunotherapy components. Besides from approaches, which test combi- nation of immunotherapy with chemotherapy, radiation therapy or cancer vaccines, novel combinations focus on the dual immune checkpoint blockade. In this regard, novel inhibitory molecules including LAG3 and TIM3 are gaining more importance as new targets. 15 37 The main
Deep brain stimulation (DBS) is a non-pharmaco- logical treatment for Parkinson’s disease (PD), and its efficacy depends largely on which anatomical struc- ture (target) is stimulated. The subthalamic nucleus (STN) is one of the most commonly used targets, but stimulation of new targets within the posterior sub- thalamic area (PSA), comprising a group of white matter fibers known as prelemniscal radiations (Raprl), as well as the caudal zonaincerta nucleus (Zic), have proven to be superior at improving certain clinical symptoms. Despite their clinical usefulness, their anatomical connectivity has not been completely de- scribed in humans. We performed constrained sphe- rical deconvolution of the signal in diffusion-weighted images and subsequent tractography as a means to non-invasively define the connectivity of the Raprl and Zic in a group of five patients with PD. Further, we used track-density imaging, a novel method to improve the spatial resolution of the acquired images, in order to visualize the small subregions that com- prise the PSA with a voxel resolution of 0.2 × 0.2 × 0.2 mm 3 . Both Raprl and Zic demonstrated high prob- ability of connectivity with the dorsal brainstem, cerebellum, subcortical nuclei (globus pallidum ven- tral, lateral thalamic nuclei), and cortical areas (or- bitofrontal cortex, primary and supplementary motor cortex areas). The connectivity patterns were re- producible between patients and were discretely or- ganized as the tracts entered/exited the PSA, depend- ing on their end points. These findings indicate that the PSA is part of the neuronal circuitry controlling movement, and the precise characterization of its connectivity will aid in our understanding of the net- works involved in PD and how they can be modulated with DBS in order to alleviate symptoms.
10 Read more
Currently, the programmed death-1/programmed death ligand-1 and the cytotoxic T-lymphocyte-associated protein 4 are the two commonly targeted immune- checkpoint inhibition pathways. These drugs have significantly improved the prognosis of many cancer types. While immune-checkpoint inhibitors have revolutionised the treatment of many cancer types, the majority of patients still progress. Several treatment strategies have been pursued to improve current results. One approach is to combine two checkpoint inhibitors, currently with promising results in melanoma, renal cell carcinoma and a subset of non-small-cell lung cancer patients. The identification of new checkpoint targets could allow the field of immuno-oncology to evolve further. We will discuss one of the most promising immune-checkpoint targets currently under investigation, the T-cell immunoglobulin and mucin domain-3.
Although not necessarily the ‘drugs of choice’, recent studies of various anticytokine (etanercept) and immunomodulating agents (IVIG and pentoxifylline) in CHF patients clearly suggest a potential for such therapies in these patients, in addition to ‘optimal’ cardiovascular treatment regimens. However, the results in these small studies will have to be confirmed in larger, placebo-controlled mortality studies. Several studies have focused on the possible pathogenic role of TNF-α, and targeted therapy against this molecule is ongoing. In order to develop more specific immunomodulat- ing agents in the immunopathogenesis of CHF, further research will need to identify precisely the important players. Regardless of these shortcomings, we believe that cytokines might lead to quite new treatment modalities in CHF, result- ing in reduced morbidity and mortality in such patients.
O ver the past decade, the pharmaceutical industry has experi- enced increasing challenges in drug development since the process has become more expensive, lengthier, and riskier. This is highlighted by the fact that even though there has been a more than 10-fold increase in drug development spending during the last few years, there has been no growth in new drug approvals (1). The most important reason for this lack of growth is the difficulty of crossing the so-called “valley of death,” the gulf between finding a promising new agent and demonstrating its safety and efficacy in humans (2). Most of the hits generated by traditional screening tools turn out to be invalid once tested in mammals, resulting in a waste of funds and efforts. In recent years, due to their genetic amenability, low cost, and culture conditions compatible with large-scale screening, several small whole-animal models, such as Caenorhabditis elegans, have gained momentum as screening tools for drug discovery (3).
11 Read more
To permit the identification of putative miRNA targets, the new web-tool ‘ MicroRNA Targets ’ was developed: http://www.athamap.de/miRNA_ident.php. After selecting the miRNA, user selected parameters are for example the sequence window to be analysed for each gene and the psRNATarget score (0.0-5.0). If a lower false positive prediction rate is preferred, a more stringent cut-off threshold (0.0-2.0) should be set. If a higher prediction coverage is desired, a more relaxed cut-off threshold (4.0-5.0) can be chosen. 0.0 means identity between miRNA and target site. Figure 1 shows a screen shot of this new tool with part of the result table obtained for a miRNA163 target site search with target search parameters. All target genes and the position of the target sites in these genes are linked to a sequence display window. Figure 2 shows a partial sequence dis- play window for position 24877969 of target gene At1g66700.1. This not only displays the miRNA selected and the miRNA target site within the genomic sequence, but also shows that small RNAs were identified in different small RNA transcriptome datasets targeting the same chromosomal position. The number of genomic hits obtained for each small RNA transcriptome dataset ranges between 36,084 and 470,537 (Table 1).
AXL, a receptor tyrosine kinase that belongs to the TAM subfamily (Tyro-3, AXL, and Mer), is a transmembrane protein that consists of extracellular two immunoglobin-like domains with two tandem fibronectin type III repeats, and a cytoplasmic kinase domain . AXL binds to its ligand Gas-6 (growth arrest-specific gene 6) and activates downstream signaling, including PI3K/AKT and NF-κB pathways . Following its identification as a transforming gene in human chronic myelogenous leukemia , AXL has been shown to be overexpressed in several types of human cancers such as lung  and gastric  cancers. Of note, we , and others , have reported AXL overexpression in esophageal AC. In fact, AXL overexpression has been associated with tumor cell migration and invasion, epithelial-to-mesenchymal transition (EMT), and poor survival in different types of cancers [66, 67]. These studies highlight AXL as a promising target for cancer therapy. In this regard, Holland and colleagues  generated and characterized a highly selective small- molecule inhibitor (R428, Rigel Pharmaceuticals) that potently blocks the catalytic activity of AXL and AXL- dependent biological functions, including tumor cell invasion and angiogenesis in tumor mouse models. In a preclinical study, Li and colleagues  have developed AXL monoclonal antibodies that suppress NSCLC xenograft growth through downregulation of AXL expression and induction of apoptosis. Preclinical studies on AXL inhibitor TP-0903 (Tolero Pharmaceuticals & Astex Pharmaceuticals) in pancreatic and lung cancers are ongoing . BergenBio & Rigel Pharmaceuticals have recently launched a clinical trial (phase I) to evaluate the AXL inhibitor BGB324 (formerly R428) in cancer patients . In another phase I clinical study, a compound (S49076, Servier) that inhibits AXL/Mer and fibroblast growth factor receptors has been evaluated in patients with advanced solid tumors . However, a new study urges caution as systemic inhibition of AXL and its closely related RTK, Mer, could promote colon cancers . Of note, AXL and Mer are expressed in macrophages and dendritic cells mediating anti-inflammatory functions
11 Read more
Hyperlipidemia is a medical condition characterized by an increase in one or more of the plasma lipids, including triglycerides, cholesterol, cholesterol esters, phospholipids and or plasma lipoproteins including very low-density lipoprotein and low-density lipoprotein along with reduced high-density lipoprotein levels. This elevation of plasma lipids is among the leading risk factors associated with cardiovascular diseases. In the meantime, statins and fibrates remain the major anti-hyperlipidemic agents for the treatment of elevated plasma cholesterol and triglycerides respectively, with the price of severe side effects on the muscles and the liver. The present review focuses mainly on the types of hyperlipidemias, lipid metabolism, treatments and new drug targets for the treatment of elevated lipid profile. Many agents such as lanosterol synthase inhibitors, squalene epoxidase inhibitors, diacyl glycerol acyl transferase inhibitors, ATP citrate lyase inhibitors have shown a promising potential in the treatment of hyperlipidemia in clinical trials.
11 Read more
In recent years, the landscape of pro- and anti-inflammatory cytokines has rapidly expanded with the identification of new members proven to be involved at different extent in the pathogenesis of chronic immune mediated inflammatory diseases including rheumatoid arthritis (RA). The advance of our understanding of mediators involved in the pathogenesis of RA and in consequence, the development of novel targeted therapies is necessary to provide patients not responding to currently available strategies with novel compounds. The aim of this review article is to provide an overview on recently identified cytokines, emphasizing their pathogenic role and therapeutic potential in RA. A systematic literature review was performed to retrieve articles related to every cytokine discussed in the review. In some cases, evidence from animal models and RA patients is already consistent to move forward into drug development. In others, conflicting observation and the paucity of data require further investigations.Forty years after the discovery of IL-1, the landscape of cytokines is continuously expanding with increasing possibilities to develop novel therapeutic strategies in RA.
13 Read more
regulated in the brain of hibernating squirrels and inhib- ition of their activities protects neuronal cells from oxygen and glucose deprivation-induced death . In a rat model of global cerebral ischemia, miR-181c regulates microglial- mediated neuronal apoptosis following ischemia/reperfu- sion injury . miR-181c directly targets the 3’ untrans- lated region of TNF-α mRNA, inhibiting apoptosis mediated by TNF-α from activated microglial cells . These data suggest that miRNAs are functionally import- ant mediators of neurological impairment in ischemic brain. Thus, miRNAs may represent not only new bio- markers for neurological prognosis but also novel candi- dates for neuroprotective therapy targets that may be investigated following cardiac arrest.
Despite a dramatic increase in our ability to catalogue variation among pathogen genomes, we have made far fewer advances in using this information to identify targets of protective immunity. epidemiological models predict that strong immune selection can cause antigenic variants to structure into genetically discordant sets of antigenic types (e.g. serotypes). A corollary of this theory is that targets of immunity may be identified by searching for non-overlapping associations of amino acids among co-circulating antigenic variants. We propose a novel population genetics methodology that combines such predictions with phylogenetic analyses to identify genetic loci (epitopes) under strong immune selection. We apply this concept to the AMA-1 protein of the malaria parasite Plasmodium falciparum and find evidence of epitopes among certain regions of low variability which could render them ideal vaccine candidates. The proposed method can be applied to a myriad of multi-strain pathogens for which vast amounts of genetic data has been collected in recent years.
resistance to cell death signals, evasion of immune surveillance, induction of angiogenesis, and activation of the metastatic potential. It is over-expressed in colon, liver, pancreatic cancer, in ICC and in their surrounding stroma cells; its overexpression seems to be associated with neoplastic progression and proliferative activities [43–46]. The silencing of each gene separately produced a statistically significant inhibition of migration, but not effect on proliferation. The simultaneous inhibition of these targets potentiates the anti-migratory effect, suggesting a crosstalk between SYK and LGALS1. In the work of Fulcher and collaborators, it has been demonstrated that Gal1, the protein encoded by LGALS1, induced cell activation and migration through the phosphorylation of Syk in dendritic cells . The lack of inhibition of proliferation demonstrated that the silencing of these genes is not sufficient to mimic trabectedin effect, suggesting that a more complex mechanism of drug-targets
15 Read more
Abstract: Urothelial carcinoma of the bladder, despite the myriad of treatment approaches and our progressively increasing knowledge into its disease processes, remains one of the most clinically challenging problems in modern urological clinical practice. New therapies target biomolecular pathways and cellular mediators responsible for regulating cell growth and metabolism, both of which are frequently overexpressed in malignant urothelial cells, with the intent of inducing cell death by limiting cellular metabolism and growth, creating an immune response, or selectively delivering or activating a cytotoxic agent. These new and novel therapies may offer a potential for reduced toxicity and an encouraging hope for better treatment outcomes, particularly for a disease often refractory or not amenable to the current therapeutic approaches.
13 Read more
Our second modification was to devise a quantitative method of estimating the probability that a given query molecule is associated with a particular bioactivity-scaffold combination defining one specific refined family. This allows us to make comparable predictions across both on-target and off-target activities based on the current 1,715,667 compounds and 10,774 targets in the ChEMBL database (Gaulton et al., 2012). Doing this requires us to create a common scale for the different affinity measures reported in the literature, (IC50, Ki, Kd, EC50, ED50, potency, activity, inhibition) relevant to bioactivity. We applied a number of rules in order to generate sets of molecules experimentally reported to be bioactive, given affinities defined using the eight different measures, separating these from sets of inactive molecules. Those empirical rules were derived by considering the distributions of the different affinity measures amongst reported active and inactive compounds. Subsequently, we use the Parzen-Rosenblatt (PR) (Rosenblatt, 1956; Parzen, 1962) kernel density estimation method to transform Tanimoto similarities into probabilities of family membership.
21 Read more