Two-Year Outcomes After Radiofrequency Neurolysis of Posterior Nasal Nerve in Chronic Rhinitis.

Objective: To assess the long-term safety and effectiveness of temperature-controlled radiofrequency (TCRF) neurolysis of the posterior nasal nerve (PNN), a minimally invasive treatment for chronic rhinitis.

Methods: A prospective, single-arm study of 129 patients at 16 centers (United States, Germany) was conducted. Patient-reported outcome measures were the 24-h reflective total nasal symptom score (rTNSS) and mini rhinoconjunctivitis quality of life questionnaire (MiniRQLQ).

Design, synthesis and characterisation of a novel type II B-RAF paradox breaker inhibitor.

The mutation V600E in B-Raf leads to mitogen activated protein kinase (MAPK) pathway activation, uncontrolled cell proliferation, and tumorigenesis. ATP competitive type I B-Raf inhibitors, such as vemurafenib (1) and PLX4720 (4) efficiently block the MAPK pathways in B-Raf mutant cells, however these inhibitors induce conformational changes in the wild type B-Raf (B-Raf) kinase domain leading to heterodimerization with C-Raf, causing paradoxical hyperactivation of the MAPK pathway. This unwanted activation may be avoided by another class of inhibitors (type II) which bind the kinase in the DFG-out conformation, such as AZ628 (3) preventing heterodimerization.

Discovery and Pharmacological Characterization of JNJ-64619178, a Novel Small-Molecule Inhibitor of PRMT5 with Potent Antitumor Activity.

The protein arginine methyltransferase 5 (PRMT5) methylates a variety of proteins involved in splicing, multiple signal transduction pathways, epigenetic control of gene expression, and mechanisms leading to protein expression required for cellular proliferation. Dysregulation of PRMT5 is associated with clinical features of several cancers, including lymphomas, lung cancer, and breast cancer. Here, we describe the characterization of JNJ-64619178, a novel, selective, and potent PRMT5 inhibitor, currently in clinical trials for patients with advanced solid tumors, non-Hodgkin's lymphoma, and lower-risk myelodysplastic syndrome.

[Clinical post-approval studies as part of the Therapy Allergen Regulation (TAV): A systematic review].

With the introduction of the Therapy Allergens Ordinance (TAV) the previously unapproved therapeutic allergens on the existing market need to be checked for their risk-benefit ratio as a basic prerequisite for approval under pharmaceutical law. This process is criticized because it can lead to long transition periods so that patients will probably be treated for two decades with preparations whose effectiveness has not yet been proven and may never be proven. The aim of this work is to list the critical preparations for which no publicly accessible study activity has been recorded since the beginning of the TAV in 2008.

A Chemical Probe for the Methyl Transferase PRMT5 with a Novel Binding Mode.

Protein arginine methyltransferase 5 (PRMT5) is an enzyme that can symmetrically dimethylate arginine residues in histones and nonhistone proteins by using -adenosyl methionine (SAM) as the methyl donating cofactor. We have designed a library of SAM analogues and discovered potent, cell-active, and selective spiro diamines as inhibitors of the enzymatic function of PRMT5. Crystallographic studies confirmed a very interesting binding mode, involving protein flexibility, where both the cofactor pocket and part of substrate binding site are occupied by these inhibitors.

A prospective, non-randomized evaluation of a novel low energy radiofrequency treatment for nasal obstruction and snoring.

Background: Weak or inward-bent cartilage of the nasal sidewall at the level of the internal nasal valve (INV) can produce narrowness or collapse of the nasal valve. This is a common cause of impaired nasal breathing during daily activities and there is also an established connection between nasal obstruction and snoring. The condition is often difficult to treat, although even a small enlargement of the lumen at the nasal valve can lead to a significant improvement in the ease of nasal breathing.

Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor.

KRAS was recently identified to be potentially druggable by allele-specific covalent targeting of Cys-12 in vicinity to an inducible allosteric switch II pocket (S-IIP). Success of this approach requires active cycling of KRAS between its active-GTP and inactive-GDP conformations as accessibility of the S-IIP is restricted only to the GDP-bound state. This strategy proved feasible for inhibiting mutant KRAS in vitro; however, it is uncertain whether this approach would translate to in vivo.

Quantitative Phosphoproteomics Analysis of ERBB3/ERBB4 Signaling.

The four members of the epidermal growth factor receptor (EGFR/ERBB) family form homo- and heterodimers which mediate ligand-specific regulation of many key cellular processes in normal and cancer tissues. While signaling through the EGFR has been extensively studied on the molecular level, signal transduction through ERBB3/ERBB4 heterodimers is less well understood. Here, we generated isogenic mouse Ba/F3 cells that express full-length and functional membrane-integrated ERBB3 and ERBB4 or ERBB4 alone, to serve as a defined cellular model for biological and phosphoproteomics analysis of ERBB3/ERBB4 signaling.

MELK-T1, a small-molecule inhibitor of protein kinase MELK, decreases DNA-damage tolerance in proliferating cancer cells.

Maternal embryonic leucine zipper kinase (MELK), a serine/threonine protein kinase, has oncogenic properties and is overexpressed in many cancer cells. The oncogenic function of MELK is attributed to its capacity to disable critical cell-cycle checkpoints and reduce replication stress. Most functional studies have relied on the use of siRNA/shRNA-mediated gene silencing.

Limited Proteolysis Combined with Stable Isotope Labeling Reveals Conformational Changes in Protein (Pseudo)kinases upon Binding Small Molecules.

Likely due to conformational rearrangements, small molecule inhibitors may stabilize the active conformation of protein kinases and paradoxically promote tumorigenesis. We combined limited proteolysis with stable isotope labeling MS to monitor protein conformational changes upon binding of small molecules. Applying this method to the human serine/threonine kinase B-Raf, frequently mutated in cancer, we found that binding of ATP or its nonhydrolyzable analogue AMP-PNP, but not ADP, stabilized the structure of both B-Raf(WT) and B-Raf(V600E).

PepShell: visualization of conformational proteomics data.

Proteins are dynamic molecules; they undergo crucial conformational changes induced by post-translational modifications and by binding of cofactors or other molecules. The characterization of these conformational changes and their relation to protein function is a central goal of structural biology. Unfortunately, most conventional methods to obtain structural information do not provide information on protein dynamics.

Structural investigation of B-Raf paradox breaker and inducer inhibitors.

The V600E missense mutation in B-Raf kinase leads to an anomalous regulation of the MAPK pathway, uncontrolled cell proliferation, and initiation of tumorigenesis. While the ATP-competitive B-Raf inhibitors block the MAPK pathway in B-Raf mutant cells, they induce conformational changes to wild-type B-Raf kinase domain leading to heterodimerization with C-Raf causing a paradoxical hyperactivation of MAPK pathway. A new class of inhibitors (paradox breakers) has been developed that inhibit B-Raf(V600E) activity without agonistically affecting the MAPK pathway in wild-type B-Raf cells.

CD74-NRG1 fusions in lung adenocarcinoma.

Unlabelled: We discovered a novel somatic gene fusion, CD74-NRG1, by transcriptome sequencing of 25 lung adenocarcinomas of never smokers. By screening 102 lung adenocarcinomas negative for known oncogenic alterations, we found four additional fusion-positive tumors, all of which were of the invasive mucinous subtype. Mechanistically, CD74-NRG1 leads to extracellular expression of the EGF-like domain of NRG1 III-β3, thereby providing the ligand for ERBB2-ERBB3 receptor complexes.

Maternal embryonic leucine zipper kinase (MELK) reduces replication stress in glioblastoma cells.

Maternal embryonic leucine zipper kinase (MELK) belongs to the subfamily of AMP-activated Ser/Thr protein kinases. The expression of MELK is very high in glioblastoma-type brain tumors, but it is not clear how this contributes to tumor growth. Here we show that the siRNA-mediated loss of MELK in U87 MG glioblastoma cells causes a G1/S phase cell cycle arrest accompanied by cell death or a senescence-like phenotype that can be rescued by the expression of siRNA-resistant MELK.

[The quality of diagnostic classification using abridged versions of the tinnitus questionnaire: comparative analysis].

Background: There are different abridged versions of the tinnitus questionnaire (TQ) and reference values for grading tinnitus-related distress, the diagnostic value of which is unclear, as is the relation of sensitivity to specificity, as well as positive and negative predictive values. The present study is aimed at clarifying these issues and at benchmarking the existing abridged TQ versions.

Patients And Methods: TQ data from 209 outpatients who had tinnitus for a period of at least 4 months were collected at the beginning of treatment.

Rhinitis sicca, dry nose and atrophic rhinitis: a review of the literature.

Despite the fact that many people suffer from it, an unequivocal definition of dry nose (DN) is not available. Symptoms range from the purely subjective sensation of a rather dry nose to visible crusting of the (inner) nose (nasal mucosa), and a wide range of combinations are met with. Relevant diseases are termed rhinitis sicca anterior, primary and secondary rhinitis atrophicans, rhinitis atrophicans with foetor (ozena), and empty nose syndrome.

Self-treatment of benign paroxysmal positional vertigo with DizzyFix, a new dynamic visual device.

Benign paroxysmal positional vertigo is one of the most common disorders of the vestibular system. It is characterized by episodes of recurrent vertigo triggered by head movements or position changes associated with nystagmus. There is scientific evidence that in the majority of cases this condition responds well to the particle repositioning maneuver (PRM) correctly performed by the physician.

Endonasal phototherapy significantly alleviates symptoms of allergic rhinitis, but has a limited impact on the nasal mucosal immune cells.

The literature documents the fact that UV irradiation of cutaneous Langerhans cells (LC) in vivo prevents the development of contact allergy and produces long-lasting immunosuppression. However, not much is known about the effect of UV irradiation on the LC of the nasal mucosa and their connection with clinical scores. Local antigen presentation may be necessary for both primary and recall T cell responses to birch pollen in patients with hay fever.

The rhinolith-a possible differential diagnosis of a unilateral nasal obstruction.

Rhinoliths are mineralised foreign bodies in the nasal cavity that are a chance finding at anterior rhinoscopy. Undiscovered, they grow appreciably in size and can cause a foul-smelling nasal discharge and breathing problems. Giant nasal stones are now a very rare occurrence, since improved diagnostic techniques, such as endoscopic/microscopic rhinoscopy, now make it possible to identify foreign bodies at an early stage of development.