Swallowing, speech and voice impairments in head and neck cancer patients treated at a multidisciplinary integrated patient unit.

Background: Head and neck cancer (HNC) is amongst the 10 most common cancers worldwide and has a major effect on patients' quality of life. Given the complexity of this unique group of patients, a multidisciplinary team approach is preferable. Amongst the debilitating sequels of HNC and/or its treatment, swallowing, speech and voice impairments are prevalent and require the involvement of speech-language pathologists (SLPs).

Geometric parameters that affect the behavior of logic-gated CAR T cells.

Clinical applications of CAR-T cells are limited by the scarcity of tumor-specific targets and are often afflicted with the same on-target/off-tumor toxicities that plague other cancer treatments. A new promising strategy to enforce tumor selectivity is the use of logic-gated, two-receptor systems. One well-described application is termed Tmod™, which originally utilized a blocking inhibitory receptor directed towards HLA-I target antigens to create a protective NOT gate.

HLA-A∗02-gated safety switch for cancer therapy has exquisite specificity for its allelic target antigen.

Innovative cell-based therapies are important new weapons in the fight against difficult-to-treat cancers. One promising strategy involves cell therapies equipped with multiple receptors to integrate signals from more than one antigen. We developed a specific embodiment of this approach called Tmod, a two-receptor system that combines activating and inhibitory inputs to distinguish between tumor and normal cells.

The Tmod cellular logic gate as a solution for tumor-selective immunotherapy.

Immune cells that are engineered with receptors to integrate signals from multiple antigens offer a promising route to achieve the elusive property of therapeutic selectivity in cancer patients. Several types of multi-signal integrators have been described, among them mechanisms that pair activating and inhibitory receptors which are termed NOT gates by analogy to logical operations performed by machines. Here we review one such NOT-gated signal integrator called the Tmod system which is being developed for patients with solid tumors.

Mesothelin-specific CAR-T cell therapy that incorporates an HLA-gated safety mechanism selectively kills tumor cells.

Background: Mesothelin (MSLN) is a classic tumor-associated antigen that is expressed in lung cancer and many other solid tumors. However, MSLN is also expressed in normal mesothelium which creates a significant risk of serious inflammation for MSLN-directed therapeutics. We have developed a dual-receptor (Tmod™) system that exploits the difference between tumor and normal tissue in a subset of patients with defined heterozygous gene loss (LOH) in their tumors.

Chimeric Antigen Receptors Directed at Mutant KRAS Exhibit an Inverse Relationship Between Functional Potency and Neoantigen Selectivity.

Unlabelled: Neoantigens are among the most intriguing potential immuno-oncology targets because, unlike many cancer targets that are expressed on normal tissues, they are by definition restricted to cancer cells. Medicines directed at common neoantigens such as mutant KRAS are especially interesting because they may offer the convenience and cost of an off-the-shelf therapy. However, all common KRAS mutations produce proteins that differ from the wild type at a single amino acid, creating challenges for molecular discrimination.

The Sheba Medical Center Protocol for Bedside Evaluation of Swallowing Disorders Among Tracheotomized Patients.

The Sheba Blue Dye Test Protocol (SBDTP) is a swallowing bedside evaluation for tracheotomized patients (TP). It is based on the Modified Evans' Blue Dye Test (MEBDT), but includes several modifications that aim to overcome previously described caveats of the traditional MEBDT. These modifications include evaluating the patient three times, with increasing quantities of bolus.

Design of TCR Structural Variants That Retain or Invert the Normal Activation Signal.

We designed variant human TCRs composed of the full-length TCRα/β or extracellular and transmembrane domains of the associated CD3 subunits fused to polypeptides derived from proteins thought to either enhance or inhibit normal T cell function. First, we showed that the C termini of both the TCR α- and β-chains can accommodate specific additional sequences, without abrogating complex formation or acute sensitivity of the receptor. Replacement of ITAMs with ITIM-containing intracellular domains inverted the TCR signal (i.

Metformin and Androgen Receptor-Axis-Targeted (ARAT) Agents Induce Two PARP-1-Dependent Cell Death Pathways in Androgen-Sensitive Human Prostate Cancer Cells.

We explored whether the anti-prostate cancer (PC) activity of the androgen receptor-axis-targeted agents (ARATs) abiraterone and enzalutamide is enhanced by metformin. Using complementary biological and molecular approaches, we determined the associated underlying mechanisms in pre-clinical androgen-sensitive PC models. ARATs increased androgren receptors (ARs) in LNCaP and AR/ARv7 (AR variant) in VCaP cells, inhibited cell proliferation in both, and induced poly(ADP-ribose) polymerase-1 (PARP-1) cleavage and death in VCaP but not LNCaP cells.

Engineered T cells directed at tumors with defined allelic loss.

We describe an approach to cancer therapy based on exploitation of common losses of genetic material in tumor cells (loss of heterozygosity) (Basilion et al., 1999; Beroukhim et al., 2010).

Structure-function relationships of chimeric antigen receptors in acute T cell responses to antigen.

Chimeric antigen receptors (CARs) and their parent signaling molecule, the T cell receptor (TCR), are fascinating proteins of increasing relevance to disease therapy. Here we use a collection of 1221 pMHC-directed CAR constructs representing 10 pMHC targets to study aspects of CAR structure-activity relationships (SAR), with particular focus on the extracellular and transmembrane structural components. These experiments that involve pMHC targets whose number/cell can be manipulated by peptide dosing in vitro enable systematic analysis of the SAR of CARs in carefully controlled experimental situations (Harris and Kranz, 2016).

[The Measurement of Psychological Mindedness: a validation study of the German version of the Balanced Index of Psychological Mindedness (BIPM)].

The aim of the study is to examine central measurement properties of the translated Balanced Index of Psychological Mindedness (BIPM) within a sample of German native speakers. Factor structure, validity and reliability of the BIPM was examined using data from a community sample of 399 participants. Additionally, associations between BIPM and socio-demographic variables were tested.

Nanoscale integration of single cell biologics discovery processes using optofluidic manipulation and monitoring.

The new and rapid advancement in the complexity of biologics drug discovery has been driven by a deeper understanding of biological systems combined with innovative new therapeutic modalities, paving the way to breakthrough therapies for previously intractable diseases. These exciting times in biomedical innovation require the development of novel technologies to facilitate the sophisticated, multifaceted, high-paced workflows necessary to support modern large molecule drug discovery. A high-level aspiration is a true integration of "lab-on-a-chip" methods that vastly miniaturize cellulmical experiments could transform the speed, cost, and success of multiple workstreams in biologics development.

[Validation of the German Version of the Psychological Mindedness Scale (PMS-D)].

Unlabelled: Validation of the German Version of the Psychological Mindedness Scale (PMS-D) Objectives: The Psychological Mindedness Scale (PMS) is one of the few established measures for psychological mindedness (PM). PM refers to a capacity and disposition to properly perceive inner processes - feelings, thoughts and conflicts. The aim of this study was the validation of the German translation of the PMS, which was conducted via TRAPDprocess.

MiR-199a-3p decreases esophageal cancer cell proliferation by targeting p21 activated kinase 4.

Although microRNA (miR) 199a-3p functions as a tumor suppressor in multiple malignancies, its expression and role in esophageal cancer have not been studied. Based on our previous observation that miR-199a-3p is markedly downregulated in esophageal cancer cell lines relative to esophageal epithelial cells, we examined the function of miR-199a-3p in these cells. MiR-199a-3p is predicted to bind with high affinity to the mRNA of p21 activated kinase 4 (PAK4).

Coxiella burnetii Infections in Small Ruminants and Humans in Switzerland.

The recent Q fever epidemic in the Netherlands raised concerns about the potential risk of outbreaks in other European countries. In Switzerland, the prevalence of Q fever in animals and humans has not been studied in recent years. In this study, we describe the current situation with respect to Coxiella (C.

The ErbB3-binding protein EBP1 modulates lapatinib sensitivity in prostate cancer cells.

Although ErbB receptors have been implicated in prostate cancer progression, ErbB-directed drugs have not proven effective for prostate cancer treatment. The ErbB3-binding protein EBP1 affects both ErbB2 and androgen receptor signaling, two components of the response to ErbB-targeted therapies. We therefore examined the effects of EBP1 expression on the response to the ErbB1/2 tyrosine kinase inhibitor lapatinib.

Regulation of ribosomal RNA synthesis in T cells: requirement for GTP and Ebp1.

Mycophenolic acid (MPA) is the active metabolite of mycophenolate mofetil, an effective immunosuppressive drug. Both MPA and mycophenolate mofetil are highly specific inhibitors of guanine nucleotide synthesis and of T-cell activation. However, the mechanism by which guanine nucleotide depletion suppresses T-cell activation is unknown.

Functional cyclic AMP response element in the breast cancer resistance protein (BCRP/ABCG2) promoter modulates epidermal growth factor receptor pathway- or androgen withdrawal-mediated BCRP/ABCG2 transcription in human cancer cells.

Phosphorylated cyclic-AMP (cAMP) response element binding protein (p-CREB) is a downstream effector of a variety of important signaling pathways. We investigated whether the human BCRP promoter contains a functional cAMP response element (CRE). 8Br-cAMP, a cAMP analogue, increased the activity of a BCRP promoter reporter construct and BCRP mRNA in human carcinoma cells.

Inhibition of secreted frizzled-related protein 5 improves glucose metabolism.

Elucidating the role of secreted frizzled-related protein 5 (SFRP5) in metabolism and obesity has been complicated by contradictory findings when knockout mice were used to determine metabolic phenotypes. By overexpressing SFRP5 in obese, prediabetic mice we consistently observed elevated hyperglycemia and glucose intolerance, supporting SFRP5 as a negative regulator of glucose metabolism. Accordingly, Sfrp5 mRNA expression analysis of both epididymal and subcutaneous adipose depots of mice indicated a correlation with obesity.

Academic model of trauma healing in post-war societies.

Objective: The aim of this paper is to examine the implications for healing in a contemporary Balkan post-war context, and to provide a bridge-building model of trauma transformation, reconciliation and recovery through academic reconstruction and cross-border dialogue. Post-war societies are marked by the effects of massive, large group traumatization, and if not properly dealt with, long-term rehabilitation and social recovery cannot be expected. Unprocessed cumulative trauma that has become deeply embedded in the collective memory of the Balkan peoples over centuries, "chosen trauma", its trans-generational transmission and periodical reactivations across the Balkan have often been addressed in recent literature, in ethno-psychology, psychoanalysis, psychiatry, sociology and anthropology.

Heregulin negatively regulates transcription of ErbB2/3 receptors via an AKT-mediated pathway.

Despite the importance of the ErbB2/3 heterodimer in breast cancer progression, the negative regulation of these receptors is still poorly understood. We demonstrate here for the first time that the ErbB3/4 ligand heregulin (HRG) reduced both ErbB2 and ErbB3 mRNA and protein levels in human breast cancer cell lines. In contrast, EGFR levels were unaffected by HRG treatment.

FGF21 can be mimicked in vitro and in vivo by a novel anti-FGFR1c/β-Klotho bispecific protein.

The endocrine hormone FGF21 has attracted considerable interest as a potential therapeutic for treating diabetes and obesity. As an alternative to the native cytokine, we generated bispecific Avimer polypeptides that bind with high affinity and specificity to one of the receptor and coreceptor pairs used by FGF21, FGFR1c and β-Klotho. These Avimers exhibit FGF21-like activity in in vitro assays with potency greater than FGF21.

Regulation of tamoxifen sensitivity by a PAK1-EBP1 signalling pathway in breast cancer.

Background: EBP1, an ErbB3-binding protein, sensitises breast cancer cells to tamoxifen in part by decreasing ErbB2 protein levels. The p21-regulated serine/threonine kinase PAK1, implicated in tamoxifen resistance, phosphorylates EBP1 in vitro and in vivo at T261. Phosphorylation of EBP1 at this site induces tamoxifen resistance.