Abstract: The present invention relates to a compound selectively binding to a sensory receptor or selectively altering the expression of a sensory receptor for use in a method for treating or preventing a disease associated with a pathologic cellular cytotoxic T cell (CTL) response. Further, the invention relates to means for detecting a sensory receptor for use in a method for diagnosing cellular resistance against CTL response in a patient. The invention further embraces a method for determining the resistance of a cell against a CTL response in vitro and to a method for identifying agents that influence the response of cells to CTLs.

Abstract: The invention is based on the identification of the intracellular kinase calcium/calmodulin-dependent protein kinase 1D (CAMK1D) as a key checkpoint inhibitor in tumour cells mediating resistance against cytotoxic T lymphocytes (CTL). CAMK1D was identified in PD-L1 refractory tumours to impair CTL-induced death receptor signalling and apoptosis via caspase inhibition. The invention offers therapeutic approaches involving impairing CAMK1D immune checkpoint function by various CAMK1D inhibitors, especially nucleic acid or small molecule inhibitors of CAMK1D and/or treatments involving CAMK1D inhibitors with death receptor agonists. The medical approaches of the invention are useful for treating subjects suffering from various proliferative disorders; preferably such proliferative disorders that are characterized by a resistance to CTL mediated immune responses, or which are refractory or resistant to treatments with other immune checkpoint therapies, such as PD1-PDL1 antagonistic treatments.

Abstract: The invention is based on the surprising finding that SIK3 is associated with resistance against anti-tumour immune responses. In particular, the invention provides methods for treating proliferative diseases using inhibitors of SIK3, especially nucleic acid or small molecule inhibitors of SIK3. Also provided are methods of sensitising cells involved with a proliferative disorder against the cytotoxic effect of certain pro-inflammatory signalling pathways, and/or to kill such cells and/or methods for treating proliferative diseases, using a SIK3 inhibitor together with ligands or agonists of such signalling pathways.

Abstract: The present invention pertains to novel modulators of tumor resistance against T-cell mediated cytotoxic immune responses. The invention provides antagonists of tumor immune escape mechanisms and methods and other aspects related thereto, and therefore provides novel approaches for treating or aiding a treatment of various cancerous diseases and/or the diagnosis thereof. The invention pertains to both negative and positive regulators of tumor cell resistance and suggests the use inhibitors or activators of these genes for therapeutic purposes. In particular aspects, the invention provides combination therapeutics and/or therapies involving such inhibitors or activators. The invention furthermore provides screening methods for novel cancer therapeutics modulating the action of the identified genes, diagnostic approaches to detect cancer resistance to cytotoxic T-cells as well as pharmaceutical compositions and diagnostic kits, for use with or related to for performing these methods.

Abstract: The invention provides antigen binding proteins that bind to one or more extracellular domains of the human olfactory receptor 10H1 (OR10H1) or variants thereof, including antigen binding proteins which can modulate the expression, function, activity and/or stability of such receptor, as well as providing nucleic acids encoding such antigen binding proteins or components thereof. Methods for detecting OR10H1 or variants thereof in a sample, including diagnostic methods, using such antigen binding proteins are also provided. Uses of such antigen binding proteins, and nucleic acids encoding the same, in medicine are further provided.

Abstract: The present invention relates to a compound selectively binding to a sensory receptor or selectively altering the expression of a sensory receptor for use in a method for treating or preventing a disease associated with a pathologic cellular cytotoxic T cell (CTL) response. Further, the invention relates to means for detecting a sensory receptor for use in a method for diagnosing cellular resistance against CTL response in a patient. The invention further embraces a method for determining the resistance of a cell against a CTL response in vitro and to a method for identifying agents that influence the response of cells to CTLs.

Abstract: The present invention pertains to novel modulators of resistance against T-cell mediated cytotoxic immune responses. The invention provides antagonists of immune escape mechanisms and therefore offers a novel approach for treating, or aiding a treatment, of various proliferative diseases such as cancerous diseases, in particular melanoma, pancreatic cancer and colorectal cancer. The invention specifically discloses the receptor Olfactory Receptor, Family 10, Subfamily H, Member 1 (OR10H1)as a checkpoint molecule in tumor resistance against cytotoxic T-cells. Provided is the inhibition of OR10H1 expression and/or function as a strategy for enhancing tumor susceptibility to a patients T-cell mediated immune response. Provided are antigen binding constructs for the detection of the OR10H1 protein, as well as inhibitory compounds, such as siRNA/shRNA molecules targeting OR10H1 and anti-OR10H1 antibodies, forimpairing the immune escape mediated by OR10H1.

Abstract: Use of BUBR1 as a biomarker for predicting the response to a compound, preferably resistance of a disease such as cancer in a subject, wherein the compound is a furazanobenzimidazole compound of general formula (I).

Abstract: The present invention pertains to novel modulators of tumor resistance against T-cell mediated cytotoxic immune responses. The invention provides antagonists of tumor immune escape mechanisms and methods and other aspects related thereto, and therefore provides novel approaches for treating or aiding a treatment of various cancerous diseases and/or the diagnosis thereof. The invention specifically discloses C—C chemokine receptor type 9 (CCR9) as a checkpoint molecule in tumor resistance against cytotoxic T-cells. Provided is the inhibition of CCR9 expression, CCR9 signalling and/or CCR9-T-Cell interaction and inhibitors or antagonists thereof. In particular aspects, the invention provides combination therapeutics and/or therapies involving such inhibitors or antagonists.

Abstract: Compounds of formula (IIc); wherein X3 and X4 independently from each other are N or CR8 wherein R8 may be same or different; Y1, Y2, Y3 and Y4 independently from each other are N or CR9 wherein R9 may be same or different and wherein up to 3 of the group Y1, Y2, Y3 and Y4 may be N; their solvates, hydrates, and pharmaceutically acceptable salts, their use for modulating the Wnt signalling pathway activity and their use as a medicament, preferably for the treatment of cancer.

Abstract: The present invention relates to a compound selectively binding to a sensory receptor or selectively altering the expression of a sensory receptor for use in a method for treating or preventing a disease associated with a pathologic cellular cytotoxic T cell (CTL) response. Further, the invention relates to means for detecting a sensory receptor for use in a method for diagnosing cellular resistance against CTL response in a patient. The invention further embraces a method for determining the resistance of a cell against a CTL response in vitro and to a method for identifying agents that influence the response of cells to CTLs.

Abstract: Compounds of formula (IIc); wherein X3 and X4 independently from each other are N or CR8 wherein R8 may be same or different; Y1, Y2, Y3 and Y4 independently from each other are N or CR9 wherein R9 may be same or different and wherein up to 3 of the group Y1, Y2, Y3 and Y4 may be N; their solvates, hydrates, and pharmaceutically acceptable salts, their use for modulating the Wnt signalling pathway activity and their use as a medicament, preferably for the treatment of cancer.

Abstract: The present invention relates to a compound selectively binding to a sensory receptor or selectively altering the expression of a sensory receptor for use in a method for treating or preventing a disease associated with a pathologic cellular cytotoxic T cell (CTL) response. Further, the invention relates to means for detecting a sensory receptor for use in a method for diagnosing cellular resistance against CTL response in a patient. The invention further embraces a method for determining the resistance of a cell against a CTL response in vitro and to a method for identifying agents that influence the response of cells to CTLs.

Abstract: Use of BUBR1 as a biomarker for predicting the response to a compound, preferably resistance of a disease such as cancer in a subject, wherein the compound is a compound of general formula I wherein R represents phenyl, thienyl or pyridinyl wherein phenyl is optionally substituted by one or two substituents independently selected from alkyl, halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, acyloxy-lower alkyl, phenyl, hydroxy, lower alkoxy, hydroxy-lower alkoxy, lower alkoxy-lower alkoxy, phenyl-lower alkoxy, lower alkylcarbonyloxy, amino, monoalkylamino, dialkylamino, lower alkoxycarbonylamino, lower alkylcarbonylamino, substituted amino wherein the two substituents on nitrogen form together with the nitrogen heterocyclyl, lower alkylcarbonyl, carboxy, lower alkoxycarbonyl, cyano, halogen, and nitro; and wherein two adjacent substituents are methylenedioxy; and wherein pyridinyl is optionally substituted by lower alkoxy, amino or halogen; X represents a group C?Y, wherein Y stands for ox

Abstract: Compounds of formula (IIc); wherein X3 and X4 independently from each other are N or CR8 wherein R8 may be same or different; Y1, Y2, Y3 and Y4 independently from each other are N or CR9 wherein R9 may be same or different and wherein up to 3 of the group Y1, Y2, Y3 and Y4 may be N; their solvates, hydrates, and pharmaceutically acceptable salts, their use for modulating the Wnt signalling pathway activity and their use as a medicament, preferably for the treatment of cancer.

Abstract: Use of BUBR1 as a biomarker for predicting the response to a compound, preferably resistance of a disease such as cancer in a subject, wherein the compound is a compound of general formula I wherein R represents phenyl, thienyl or pyridinyl wherein phenyl is optionally substituted by one or two substituents independently selected from alkyl, halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, acyloxy-lower alkyl, phenyl, hydroxy, lower alkoxy, hydroxy-lower alkoxy, lower alkoxy-lower alkoxy, phenyl-lower alkoxy, lower alkylcarbonyloxy, amino, monoalkylamino, dialkylamino, lower alkoxycarbonylamino, lower alkylcarbonylamino, substituted amino wherein the two substituents on nitrogen form together with the nitrogen heterocyclyl, lower alkylcarbonyl, carboxy, lower alkoxycarbonyl, cyano, halogen, and nitro; and wherein two adjacent substituents are methylenedioxy; and wherein pyridinyl is optionally substituted by lower alkoxy, amino or halogen; X represents a group C?Y, wherein Y stands for

Abstract: The present invention relates to a compound selectively binding to a sensory receptor or selectively altering the expression of a sensory receptor for use in a method for treating or preventing a disease associated with a pathologic cellular cytotoxic T cell (CTL) response. Further, the invention relates to means for detecting a sensory receptor for use in a method for diagnosing cellular resistance against CTL response in a patient. The invention further embraces a method for determining the resistance of a cell against a CTL response in vitro and to a method for identifying agents that influence the response of cells to CTLs.

Abstract: Compounds of formula (IIc); wherein X3 and X4 independently from each other are N or CR8 wherein R8 may be same or different; Y1, Y2, Y3 and Y4 independently from each other are N or CR9 wherein R9 may be same or different and wherein up to 3 of the group Y1, Y2, Y3 and Y4 may be N; their solvates, hydrates, and pharmaceutically acceptable salts, their use for modulating the Wnt signalling pathway activity and their use as a medicament, preferably for the treatment of cancer.

Abstract: The present invention relates to modulators of G protein-coupled receptor 177 (Gpr177) for use in the treatment, alleviation, prevention and/or diagnosis of cancer as well as to methods for the diagnosis of such cancer.

Abstract: The present disclosure describes a rehabilitation flexor having a center piece and two twisting assemblies. The center piece may include a top section, a bottom section, and a curved section longitudedly connected to form a continuous body partially surrounding a leg recess, which is configured to accommodate a human leg behind the knee. Each twisting assembly has at least a handle bar that can be held by the user and used to manipulate the rehabilitation flexor. The rehabilitation flexor may be used to improve the rehabilitation and recovery of a person's leg mobility and flexibility after injury or surgery. In one alternate embodiment, the center piece and twisting assemblies are one piece formed from an injection molding or similar process. In this alternate embodiment, the leg recess has a padded covering such as memory foam to help support and cushion the user.