The present invention relates to compounds 4-[5-[(rac)-1-[5-(3-Chlorophenyl)-3-isoxazolyl]ethoxy]-4-methyl-4 H-1,2,4-triazol-3-yl]pyridine (TT00, TT001 and/or TT002), or a pharmaceutical composition comprising said TT00, TT001 and/or TT002, for use in prevention and/or treatment of surmenage, optionally in combination with one or more disorders selected from operative gastroesophageal reflux, anxiety, ulcer, renal and vascular disorders, wound healing and/or inappetence in a mammal, such as dogs, pigs, cats or horses.

Disclosed herein are compositions and methods for treating pulmonary hypertension whereby a SCUBE1 polynucleotide or polypeptide is administered. Also disclosed herein are methods for diagnosing and/or prognosing pulmonary arterial hypertension or pulmonary hypertension with high pulmonary vascular resistance that include detecting an amount of a SCUBE1 polynucleotide or polypeptide.

The methods described herein are for treating infections in individuals having cancer and who are receiving cancer immunotherapy, preferably employing a CRISPR system to selectively kill or reduce the numbers of pathogenic bacteria within the individual and thereafter, administering an immune checkpoint inhibitor thereto. In particular embodiments, the pathogenic bacteria is one of E. coli, Pseudomonas aeruginosa, Klebsiella bacteria, Staphylococcus aureus; Streptoccocus; Salmonella; Shigella; Mycobacterium tuberculosis; Enterococcus; Clostridium; Neisseria gonnorrhoea; Acinetobacter baumannii; and Campylobacter bacteria and the checkpoint inhibitor is selected from the group consisting of nivolumab, pembrolizumab, pidilizumab, AMP-224, AMP-514, STI-A1110, TSR-042, RG-7446, BMS-936559, MEDI-4736, MSB-0020718C, AUR-012 and STI-A1010. Further embodiments include enhancing the growth of a second bacteria in the individual, such bacteria including Akkermansia, Bacteroides, Bifidobacterium, Enterococcus, Fusobacterium, Coprococcus, LactoBacillus, Propionibacterium, Ruminococcus, Veillonella, Prevotella, and F. prausnitzii. The CRISPR system may include Cas9, Cpf1 and Cas3, and may be delivered using a bacteriophage.

Chemical entities that modulate PI3 kinase activity, and chemical entities, pharmaceutical compositions, and methods of treatments of diseases and conditions associated with P13 kinase activity are described herein.

Materials and methods for treating polycystic kidney disease (e.g., autosomal dominant polycystic kidney disease (ADPKD)) are provided herein that include using one or more inhibitors of pregnancy associated plasma protein A (PAPP-A) polypeptide expression or activity.

The present invention provides compounds having the general structural formula (I) ##STR00001##
and pharmaceutically acceptable derivatives thereof, as described generally and in classes and subclasses herein, and additionally provides pharmaceutical compositions thereof, and methods for the use thereof for the treatment of any of a number of conditions or diseases involving abnormal or excessive fibrosis.

Embodiments of the disclosure concern methods and compositions for immunotherapy for human papillomavirus infection and diseases associated therewith. In specific embodiments, methods concern production of immune cells that target one or more antigens of HPV16 and/or HPV18, including methods with stimulation steps that employ IL-7 and IL-15, but not IL-6 and/or IL-12. Other specific embodiments utilize stimulations in the presence of certain cells, such as costimulatory cells and certain antigen presenting cells.

The present invention relates to 1,3-thiazol-2-yl substituted benzamide compounds of general formula (I) as described and defined herein, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of neurogenic disorder, as a sole agent or in combination with other active ingredients.

The present invention relates to 1,3-thiazol-2-yl substituted benzamide compounds of general formula (I) as described and defined herein, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of neurogenic disorder, as a sole agent or in combination with other active ingredients.

An earplug (1) for administering a fluid agent into an ear canal is provided. The earplug (1) comprises a first part (10) adapted for insertion in the ear canal. The first part comprises an elongated member (11) having a chamber (12) for containing the fluid agent, the chamber (12) having at least one outlet (13) at a proximal end (14) of the elongated member (11); and a malleable member (17) disposed laterally of the elongated member (11). The earplug (1) further comprises a second part (20) comprising a piston (21). The piston (21) has a first end (22) which is insertable in the elongated member (11), and a second end (23) which has a push member (24). The piston (21) is displaceable from a first position (A) distally of the chamber (12) to a second position (B) within the chamber (12), such that the fluid agent is injected from the chamber (12) through the outlet (13) into the ear canal.