Provided are methods of generating chimeric antigen receptors (CAR). In some embodiments, library screening of CAR is performed by generating a vector encoding the CAR from random attachment of vectors from libraries of vectors encoding antigen-binding domains (e.g., scFv regions), hinge regions, and endodomains. In some embodiments, the vectors contain a transposon.

Provided in some embodiments are antibodies comprising a heavy chain having no native interchain cysteine amino acids, a light chain having no native interchain cysteine amino acids, and having no native interchain disulphide linkages between the heavy chain and the light chain. Also provided in certain embodiments are antibodies comprising a heavy chain having no native interchain cysteine amino acids, a light chain having no native interchain cysteine amino acids, and having no native interchain disulphide linkages between the heavy chain and the light chain where the native interchain cysteine amino acids have been replaced by amino acids having no thiol moiety.

The present invention provides compositions and methods relating to or derived from antigen binding proteins capable of inducing B-Klotho, and or FGF21-like mediated signaling. In embodiments, the antigen binding proteins specifically bind to a complex comprising β-Klotho and at least one of (i) FGFR1c, (ii) FGFR2c and (iii) FGFR3c. In some embodiments the antigen binding proteins induce FGF21-like signaling. In some embodiments, an antigen binding protein is a fully human, humanized, or chimeric antibodies, binding fragments and derivatives of such antibodies, and polypeptides that specifically bind to a complex comprising β-Klotho and at least one of (i) FGFR1c, (ii) FGFR2c and (iii) FGFR3c. Other embodiments provide nucleic acids encoding such antigen binding proteins, and fragments and derivatives thereof, and polypeptides, cells comprising such polynucleotides, methods of making such antigen binding proteins, and fragments and derivatives thereof, and polypeptides, and methods of using such antigen binding proteins, fragments and derivatives thereof, and polypeptides, including methods of treating or diagnosing subjects suffering from type 2 diabetes, obesity, NASH, metabolic syndrome and related disorders or conditions.

The present invention relates to Chimeric Antigen Receptors (CAR) that are recombinant chimeric proteins able to redirect immune cell specificity and reactivity toward selected membrane antigens, and more particularly in which extracellular ligand binding is a scFV derived from a CD123 monoclonal antibody, conferring specific immunity against CD123 positive cells. The engineered immune cells endowed with such CARs are particularly suited for treating lymphomas and leukemia.

Cysteine engineered antibodies useful for the site-specific conjugation to a variety of agents are provided. Methods for the design, preparation, screening, selection and use of such antibodies are also provided.

The invention provides compositions and methods for treating leukemia, for example, acute myeloid leukemia (AML) and B-cell acute lymphoid leukemia (B-ALL). The invention also relates to at least one chimeric antigen receptor (CAR) specific to CD123, vectors comprising the same, and recombinant T cells comprising the CD123 CAR. The invention also includes methods of administering a genetically modified T cell expressing a CAR that comprises a CD123 binding domain. The invention also includes methods of bone marrow ablation for use in treatments necessitating bone marrow reconditioning or transplant.

The present invention relates to Chimeric Antigen Receptors (CAR) that are recombinant chimeric proteins able to redirect immune cell specificity and reactivity toward selected membrane antigens, and more particularly in which extracellular ligand binding is a scFV derived from a BCMA monoclonal antibody, conferring specific immunity against BCMA positive cells. The engineered immune cells endowed with such CARs are particularly suited for treating lymphomas, multiple myeloma and leukemia.

Provided herein are methods of treatment to regenerate, restore or rejuvenate a tissue. Methods include making adult somatic and germ cells pluripotent for administration to a patient. Alternatively, created pluripotent cells may be differentiated to the desired tissue type and administered to a patient to repair or enhance the target tissue.

Materials and methods for treating and preventing American Foulbrood disease in honeybees, such as materials and methods for using phage lysin enzymes to lyse Paenibacillus larvae, are provided herein.

The present invention relates to the use of the miRNA expression profile, particularly of miR-199a-5p, and the target genes regulated thereby for the diagnosis, prognosis and use of miR-199a-5p inhibitors for treating fibroproliferative disorders.

Provided herein are compositions and methods for modifying a predetermined nucleic acid sequence. A programmable nucleoprotein molecular complex containing a polypeptide moiety and a specificity conferring nucleic acid (SCNA) which assembles in-vivo, in a target cell, and is capable of interacting with the predetermined target nucleic acid sequence is provided. The programmable nucleoprotein molecular complex is capable of specifically modifying and/or editing a target site within the target nucleic acid sequence and/or modifying the function of the target nucleic acid sequence.

The invention provides diagnostic and therapeutic targets for pulmonary disease, in particular, fibrotic lung disease. The inventors have found that a genetic variant MUC5B gene is associated with increased expression of the gene, increased risk of developing a pulmonary disease, and an improved prognosis and survival among those developing the pulmonary disease.

By a genome-wide gene analysis of expression profiles of known or putative gene sequences in peripheral blood and biopsy samples, the present inventors have identified a consensus set of gene expression-based molecular biomarkers for distinguishing liver transplantation patients who have Acute Rejection (AR), Hepatitis C Virus Recurrence (HCV-R), both AR/HCV-R, or Acute Dysfunction No Rejection (ADNR). These molecular biomarkers are useful for diagnosis, prognosis and monitoring of liver transplantation patients.

Provided herein are methods for the prognosis of prostate cancer progression in a patient by analyzing the gene expression in a tumor sample obtained from the patient the prognosis of prostate cancer progression in a patient by analyzing the gene expression in a tumor sample obtained from the patient. In particular, gene expression levels of GCOM1, MEX3D, TRPM4, ATPAF1, PTRF, GLYATL1, FLNA, OBSCN, STRA13, WHSCl, ARFGAP3, KDM2A, FAM83H, CLDN7, CNOT6, and B3GNT9 are measured. Kits containing means for the measurement of gene expression as described herein and methods for treatment of prostate cancer are also provided.

The present invention concerns cancer biomarkers. In particular, the invention concerns HGF as a biomarker for patient selection and patient prognosis in cancer, as well as methods of therapeutic treatment, articles of manufacture and methods for making them, diagnostic kits, methods of detection and methods of advertising related thereto.

This disclosure relates to methods, computer products, computer-implemented methods, and systems for predicting the probability or risk of prostate cancer recurrence and tumor aggressiveness in a patient. The method is based, in part, on the patient's risk profile that includes the presence/degree of specific copy number variations and predictive clinical factors. The methods and systems can be used to aid in treatment selection.

Fibrous structures that exhibit a novel combination of properties and to methods for making such fibrous structures are provided.

The invention provides for a proteomic approach for identification of specific bacterial protein profiles that may be used in the development of methods for the diagnosis of bacterial chronic sinusitis. The invention provides for methods for determining the presence of pathogenic bacteria in the upper respiratory tract of a subject using protein profiles of the pathogenic bacteria. The invention also provides for methods of diagnosing a bacterial infection of the upper respiratory tract of a subject using protein profiles of a pathogenic bacteria. In addition, the invention provides for devices, immunoassays and kits for identifying pathogenic bacteria in the upper respiratory tract.

This invention relates to novel monoclonal antibodies that specifically bind to the alpha-folate receptor. In some embodiments, the antibodies inhibit a biological activity of folate receptor-α (FR-α). The antibodies are useful in the treatment of certain cancers, particularly cancers that have increased cell surface expression of the alpha-folate receptor (“FR-α”), such as ovarian, breast, renal, colorectal, lung, endometrial, or brain cancer. The invention also relates to cells expressing the monoclonal antibodies, antibody derivatives, such as chimeric and humanized monoclonal antibodies, antibody fragments, and methods of detecting and treating cancer using the antibodies, derivatives, and fragments.

Described herein are methods and compositions for treatment of immune-related diseases or disorders by modulating DD1α activity, alone or in combination with modulation of PD-1 activity. In some embodiments, the methods and compositions described herein are directed to treatment of cancer and/or infections (e.g., bacterial infection, and/or fungal infection). In some embodiments, the methods and compositions described herein are directed to treatment of autoimmune diseases and/or inflammation. In some embodiments, the methods and compositions described herein are directed to treatment of asthma, and allergy. Methods for identifying patients who are more likely to be responsive to and benefit from an immunotherapy that targets DD1α and/or PD-1 activity or expression are also described herein.

The present invention provides methods for assessing whether a subject is at risk of developing a neurological disorder, diagnosing or confirming whether a subject is afflicted with a neurological disorder, assessing whether PD has progressed in a subject afflicted with PD, assessing whether a neurological disorder is developing in a subject who has been identified as being at risk of developing the neurological disorder, assessing whether a subject afflicted with a neurological disorder is likely to benefit from a therapy, assessing whether a subject afflicted with a neurological disorder has benefited from a therapy, treating a subject afflicted with a neurological disorder, and prophylactically treating a subject who has been identified as being at risk of developing a neurological disorder. The present invention also provides epitopes, compounds and compositions relating to these methods.

A cold rolling mill is described wherein the unstressed shape of metal sheet is continuously sensed during rolling by a plurality of negligible displacement force sensors perpendicularly disposed relative to the pass line at a mill location producing a tensile stress above 4,000 p.s.i. in the metal sheet being rolled. The output signals from those sensors underlying opposite edges of the metal sheet are compared to equalize reduction at the sheet edges while the difference between the force measured by a centrally situated sensor and the average force measured by the sensors underlying opposite edges of the sheet provide a signal indicative of the roll bending force required to produce flat sheet.

A button and pin assembly machine for producing badges and the like comprising buttons having rearwardly extending rims adapted to receive and retain respective pin structures therein, in which the buttons are sequentially supplied to a pin-forming head and supported thereat with the button rim encircling the end of such head, straight pin blanks being sequentially supplied to said head, with a portion of a pin blank being inserted into the head and rotated thereby with respect to a stationary abutment to curl an end of such blank sufficiently to enable its insertion in the rim of a button disposed thereat, said head having means for forming a bend in the portion of the pin blank inserted in such head to resiliently bias the pointed end of the pin blank toward the button.

Portions of a pin-on button are cut and assembled as a result of a plurality of operations in a machine having a vertical press. Cutter and work deforming tools are displaced by a single press ram to cut blanks and deform the blanks onto a button top placed in one of two die assemblies positioned in alignment below the work deforming tool on the lower end of the ram.

Device for forming buttons from a pin-on back plate, a front plate, and a cover over the front plate, with the device having a pair of button-forming dies alternately shiftable into operation alignment with a forming punch which on descent with the successively aligned dies cooperates with the latter to assemble the separate button parts into a button, and a cover-blanking punch and die set above the forming punch, of which the blanking die is topmost and has a die aperture open at the top and bottom and a cutting edge at the bottom of the aperture, with the blanking die being by the forming punch raised into blanking cooperation with the blanking die, and the forming punch being moved upwardly and downwardly by manually operable means.

Device for forming buttons from a pin-on back plate, a front plate, and a cover over the front plate, with the device having a pair of button-forming dies alternately shiftable into operative alignment with a forming punch which on descent into the successively aligned dies cooperates with the latter to assemble the separate button parts into a button, and a blanking punch and die set above the forming punch, of which the blanking punch is raised into cooperation with the blanking die for blanking a cover from a supply sheet, and a handlever operatively connected with the punches for simultaneously lowering the forming punch and raising the blanking punch.

Apparatus for the manufacture of a laminated button comprising a metallic backing plate having a transverse peripheral edge and an outwardly extending flange, an illustrated paper sheet and a protective acetate covering. The apparatus comprises a pneumatically operated press which receives the plate, illustrated sheet and covering, and, with a single downward movement, causes the sheet to conform to the plate and be crimped between the transverse edge and flange.

Apparatus for covering buttons operable in an automatic, semi-automatic or manual mode. The apparatus includes a rotatable table having alternately positioned shell and back receiving lower dies, means for automatically delivering the shells and backs to their respective lower dies, a reciprocating upper die synchronized for movement with the rotation of the rotatable table and engageable with the lower dies at a first station to transfer a shell and fabric covering from a shell receiving lower die to the upper die and press-fit a back from a back receiving lower die into the covered shell in the upper die to form an assembled covered button and having means permitting its use with a range of fabric cover thicknesses, and means for ejecting the assembled covered buttons.

A machine for the manufacture of buckles, buttons or the like which comprises an upper tool and a lower tool. The lower tool has an outer, spring-mounted frame and an inner core piece displaceable vertically with respect to the surrounding frame. The lower tool is adapted to support the assembled button after the opening stroke of the upper tool. A device is provided for lifting the core piece of the lower tool relative to the surrounding frame up to about the height of a transversely directed stream of blast air serving for discharging the product from the lower tool.

A method for fabrication of a relatively low cost display or communicative novelty button in which a consumable restrictor sheet is placed over a vacuum draw type female mold cavity. The restrictor sheet may be of cardboard and be apertured with a diameter smaller than the mold cavity diameter. A thermoplastic sheet material is then placed over the restrictor sheet, heated to reach a formable state and vacuum drawn through the restricted aperture and down so that the sheet comes into contact with and generally conforms to the desired shape defined by the mold cavity. The plastic sheet material may then be trimmed near the edge of the restrictor sheet to leave a button shell mounted on a restrictor sheet which may then be used for purposes of display. The restrictor sheet also enables fabrication with an inwardly facing peripheral groove that may be used to secure a pin fastener. An alternate form of fastener in which a portion of the remaining plastic sheet is used is also disclosed.

Pigmented substantially crack-free casein plastic compositions containing a minor, luster-imparting quantity of coated mica platelets, wherein at least 75% of the pigment particles possess an average platelet size of below 10 μm., a thickness of about 0.1 to 0.7 μm. and a ratio of diameter to thickness of about 10 to 200.

A fabric covered button comprising a button head having a peripheral groove for receiving a locking ring. The fabric is secured to the button head and the marginal edge thereof is retained within the groove by the locking ring.

Apparatus for assembling covered buttons in which a first die assembly including a first punch carrying a first sleeve which sequentially receives a piece of covering material and the button shell with its flange extending toward the open end of the sleeve. A second assembly including a second sleeve having a bore one end of which is formed with a first cam surface extending axially inwardly of the above. The second sleeve is spring loaded to an extended position on a supporting post having a centrally located button back fastener receiving cavity in the end thereof with a second cam surface extending inwardly from the outer edge of the end to the bottom of a recess surrounding the cavity. An annular boss at the inner edge of the recess around the cavity is elevated to allow the material and the shell flange to curl inwardly under the button back. In the retracted position of the second sleeve on the post, the second cam surface forms a continuation of the first. In operation, when the first assembly carrying the covering piece and the shell moves toward the second assembly, the first sleeve stops against the spring loaded bottom sleeve and the punch continues forcing the material down so that the material is tucked inward by the beveled or curved surface of the second sleeve. Upon continued relative movement of the assemblies, the shell flange acts on the cam surface of the second sleeve to force the sleeve to its retracted position and the shell flange is moved inwardly of the back wall under the continued action of the first post, the extent of the inward movement of the shell flange being determined by the thickness of the material of the covering piece, as well as the height of the shell and the type of back used.

An improved method of forming and assembling two-part merchandise display hooks, including new design features of the hook itself, enable two-part hooks to be manufactured and assembled at extremely low cost. Wire from a continuous length is gripped and bent to form the outer portion of the hook. The wire is then severed and bent in a single operation to form a hook-mounting portion. While the severed wire remains gripped by its shaped outer end, a preoriented and guided base member is applied over the just-formed mounting portion of the wire. A retractable bend-forming member is withdrawn when the base member is applied to the wire, to enable the bent portion to be fully received within the plastic base. Major manufacturing economies are realized.

A device is disclosed for pressing objects by lifting the objects into a waiting pressing shaft. The shaft includes a forming element at its lower end for forming the object, and the shaft is engaged by its upper end through a pivot member to an air cylinder in a manner which provides a force advantage to the air cylinder. Also, a system for pressing objects is disclosed, in which the press device is employed in conjunction with a turntable for sequential and continuous pressing operations.

A universal assembly machine manufactures conventional buttons with formed backs. The machine comprises a rotatably indexable die table to which are mounted pickup and crimp dies. The die table indexes about a center column of the machine frame. A ram die is advancable and retractable in a pickup stroke and a crimp stroke by means of a handle. The ram die includes a ram outer ring that is rotatable by means of a shifter post joined to the die table. Indexing the die table causes the shifter post to rotate the ram outer ring into a pickup mode or a crimp mode to suit the ram pickup and crimp strokes, respectively. The universal assembly machine also manufactures buttons with flat backs by using a different crimp die pedestal than is used with the formed backs. An adapter on the crimp die pedestal used with formed backs allows that crimp die pedestal to also be used for manufacturing buttons with flat backs. The invention also embraces button medallions. A flat back button is loaded into the pickup die, and the die table is indexed. The ram die is advanced in a third press to form the shell frusto-conical wall of the flat back button inwardly to be flat and parallel to the flat back.

A universal assembly machine manufactures conventional buttons with formed backs. The machine comprises a rotatably indexable die table to which are mounted pickup and crimp dies. The die table indexes about a center column of the machine frame. A ram die is advancable and retractable in a pickup stroke and a crimp stroke by means of a handle. The ram die includes a ram outer ring that is rotatable by means of a shifter post joined to the die table. Indexing the die table causes the shifter post to rotate the ram outer ring into a pickup mode or a crimp mode to suit the ram pickup and crimp strokes, respectively. The universal assembly machine also manufactures buttons with flat backs by using a different crimp die pedestal than is used with the formed backs. An adapter on the crimp die pedestal used with formed backs allows that crimp die pedestal to also be used for manufacturing buttons with flat backs. The invention also embraces button medallions. A flat back button is loaded into the pickup die, and the die table is indexed. The ram die is advanced in a third press stroke to bend the shell frusto-conical wall of the flat back button inwardly to be flat and parallel to the flat back.

A button system and method of manufacturing the same are provided for identifying fiber from which an article of apparel is manufactured. Initially, an article of apparel manufactured with a predetermined fiber is identified. Next, indicia indicative of the predetermined fiber is selected. Next, at least one button is manufactured with the indicia thereon for identifying the fiber from which the article of apparel is manufactured.

An adapter enables a universal assembly machine to manufacture buttons with either flat backs or formed backs. The machine comprises a rotatably indexable die table to which are mounted pickup and crimp dies. A ram die is advancable and retractable in a pickup stroke and a crimp stroke. Indexing the die table causes a shifter post to rotate a ram outer ring into a pickup mode or a crimp mode to suit the ram pickup and crimp strokes, respectively. The universal assembly machine manufactures buttons with flat backs by using the adapter on the same crimp die pedestal as is used for manufacturing buttons with formed backs. The adapter has a top surface that is in the location relative to the ram die that suits flat back buttons. The adapter enables the same crimp die pedestal to be used for manufacturing both flat back and formed back buttons.

A machine manufactures buttons having coplanar shell flanges in a two-stroke operation. The machine comprises a crimp die having different resistances to advancement of a ram. The first resistance enables a metal shell margin to partially bend under a flat back that is placed on a first surface of the crimp die. The second resistance enables the shell wall to completely bend against a second surface of the crimp die so as to form flanges that lie in a single plane. Both round and rectangular buttons are manufacturable using the same basic machine. The rectangular machine uses a shifter cage on the ram that rotates in response to indexing a die table on which the crimp die and a pickup die are attached. The round machine uses a rotatable frame on the ram. With the rectangular machine, the shell is initially bent during a pickup stroke of the ram.

A method for forming a multi-colored cap part of a snap button including the steps of forming a design portion of the cap part of snap button using a first group of molds, which includes a first female mold, a first male mold, and a plate-shaped middle mold, and a slide-plate mold adapted to movably assembled to the first male mold and having a plurality of mold cavities for forming the design portion; removing the slide-plate mold having the design portion molded therein from the first male mold; movably positioning the slide-plate mold into a second female mold included in a second group of molds for forming a body portion of the cap part of snap button; positioning a post for the cap part of snap button in a second male mold of the second group of molds; and forming the body portion.

A button, knob or control key with an etchable support plate which is engraved on the backside with a fine symbol by laser, erosion or mechanical engraving, which only cuts into the material of the support plate, but not through the support plate. The backside of the support plate is optionally coated. A foil is applied on the laminated layer and affixed thereto. The front side of the support plate is treated with a material-removing substance. The material removal with the material-removing substance is performed until the engraving extending into the support plate is at least partially or completely exposed on the front side. Application of a protective layer to the front side of the support plate from which the material was removed. A function symbol is provided on the button such that it can be backlit. It is engraved in a fine line width providing a sharp optical definition erosion, mechanical engraving.

A mounting device, for mounting a plurality of buttons on a product, includes a supporting member, a punching member, and a driving member The supporting member includes a supporting panel, a plurality of holding portions fixed on the supporting panel for supporting the product, a molding board having a plurality of molding holes a platform, and a base fixed on the platform for supporting the molding board. The punching member includes a retaining member positioned above the supporting member, and a plurality of cutters fixed to the retaining member The cutters cut the buttons off a button assembly, and couple to a vacuum generator for creating suction to hold the buttons. The driving member drives the punching member to mount the buttons on the product.