Abstract: Disclosed are means, methods and compositions of matter useful for stimulation enhancement of T cell homing into tumors and overcoming tumor microenvironment. In one embodiment the invention provides an engineered T cell in which engagement of T cell receptor on said T cell results in upregulation of T cell attracting chemokines so as to induce an increased proportion of T cells to tumor cells. In another embodiment, T cell chemokine secreting cells are administrated intratumorally in order to augment T cell infiltration into said tumors. In other embodiments administration of lymphopoietic cytokines is performed intratumorally to enhance viability of T cells approaching and residing in the microenvironment. Combinations of agents which counteract tumor microenvironment induced immune suppression are also disclosed.

Abstract: Disclosed are aptamers designed to bind immunological checkpoint molecules while concurrently suppressing tumor associated gene expression through delivery of DNA molecules encoding short hairpin DNA. In one embodiment the invention provides an aptamer capable of binding PD-1 and/or PD-1 ligand while concurrently possessing ability to induce RNA interference to one more multiple other immune inhibitory and/or oncogenesis related genes. In one embodiment such a dual-targeting aptamer is utilized to induce systemic tumor abscopal effect.

Abstract: Disclosed are combination therapies for cancer utilizing the leverage of the adaptive immune system through chimeric antigen receptor (CAR) T cells, combined with leveraging the innate immune system by using CAR-macrophages (CAR-M) and CAR-natural killer (NK) cells. In some embodiments, the invention teaches the initial modification of the tumor microenvironment by administration of CAR-M and CAR-NK. The alteration of the tumor microenvironment results in reduction of barriers for CAR-T cells to enter the tumor, which allows for efficacy of CAR-T in treatment of solid tumors. In some embodiments adjuvant immunotherapies are utilized to expand immunological attack such as addition of complement, immunotherapeutic antibodies, chemotherapy and radiotherapy approaches.

Abstract: Disclosed are methods, and compositions useful for stimulation of immunity towards cancer by utilizing dendritic cells and products therefrom that have been stimulated and/or incorporated mRNA encoding survivin and/or related gene sequences, defined herein as “survivin modified mRNA”. In one embodiment dendritic cells generated from allogeneic “off the shelf” sources are transfected with survivin modified mRNA and the cells are administered in an immunogenic manner. In some embodiments transfected dendritic cells are induced to undergo immunogenic cell death ex vivo subsequently to which they are used as immunogenic stimuli. In other embodiments preparation of the injection site is performed prior to administration of dendritic cells that have been transfected with survivin modified mRNA by pre-administration of agents increasing the number of local dendritic cells in the skin.

Abstract: An intake device for a gas turbine engine includes a snorkel and a particle separator. The snorkel is configured to be mounted to a panel defining at least a portion of a gas flow path within the gas turbine engine. The snorkel includes a tubular body extending between a closed end and an open end opposite the closed end. The snorkel further includes an inlet aperture formed through the tubular body adjacent the closed end. At least a portion of the snorkel is configured to be disposed within the gas flow path. The particle separator is mounted to the snorkel downstream of the inlet aperture. The particle separator includes at least one gas flow passage extending between a flow inlet and a flow outlet. The at least one gas flow passage is configured to remove particulate matter from the at least one gas flow passage upstream of the flow outlet.

Abstract: An intake device for a gas turbine engine includes a snorkel and a particle separator. The snorkel is configured to be mounted to a panel defining at least a portion of a gas flow path within the gas turbine engine. The snorkel includes a tubular body extending between a closed end and an open end opposite the closed end. The snorkel further includes an inlet aperture formed through the tubular body adjacent the closed end. At least a portion of the snorkel is configured to be disposed within the gas flow path. The particle separator is mounted to the snorkel downstream of the inlet aperture. The particle separator includes at least one gas flow passage extending between a flow inlet and a flow outlet. The at least one gas flow passage is configured to remove particulate matter from the at least one gas flow passage upstream of the flow outlet.

Abstract: A gas turbine engine includes an intake device. The intake device includes a snorkel and a filter case. The snorkel includes a tubular body and an inlet aperture. The tubular body extends between a closed end and an open end opposite the closed end. The inlet aperture is formed through the tubular body proximate the closed end. The tubular body forms a first portion of a gas flow path for a bleed gas from the inlet aperture to the open end. The filter case is connected to the tubular body. The filter case extends between a first end and a second end. The filter case includes a sidewall extending from the first end to the second end. The sidewall surrounds a filter cavity. The filter case is configured to receive the bleed gas from the open end of the tubular body. The filter case and the snorkel form a unitary component.

Abstract: Disclosed are means of stimulating systemic immunity and reduction of post-surgery tumor metastasis through the concurrent intralymphatic inhibition of NR2F6 and treatment with cannabidiol. In some embodiments NR2F6 is inhibited by high pressure transient delivery of short interfering RNA into tumor draining lymph nodes concurrent with systemic administration of cannabidiol. This combination may be performed together with means that induce immunogenic tumor cell death. Through the combination of immunogenic cell death and immune stimulation, the invention provides a means of enhancing the abscopal effect and in some embodiments to cause immunological mediated destruction primary and secondary neoplasia.

Abstract: Disclosed are means, methods and compositions of matter useful for suppressing pathological production of new blood vessels in conditions such as cancer and wet macular degeneration. In one embodiment the invention provides silencing of NR2F6 using nucleic acid based approaches such as RNA interference, antisense oligonucleotides, or DICER. In another embodiment, the invention teaches the administration of small molecule NR2F6 inhibitors as means of selectively inhibiting pathological but not healthy angiogenesis.

Abstract: An intake device for a gas turbine engine includes a snorkel and a housing. The snorkel includes a tubular body and an inlet aperture. The tubular body extends between a closed end and an open end opposite the closed end. The inlet aperture is formed through the tubular body proximate the closed end. The housing is mounted to the snorkel. The housing includes an inner wall, an outer wall, a side wall, a settling chamber, and an outlet tube. The inner wall is adjacent the snorkel. The outer wall is opposite the inner wall. The side wall extends from the inner wall to the outer wall. The settling chamber is within the side wall between the inner wall and the outer wall. The settling chamber is fluidly coupled with the open end. The outlet tube extends through the housing from the settling chamber to an exterior of the housing.

Abstract: Disclosed are means, methods and compositions of matter useful for suppressing pathological production of new blood vessels in conditions such as cancer and wet macular degeneration. In one embodiment the invention provides silencing of NR2F6 using nucleic acid based approaches such as RNA interference, antisense oligonucleotides, or DICER. In another embodiment, the invention teaches the administration of small molecule NR2F6 inhibitors as means of selectively inhibiting pathological but not healthy angiogenesis.

Abstract: The teachings herein are directed to methods of treating a tumor comprising identifying a patient having a tumor; and administering a combination of a chemotherapeutic agent and an immunomodulatory agent for cancer therapy into the tumor in an amount sufficient to treat the tumor.

Abstract: Disclosed are compounds useful for alteration of NR2F6 activity. In some embodiments of the invention compounds disclosed are utilized for stimulation of NR2F6 activity, alone, or in combination with PKC activation. In other embodiments, the invention teaches use of compounds for inhibition of NR2F6 activation. Stimulation of NR2F6 within the context of the invention is useful, intra alia, for induction of immune inhibition, or stimulation of cellular proliferation without significant induction of differentiation. Inhibition of NR2F6 is desired in situations where the practitioner of the invention seeks to augment immune response, or induce cellular differentiation. In another embodiment, inhibition of NR2F6 expression is desired in situations where inhibition of cancer or cancer stem cells is needed.

Abstract: Disclosed are methods, devices, and techniques useful for enhancing function of an organ or cellular graft through photoceutical manipulation. In one embodiment a hematopoietic graft is treated with one or more wavelengths of low level laser irradiation at a sufficient energy to enhance homing and engraftment. In another embodiment the recipient long bones are treated with one or more wavelengths of low level laser irradiation at a sufficient energy to enhance chemoattraction and growth factor secretion on recipient stromal cells. Application of the invention includes areas of cellular transplants such as islet and hepatic cell grafts.

Abstract: Cancer associated inflammation has been reported to act as an immune suppressive mechanism through augmentation of myeloid suppressor cells, as well as downregulation of T cell receptor (TCR) signaling through the cleavage of the CD3 zeta chain. The teachings herein show the effects of concurrent anti-inflammatory treatment of dendritic cells (DC) using cannabidiol (CBD) together with inhibition of an immunological checkpoint, that is, silencing of NR2F6. Mixed lymphocyte cultures are used to increased potency of dendritic cells to stimulate allogeneic T cell proliferative and cytokine responses by the combination of NR2F6 gene silencing together with CBD. CBD alone appeared to inhibit DC maturation and allogestimulatory activity. These data support the utilization of small molecule inhibitors of NR2F6 together with CBD as combination therapies for immune modulation.

Abstract: Disclosed are means of stimulating systemic immunity and reduction of post-surgery tumor metastasis through the concurrent intralymphatic inhibition of NR2F6 and treatment with cannabidiol. In some embodiments NR2F6 is inhibited by high pressure transient delivery of short interfering RNA into tumor draining lymph nodes concurrent with systemic administration of cannabidiol. This combination may be performed together with means that induce immunogenic tumor cell death. Through the combination of immunogenic cell death and immune stimulation, the invention provides a means of enhancing the abscopal effect and in some embodiments to cause immunological mediated destruction primary and secondary neoplasia.

Abstract: Disclosed are compositions of matter, cells, and methodologies for generation of chimeric antigen receptor (CAR) cells with inhibited or absent NR2F6 activity. In one embodiment, a CAR possessing affinity to a tumor antigen is transfected onto T cells that possess reduced or absent NR2F6 activity, said reduction or absence of NR2F6 activity leading to increased production of cytokines associated with inhibition of tumor growth, metastasis or angiogenesis, and/or augmentation of tumor cytotoxicity. Inhibition of NR2F6 activity may be performed ex vivo on said T cells or in vivo by administration of small molecule inhibitors, siRNA, shRNA or gene editing. In some embodiments other immune cells are substituted for CAR-T cells.

Abstract: Disclosed are compositions of matters, cells, and treatment protocols useful for induction of anticancer responses in a patient suffering from cancer. In one embodiment the invention provides the use of NR2F6 silencing or gene editing in cord blood cells possessing anti-tumor activity in order to induce potentiated killer cells suitable for therapeutic use. In one embodiment said allogeneic cord blood killer cells are administered to initiate a cascade of antitumor immune responses, with initially responses mediated by allogeneic killer cells, and followed by endogenous immune responses.

Abstract: Disclosed are antigen specific cancer vaccines in which immunogenic epitopes are produced intracellularly by administration of modified mRNA encoding said immunogenic epitopes. In one embodiment of the invention, said modified mRNA encodes peptides derived from the protein survivin. By directly inducing gene expression of the antigens to which an immune response is desired, immunogenic peptides are generated intracellularly, thus allowing for a wider repertoire of epitopes to be presented to the adaptive immune system, which augments likelihood of successful induction of immunity.

Abstract: Disclosed are means, methods, and compositions of matter useful for generation of cancer inhibitory effector cells producing interleukin-17 (IL-17). In one embodiment a cellular population is obtained, said cellular population is exposed to agents capable of inhibiting NR2F6, whereby said inhibition of NR2F6 results in upregulation of IL-17 production, said upregulation of IL-17 production associated with acquisition of anti-tumor activity.