There is more to accommodation of the eye than simply minimizing retinal blur.

Eyes of children and young adults change their optical power to focus nearby objects at the retina. But does accommodation function by trial and error to minimize blur and maximize contrast as is generally accepted? Three experiments in monocular and monochromatic vision were performed under two conditions while aberrations were being corrected. In the first condition, feedback was available to the eye from both optical vergence and optical blur. In the second, feedback was only available from target blur. Accommodation was less precise for the second condition, suggesting that it is more than a trial-and-error function. Optical vergence itself seems to be an important cue for accommodation

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Monoclonal antibodies recognizing a coagulase-negative staphylococcal protein

Monoclonal antibodies which can bind to the SdrF protein of Staphylococcus epidermidis are provided which can be useful in the treatment and protection against infection from staphylococcal bacteria such as Staphylococcus epidermidis. The monoclonal antibodies of the invention are advantageous in that they can also recognize binding domains and subdomains of the S. epidermidis SdrF protein in addition to the protein itself. Suitable compositions and passive vaccines based on the monoclonal antibodies of the invention, as well as methods for their use, are also provided.U

Surface proteins from coagulase-negative staphylococci and Staphylococcus aureus that generate cross-reactive monoclonal and polyclonal antibodies

Surface proteins are provided which generate polyclonal and monoclonal antibodies which are cross-reactive to both coagulase-positive staphylococcus bacteria, such as S. aureus and to coagulase-negative bacteria, such as S. epidermidis and S. hemolyticus. The antibodies may be generated from surface proteins that have been isolated on the basis of characteristics that may be common between S. aureus and coagulase-negative staphylococci, or the A domains of those surface proteins, and these recombinant surface proteins are used to generate the cross-reactive antibodies. Vaccines comprising an immunologically effective amount of the proteins are also provided, and these vaccines are used in methods for the treatment or protection against a wide variety of staphylococcal infections

Cross- reactive monoclonal and polyclonal antibodies which recognize surface proteins from coagulase-negative staphylococci and Staphylococcus aureus

Polyclonal and monoclonal antibodies which are cross-reactive to both coagulase-positive staphylococcus bacteria, such as S. hemolyticus, are provided which can recognize surface proteins from both coagulase-positive and coagulase negative staph bacteria. The antibodies may be generated from surface proteins that have been isolated on the basis of characteristics that may be common between S. aureus and coagulase-negative staphylococci, and these recombinant surface proteins are used to generate the antibodies of the invention. There is also provided vaccines and methods which utilize these proteins and antibodies for the treatment or protection against awide variety of staphylococcal infections

Phosphatidylserine-targeting antibodies augment the anti-tumorigenic activity of anti-PD-1 therapy by enhancing immune activation and downregulating pro-oncogenic factors induced by T-cell checkpoint inhibition in murine triple-negative breast cancers.

BackgroundThe purpose of this study was to investigate the potential of antibody-directed immunotherapy targeting the aminophospholipid phosphatidylserine, which promotes immunosuppression when exposed in the tumor microenvironment, alone and in combination with antibody treatment towards the T-cell checkpoint inhibitor PD-1 in breast carcinomas, including triple-negative breast cancers.MethodsImmune-competent mice bearing syngeneic EMT-6 or E0771 tumors were subjected to treatments comprising of a phosphatidylserine-targeting and an anti-PD-1 antibody either as single or combinational treatments. Anti-tumor effects were determined by tumor growth inhibition and changes in overall survival accompanying each treatment. The generation of a tumor-specific immune response in animals undergoing complete tumor regression was assessed by secondary tumor cell challenge and splenocyte-produced IFNγ in the presence or absence of irradiated tumor cells. Changes in the presence of tumor-infiltrating lymphocytes were assessed by flow cytometry, while mRNA-based immune profiling was determined using NanoString PanCancer Immune Profiling Panel analysis.ResultsTreatment by a phosphatidylserine-targeting antibody inhibits in-vivo growth and significantly enhances the anti-tumor activity of antibody-mediated PD-1 therapy, including providing a distinct survival advantage over treatment by either single agent. Animals in which complete tumor regression occurred with combination treatments were resistant to secondary tumor challenge and presented heightened expression levels of splenocyte-produced IFNγ. Combinational treatment by a phosphatidylserine-targeting antibody with anti-PD-1 therapy increased the number of tumor-infiltrating lymphocytes more than that observed with single-arm therapies. Finally, immunoprofiling analysis revealed that the combination of anti-phosphatidylserine targeting antibody and anti-PD-1 therapy enhanced tumor-infiltrating lymphocytes, and increased expression of pro-immunosurveillance-associated cytokines while significantly decreasing expression of pro-tumorigenic cytokines that were induced by single anti-PD-1 therapy.ConclusionsOur data suggest that antibody therapy targeting phosphatidylserine-associated immunosuppression, which has activity as a single agent, can significantly enhance immunotherapies targeting the PD-1 pathway in murine breast neoplasms, including triple-negative breast cancers

Phosphatidylserine-targeting antibodies augment the anti-tumorigenic activity of anti-PD-1 therapy by enhancing immune activation and downregulating pro-oncogenic factors induced by T-cell checkpoint inhibition in murine triple-negative breast cancers.

BackgroundThe purpose of this study was to investigate the potential of antibody-directed immunotherapy targeting the aminophospholipid phosphatidylserine, which promotes immunosuppression when exposed in the tumor microenvironment, alone and in combination with antibody treatment towards the T-cell checkpoint inhibitor PD-1 in breast carcinomas, including triple-negative breast cancers.MethodsImmune-competent mice bearing syngeneic EMT-6 or E0771 tumors were subjected to treatments comprising of a phosphatidylserine-targeting and an anti-PD-1 antibody either as single or combinational treatments. Anti-tumor effects were determined by tumor growth inhibition and changes in overall survival accompanying each treatment. The generation of a tumor-specific immune response in animals undergoing complete tumor regression was assessed by secondary tumor cell challenge and splenocyte-produced IFNγ in the presence or absence of irradiated tumor cells. Changes in the presence of tumor-infiltrating lymphocytes were assessed by flow cytometry, while mRNA-based immune profiling was determined using NanoString PanCancer Immune Profiling Panel analysis.ResultsTreatment by a phosphatidylserine-targeting antibody inhibits in-vivo growth and significantly enhances the anti-tumor activity of antibody-mediated PD-1 therapy, including providing a distinct survival advantage over treatment by either single agent. Animals in which complete tumor regression occurred with combination treatments were resistant to secondary tumor challenge and presented heightened expression levels of splenocyte-produced IFNγ. Combinational treatment by a phosphatidylserine-targeting antibody with anti-PD-1 therapy increased the number of tumor-infiltrating lymphocytes more than that observed with single-arm therapies. Finally, immunoprofiling analysis revealed that the combination of anti-phosphatidylserine targeting antibody and anti-PD-1 therapy enhanced tumor-infiltrating lymphocytes, and increased expression of pro-immunosurveillance-associated cytokines while significantly decreasing expression of pro-tumorigenic cytokines that were induced by single anti-PD-1 therapy.ConclusionsOur data suggest that antibody therapy targeting phosphatidylserine-associated immunosuppression, which has activity as a single agent, can significantly enhance immunotherapies targeting the PD-1 pathway in murine breast neoplasms, including triple-negative breast cancers

DMPK and Metabolism Studies of Nucleoside Phosphoramidates Including INX-08189, A Novel Double Pro-drug and Clinical Candidate for Hepatitis C Virus Therapy

Hepatitis C Virus (HCV) infection is a serious health problem that leads to chronic liver disease, such as cirrhosis and hepatocellular carcinoma, in an estimated 2–15% of the world's population. A collaboration between Inhibitex and the University of Caridiff in Wales has produced a novel double pro-drug approach to the anti-HCV agent 2′-β-C-methylguanosine. A phosphoramidate (ProTide) motif and a C6-methoxy base pro-drug moiety are combined to generate lipophilic prodrugs of the monophosphate of the guanine nucleoside. Extensive DMPK studies in multiple species which supported the selection of the lead compound will be discussed. Details of the pre-clinical development of INX-08189 including radiolabeled metabolism studies will be described. INX-08189 has completed investigational new drug enabling studies and has been progressed into human clinical trials for the treatment of chronic HCV infection

Bioinformatic method for identifying surface-anchored proteins from gram-positive bacteria and proteins obtained thereby

A bioinformatic method is provided for identifying and isolating proteins with MSCRAMM®—like characteristics from Gram positive bacteria, such as Enterococcus, Staphylococcus, Streptococcus and Bacillus bacteria, which can then be utilized in methods to prevent and treat infections caused by Gram-positive bacteria. The method involves identifying from sequence information those proteins with a putative C-terminal LPXTG (SEQ ID NO:1) cell wall sorting signal and other structural similarities to MSCRAMM® proteins having the LPXTG-anchored cell wall proteins. The MSCRAMM® proteins and immunogenic regions therein that are identified and isolated using the present invention may be used to generate antibodies useful in the diagnosis, treatment or prevention of Gram positive bacterial infections.U