During adolescence the breasts undergo rapid growth and development under the influence of sex hormones. Although the hormonal etiology of breast cancer is hypothesized, it remains unknown whether adolescent sex hormones are associated with adult breast density, which is a strong risk factor for breast cancer.
Percentage of dense breast volume (%DBV) was measured in 2006 by magnetic resonance imaging in 177 women aged 25-29 years who had participated in the Dietary Intervention Study in Children from 1988 to 1997. They had sex hormones and sex hormone-binding globulin (SHBG) measured in serum collected on one to five occasions between 8 and 17 years of age. Multivariable linear mixed-effect regression models were used to evaluate the associations of adolescent sex hormones and SHBG with %DBV.
Dehydroepiandrosterone sulfate (DHEAS) and SHBG measured in premenarche serum samples were significantly positively associated with %DBV (all P trend ≤0.03) but not when measured in postmenarche samples (all P trend ≥0.42). The multivariable geometric mean of %DBV across quartiles of premenarcheal DHEAS and SHBG increased from 16.7 to 22.1 % and from 14.1 to 24.3 %, respectively. Estrogens, progesterone, androstenedione, and testosterone in pre- or postmenarche serum samples were not associated with %DBV (all P trend ≥0.16).
Our results suggest that higher premenarcheal DHEAS and SHBG levels are associated with higher %DBV in young women. Whether this association translates into an increased risk of breast cancer later in life is currently unknown.
ClinicalTrials.gov Identifier, NCT00458588 April 9, 2007; NCT00000459 October 27, 1999.

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On April 19, 2016 Endocyte, Inc. (NASDAQ:ECYT), a leader in developing targeted small molecule drug conjugates (SMDCs) and companion imaging agents for personalized therapy, reported in a late-breaking poster session the presentation of new research from investigators and faculty at the Purdue University Center for Drug Discovery on the application of Endocyte’s SMDC technology in a chimeric antigen receptor (CAR) therapy setting (Poster #LB-254 – A Universal Remedy for CAR T cell limitations) at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 in New Orleans (Press release, Endocyte, APR 19, 2016, View Source [SID:1234511043]).

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"This technology and these data reflect a potentially significant advance in overcoming several challenges specific to CAR therapies as well as the powerful versatility of Endocyte’s SMDC platform," said Ron Ellis, president and CEO at Endocyte. "This is still in the early stages of research, and we look forward to our continued collaboration with Phil Low and his lab at the Purdue Drug Discovery Center to further explore the potential of this CAR therapeutic approach as we look to build our SMDC platform in immuno-oncology."

The presentation discusses a novel approach that makes possible the engineering of a single universal CAR T cell, which binds with extraordinarily high affinity to a benign molecule designated as FITC. These cells are then used to treat various cancer types when co-administered with bispecific SMDC adaptor molecules. These unique bispecific adaptors are constructed with a FITC molecule and a tumor-homing molecule to precisely bridge the universal CAR T cell with the cancer cells, which causes localized T cell activation. Data in this poster show that anti-tumor activity in mice is induced only when both the universal CAR T cells plus the correct antigen-specific adaptor molecules are present. Findings also show that anti-tumor activity and toxicity can be sensitively controlled by adjusting the dosing of the administered adaptor molecule. Furthermore, treatment of antigenically heterogeneous tumors can be achieved by administration of a mixture of the desired antigen-specific adaptors. Thus, several challenges of current CAR T cell therapies, such as i) the inability to control the rate of cytokine release and tumor lysis, ii) the absence of an "off switch" that can terminate cytotoxic activity when tumor eradication is complete, and iii) a requirement to generate a different CAR T cell for each unique tumor antigen, may be solved or mitigated using this novel universal CAR T cell approach.

"Through our strong, ongoing collaboration with Endocyte, we are optimistic that this exciting approach might advance the enormous potential of CAR T cell therapies to benefit patients in truly meaningful ways," said Phil Low, Ph.D., professor of chemistry and director of the Center for Drug Discovery at Purdue University. Dr. Low is the chief scientific officer, a board member and founder of Endocyte.

Endocyte and Purdue University have an exclusive agreement to research, develop and commercialize SMDC therapeutics and companion imaging agents for the treatment of disease through a long-standing partnership with Dr. Low and Purdue University. Endocyte holds the global rights to the CAR and SMDC adaptors for all indications. Additionally, Endocyte and Purdue University jointly own this technology, which is covered by both allowed and pending patent applications.

Jasmonates are plant lipid-derived oxylipins that act as key signaling compounds in plant immunity, germination, and development. Although some physiological activities of natural jasmonates in mammalian cells have been investigated, their anti-inflammatory actions in mammalian cells remain unclear. Here, we investigated whether jasmonates protect mouse microglial MG5 cells against lipopolysaccharide (LPS)-induced inflammation. Among the jasmonates tested, only 12-oxo-phytodienoic acid (OPDA) suppressed LPS-induced expression of the typical inflammatory cytokines interleukin-6 and tumor necrosis factor α. In addition, only OPDA reduced LPS-induced nitric oxide production through a decrease in the level of inducible nitric oxide synthase. Further mechanistic studies showed that OPDA suppressed neuroinflammation by inhibiting nuclear factor κB and p38 mitogen-activated protein kinase signaling in LPS-activated MG5 cells. In addition, OPDA induced expression of suppressor of cytokine signaling-1, a negative regulator of inflammation, in MG5 cells. Finally, we found that the nuclear factor erythroid 2-related factor 2 signaling cascade induced by OPDA is not involved in the anti-inflammatory effects of OPDA. These results demonstrate that OPDA inhibited LPS-induced cell inflammation in mouse microglial cells via multiple pathways, including suppression of nuclear factor κB, inhibition of p38, and activation of SOCS-1 signaling.
Copyright © 2016. Published by Elsevier Inc.

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On April 19, 2016 Innate Pharma and OREGA Biotech today presented preclinical data on IPH52, a new CD39 checkpoint inhibitor program, at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 in New Orleans, Louisiana, USA (Press release, Innate Pharma, APR 19, 2016, View Source [SID:1234511088]).

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Poster #3222 presents IPH52, Innate’s humanized anti-CD39 blocking antibody. This novel antibody exhibits high affinity and specificity for CD39 and potently inhibits ATPase activity in in vitro assays and ex vivo models with patient biopsies. In a murine tumor model, treatment with anti-CD39 antibody results in a significant decrease in tumor volume, and improved survival.

Poster #3218 presents for the first time the impact of CD39 disruption on the efficacy of other cancer therapeutics by comparing their effects in wildtype versus CD39 knock-out mice. The results revealed that CD39 deficiency sensitized to anti-PD1 treatment in animals that failed to respond to anti-PD-1 treatment. The antitumor efficacy of CD39 disruption is further improved when combined with an immunogenic chemotherapy. In animals bearing PD-1 insensitive tumors, combination of immunogenic chemotherapy, anti-PD1 antibody and CD39 disruption led to complete tumor eradication and long term protection (specific anti-tumor immunity) in most animals. The efficacy of an ADCC-inducing cytotoxic antibody was also improved in CD39 knock-out mice compared to wildtype.

Nicolai Wagtmann, CSO of Innate Pharma, said: "Taken together, the data presented by Innate and our partner OREGA Biotech form a very promising body of evidence supporting the development of this new, first-in-class checkpoint inhibitor antibody. The results presented today raise exciting perspectives for the development of IPH52, both as single-agent and in combination with other checkpoint inhibitors, and we are eager to now take this first-in-class candidate forward into the preclinical development phases".

Jeremy Bastid, COO of OREGA Biotech, further commented: "CD39 mediates immunosuppression through a different mechanism than other immune checkpoints and may broadly impede the efficacy of cancer therapies. The exciting data released today using both antibody blockade and genetic CD39 deficiency shed light on the capacity of CD39 disruption to drive antitumor immune responses, either alone or in combination with PD-1 checkpoint blockers, ADCC antibodies and immunogenic chemotherapy, suggesting broad development potential".

Based on the central role of the ubiquitin-proteasome system (UPS) in the degradation of cellular proteins, proteasome inhibition has been considered an attractive approach for anticancer therapy. Deubiquitinases (DUBs) remove ubiquitin conjugates from diverse substrates; therefore, they are essential regulators of the UPS. DUB inhibitors, especially the inhibitors of proteasomal DUBs are becoming a research hotspot in targeted cancer therapy. Previous studies have shown that metal complexes, such as copper and zinc complexes, can induce cancer cell apoptosis through inhibiting UPS function. Moreover, we have found that copper pyrithione inhibits both 19S proteasome-associated DUBs and 20S proteasome activity with a mechanism distinct from that of the classical 20S proteasome inhibitor bortezomib. In the present study, we reveal that (i) nickel pyrithione complex (NiPT) potently inhibits the UPS via targeting the 19S proteasome-associated DUBs (UCHL5 and USP14), without effecting on the 20S proteasome; (ii) NiPT selectively induces proteasome inhibition and apoptosis in cultured tumor cells and cancer cells from acute myeloid leukemia human patients; and (iii) NiPT inhibits proteasome function and tumor growth in nude mice. This study, for the first time, uncovers a nickel complex as an effective inhibitor of the 19S proteasomal DUBs and suggests a potentially new strategy for cancer treatment.Oncogene advance online publication, 18 April 2016; doi:10.1038/onc.2016.114.

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