Phagocytosis is an initial step in innate immunity, which is also stimulated by signals via Toll-like receptors (TLRs); however, the cooperation of phagocytosis with signals through TLRs to establish acquired immunity is unknown. We found that phagocytosis is an essential process to induce an immune reaction against an insoluble TLR ligand. Cell-wall skeleton prepared from Mycobacterium bovis BCG (BCG-CWS), an insoluble TLR2 ligand, activated and matured murine splenic dendritic cell (DC) line BC-1 as well as a soluble TLR2 ligand, Pam3CSK4. Surprisingly, BC-1 maturation with BCG-CWS was completely suppressed by inhibiting phagocytosis, while that with Pam3CSK4 was not affected. Moreover, BCGCWS induced intense delayed-type hypersensitivity (DTH) reactions against mitomycin C-inactivated Lewis lung carcinoma cells but Pam3CSK4 did not. These results suggested that the phagocytosis process enables the insoluble TLR2 ligand to activate DCs via TLR2 comparable to a soluble TLR2 ligand in vitro, and stimulating TLR2 alone is not sufficient to establish T cell-mediated immunity in vivo. It is therefore conceivable that the process of phagocytosis induces additional effects on TLR2-stimulated DCs to activate cellmediated immunity in vivo.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The androgen receptor (AR) is a member of the nuclear hormone receptor super family of transcription factors. Androgens play an essential role in the development, growth, and maintenance of male sex organs, as well as the musculoskeletal and central nervous systems. Yet with advancing age, androgens can drive the onset of prostate cancer, the second leading cause of cancer death in males within the United States. Androgen deprivation therapy (ADT) by pharmacologic and/or surgical castration induces apoptosis of prostate cells and subsequent shrinkage of the prostate and prostate tumors. However, ADT is associated with significant musculoskeletal and behavioral adverse effects. The unique pharmacological activity of selective androgen receptor modulator (SARM) MK-4541 recently has been reported as an AR antagonist with 5α-reductase inhibitor function. The molecule inhibits proliferation and induces apoptosis in AR positive, androgen dependent prostate cancer cells. Importantly, MK-4541 inhibited androgen-dependent prostate growth in male rats yet maintained lean body mass and bone formation following ovariectomy in female rats. In the present study, we evaluated the effects of SARM MK-4541 in the androgen-dependent Dunning R3327-G prostate carcinoma xenograft mouse model as well as on skeletal muscle mass and function, and AR-regulated behavior in mice. MK-4541 significantly inhibited the growth of R3327-G prostate tumors, exhibited anti-androgen effects on the seminal vesicles, reduced plasma testosterone concentrations in intact males, and inhibited Ki67 expression. MK-4541 treated xenografts appeared similar to xenografts in castrated mice. Importantly, we demonstrate that MK-4541 exhibited anabolic activity in androgen deficient conditions, increasing lean body mass and muscle function in adult castrated mice. Moreover, MK-4541 treatment restored general activity levels in castrated mice. Thus, MK-4541 exhibits an optimum profile as an adjuvant therapy to ADT which may provide potent anti-androgenic activity at the prostate yet protective activity on skeletal muscle and behavior in patients.
Copyright © 2016. Published by Elsevier Ltd.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The objective of this study was to compare rates of nephrectomy (Nx) in, and characteristics of, patients with metastatic renal cell carcinoma (mRCC) enrolled in prospective clinical trials of tyrosine kinase inhibitors (TKIs) that were completed through (Group 1) versus after (Group 2) 2007.
Searching online databases, we retrospectively identified phase I to III trials with ≥ 15 patients with mRCC treated with first-line TKIs, alone or in combination with other agent(s).
Of 70 trials identified, 42 were included in the analysis (n = 6074 patients). Compared with Group 1, Group 2 patients had significantly less Nx (85.7% vs. 93.7%; P < .001) and prior cytokine therapy (11.1% vs. 46.8%; P < .001). Group 2 also had significantly fewer patients with good prognostic risk (based on Memorial Sloan-Kettering Cancer Center criteria) or performance status (both P < .001). Group 2 patients had a significantly greater objective response rate than Group 1 patients (intent-to-treat analysis: 28.6% vs. 23.1%, respectively; P < .001), whereas Group 1 patients had significantly more stable disease. Clinical benefit was similar in both groups (P = .157), and the means of median progression-free survival were comparable (8.2 and 9.0 months in Groups 1 and 2, respectively; P = .2528).
Use of Nx in mRCC patients participating in clinical trials has declined in the TKI era. More patients with worse prognostic risk profiles are participating in first-line TKI trials after 2007, but objective response rates are higher. Despite patient characteristics that favor the earlier group, progression-free survival is similar as TKIs have replaced cytokines as first-line therapy.
Copyright © 2016 Elsevier Inc. All rights reserved.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Ischemic stroke, which is mainly caused by thromboembolic occlusion of brain arteries, is the second leading cause of death and disability worldwide with limited treatment options. The platelet collagen receptor glycoprotein VI is a key player in arterial thrombosis and a critical determinant of stroke outcome, making its signaling pathway an attractive target for pharmacological intervention. The spleen tyrosine kinase (Syk) is an essential signaling mediator downstream of not only GPVI but also other platelet and immune cell receptors. We sought to assess whether Syk might be an effective antithrombotic target.
We demonstrate that mice lacking Syk in platelets specifically are protected from arterial thrombus formation and ischemic stroke but display unaltered hemostasis. Furthermore, we show that mice treated with the novel, selective, and orally bioavailable Syk inhibitor BI1002494 were protected in a model of arterial thrombosis and had smaller infarct sizes and a significantly better neurological outcome 24 hours after transient middle cerebral artery occlusion, also when BI1002494 was administered therapeutically, that is, after ischemia.
These results provide direct evidence that pharmacological Syk inhibition might provide a safe therapeutic strategy to prevent arterial thrombosis and to limit infarct progression in acute stroke.
© 2016 American Heart Association, Inc.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Menopausal symptoms (eg, hot flushes and vaginal symptoms) are common, often bothersome, and can adversely impact women’s sexual functioning, relationships, and quality of life. Estrogen-progestin therapy was previously considered the standard care for hormone therapy (HT) for managing these symptoms in nonhysterectomized women, but has a number of safety and tolerability concerns (eg, breast cancer, stroke, pulmonary embolism, breast pain/tenderness, and vaginal bleeding) and its use has declined dramatically in the past decade since the release of the Women’s Health Initiative trial results. Conjugated estrogens paired with bazedoxifene (CE/BZA) represent a newer progestin-free alternative to traditional HT for nonhysterectomized women. CE/BZA has demonstrated efficacy in reducing the frequency and severity of vasomotor symptoms and preventing loss of bone mineral density in postmenopausal women. CE/BZA provides an acceptable level of protection against endometrial hyperplasia and does not increase mammographic breast density. Compared with traditional estrogen-progestin therapy, it is associated with lower rates of breast pain/tenderness and vaginal bleeding. Patient-reported outcomes indicate that CE/BZA improves menopause-specific quality of life, sleep, some measures of sexual function (especially ease of lubrication), and treatment satisfaction. This review looks at the rationale for selection and combination of CE with BZA at the dose ratio in the approved product and provides a detailed look at the efficacy, safety, tolerability, and patient-reported outcomes from the five Phase III trials. Patient considerations in the choice between CE/BZA and traditional HT (eg, tolerability, individual symptoms, and preferences for route of administration) are also considered.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!