Loss of periostin/OSF-2 in ErbB2/Neu-driven tumors results in androgen receptor-positive molecular apocrine-like tumors with reduced Notch1 activity

INTRODUCTION: Periostin (Postn) is a secreted cell adhesion protein that activates signaling pathways to promote cancer cell survival, angiogenesis, invasion, and metastasis. Interestingly, Postn is frequently overexpressed in numerous human cancers, including breast, lung, colon, pancreatic, and ovarian cancer.METHODS: Using transgenic mice expressing the Neu oncogene in the mammary epithelium crossed into Postn-deficient animals, we have assessed the effect of Postn gene deletion on Neu-driven mammary tumorigenesis.RESULTS: Although Postn is exclusively expressed in the stromal fibroblasts of the mammary gland, Postn deletion does not affect mammary gland outgrowth during development or pregnancy. Furthermore, we find that loss of Postn in the mammary epithelium does not alter breast tumor initiation or growth in mouse mammary tumor virus (MMTV)-Neu expressing mice but results in an apocrine-like tumor phenotype. Surprisingly, we find that tumors derived from Postn-null animals express low levels of Notch protein and Hey1 mRNA but increased expression of androgen receptor (AR) and AR target genes. We show that tumor cells derived from wild-type animals do not proliferate when transplanted in a Postn-null environment but that this growth defect is rescued by the overexpression of active Notch or the AR target gene prolactin-induced protein (PIP/GCDFP-15).CONCLUSIONS: Together our data suggest that loss of Postn in an ErbB2/Neu/HER2 overexpression model results in apocrine-like tumors that activate an AR-dependent pathway. This may have important implications for the treatment of breast cancers involving the therapeutic targeting of periostin or Notch signaling

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo

Loss of antigen cross-presentation after complete tumor resection is associated with the generation of protective tumor-specific CD8+ T-cell immunity

An incomplete understanding on the effect of surgery on tumor-specific immunity continues to hamper efforts to combine surgery with immunotherapy in the clinic. Herein, we describe the impact of tumor resection on the tumor-specific T-cell response, showing that complete tumor resection is associated with (1) a decline in the amount of cross-presented tumor antigens, (2) a decline of cytolytic tumor-specific CD8+ T cell activity, and (3) the development of systemic CD8+ T cell-mediated protective immunity. Our findings are consistent with a model whereby tumor resection releases antitumor CD8+ T cells from chronic antigen exposure, allowing a gradual differentiation toward functional antitumor memory T cells. This process depends on sentinel lymph nodes, as their removal at the time of surgery was associated with a strong negative effect on survival. We conclude that complete tumor resection provides a unique environment that boosts protective immunological memory and might provide a powerful platform for immunotherapy. Our findings also carry important implications for the design and timing of post-surgery immunotherapeutic regimens

Agonistic anti-CD40 antibody therapy is effective against postoperative cancer recurrence and metastasis in a murine tumor model

Postresection recurrences of cancer arising from occult tumor deposits, either local or metastatic, represent major causes of death in patients with operable solid tumors. Thus, new therapies are required that complement existing treatments to eradicate these occult deposits. Agonistic anti-CD40 antibody is one of the most powerful new cancer immunotherapies, enhancing immune priming of effector CD8 T cells by dendritic cells, leading to increased antitumor activity. We investigated the use of anti-CD40 antibody for the treatment of postoperative recurrence and metastasis, with regional lymphadenectomy, in a murine model of cancer. Subcutaneous AB1-HA mesothelioma tumors were induced in BALB/c mice. Established tumors were surgically excised on day 16, with or without sentinel lymph node removal. On the day of surgery, animals were rechallenged with AB1-HA tumor cells at the surgical site (local recurrence) or the opposite flank (metastasis). Postoperative tumors were treated with anti-CD40 (FGK45) on emergence, delivered either intratumorally, peritumorally, or systemically. Local or systemic anti-CD40 treatment slowed postsurgical metastatic growth relative to untreated controls (P=0.020) and improved survival from metastasis. Anti-CD40 also retarded the growth of local recurrences (P=0.004) and improved survival from recurrence. Sentinel lymph node dissection did not impair efficacy (P>0.05). This study demonstrates that anti-CD40 therapy, given either locally or systemically, may be a powerful and readily translatable adjuvant to cancer surgery, including in cases where regional lymphadenectomy is indicated

To manage inland fisheries is to manage at the social-ecological watershed scale

Approaches to managing inland fisheries vary between systems and regions but are often based on large-scale marine fisheries principles and thus limited and outdated. Rarely do they adopt holistic approaches that consider the complex interplay among humans, fish, and the environment. We argue that there is an urgent need for a shift in inland fisheries management towards holistic and transdisciplinary approaches that embrace the principles of social-ecological systems at the watershed scale. The interconnectedness of inland fisheries with their associated watershed (biotic, abiotic, and humans) make them extremely complex and challenging to manage and protect. For this reason, the watershed is a logical management unit. To assist management at this scale, we propose a framework that integrates disparate concepts and management paradigm