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Targeting KRAS downstream signaling remains an important therapeutic approach in pancreatic cancer. We used primary pancreatic ductal epithelial cells and mouse models allowing the conditional expression of oncogenic Kras G12D , to investigate KRAS signaling integrators. We observed that the AP1 family member FRA1 is tightly linked to the KRAS signal and expressed in pre-malignant lesions and the basal-like subtype of pancreatic cancer. However, genetic-loss-of-function experiments revealed that FRA1 is dispensable for Kras G12D -induced pancreatic cancer development in mice. Using FRA1 gain- and loss-of-function models in an unbiased drug screen, we observed that FRA1 is a modulator of the responsiveness of pancreatic cancer to inhibitors of the RAF–MEK–ERK cascade. Mechanistically, context-dependent FRA1-associated adaptive rewiring of oncogenic ERK signaling was observed and correlated with sensitivity to inhibitors of canonical KRAS signaling. Furthermore, pharmacological-induced degradation of FRA1 synergizes with MEK inhibitors. Our studies establish FRA1 as a part of the molecular machinery controlling sensitivity to MAPK cascade inhibition allowing the development of mechanism-based therapies.

KLK9, 10, 11, and 15 may represent potential cancer biomarkers for evaluating ovarian cancer prognosis. In the present study, we selected a homogeneous cohort including 139 patients of advanced high-grade serous ovarian cancer (FIGO stage III/IV) and assessed the mRNA levels of KLK9, 10, 11, and 15 in tumor tissue by quantitative PCR. No significant associations of KLK9, 10, 11, and 15 mRNA with established clinical parameters (residual tumor mass, ascitic fluid volume) were found. Pronounced correlations between KLK10/KLK11 (rs = 0.647) and between KLK9/KLK15 (rs = 0.716) mRNA, but not between other combinations, indicate coordinate expression of distinct pairs of peptidases. In univariate Cox regression analysis, elevated KLK11 mRNA levels were significantly linked with prolonged overall survival (OS; p = 0.021) and progression-free survival (PFS; p = 0.008). KLK15 mRNA levels showed a trend towards significance in case of OS (p = 0.06); KLK9 and KLK10 mRNA expression levels were not associated with patients' outcome. In multivariable Cox analysis, KLK11 mRNA expression levels, apart from residual tumor mass, remained an independent predictive marker for OS (p = 0.007) and PFS (p = 0.015). Here, elevated KLK15 mRNA expression levels turned out to be significantly related to prolonged OS (p = 0.025) as well. High KLK11 but not the other KLK mRNA levels can be considered as strong independent favorable prognostic factor in this major ovarian cancer subtype.

Background Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors with a dismal prognosis and no effective conservative therapeutic strategies. Although it is demonstrated that histone deacetylases (HDACs), especially the class I HDACs HDAC1, 2 and 3 are highly expressed in this disease, little is known about HDAC isoenzyme specific functions. Results Depletion of HDAC2, but not HDAC1, in the pancreatic cancer cell lines MiaPaCa2 and Panc1 resulted in a marked sensitization towards the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Correspondingly, the more class I selective HDAC inhibitor (HDACI) valproic acid (VPA) synergized with TRAIL to induce apoptosis of MiaPaCa2 and Panc1 cells. At the molecular level, an increased expression of the TRAIL receptor 1 (DR5), accelerated processing of caspase 8, pronounced cleavage of the BH3-only protein Bid, and increased effector caspase activation was observed in HDAC2-depleted and TRAIL-treated MiaPaCa2 cells. Conclusions Our data characterize a novel HDAC2 function in PDAC cells and point to a strategy to overcome TRAIL resistance of PDAC cells, a prerequisite to succeed with a TRAIL targeted therapy in clinical settings.

Purpose Gene expression of a variety of the 15 members of the KLK serine protease family is dysregulated in ovarian cancer. We aimed at determining the clinical relevance of KLK13 and KLK14 mRNA expression in tumor tissues of a homogeneous patient cohort afflicted with advanced high-grade serous ovarian cancer (FIGO stage III/IV). Methods mRNA expression levels of KLK13 and KLK14 were assessed by quantitative PCR in tumor tissue of 91 patients and related with clinical factors and patients’ outcome. Results There was no significant association of KLK13 and KLK14 mRNA expression with the clinical factors ascitic fluid volume or residual tumor mass. In univariate Cox regression analysis, elevated KLK13 mRNA levels were significantly linked with shorter progression-free (PFS; hazard ratio [HR] = 1.97, P  = 0.020) and overall survival (OS; HR = 1.81, P  = 0.041). High KLK14 mRNA levels were significantly associated with prolonged PFS (HR = 0.44, P  = 0.017) and showed a trend towards significance for OS (HR = 0.55, P  = 0.070). In multivariable analysis, including the factors age, residual tumor mass, ascitic fluid volume, KLK13 , and KLK14 , both KLKs, apart from residual tumor mass, remained statistically independent predictive markers: patients with high KLK13 mRNA expression levels displayed a more than twofold increase risk for shorter PFS (HR = 2.14, P  = 0.020) as well as OS (HR = 2.05, P  = 0.028), whereas elevated KLK14 mRNA values were found to be significant for both, prolonged PFS (HR = 0.36, P  = 0.007) and OS (HR = 0.46, P  = 0.037). Conclusion These results indicate that in advanced high-grade serous ovarian cancer KLK13 may become proficient for tumor-supporting functions, whereas KLK14 may have adopted tumor-suppressing activity.

Epidermal growth factor receptor (EGFR) signaling has a critical role in oncogenic Kras-driven pancreatic carcinogenesis. However, the downstream targets of this signaling network are largely unknown. We developed a novel model system utilizing murine primary pancreatic ductal epithelial cells (PDECs), genetically engineered to allow time-specific expression of oncogenic Kras G12D from the endogenous promoter. We show that primary PDECs are susceptible to Kras G12D -driven transformation and form pancreatic ductal adenocarcinomas in vivo after Cdkn2a inactivation. In addition, we demonstrate that activation of Kras G12D induces an EGFR signaling loop to drive proliferation. Interestingly, pharmacological inhibition of EGFR fails to decrease Kras G12D -activated ERK or PI3K signaling. Instead our data provide novel evidence that EGFR signaling is needed to activate the oncogenic and pro-proliferative transcription factor c-MYC. EGFR and c-MYC have been shown to be essential for pancreatic carcinogenesis. Importantly, our data link both pathways and thereby explain the crucial role of EGFR for Kras G12D -driven carcinogenesis in the pancreas.

As [Chris] struggles to understand [Danelle], she reaches out for help from school counselors and other friends. She spends more time with her down-to-earth friend, Alana, and deepens her relationship with handsome Jack. Chris works towards her high school graduation while Danelle's risky behaviour continues and their friendship crumbles. Chris experiences frustration, helplessness and anger as she watches Danelle careen wildly between mania and depression. Chris is unsure about how to help Danelle, but she receives her best advice from Jack: \"You're a great friend Chris,\" he tells me. \"Just stick close and let her know that you're there for her.\"

Hi-lo books, aka high interest low vocabulary books, absolutely must have that first ingredient high interest if they are to have any hope of keeping reluctant readers actually reading. Because Play On lacks a strong central focus, it will likely lose many of its readers as they search for something to sustain their interest. Alecia Parker, almost 14, plays for the Burrards, a Vancouver soccer team that is coached by her stepfather, Jeremy, who has just recently also become her adoptive father. Two of Alecia's friends, Conner and Laurie, are dating, but Conner believes that Laurie, who is also Alecia's teammate on the Burrards, wants to break up with him, and Alecia finds herself in the middle, not wanting to have to choose between them. Alecia becomes involved in yet another romance as a further teammate and friend, Anne Yeung, wishes to see a boy, Tyler, romantically but knows her father would not approve of her dating.

The realistic plot unfolds through the eyes of Alecia, a 13-year-old entering Grade 8. She is very fortunate to have a good friend, Connor, and another friend, Annie, who tests their friendship by daring to pursue different interests. Alecia's mom and new stepdad are very understanding and are the most patient, supportive parents. She receives good advice and loving support in her internal and external struggles. The test for her new attitude occurs during the weekend soccer tournament. Her oldest friend, Connor, seems more interested in her teammate, Laurie. Alecia feels lost and bereft. New faces and commitment carry Alecia through to a new reality. It's OK to move on and be different - and to keep the best of the past, too. It's called growing up.

Caitlynn's role in her family changes as a result of her grandfather's stroke. When Grandpa becomes frustrated with his recovery process, it is Caitlynn this time who must remind him of their deal to both work hard to get better. Also, when Grandpa is no longer available to help Caitlynn with her homework, she asks her brother Colin for help. Instead of fighting with her brother, Caitlynn learns how to ask for help and to forge a new relationship with her brother who is also upset about his grandfather's state. Perhaps most importantly, Caitlynn learns to be patient with her mother. Instead of complaining and becoming angry at her mother when she is upset about her grandfather, Caitlynn realizes that her mother is also suffering. Caitlynn matures into a more thoughtful and understanding young woman. False Start follows a simple but believable plot line, and it should especially interest children who are interested in sports or animals. Caitlynn Sinclair is an energetic and passionate nine-year old in Grade 4 who lives with her mother and her older brother, Colin. Since Caitlynn's mother and father have separated and her father has moved away, Caitlynn's grandfather has also come to live with them in a suite in the basement. An injured Caitlynn resists joining the swim team at first because she loves soccer, but Grandpa promises to take her to each practice, and their relationship becomes even stronger as a result. Indeed, the theme that makes this book special is the relationship between Caitlynn and her grandfather. Through this relationship, Caitlynn learns about commitment, helping others, and how her role in the family is changing and becoming more important.

This fast-paced novel revolves around the conflict within the soccer team as well as some family and personal questions for [Alecia]. It places emphasis on many desirable values such as respect for others, empathy for another's situation, standing up for one's beliefs, loyalty, etc. Issues such as dealing with emotions around accepting and appreciating a stepparent versus loyalty to the birth parent are positively and sensitively incorporated into realistic situations. These provide modelling and food for thought for many readers.