Consequence of the tumor-associated conversion to cyclin D1b.

Clinical evidence suggests that cyclin D1b, a variant of cyclin D1, is associated with tumor progression and poor outcome. However, the underlying molecular basis was unknown. Here, novel models were created to generate a genetic switch from cyclin D1 to cyclin D1b. Extensive analyses uncovered overlapping but non-redundant functions of cyclin D1b compared to cyclin D1 on developmental phenotypes, and illustrated the importance of the transcriptional regulatory functions of cyclin D1b in vivo. Data obtained identify cyclin D1b as an oncogene, wherein cyclin D1b expression under the endogenous promoter induced cellular transformation and further cooperated with known oncogenes to promote tumor growth in vivo. Further molecular interrogation uncovered unexpected links between cyclin D1b and the DNA damage/PARP1 regulatory networks, which could be exploited to suppress cyclin D1b-driven tumors. Collectively, these data are the first to define the consequence of cyclin D1b expression on normal cellular function, present evidence for cyclin D1b as an oncogene, and provide pre-clinical evidence of effective methods to thwart growth of cells dependent upon this oncogenic variant

Status of the PALM-3000 high-order adaptive optics system

The PALM-3000 upgrade to the Palomar Adaptive Optics system on the 5.1 meter Hale telescope will deliver extreme adaptive optics correction in near-infrared wavelengths and diffraction-limited images in visible wavelengths. PALM-3000 will use a 3388-actuator tweeter and a 241-actuator woofer deformable mirror, a Shack-Hartmann wavefront sensor with selectable pupil sampling, and an innovative wavefront control computer based on a cluster of 17 graphics processing units to correct wavefront aberrations at scales as fine as 8.1 cm at the telescope pupil using natural guide stars. The system is currently undergoing integration and testing, with deployment at Palomar Observatory planned in early 2011. We present the detailed design of key aspects of the adaptive optics system, and the current status of the deformable mirror characterization, wavefront sensor performance, and testbed activities

Phase 1 dose-finding and pharmacokinetic study of eribulin-liposomal formulation in patients with solid tumours

Background: This phase 1 study examined the safety, tolerability, pharmacokinetics and preliminary efficacy of eribulin-liposomal formulation (eribulin-LF) in patients with advanced solid tumours. Methods:\ud Eligible patients with ECOG PS 0–1 were treated with eribulin-LF either on day 1 every 21 days (Schedule 1), or on days 1 and 15 every 28 days (Schedule 2). Doses ranged from 1.0 to 3.5 mg/m2, with dose escalation in a 3 + 3 design. The dose-expansion phase evaluated eribulin-LF in select tumour types. Primary objectives: maximum tolerated dose (MTD) and the recommended dose/schedule of eribulin-LF. Results: Totally, 58 patients were enroled (median age = 62 years). The MTD was 1.4 mg/m2 (Schedule 1) or 1.5 mg/m2 (Schedule 2), the latter dose selected for the dose-expansion phase. Dose-limiting toxicity (DLTs) in Schedule 1: hypophosphatemia and increased transaminase levels. DLTs in Schedule 2: stomatitis, increased alanine aminotransferase, neutropenia and febrile neutropenia. The pharmacokinetic profile of eribulin-LF showed a similar half-life to that of eribulin (~30 h), but with a 5-fold greater maximum serum concentration and a 40-fold greater area-under-the-curve. Eribulin-LF demonstrated clinical activity with approximately 10% of patients in both schedules achieving partial responses. Conclusions: Eribulin-LF was well tolerated with a favourable pharmacokinetic profile. Preliminary evidence of clinical activity in solid tumours was observed

DNA-PKcs-Mediated Transcriptional Regulation Drives Prostate Cancer Progression and Metastasis.

Emerging evidence demonstrates that the DNA repair kinase DNA-PKcs exerts divergent roles in transcriptional regulation of unsolved consequence. Here, in vitro and in vivo interrogation demonstrate that DNA-PKcs functions as a selective modulator of transcriptional networks that induce cell migration, invasion, and metastasis. Accordingly, suppression of DNA-PKcs inhibits tumor metastases. Clinical assessment revealed that DNA-PKcs is significantly elevated in advanced disease and independently predicts for metastases, recurrence, and reduced overall survival. Further investigation demonstrated that DNA-PKcs in advanced tumors is highly activated, independent of DNA damage indicators. Combined, these findings reveal unexpected DNA-PKcs functions, identify DNA-PKcs as a potent driver of tumor progression and metastases, and nominate DNA-PKcs as a therapeutic target for advanced malignancies

Status of the PALM-3000 high-order adaptive optics system

The PALM-3000 upgrade to the Palomar Adaptive Optics system on the 5.1 meter Hale telescope will deliver extreme adaptive optics correction in near-infrared wavelengths and diffraction-limited images in visible wavelengths. PALM-3000 will use a 3388-actuator tweeter and a 241-actuator woofer deformable mirror, a Shack-Hartmann wavefront sensor with selectable pupil sampling, and an innovative wavefront control computer based on a cluster of 17 graphics processing units to correct wavefront aberrations at scales as fine as 8.1 cm at the telescope pupil using natural guide stars. The system is currently undergoing integration and testing, with deployment at Palomar Observatory planned in early 2011. We present the detailed design of key aspects of the adaptive optics system, and the current status of the deformable mirror characterization, wavefront sensor performance, and testbed activities

Differential Impact of Tumor Suppressor Pathways on DNA Damage Response and Therapy-Induced Transformation in a Mouse Primary Cell Model

The RB and p53 tumor suppressors are mediators of DNA damage response, and compound inactivation of RB and p53 is a common occurrence in human cancers. Surprisingly, their cooperation in DNA damage signaling in relation to tumorigenesis and therapeutic response remains enigmatic. In the context of individuals with heritable retinoblastoma, there is a predilection for secondary tumor development, which has been associated with the use of radiation-therapy to treat the primary tumor. Furthermore, while germline mutations of the p53 gene are critical drivers for cancer predisposition syndromes, it is postulated that extrinsic stresses play a major role in promoting varying tumor spectrums and disease severities. In light of these studies, we examined the tumor suppressor functions of these proteins when challenged by exposure to therapeutic stress. To examine the cooperation of RB and p53 in tumorigenesis, and in response to therapy-induced DNA damage, a combination of genetic deletion and dominant negative strategies was employed. Results indicate that loss/inactivation of RB and p53 is not sufficient for cellular transformation. However, these proteins played distinct roles in response to therapy-induced DNA damage and subsequent tumorigenesis. Specifically, RB status was critical for cellular response to damage and senescence, irrespective of p53 function. Loss of RB resulted in a dramatic evolution of gene expression as a result of alterations in epigenetic programming. Critically, the observed changes in gene expression have been specifically associated with tumorigenesis, and RB-deficient, recurred cells displayed oncogenic characteristics, as well as increased resistance to subsequent challenge with discrete therapeutic agents. Taken together, these findings indicate that tumor suppressor functions of RB and p53 are particularly manifest when challenged by cellular stress. In the face of such challenge, RB is a critical suppressor of tumorigenesis beyond p53, and RB-deficiency could promote significant cellular evolution, ultimately contributing to a more aggressive disease

Therapeutic CDK46 inhibition in breast cancer and the importance of reestablishing cell cycle control through RB activation

A functional RB/E2F pathway is requisite for maintenance of genome integrity and orderly cell cycle progression. As such, functional inactivation of the RB/E2F signaling axis occurs in the majority of human cancers, resulting in a disconnect of mitogenic signaling from cell cycle regulation. At the most basic level, such functional inactivation results in increased rates of cell cycle progression. However, it is currently unknown how increased proliferation translates to biological consequence in regards to tumor initiation and progression. Herein, we have examined the ability of genetic RB loss to cooperate with several prominent oncogenes and promote characteristics relevant to human tumor biology. As described, the effects of RB1 deletion were highly context dependant and exacerbated in the presence of cellular stresses that occur during tumorigenesis. With an increased understanding of the importance of retaining a functional RB/E2F pathway, a small molecule CDK4/6 inhibitor was employed to determine the utility of RB activation in the treatment of breast cancer. Again, a varied requirement for RB/E2F/cyclin D activity was observed. While durable cytostatic response was achieved in specific settings, it was also observed that therapeutic bypass can be achieved through redundancies in cyclin/CDK biology. Furthermore, as CDK4/6 inhibitors are currently undergoing phase I/II clinical study there is a clear need to understand how they can cooperate with current standard of care therapies. Through combination exposure of breast cancer cells to CDK4/6 inhibition and chemotherapeutic agents which are known to require active cell cycle for maximal effect, it was observed that CDK4/6 inhibition could modify the acute cell cycle and biochemical response to chemotherapy. In response to gamma-irradiation, overall rates of DNA break repair were not altered. However, a significant shift to the use of error-prone DNA repair pathways was observed through RB-dependent decreases in Rad51 protein. Together, these data illustrate a context-dependant requirement for functional RB protein; a characteristic that can be exploited through the clinical application of CDK4/6 inhibitors. However, before such agents reach widespread clinical application, consideration of the proximal cell cycle and transcriptional effects of such agents much be undertaken to derive maximum therapeutic benefit

Immediate Effect of Couple Relationship Education on Low-Satisfaction Couples: A Randomized Clinical Trial Plus an Uncontrolled Trial Replication

Couple relationship education (RE) usually is conceived of as relationship enhancement for currently satisfied couples, with a goal of helping couples sustain satisfaction. However, RE also might be useful as a brief, accessible intervention for couples with low satisfaction. Two studies were conducted that tested whether couples with low relationship satisfaction show meaningful gains after RE. Study 1 was a three-condition randomized controlled trial in which 182 couples were randomly assigned to RELATE with Couple CARE (RCC), a flexible delivery education program for couples, or one of two control conditions. Couples with initially low satisfaction receiving RCC showed a moderate increase in relationship satisfaction (d = 0.50) relative to the control. In contrast, couples initially high in satisfaction showed little change and there was no difference between RCC and the control conditions. Study 2 was an uncontrolled trial of the Couple Coping Enhancement Training (CCET) administered to 119 couples. Couples receiving CCET that had initially low satisfaction showed a moderate increase in satisfaction (g = .44), whereas initially highly satisfied couples showed no change. Brief relationship education can assist somewhat distressed couples to enhance satisfaction, and has potential as a cost-effective way of enhancing the reach of couple intervention

Immediate effect of couple relationship education on low-satisfaction couples: a randomized clinical trial plus an uncontrolled trial replication

Couple relationship education (RE) usually is conceived of as relationship enhancement for currently satisfied couples, with a goal of helping couples sustain satisfaction. However, RE also might be useful as a brief, accessible intervention for couples with low satisfaction. Two studies were conducted that tested whether couples with low relationship satisfaction show meaningful gains after RE. Study 1 was a three-condition randomized controlled trial in which 182 couples were randomly assigned to RELATE with Couple CARE (RCC), a flexible delivery education program for couples, or one of two control conditions. Couples with initially low satisfaction receiving RCC showed a moderate increase in relationship satisfaction (d=0.50) relative to the control. In contrast, couples initially high in satisfaction showed little change and there was no difference between RCC and the control conditions. Study 2 was an uncontrolled trial of the Couple Coping Enhancement Training (CCET) administered to 119 couples. Couples receiving CCET that had initially low satisfaction showed a moderate increase in satisfaction (g=.44), whereas initially highly satisfied couples showed no change. Brief relationship education can assist somewhat distressed couples to enhance satisfaction, and has potential as a cost-effective way of enhancing the reach of couple interventions