Myc and Mammary Cancer: Myc is a Downstream Effector of the ErbB2 Receptor Tyrosine Kinase

The proto-oncogene c-myc encodes a transcription factor which plays a major role in the regulation of normal cellular proliferation and is aberrantly expressed in many breast tumors. In a normal cell Myc expression levels are tightly regulated being subject to many layers of control. Errantly expressed Myc collaborates with other oncogenes to promote transformation. In this review we will focus on the association between abnormal Myc expression and mammary cancer. In particular, we will discuss the role of Myc as a downstream effector of the ErbB2 receptor tyrosine kinase which is overexpressed and constitutively activate in many mammary tumors. The cooperation between Myc and ErbB2 in transformation will be discussed in relation to clinical studies on Myc in human cancer and with consideration of transgenic models of Myc-induced mammary cancer. Data from our laboratory will be presented showing that deregulated ErbB2 activity strongly stimulates cytoplasmic signaling pathways which in turn impinge on Myc at multiple levels causing its deregulated expressio

Myc and Mammary Cancer: Myc is a Downstream Effector of the ErbB2 Receptor Tyrosine Kinase

The proto-oncogene c-myc encodes a transcription factor which plays a major role in the regulation of normal cellular proliferation and is aberrantly expressed in many breast tumors. In a normal cell Myc expression levels are tightly regulated being subject to many layers of control. Errantly expressed Myc collaborates with other oncogenes to promote transformation. In this review we will focus on the association between abnormal Myc expression and mammary cancer. In particular, we will discuss the role of Myc as a downstream effector of the ErbB2 receptor tyrosine kinase which is overexpressed and constitutively activate in many mammary tumors. The cooperation between Myc and ErbB2 in transformation will be discussed in relation to clinical studies on Myc in human cancer and with consideration of transgenic models of Myc-induced mammary cancer. Data from our laboratory will be presented showing that deregulated ErbB2 activity strongly stimulates cytoplasmic signaling pathways which in turn impinge on Myc at multiple levels causing its deregulated expressio

Equivalent benefit of mTORC1 blockade and combined PI3K-mTOR blockade in a mouse model of tuberous sclerosis

<p>Abstract</p> <p>Background</p> <p>Tuberous sclerosis (TSC) is a hamartoma syndrome in which renal and lung tumors cause the greatest morbidity. Loss of either TSC1 or TSC2 in TSC hamartomas leads to activation of mTORC1 and suppression of AKT. Recent studies indicate that inhibition of mTORC1 with RAD001 (everolimus) leads to rebound activation of AKT, which could protect tumors from drug-induced cell death. Here we examine the potential benefit of inhibition of both mTOR and AKT signaling in a mouse model of TSC, using a dual pan class I PI3K/mTOR catalytic small molecule inhibitor NVP-BEZ235.</p> <p>Results</p> <p>Using ENU to enhance <it>Tsc2</it>^+-kidney tumor development, both RAD001 (10 mg/kg PO 5 d/week) and NVP-BEZ235 (45 mg/kg PO QD) had equivalent effects in suppressing tumor development during a 4 week treatment period, with a 99% reduction in tumor cell mass. Marked reduction in activation of mTORC1, induction of cell cycle arrest, and absence of apoptotic cell death was seen in mice treated with either drug. However, when either was discontinued, there was prompt recovery of tumor growth, with extensive proliferation.</p> <p>Conclusion</p> <p>Both mTORC1 blockade alone and combined PI3K-mTOR blockade lead to suppression of tumor development but not tumor elimination in this TSC model.</p

Response of a neuronal model of tuberous sclerosis to mammalian target of rapamycin (mTOR) inhibitors: Effects on mTORC1 and Akt signaling lead to improved survival and function

Tuberous sclerosis (TSC) is a hamartoma syndrome due to mutations in either TSC1 or TSC2 in which brain involvement causes epilepsy, mental retardation, and autism. We have recently reported (Meikle et al., J Neurosci 2007) a mouse neuronal model of TSC in which Tsc1 is ablated in most neurons during cortical development. We have tested rapamycin and RAD001, both mTORC1 inhibitors, as potential therapeutic agents in this model. Median survival is improved from 33 days to over 100 days; behavior, phenotype, and weight gain are all also markedly improved. There is brain penetration of both drugs, with accumulation over time with repetitive treatment, and effective reduction of levels of phospho-S6, a downstream target of mTORC1. In addition, there is restoration of phospho-Akt and phospho-GSK3 levels in the treated mice, consistent with restoration of Akt function. Neurofilament abnormalities, myelination, and cell enlargement are all improved by the treatment. However, dysplastic neuronal features persist, and there are only modest changes in dendritic spine density and length. Strikingly, mice treated with rapamycin or RAD001 for 23 days only (P7 — P30) displayed a persistent improvement in phenotype with median survival of 78 days. In summary, rapamycin/RAD001 are highly effective therapies for this neuronal model of TSC, with benefit apparently due to effects on mTORC1 and Akt signaling, and consequently cell size and myelination. Although caution is appropriate, the results suggest the possibility that rapamycin/RAD001 may have benefit in the treatment of TSC brain disease, including infantile spasms

An Introduction to Psychological Statistics

This work has been superseded by Introduction to Statistics in the Psychological Sciences available from https://irl.umsl.edu/oer/25/. - We are constantly bombarded by information, and finding a way to filter that information in an objective way is crucial to surviving this onslaught with your sanity intact. This is what statistics, and logic we use in it, enables us to do. Through the lens of statistics, we learn to find the signal hidden in the noise when it is there and to know when an apparent trend or pattern is really just randomness. The study of statistics involves math and relies upon calculations of numbers. But it also relies heavily on how the numbers are chosen and how the statistics are interpreted. This work was created as part of the University of Missouri’s Affordable and Open Access Educational Resources Initiative (https://www.umsystem.edu/ums/aa/oer). The contents of this work have been adapted from the following Open Access Resources: Online Statistics Education: A Multimedia Course of Study (http://onlinestatbook.com/). Project Leader: David M. Lane, Rice University. Changes to the original works were made by Dr. Garett C. Foster in the Department of Psychological Sciences to tailor the text to fit the needs of the introductory statistics course for psychology majors at the University of Missouri – St. Louis. Materials from the original sources have been combined, reorganized, and added to by the current author, and any conceptual, mathematical, or typographical errors are the responsibility of the current author

The mTOR Inhibitor RAD001 Sensitizes Tumor Cells to DNA-Damaged Induced Apoptosis through Inhibition of p21 Translation

SummaryAlthough DNA damaging agents have revolutionized chemotherapy against solid tumors, a narrow therapeutic window combined with severe side effects has limited their broader use. Here we show that RAD001 (everolimus), a rapamycin derivative, dramatically enhances cisplatin-induced apoptosis in wild-type p53, but not mutant p53 tumor cells. The use of isogenic tumor cell lines expressing either wild-type mTOR cDNA or a mutant that does not bind RAD001 demonstrates that the effects of RAD001 are through inhibition of mTOR function. We further show that RAD001 sensitizes cells to cisplatin by inhibiting p53-induced p21 expression. Unexpectedly, this effect is attributed to a small but significant inhibition of p21 translation combined with its short half-life. These findings provide the molecular rationale for combining DNA damaging agents with RAD001, showing that a general effect on a major anabolic process may dramatically enhance the efficacy of an established drug protocol in the treatment of cancer patients with solid tumors

Recommendations for Child Care Centers

Design guide for planning, programming and designing different types of child care facilities. Includes 115 patterns for the policy, planning and design of large centers, neighborhood centers and family day-care homes. Based on current research information. Highly illustrated with photographs and sketches. Received an Award for Applied Research from Progressive Architecture, 1980, and received the 1980 UWM Foundation Research Award. Reprinted 1981, with new photographs in 1984, 1988 and in 1991. Revised edition 1994.https://dc.uwm.edu/caupr_mono/1032/thumbnail.jp

Safety and anti-tumor activity of lisavanbulin administered as 48-hour infusion in patients with ovarian cancer or recurrent glioblastoma: a phase 2a study

Lisavanbulin (BAL101553) is the prodrug of avanbulin (BAL27862), a microtubule-destabilizing agent. The goal of this study (NCT02895360) was to characterize the safety, tolerability and antitumor activity of lisavanbulin administered as a 48-hour intravenous (IV) infusion at the recommended Phase 2 dose (RP2D) of 70 mg/m$^{2}$. Results from the Phase 1 dose-escalation portion of the study identifying the RP2D have been previously reported. Here, we present the findings from the Phase 2a portion of this study. Methods. This multi-center, open-label study included patients with ovarian, fallopian-tube, or primary peritoneal cancer that was either platinum-resistant or refractory (11 patients), or with first recurrence of glioblastoma (12 patients). Lisavanbulin was administered as a 48-hour IV infusion on Days 1, 8, and 15 of a 28-day cycle. Results. Lisavanbulin was well tolerated in both patient cohorts. Thirteen patients (56.5%) developed 49 adverse events assessed as related to study treatment. The majority were mild or moderate; four were grade 3/4. Sixteen SAEs were reported in nine patients (39.1%), with none considered related to study treatment. No AEs led to permanent treatment discontinuation. Three patients in the ovarian cancer cohort had stable disease with lesion size reductions after two cycles of treatment; in the glioblastoma cohort, one patient showed partial response with a > 90% glioblastoma area reduction as best response, and one patient had stable disease after eight cycles of treatment. Conclusion. This study demonstrated a favorable safety and tolerability profile of 48-hour continuous IV infusion of lisavanbulin in patients with solid extracranial tumors or glioblastoma

Humanising medicine: teaching on tri-morbidity using expert patient narratives in medical education

Expert patients have recognised benefits for both students and patients in medical education. However, marginalised patients such as homeless patients are less likely to participate. Learning from such individuals is crucial for future doctors, who can, in turn, aid their inclusion in society and improve access to health care. A 'humanising medicine' lecture was delivered to Year Four medical students at Norwich Medical School. The lecture utilised narratives from patients with experience of homelessness and tri-morbidity (physical and mental health problems and substance abuse). We used a qualitative approach to evaluate this teaching and understand the experience of both students and patients. Students were asked to complete questionnaires, whereas expert patients were interviewed. We thematically analysed data using an inductive approach. Students reported an increased understanding, empathy and preparedness to consult with marginalised patients. Expert patients described positive feelings about their involvement, giving something back, and the therapeutic benefits of telling their story. We found that including marginalised patients in medical education had positive benefits for both students and patients. Our findings suggest that expert patient narratives are valuable in medical education particularly in teaching and learning about medical complexity and tri-morbidity