The Search for Low Energy Conformational Families of Small Peptides: Searching for Active Conformations of Small Peptides in the Absence of a Known Receptor

Breast cancer is the most common cancer among women. Tamoxifen is the preferred drug for estrogen receptor-positive breast cancer treatment, yet many of these cancers are intrinsically resistant to tamoxifen or acquire resistance during treatment. Therefore, scientists are searching for breast cancer drugs that have different molecular targets. Previous work revealed that 8-mer and cyclic 9-mer peptides inhibit breast cancer in mouse and rat model systems, interacting with an unknown receptor, while peptides smaller than eight amino acids did not inhibit breast cancer. We have shown that the use of replica exchange molecular dynamics predicts structure and dynamics of active peptides, leading to the discovery of smaller peptides with full biological activity. These simulations identified smaller peptide analogs with a conserved turn, a β-turn formed in the larger peptides. These analogs inhibit estrogen-dependent cell growth in a mouse uterine growth assay, a test showing reliable correlation with human breast cancer inhibition. We outline the computational methods that were tried and used with the experimental information that led to the successful completion of this research.

Razor Thin Win: The 1972 Constitution Ballot, Campaign, Ratification & the Courts -- Mae Nan (Robinson) Ellingson & Mick McKeon “In the Crucible of Change”

Beyond the challenge of crafting a new state Constitution that empowered the people and modernized and opened up state and local government in Montana, the Constitutional Convention delegates, as they signed the final document, looked forward to the arduous task of getting it ratified by the electorate in a short ten week period between the end of the convention on March 24 and the ratification election of June 6, 1972. While all 100 delegates signed the draft Constitution, not all supported its adoption. But the planning about how to get it adopted went back to the actions of the Convention itself, which carefully crafted a ballot that kept “hot political issues” from potentially killing the entire document at the polls. As a result, three side issues were presented to the electorate on the ballot. People could vote for or against those side issues and still vote to ratify the entire document. Thus, the questions of legalizing gambling, having a unicameral legislature and retaining the death penalty were placed separately on the ballot (gambling passed, as did the retention of the death penalty, but the concept of a one-house legislature was defeated). Once the ballot structure was set, delegates who supported the new Constitution organized a grassroots, locally focused effort to secure ratification – thought hampered by a MT Supreme Court decision on April 28 that they could not expend $45,000 in public monies that they had set aside for voter education. They cobbled together about $10,000 of private money and did battle with the established political forces, led by the MT Farm Bureau, MT Stockgrowers’ Assn. and MT Contractors Assn., on the question of passage. Narrow passage of the main document led to an issue over certification and a Montana Supreme Court case challenging the ratification vote. After a 3-2 State Supreme Court victory, supporters of the Constitution then had to defend the election results again before the federal courts, also a successful effort. Montana finally had a new progressive State Constitution that empowered the people, but the path to it was not clear and simple and the win was razor thin. The story of that razor thin win is discussed in this chapter by the two youngest delegates to the 1972 Constitutional Convention, Mae Nan Ellingson of Missoula and Mick McKeon, then of Anaconda. Both recognized “Super Lawyers in their later professional practices were also significant players in the Constitutional Convention itself and actively participated in its campaign for ratification. As such, their recollections of the effort provide an insider’s perspective of the struggle to change Montana for the better through the creation and adoption of a new progressive state Constitution “In the Crucible of Change.” Mae Nan (Robinson) Ellingson was born Mae Nan Windham in Mineral Wells, TX and graduated from Mineral Wells High School in 1965 and Weatherford College in Weatherford, TX in 1967. Mae Nan was the youngest delegate at the 1972 Convention from Missoula. She moved to Missoula in 1967 and received her BA in Political Science with Honors from the University of MT in 1970. She was a young widow known by her late husband’s surname of Robinson while attending UM graduate school under the tutelage of noted Professor Ellis Waldron when he persuaded her to run for the Constitutional Convention. Coming in a surprising second in the delegate competition in Missoula County she was named one of the Convention’s “Ten Outstanding Constitutional Convention Delegates,” an impressive feat at such a young age. She was 24 at the time, the youngest person to serve at the ConCon, and one of 19 women out of 100 delegates. In the decade before the Convention, there were never more than three women Legislators in any session, usually one or two. She was a member of the American Association of University Women, a Pi Sigma Alpha political science honorary, and a Phi Alpha Theta historical honorary. At the Convention, she led proposals for the state's bill of rights, particularly related to equal rights for women. For years, Ellingson kept a copy of the preamble to the Constitution hanging in her office; while all the delegates had a chance to vote on the wording, she and delegate Bob Campbell are credited with the language in the preamble. During the convention, she had an opportunity that opened the door to her later career as an attorney. A convention delegate suggested to her that she should go to law school. Several offered to help, but at the time she couldn't go to school. Her mom had died in Texas, and she ended up with a younger brother and sister to raise in Missoula. She got a job teaching, but about a year later, intrigued with the idea of pursuing the law as a career, she called the man back to ask about the offer. Eventually another delegate, Dave Drum of Billings, sponsored her tuition at the UM School of Law. After receiving her JD with Honors (including the Law Review and Moot Court) from the UM Law School Ellingson worked for the Missoula city attorney's office for six years (1977-83), and she took on landmark projects. During her tenure, Missoula became the first city to issue open space bonds, a project that introduced her to Dorsey & Whitney. The city secured its first easement on Mount Sentinel, and it created the trail along the riverfront with a mix of playing fields and natural vegetation. She also helped develop a sign ordinance for the city of Missoula. She ended up working as bond counsel for Dorsey & Whitney, and she opened up the firm's full-fledged Missoula office after commuting a couple of years to its Great Falls office. She was a partner at Dorsey Whitney, working there from 1983 until her retirement in 2012. The area of law she practiced there is a narrow specialty - it requires knowledge of constitutional law, state and local government law, and a slice of federal tax law - but for Ellingson it meant working on great public projects – schools, sewer systems, libraries, swimming pools, ire trucks. At the state level, she helped form the Montana Municipal Insurance Authority, a pooled insurance group for cities. She's shaped MT’s tax increment law, and she was a fixture in the MT Legislature when they were debating equal rights. As a bond lawyer, though, Ellingson considers her most important work for the state to be setting up the Intercap Program that allowed local governments to borrow money from the state at a low interest rate. She has been a frequent speaker at the League of Cities and Towns, the Montana Association of Counties, and the Rural Water Users Association workshops on topics related to municipal finance, as well as workshops sponsored by the DNRC, the Water and Sewer Agencies Coordination Team, and the Montana State University Local Government Center. In 2002, she received an outstanding service award from the Montana Rural Water Users Association. In addition to being considered an expert on Montana state and constitutional law, local government law and local government finance, she is a frequent teacher at the National Association of Bond Lawyers (NABL) Fundamentals of Municipal Bond Law Seminar and the NABL Bond Attorney’s Workshop. For over 30 years Mae Nan has participated in the drafting of legislation in Montana for state and local finance matters. She has served on the Board of Directors of NABL, as Chairman of its Education Committee, was elected as an initial fellow in 1995 to the American College of Bond Counsel, and was recognized as a Super Lawyer in the Rocky Mountain West. Mae Nan was admitted to practice before the MT and US Supreme Courts, was named one of “America’s Leading Business Lawyers” by Chambers USA (Rank 1), a Mountain States Super Lawyer in 2007 and is listed in Best Lawyers in America; she is a member and former Board Member of NABL, a Fellow of the American College of Bond Counsel and a member of the Board of Visitors of the UM Law School. Mae Nan is also a philanthropist who serves on boards and applies her intelligence to many organizations, such as the Missoula Art Museum. [Much of this biography was drawn from a retirement story in the Missoulian and the Dorsey Whitney web site.] Mick McKeon, born in Anaconda in 1946, is a 4th generation Montanan whose family roots in this state go back to the 1870’s. In 1968 he graduated from Notre Dame with a BA in Communications and received a Juris Doctorate degree from the University of Montana Law School in 1971. Right after graduating from law school, Mick was persuaded by his father, longtime State Senator Luke McKeon, and his uncle, Phillips County Attorney Willis McKeon, to run for delegate to Montana’s Constitutional Convention and was elected to represent Deer Lodge, Philipsburg, Powell, and part of Missoula Counties. Along with a coalition of delegates from Butte and Anaconda, he fought through the new Constitution to eliminate the legal strangle hold, often called “the copper collar,” that corporate interests -- the Anaconda Company and its business & political allies -- had over state government for nearly 100 years. The New York Times called Montana’s Constitutional Convention a “prairie revolution.” After helping secure the ratification of the new Constitution, Mick began his practice of law in Anaconda where he engaged in general practice for nearly 20 years. Moving to Butte in 1991, Mick focused has practice in personal injury law, representing victims of negligence and corporate wrongdoing in both Montana district courts and federal court. As such, he participated in some of the largest cases in the history of the state. In 1992 he and his then law partner Rick Anderson obtained a federal court verdict of $11.5 million -- the largest verdict in MT for many years. Mick’s efforts on behalf of injured victims have been recognized by many legal organizations and societies. Recently, Mick was invited to become a member of the International Academy of Trial Lawyers - 600 of the top lawyers in the world. Rated as an American Super Lawyer, he has continuously been named one of the Best Lawyers in America, and an International Assn. of Trial Lawyers top 100 Trial Lawyer. In 2005, he was placed as one of Montana’s top 4 Plaintiff’s lawyers by Law Dragon. Mick is certified as a civil trial specialist by the National Board of Trial Advocacy and has the highest rating possible from Martindale-Hubble. Mick was awarded the Montana Trial Lawyers Public Service Award and provided pro bono assistance to needy clients for his entire career. Mick’s law practice, which he now shares with his son Michael, is limited to representing individuals who have been injured in accidents, concentrating on cases against insurance companies, corporations, medical providers and hospitals. Mick resides in Butte with his wife Carol, a Butte native. Mick, Carol, Michael and another son, Matthew, who graduated from Dartmouth College and was recently admitted to the Montana bar, enjoy as much of their time together in Butte and at their place on Flathead Lake.

Combining Enzalutamide with Abiraterone, Prednisone, and Androgen Deprivation Therapy in the STAMPEDE Trial.

There are compelling reasons to study the addition of both enzalutamide and abiraterone, in combination, to standard-of-care for hormone-naïve prostate cancer. Through a protocol amendment, this will be assessed in the STAMPEDE trial, with overall survival as primary outcome measure.

Survival with Newly Diagnosed Metastatic Prostate Cancer in the "Docetaxel Era": Data from 917 Patients in the Control Arm of the STAMPEDE Trial (MRC PR08, CRUK/06/019)

BACKGROUND Prostate cancer (PCa) is the second most common disease among men worldwide. It is important to know survival outcomes and prognostic factors for this disease. Recruitment for the largest therapeutic randomised controlled trial in PCa-the Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy: A Multi-Stage Multi-Arm Randomised Controlled Trial (STAMPEDE)-includes men with newly diagnosed metastatic PCa who are commencing long-term androgen deprivation therapy (ADT); the control arm provides valuable data for a prospective cohort. OBJECTIVE Describe survival outcomes, along with current treatment standards and factors associated with prognosis, to inform future trial design in this patient group. DESIGN, SETTING, AND PARTICIPANTS STAMPEDE trial control arm comprising men newly diagnosed with M1 disease who were recruited between October 2005 and January 2014. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Overall survival (OS) and failure-free survival (FFS) were reported by primary disease characteristics using Kaplan-Meier methods. Hazard ratios and 95% confidence intervals (CIs) were derived from multivariate Cox models. RESULTS AND LIMITATIONS A cohort of 917 men with newly diagnosed M1 disease was recruited to the control arm in the specified interval. Median follow-up was 20 mo. Median age at randomisation was 66 yr (interquartile range [IQR]: 61-71), and median prostate-specific antigen level was 112 ng/ml (IQR: 34-373). Most men (n=574; 62%) had bone-only metastases, whereas 237 (26%) had both bone and soft tissue metastases; soft tissue metastasis was found mainly in distant lymph nodes. There were 238 deaths, 202 (85%) from PCa. Median FFS was 11 mo; 2-yr FFS was 29% (95% CI, 25-33). Median OS was 42 mo; 2-yr OS was 72% (95% CI, 68-76). Survival time was influenced by performance status, age, Gleason score, and metastases distribution. Median survival after FFS event was 22 mo. Trial eligibility criteria meant men were younger and fitter than general PCa population. CONCLUSIONS Survival remains disappointing in men presenting with M1 disease who are started on only long-term ADT, despite active treatments being available at first failure of ADT. Importantly, men with M1 disease now spend the majority of their remaining life in a state of castration-resistant relapse. PATIENT SUMMARY Results from this control arm cohort found survival is relatively short and highly influenced by patient age, fitness, and where prostate cancer has spread in the body.

Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial

BACKGROUND Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone. METHODS Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m(2)) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544). FINDINGS 2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60-71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23-184). Median follow-up was 43 months (IQR 30-60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0·94, 95% CI 0·79-1·11; p=0·450), 81 months (41 to not reached) for SOC + Doc (0·78, 0·66-0·93; p=0·006), and 76 months (39 to not reached) for SOC + ZA + Doc (0·82, 0·69-0·97; p=0·022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3-5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc. INTERPRETATION Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy. FUNDING Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research.

El papel de la sensibilidad en el discernimiento de la naturaleza del alma : la posición del Canciller Felipe

El presente estudio tiene por objeto abordar el esfuerzo especulativo del Canciller Felipe por desarrollar, en el contexto del tratamiento sistemático de su Summa de bono, y de la consideración específica de bono naturae que conviene al ámbito del viviente, su examen acerca de la diferenciación de las potencias cognoscitivas y motivas y, asimismo, de las sensibles y de las racionales, en su reflexión orgánica sobre el alma del hombre. En el dominio de dicha elaboración de doctrina será objeto central de mi trabajo discernir el valor cognitivo del sensus y su vinculación con el objeto de la intelligentia. La psicología de la sensibilidad humana de Felipe el Canciller supone su concepción cósmico-antropológica a propósito de lo que es simpliciter a natura (aún en el ámbito de lo humano) y de lo que participa -en diversos grados jerárquicos- de la natura que emerge ut ratio. Desde un punto de vista histórico-filosófico su determinación ante el tema forma parte de un laborioso derrotero del pensamiento de autores patrísticos y medievales en torno a la naturaleza del alma y a la psicología del acto humano, en el que se hacen presentes las aportaciones de la antigüedad. Fuentes que revela la elaboración del Canciller en su análisis de sentencias de Aristóteles, de Agustín, de Juan Damasceno -entre otros antecedentes-, y que serán objeto de una compulsa dirigida a ponderar en mi trabajo el alcance de la aportación del Canciller.

Observaciones sobre la belleza y su trascendentalidad en Alberto Magno

La belleza, como tema eterno de reflexión filosófica ha tenido entre los pensadores del siglo XIII un lugar particular. Ellos, desde una matriz intelectual neoplatónica, han intentado tender puentes, en algunos casos, con el aristotelismo recientemente descubierto. Este hecho parece ofrecer la posibilidad de pensar el pulchrum no sólo desde su unidad con el bonum, sino también desde su especificidad. Es aquí donde Alberto Magno ha tenido un lugar importante. Es por ello que el presente trabajo quiere ocuparse del Magno en el singular tratamiento que hace de lo bello en dos de sus obras: la Summa de Bono y el In de Divinis Nominibus. Un sucinto recorrido por estos textos permitirá advertir el esfuerzo de Alberto para perfilar un concepto de belleza que, respetando la tradición neoplatónica de su unidad con el bien, parecería encontrar su lugar propio al introducir algunos elementos pertenecientes a la filosofía del Estagirita.

Deslocalización, subcontratación laboral y acción sindical : Una reflexión a partir de la experiencia reciente en actividades de servicio

Fil: Del Bono, Andrea. Universidad Nacional de La Plata. Facultad de Humanidades y Ciencias de la Educación; Argentina.

Empresas recuperadas ¿Democratización versus mercado? : Análisis de las tensiones entre autonomía y capital en el caso de la Cooperativa de Trabajo metalúrgica 'Los Constituyentes'

Los análisis sobre los procesos de recuperación y autogestión de empresas por sus trabajadores tienden a subestimar las determinaciones estructurales del fenómeno. Se analizará el proceso autogestivo de una empresa recuperada a través de un estudio de caso, entendiendo que en tanto orienta su producción al intercambio, se inscribe en un ciclo completo de producción, circulación, consumo y reproducción, cuya dinámica no controla. En la medida que en dicho ciclo predomina la lógica del capital, a través de las relaciones que establece la empresa con el mercado (re)ingresan a ella determinaciones que limitan los procesos de democratización de la producción operados en la autogestión. A través del análisis del caso empírico de la Cooperativa de Trabajo metalúrgica 'Los Constituyentes' se enfocará cómo opera esta reincorporación en el proceso autogestivo; tanto en la organización y dirección de la producción, como en los procesos de toma de decisiones. Así, persistencia de problemas disciplinares, tendencias a la corporativización, dificultades de viabilidad económica, autoexplotación y reburocratización, emergen como resultados de la tensión autogestión - mercado.

Call centers terciarizados : Los desafíos para la organización de los trabajadores en una actividad económica emergente

En el presente trabajo pretendemos explorar cuáles son las posibilidades de organización de los trabajadores en una actividad económica emergente como son los call centers terciarizados. En este sentido, nuestra meta principal será identificar ciertos dilemas y ejes problemáticos en el campo de la organización colectiva para estos espacios laborales atravesados por estrategias de flexibilización empresarial tales como la subcontratación y la deslocalización. En este marco de reflexión, indagamos hacia dónde se dirigen las estrategias de los sindicatos ante las transformaciones productivas en marcha -que han sido muy aceleradas en el sector de las telecomunicaciones-, cuál es la dinámica de estos actores y cuáles son los obstáculos mayores a su accionar. Asimismo, exploramos la existencia de nuevas formas de organización colectiva alternativas que dan voz a los intereses de los trabajadores por fuera de los sindicatos tradicionales. Describimos sus rasgos distintivos, sus condiciones de surgimiento y las ventajas y limitaciones respecto de los sindicatos clásicos. Finalmente, examinamos de qué manera ciertos aspectos ligados a los trabajadores y a la conformación de experiencias subjetivas en estos espacios laborales se relacionan con un mayor o menor grado de inclinación hacia la organización colectiva

Regulación social del mercado de trabajo en contextos productivos flexibles : Una mirada desde la contribución de los trabajadores en la producción de cine publicitario argentino

En esta tesina presentamos los resultados de un proceso de investigación orientado a describir y analizar las influencias que tienen los mecanismos desarrollados por los trabajadores sobre la estructuración de algunas dimensiones claves del mercado de trabajo en el sector de producción de cine publicitario (PcP). La PCP se caracteriza por una modalidad de organización muy flexible y efímera, basada en proyectos individuales, que congrega a los trabajadores y recursos necesarios de forma temporaria. La transitoriedad de los proyectos plantea desafíos formidables con respeto a su coordinación y regulación en el tiempo. Sin embargo, los mismos funcionan sobre una organización permanente sustentada sobre una red de contactos sociales gestados entre los miembros. En este marco, surge nuestro interrogante acerca del papel que juegan las lógicas de los propios trabajadores en el incierto mercado de trabajo de la PCP. La perspectiva teórica adoptada en nuestro trabajo, parte de la consideración de que los mercados de trabajo son producto de construcciones sociales que se diferencian histórica y espacialmente y que por tanto, se hallan socialmente regulados por una diversidad de influencias. Por ello, hemos priorizado la investigación empírica del caso particular. Nuestro objetivo principal, ha supuesto la indagación de distintas dimensiones analíticas. Así, en primer lugar, presentamos las características socioproductivas y económicas más relevantes del sector para luego centrarnos en las cuestiones nodales de nuestro estudio que contemplaron un análisis detallado de los procesos de regulación de algunas dimensiones del mercado de trabajo, a saber: acceso, reclutamiento, calificación y movilidad. Así, esta tesina pretende ser un aporte al análisis de la dinámica de los mercados de trabajo en contextos productivos flexibles, así como una contribución al conocimiento de sectores escasamente abordados por los estudios del trabajo

El mundo del trabajo en cambio : Trayectorias laborales de los ex - trabajadores de OFA

Fil: Frassa, María Juliana. Universidad Nacional de La Plata. Facultad de Humanidades y Ciencias de la Educación; Argentina.

Políticas de management e identidad laboral : El caso de la unidad de negocios de empresa en Telefónica de Argentina

Fil: Ynoub, Emanuel. Universidad Nacional de La Plata. Facultad de Humanidades y Ciencias de la Educación; Argentina.