Gotowa bibliografia na temat „Steinbeck Research Center”

This article examines the intertidal ecological research of the commercial lab owner and popular science writer Edward F. Ricketts, best known as the prototype for John Steinbeck’s character “Doc” in the novel Cannery Row (1945). Ricketts’s friendship with Steinbeck and unconventional philosophical style have regrettably overshadowed his scientific work, particularly his novel faunal zonation surveys of the North American Pacific littoral in the 1930s and 1940s. These surveys resulted in a landmark handbook, Between Pacific Tides (1939), designed for novices and specialists alike. Ricketts’s work demonstrates how the place of ecological investigation (Billick and Price)—here Monterey Bay’s pounding surf, storm-tossed debris, eclectic bohemianism, and the collaborative energies at Hopkins Marine Station—“imprinted” West Coast animal ecology. At first, Ricketts adopted the physiological methods and conceptions of ecological holism he had learned at the University of Chicago under mentor Warder C. Allee in the early 1920s. Allee had conducted his investigations of intertidal organisms in the relatively placid bays and estuaries at the Woods Hole research center on Cape Cod, Massachusetts. Allee envisioned animal aggregations as higher-order societies guided by “unconscious cooperation” and evolving toward a climax state. Yet Ricketts found that physiochemical factors, such as temperature and salinity, could not explain the distribution of organisms amid the Pacific’s far more precarious rough-and-tumble surf, nor could they account for fierce competition among organisms. Rejecting Allee’s cooperative metaphors, Ricketts came to see community structure as an unintended result of tidepool invertebrates’ Darwinian struggle to occupy resource niches—a “set of sieves” that transferred nourishment from one part of the aggregation to the next, binding it together in interlocking food webs. Through dialogue with Steinbeck about the implications of modern physics during their Sea of Cortez voyage (1940), Ricketts developed a “unified field hypothesis” to conceptualize the dynamic interwovenness created by transfers of metabolic energy. Yet Steinbeck ultimately held fast to a super-organismic understanding of ecological holism—a hierarchical relationship between constituents and the whole that underlays the novelist’s idea of the human “phalanx” in Grapes of Wrath and other works. The article offers new insights about the ecological origins of Steinbeck and Ricketts’s disputes over “non-teleological” reasoning and the pair’s divergent understandings of nature, society, and progressive politics.

Im Rahmen eines vom BMBF (Bundesministerium für Bildung und Forschung) geförderten Projektes erforschte die Firma Optik-Elektro Huber GmbH in Zusammenarbeit mit dem Steinbeis-Transferzentrum für Produktion und Organisation ein neuartiges Reinigungsverfahren von komplexen, oberflächenempfindlichen Bauteilen. Im Fokus des Beitrags steht der Aufbau und die Wirkungsweise des Systems, welches auf der Einzelteilhandhabung der einzelnen Werkstücke in direkter Kopplung mit dem Fertigungsprozess beruht.   As part of a project, funded by the Federal Ministry of Education and Research (BMBF), the company Optik-Elektro Huber GmbH, in cooperation with the Steinbeis-Transfer Center for Production and Organization, developed a novel cleaning process for complex, surface-sensitive components. The article is focused on the structure and mode of operation by the system which is based on the handling of individual components directly interacting with the manufacturing process.

Adaptation to modern requirements of buildings, which have got a status of architectural landmarks, is always a compromise between the preservation of authentic elements and bringing the building into line with current standards. In the Building of the Institute of Radio Electronics, the architectural landmark of Kharkiv region, it was necessary to build an elevator to provide barrier-free access to the premises.The goal of this research is to find the best place for a new elevator, where meddling into the building’s body from one side will make minimum damage for its structure and interior design and from another side can be most convenient for users.To solve this problem, it was necessary to collect materials about “Institute of radio electronics” building: conduct bibliographic surveys and search materials in different archives. Historical documents, photos, sketches and historical drawings and field research materials about this building must be put together. Analysis of the collected materials showedthat building was designed in the second part of 1930 for new Kharkov Civil Engineering Institute (KhCEI), which was found in April 1930. In 1930 the place for the building structure was chosen. A KhCEI building architectural competition took place in 1930. The authors of the winning project were Yakiv Steinberg, Rosaliya Fridman. For the KhCEI building J. Steinberg suggested to make experimental constructivist complex. The architect paid special attention to the functioning of the building. Taking into attention that the formation of the department structure of the institute continued until 1932, the architects had only approximate characteristics of the functioning of the house.The building had a long distributor block to which other blocks, intended for separate specializations, were adjoined at right angles. The stairways or ramps were in the corridors of the distributor block as well as in the opposite edges of the transverse blocks. The ground floors and second floors had corridors, which distributedstudents to the necessary premises. The first floor and partly the ground floor were intended for laboratories. The second floor, which had a corridor system, was divided into small rooms for group classes, and the third floor contained large halls for drawing classes had free planning (later became enfilades). Near the stairs there were also the servicing premises combined in one block –toilets, tool rooms and archives, professors' offices with small subdepartment libraries.Only one half of this project was finished in 1933. The complex was damaged during the II World war. In August 1943, the destroyed building was handed to Kharkiv Mining Engineering Institute (KhMEI).In 1944-1945 Dmitry Torubarov developed the project of reconstruction of this complex. His solution preserved Steinberg's idea, but added new parts to it. Torubarov changed the outer view of the complex, because the environment around it had been modified.In 1930 Steinberg worked with an empty area, where were only the main road and the ravine. He made a composition, which was supposed to look from the view point between the main road and the ravine best of all. In 1946 Torubarov worked in the new town area, where the ravine created an empty space in front of the composition. The corner between the main road (that became a significant avenue later) and the ravine wasn't so important. Torubarov moved the center of the composition to the center of facade facing to the ravine.

Abstract Background: Priapism is a serious complication associated with Sickle Cell Disease (SCD) that may be a manifestation of underlying vasculopathy. The Centers for the Study of Complex Diseases of Childhood (CSCCD), comprising independent Comprehensive Sickle Cell Centers, demonstrated an association of priapism with hemolysis.1 Previously, we identified two groups of people with SCD based on red blood cell (RBC) adhesion under hypoxic conditions: those patients whose RBCs showed hypoxia-enhanced adhesion (HEA) and those whose did not (non-HEA).2 Patients with HEA had evidence for more hemolysis in vivo. Here, we aimed to examine (1) the association of HEA with hypoxia in vivo, and (2) RBC adhesion in normoxic and hypoxic conditions in male patients with or without a history of priapism. Methods: This retrospective study was conducted at the Adult Sickle Cell Disease Clinic at the University Hospitals Seidman Cancer Center, in Cleveland, OH between 2015 to 2018. Blood samples were obtained from 26 male subjects (29 samples, 25 HbSS and 1 HbSS HPFH). Adhesion experiments were performed as previously reported by passing surplus whole blood through LN-immobilized microchannels at physiological conditions under both normoxic and hypoxic conditions.2,3 Adherent RBCs were then quantified with microscope after a wash step. The median value was used for data analyses from multiple samples obtained from an individual. Chart review was conducted to examine results of hypoxia testing obtained in vivo as part of routine clinical care. Results: Male subjects with HbSS and a history of priapism had higher HEA in comparison to subjects without a history of priapism (3268 ± 5647 vs. 122 ± 1218, p=0.016). However, there was no significant difference between RBC adhesion of the two groups under normoxic conditions (529 ± 1528 vs. 402 ± 280). More male subjects with priapism had hypoxia in vivo (10 out of 14) than subjects without priapism (5 out of 12). Compared to male subjects with a history of priapism, those without a history of priapism had lower lactate dehydrogenase levels (474 ± 267 vs. 290 ± 215, p=0.008). Conclusions: Our data showed that subjects with a history of priapism had a higher HEA and tended to have more evidence for hypoxia in vivo than did subjects without a history of priapism. Further, male subjects with hypoxia in vivo had more HEA than did those without hypoxia in vivo (not shown). Hypoxia in vivo may cause increased RBC damage (reflected by HEA), hemolysis, nitric oxide depletion, and consequent vasculopathy, resulting in priapism. Hypoxia may be treatable, when identified in subjects with a history priapism in vivo or possibly with HEA in vitro. This could plausibly modify disease severity in some cases. References: Nolan VG, Wyszynski DF, Farrer LA, Steinberg MH. Blood. 20015 Nov;106(9):3264-7. doi: 10.1182/blood-2005-04-1594 Kim M, Alapan Y, Adhikari A, Little JA, Gurkan Microcirculation. 2017 Jul;24(5). doi: 10.1111/micc.12374. Alapan Y, Kim C, Adhikari A, Gray KE, Gurkan-Cavusoglu E, Little JA, Gurkan Transl Res. 2016 Jul;173:74-91.e8. doi: 10.1016/j.trsl.2016.03.008. Epub 2016 Mar 19. Disclosures Little: NHLBI: Research Funding; PCORI: Research Funding; Hemex: Patents & Royalties: Patent, no honoraria; Doris Duke Charitable Foundations: Research Funding.

Abstract Background: Adenosquamous carcinoma of the pancreas (ASCP) is a very rare and highly aggressive variant of pancreatic ductal adenocarcinoma (PDA), accounting for 0.5-4% of all pancreatic cancer cases in the US. Current data indicates that epigenetic changes and Myc overexpression lead to squamous transdifferentiation of pancreatic tumor cells and development of ASCP. Minnelide is an oral anti-super-enhancer drug that inhibits Myc expression in preclinical models of ASCP. Oral Minnelide has been previously tested in the clinic where a Phase I study determined a recommended phase 2 dose of 2 mg/day. Major toxicities included neutropenia and sepsis. We hypothesize that Minnelide will be safe and effective in patients with advanced ASCP. Methods: This Phase II open label, single arm study being conducted at the NIH Clinical Center in Bethesda, MD (NCT04896073) will enroll up to 25 evaluable participants with advanced ASCP that has been previously treated. Eligibility criteria include: histologically confirmed ASCP (≥30% malignant squamous component), presence of metastatic, recurrent, or locally advanced unresectable disease, and progression or intolerance ≥1 prior systemic treatment for advanced disease. All participants will self-administer Minnelide at 2mg PO daily on days 1-21 of each 28-day cycle, for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Restaging scans will be performed every 8 weeks. Optional biopsies will be requested at baseline, mid-cycle 1 and at time of progression. The primary objective is to determine the antitumor activity of Minnelide by evaluating the disease control rate. Secondary objectives are determination of drug safety in this patient population, progression free survival, and overall survival. Exploratory objectives include assessment of Minnelide effect on tumor cell epigenetics, Myc expression and immune cell populations using on-treatment tumor biopsy tissues. Changes in circulating tumor DNA and circulating immune cell populations upon treatment will also be evaluated. A Simon optimal two-stage phase II trial design will be used. If 3 of the first 12 patients experience disease control, then enrollment will continue up to 25 evaluable participants. If ≥8 of 25 participants experience disease control this would rule out an unacceptably low clinical benefit of 20% in favor of 40% (α = 0.1, β = 0.2). This trial opened for accrual in July 2021. Citation Format: Nebojsa Skorupan, Mehwish I. Ahmad, Seth M. Steinberg, Jane B. Trepel, Derek Cridebring, Haiyong Han, Daniel D. Von Hoff, Christine Alewine. A phase II trial of the super-enhancer inhibitor Minnelide in advanced refractory adenosquamous carcinoma of the pancreas (ASCP) [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-054.

Abstract Background: Patients with relapsed small cell lung cancer (SCLC) have a poor prognosis and few therapeutic options, especially after standard treatment of platinum doublet chemotherapy +/- immunotherapy. SCLC is characterized with high replication stress. A previous single-arm phase 2 study showed anti-tumor activity with the addition of ataxia-telangiectasia–mutated and rad3-related (ATR) kinase inhibitor berzosertib to topotecan. This study aimed to investigate whether the addition of berzosertib to topotecan improves clinical outcomes in patients with relapsed SCLC. Patients and methods: The randomized, open-labeled phase 2 study recruited patients with SCLC and relapse after one or more prior therapies from 16 US cancer centers as members of the National Cancer Institute Cancer Therapy Evaluation Program. Patients previously treated with topotecan were not eligible. Eligible patients were randomly assigned to receive topotecan (arm 1: 1.25 mg/m2 intravenously on days 1 through 5) alone or with berzosertib (arm 2: 210 mg/m2 intravenously on days 2 and 5), in 21-day cycles. Randomization was stratified by sensitivity to first-line platinum-based chemotherapy. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. Secondary endpoints included overall survival (OS), objective response rate (ORR), and duration of response (DOR) in the overall population and in platinum-sensitive or -resistant patients. Results: Between December 2019 and December 2022, sixty patients were randomly assigned to receive topotecan alone (n=20) or in combination of with berzosertib (n=40). After a median potential follow-up of 21.3 months, there was no difference in PFS between the two arms [median: 3.0 months in arm 1 versus 3.9 months in arm 2, hazard ratio (HR) (95% CI): 0.80 (0.46 to 1.41), P = 0.44]. OS was significantly longer with the combination [5.4 months in arm 1 versus 8.9 months in arm 2, HR (95% CI): 0.53 (0.29 to 0.96), P = 0.033]. Of 57 evaluable patients, a numerically higher ORR was observed in patients receiving the combination: 5.6% (1/18, 95% CI: 0.1% to 27.3%) in arm 1 versus 25.6% (10/39, 13.0% to 42.1%) in arm 2. In an unplanned post hoc analysis, the depth of target lesion responses was significantly associated with better OS in patients on the combination arm (adjusted P = 0.022 by landmark analysis), suggesting that the deeper tumor regressions by the combination of berzosertib and topotecan may have eventually contributed to OS improvement. Adverse event profiles were similar between the two arms. Conclusions: In this randomized clinical trial, berzosertib plus topotecan did not improve PFS compared with topotecan alone in patients with relapsed SCLC. However, the combination significantly improved OS, suggesting potential efficacy of replication-stress targeted therapies in SCLC. Citation Format: Nobuyuki Takahashi, Zhonglin Hao, Liza C Villaruz, Jun Zhang, Jimmy Ruiz, W. Jeffrey Petty, Hirva Mamdani, Jonathan W Riess, Jorge Nieva, Jose M Pachecho, Alexander D Fuld, Elaine Shum, Aman Chauhan, Samantha Nichols, Hirity Shimellis, Jessie McGlone, Linda Sciuto, Danielle Pinkiert, Chante Graham, Meenakshi Shelat, Robbie Kattappuram, Melissa Abel, Brett Schroeder, Deep Upadhyay, Manan Krishnamurthy, Ajit Kumar Sharma, Rajesh Kumar, Justin Malin, Christopher W Schultz, Shubhank Goyal, Christophe E Redon, Yves Pommier, Mirit I Aladjem, Steven D Gore, Seth M Steinberg, Rasa Vilimas, Parth Desai, Anish Thomas. Efficacy of ATR inhibitor berzosertib plus topotecan or topotecan alone in patients with relapsed small cell lung cancer: A randomized clinical trial [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_A10.

Abstract Background. Avascular necrosis (AVN) is a serious complication of sickle cell disease (SCD) that can lead to significant morbidity including chronic pain and physical impairment with treatment depending on the patient's pain severity and functional limitation. Patient age, hemoglobin levels, and abnormal rheology, particularly high blood viscosity, or thickness, and percentage of dense red blood cells, defined as cells >1.11 mg/mL have been identified as risk factors for the development of AVN, but their contributions to the subsequent clinical course has not been described. The natural history of AVN has been described as chronic and progressive without significant surgical or physical therapy based intervention. However, this description was established before widespread MRI use in diagnosis, or hydroxyurea (HU). A new evaluation of the natural history of AVN is needed. Objective: Review the natural history of AVN at our institution in patients for whom repeat imaging is available, and determine if patient demographics, treatment type, and laboratory data, including rheological values, predict of clinical course. Methods. We identified all patients with a diagnosis of AVN with diagnostic and follow-up imaging studies (pelvic X-rays or MRI of the hip), receiving care at Texas Children's Hospital Hematology Center 2006 to 2018, and collected demographic, treatment, rheological and clinical laboratory data. Patient radiographic images at diagnosis and follow up were reviewed and scored by a board certified pediatric radiologist using the Steinberg criteria. Laboratory values for each patient were collected as available from time of diagnosis through to the date of follow up imaging. Longitudinal patient blood samples were collected for rheological measurements under an IRB approved protocol. Whole blood viscosity was measured on a cone and plate viscometer (DV3T Rheometer, AMETEK Brookfield, Middleboro, MA, USA) at 45 and 225 s-1 at 37oC within 4 hours of sample collection in an EDTA vacutainer tube. Percent dense red blood cells (%DRBCs) were measured by an ADVIA 120 Hematology System (Siemens Medical Solutions USA, Inc., Malvern, PA, USA). Statistical analysis comparing groups with and without radiographic improvement was performed using a two-tailed Student's t-test. Results. 16 patients had repeat imaging, allowing for assessment of radiographic improvement (Table1). All were diagnosed via X ray or MRI of the pelvis. Five of 16 patients had resolution or significant radiographic improvement of AVN without orthopedic intervention or prolonged physical therapy, while 11 patients had stable or worsening disease. In the group with radiographic improvement, the mean age was 9.9 years (SD=2.5) and 14.6 years (SD=2.2) in the group without radiographic improvement (p= 0.002). Five patients underwent core decompression with bone marrow aspirate concentrate injection; one progressed to complete femoral head collapse while the rest had stable or worsening disease. Mean hemoglobin (Hb), fetal hemoglobin (HbF), percent DRBCs, whole blood viscosity, and extent of AVN at diagnosis by Steinberg criteria were not statistically different between the patients that showed improvement and those that did not. Conclusions. Our results challenge the paradigm of untreated AVN in SCD as an inexorably progressive disease. Here we present 5 cases of significant radiographic improvement of AVN without surgical or significant physical therapy interventions. Conversely, 5 AVN cases treated with core decompression remained stable or worsened. Given our small cohort, we were unable to establish laboratory or rheological predictors of spontaneous resolution. However, patients in the radiographic improvement group were younger than patients with progressive disease. HU has shown promise in improving vascular complications in SCD patients however more research is needed to delineate its role as a modifier of AVN natural history as it was not correlated with the improved group in our study (all our study patients were on HU either prior to diagnosis or started during the follow up period). Given the findings that significant radiographic improvement is possible with minimal or no intervention, providers should closely weigh the risks and benefits of observation versus surgical intervention, particularly in young patients with SCD. Disclosures No relevant conflicts of interest to declare.

Background: Vaso-occlusive crisis (VOC) is the hallmark complication of sickle cell disease (SCD) (1), and usually requires intravenous (IV) opioid treatment in emergency room (ER) or acute care center (ACC), a designated observation unit to manage uncomplicated VOC (2). Starting October 2017, there was a critical nationwide drug shortage in parental hydromorphone, a commonly used medication to treat VOC. In April 2018 the University of Illinois Health System (UI Health) adopted a standardized pain management protocol that limited opioids in the ER or ACC to two doses of IV or IM morphine and/or oral opioid. This study evaluates the impact of this standardized pain management protocol on managing VOC in SCD. Methods: A total of 373 SCD adults treated at UI Health from May 2017 to Oct 2018 had at least one ER or ACC visit or hospitalization for VOC. Data on VOC-related patient visits to the ACC, ER, and admissions to the inpatient floors were collected from the electronic medical record and evaluated based on three time periods (prior to shortage: May 2017-Oct 2017; transition: Oct 2017-Apr 2018; and post protocol: Apr 2018-Oct 2018). Descriptive statistics, the Cochrane trend test and Jonckheere-Terpstra trend test were used for data analysis. The study was approved by the Institutional Review Board prior to the initiation of chart review. Results: Between May 2017 and Oct 2018, the 373 SCD adult patients had a total of 1,915 ACC, 2,635 ER and 1,832 inpatient visits. After implementation in April 2018, the compliance rate with the standardized pain protocol was 99.7% in the ACC and 85.1% in the ER. In the ACC, the number of visits decreased after standardized pain protocol implementation, whereas the number of visits increased in the ER (Figure 1). The admission rate to the inpatient service from the ACC increased significantly while the admission rate from the ER remained relatively stable (Table 1). The numbers of opioid doses and the total opioid dose to treat VOC decreased in the ACC, but not in ER. Utilization of oral opioids increased in both settings (Table 1). The number of inpatient hospitalizations increased with implementation of the standardized protocol (542 vs. 626 vs. 664), and the 30-day readmission rate increased (49% vs. 51% vs. 57%, p = 0.003), but the length of hospital stay was reduced (p < 0.001). Summary: Implementation of a standardized pain treatment protocol due to the parenteral hydromorphone shortage decreased the utilization of the ACC compared to the ER and the inpatient service, and resulted in reduced opioid dose but increased admission rates from the ACC. The 30-day readmission rate to inpatient service increased but the length of stay was reduced. A standardized pain protocol that limits opioids to two doses in the acute setting may not be an optimal approach. Reference: F. B. Piel, M. H. Steinberg, D. C. Rees, Sickle Cell Disease. N Engl J Med376, 1561-1573 (2017).J. Han et al., Program expansion of a day hospital dedicated to manage sickle cell pain. Am J Hematol93, E20-E21 (2018). Disclosures Saraf: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding. Gordeuk:CSL Behring: Consultancy, Honoraria, Research Funding; Global Blood Therapeutics: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Modus Therapeutics: Consultancy, Honoraria; Imara: Research Funding; Ironwood: Research Funding; Inctye: Research Funding; Pfizer: Research Funding; Emmaus: Consultancy, Honoraria.

Hydroxyurea (HU) is approved in the EU and USA for prevention of vaso-occlusive crises (VOC) including acute chest syndromes (ACS) in patients over 2 years with sickle-cell disease (SCD). The major benefits of HU in SCD are directly related to its abilities to increase HbF, decrease sickling of red blood cells and hemolysis, leading to reduction of vaso-occlusive episodes, need for blood transfusions and consequently reduction of morbidity and mortality. Adherence to the treatment is paramount for effectiveness, but in spite of proven benefits, barriers to adherence persist.[1] ESCORT-HU study (European Sickle Cell Disease COhoRT - HydroxyUrea), is a multicentric, prospective, non-interventional European study designed to evaluate the safety profile of HU in real life. Patients were enrolled from January 2009 to June 2017 with a follow-up of up to 10 years. All interruptions and resumptions of HU treatment exceeding 15 days were recorded in this study. We hereby present the analysis of the group of patients who self-discontinued HU at least once during the study before informing their caregiver, with a view to identify potential barriers to long-term adherence. In total, 1906 patients were enrolled in ESCORT-HU from 63 centers in France, Germany, Greece and Italy. Of these, 619 patients (32%) stopped HU for over 15 days at least once, and around a third (11% of all patients) were due to patient's will. The mean duration of HU treatment before the first discontinuation was 4.8 ± 5.1 years. Data are summarized in table 1. Compared to the rest of the cohort, the 'treatment discontinuation' group had similar distribution by gender and indication for HU prescription, but a higher proportion of adults stopped HU more than 15 days. It is notable that the proportion of patients with SC genotype was higher in the 'treatment discontinuation' group (4.5% vs 1.7%). The patients in the 'treatment discontinuation' group had more frequent SCD symptoms before enrolment in the study (table 2). Hematological and clinical improvement compared to the baseline was observed in both groups. However, average mean Corpuscular Volume (MCV) and Fetal Hemoglobin percentage (HbF%) were lower and mean percentages of patients with SCD symptoms were higher over the three years of follow-up in the 'treatment discontinuation' group, suggesting that HU daily dose was insufficient (table 2). Sixty patients have no treatment resumption date reported which suggest a permanent interruption of their treatment. Among them 32% preferred to switch to another HU medicinal product and 13% have safety issue (table 3). Understanding and managing self-discontinuation of HU before taking medical advice is challenging for the physician. It is tempting to speculate that it may be due, at least in part, to lack of effectiveness potentially due to an underdosage of the treatment. Resistance to the treatment may also be suggested based on past literature data revealing a great variability in the response (determined by HbF%) to HU therapy. There is evidence that genetic modifiers affect individual response to HU.[2],[3] Finally, weariness from long-term use may also explain the patient's wish to discontinue HU. But treatment at optimal effective should be the primary goal of caregivers. [1]Smaldone A., Manwani D., Green NS, Greater number of perceived barriers to hydroxyurea associated with poorer health-related quality of life in youth with sickle cell disease, Pediatr Blood Cancer. 2019 [2] Steinberg MH, Voskaridou E, Kutlar A, Loukopoulos D, Koshy M, et al. (2003). Concordant fetal hemoglobin response to hydroxyurea in siblings with sickle cell disease. Am J Hematol 72: 121-126 [3] Ware RE, Despotovic JM, Mortier NA, Flanagan JM, He J, et al. (2011) Pharmacokinetics, pharmacodynamics, and pharmacogenetics of hydroxyurea treatment for children with sickle cell anemia. Blood 118: 4985-4991 Disclosures Galactéros: Addmedica: Membership on an entity's Board of Directors or advisory committees. Voskaridou:Celgene Corporation: Consultancy, Research Funding; Protagonist: Research Funding; Genesis: Consultancy, Research Funding; Acceleron: Consultancy, Research Funding; Addmedica: Membership on an entity's Board of Directors or advisory committees. Cannas:Addmedica: Membership on an entity's Board of Directors or advisory committees.

Abstract Hydroxyurea (HU) is approved in EU and USA for preventing vaso-occlusive crises (VOC) including acute chest syndromes (ACS) in adults, adolescents and children ≥2 years with sickle-cell disease (SCD). Further to the double blinded, randomized controlled Multicenter Study of Hydroxyurea administration (MSH) which provided the first data on clinical efficacy of HU (Charache 1995), a few follow-up studies suggested that long-term use of HU resulted in significant clinical benefit on patient outcome. This was reflected by lower mortality rates in HU-treated patients compared to conventionally treated patients (Steinberg 2003 & 2010, Voskaridou 2010, Lê 2015). Sustained hematological and clinical response after several years of follow-up at maximal tolerated dose was further shown in subsequent studies, especially the LaSHS study (Voskaridou 2010). Based on these data, the ESCORT-HU (European Sickle Cell Disease COhoRT - HydroxyUrea) study was launched aiming in the establishment of the safety and the sustainability of hematological and clinical benefits to HU administration in the prevention of sickle-cell vaso-occlusive crises in routine practice. We hereby present preliminary results from a large cohort of patients enrolled in the study between January 2009 and June 2017. 1920 patients were enrolled from 63 centers in France, Germany, Greece and Italy, For 147 of the 600 HU-naive patients (never treated with HU before enrolment) and started on HU for VOC or ACS, there was documented clinical outcome (number of VOC >48h and ACS episodes per year) over a 4-year follow-up period. These patients were selected for analysis to evaluate sustainability of clinical and hematological HU response in routine practice. Demographic data and Hb genotypes are displayed in table 1. The children group was mainly composed of βS/βS patients, while adults were mainly βS/βS and βS/β-thal patients. As shown in figure 1 and 2, there was a dramatic reduction in the number of VOC >48h and ACS episodes (-79%) from year 1 in adults and children, with results comparable to previous randomised clinical trials in adults (Charache et al., 1995) and children (Jain et al, 2012). Overall, the reduction in number of VOC (>48h) and ACS was stable over the 4 years of follow-up. This reduction is inversely proportional to the increase in HbF. There were however a moderate rebound in children from year 2 while adults remained stable. Similarly, there was reduction in the proportion of adults and children requiring transfusion (figure 3). The clinical benefit of HU was higher in severe forms of SCD, as displayed by the markedly reduced number of patients with ≥ 3 VOC episodes (>48h)/year at year 1 (figure 4). Hematological response to HU was evidenced as soon as year 1 with a marked increase in HbF% (+6-10) and were maintained over subsequent years of treatment (figure 1 and 2) as the dose of HU was further increased. While there was no striking differences in HbF% variation between age groups and genotypes, the requirement for increase in HU dose over the 4 years of follow-up was markedly higher in children, probably reflecting the different severity between the two population at entry (figure 5). The red cell red cell mean corpuscular volume (MCV) could be used as a measurement of compliance, showing differences between age group (figure 5). There was, as expected, an apparent negative correlation between induction of HbF synthesis and number of VOC >48h and ACS episodes at year 1, attesting to reduced effectiveness of treatment in some patients (figure 6). Improvement in blood parameters was accompanied by mild reduction of absolute neutrophil and platelet count although not to the point of myelosuppression (defined as ANC < 2 x 109/L), showing that MTD was not targeted in routine practice. Treatment-emergent adverse reactions occurring in the 147 patients of the cohort over the 4 years of follow-up were consistent with the known safety profile of hydroxyurea. The commonest effects included neutropenia and thrombocytopenia (25 events in 13 patients) and were easily manageable with temporary discontinuation of treatment. No tumorigenesis was reported. In conclusion, preliminary results from ESCORT-HU in 147 patients treated with HU showed sustained hematological and clinical response while MTD was not targeted, with differences between adults and children which may be attributed in part to reduced compliance in the latter group. Disclosures Voskaridou: Celgene Corp: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acceleron: Membership on an entity's Board of Directors or advisory committees, Research Funding. Oevermann:Addmedica: Membership on an entity's Board of Directors or advisory committees. Thuret:Addmedica: Research Funding; bluebird bio: Research Funding; Novartis: Research Funding. Steschenko:Novartis: Membership on an entity's Board of Directors or advisory committees.

Although John Steinbeck's novellasOf Mice and Men,The Red Pony, andThe Pearlare works of fiction, they provide a window on the history of the times and places they portray. Studying the historical, social, economic, and regional background of each novella is important to fully understanding each work. This interdisciplinary collection of rich collateral materials features a variety of primary documents that shed light on the background of each of these novellas—the pioneer days and life on the Western frontier, the early history of California, the gold rush, the plight of the migrant worker during the Great Depression, the problems of the homeless and the hopeless, and oppression in Mexico in the early 20th century. Documents include memoirs of mountain men and pioneers, books of travel, sociological studies, a political treatise, a journal, reports of U.S. commissions, a comic memoir, and an interview with a Salvation Army general who worked with the downtrodden during the 1930s. Most of these materials are not available in printed form anywhere else. The purpose of this volume is to explore through analysis and collateral readings the pervasive theme in these novellas: the universality of humankind's often futile struggle for a better existence. Steinbeck shows that the American vision is shaped by the dream of a better life represented in the myth of the West. A social and political commentator, he dramatizes in all three novellas the social issues of the time. The first chapter of this study, a literary analysis, examines key themes common to all three novellas. The remaining chapters place the works in historical context. Old California and the West includes accounts of 18th- and 19th-century travelers to California who dreamed of a better life. Land Ownership examines the meaning of land ownership in the West and its corruption. The Vagrant Farm Worker: Homeless in Paradise features memoirs and journals of itinerant workers as well as Mark Twain'sRoughing Itand a study of the hobo. Losers of the American Dream deals with the homeless and hopeless during the early years of this century and the Great Depression. The American Dream in a Mexican Setting illuminates the lives of the oppressed in Mexico which provoked a century of revolutions. Each chapter concludes with study questions, ideas for class discussion and student projects and papers, and a list of books for further reading. This is an ideal companion for teacher use and student research in English and American history classes.

Focusing on the intersection of literature and politics since the beginning of the 20th century, this book examines authors, historical figures, major literary and political works, national literatures, and literary movements to reveal the intrinsic links between literature and history. Literary works have often engaged political issues, and many political writings give close attention to literary concerns. This encyclopedia explores the complex relationship between literature and politics through detailed entries written by expert contributors on authors, historical figures, major literary and political works, national literatures, and literary movements, covering specific themes, concepts, and genres related to literature and politics from the 20th century to the present. The work covers cover authors that include Margaret Atwood, James Baldwin, Philip K. Dick, W.E.B. Du Bois, William Faulkner, Ernest Hemingway, Jack London, Toni Morrison, George Orwell, John Steinbeck, and Virginia Woolf, just to mention a few. International in scope, Literature and Politics Today: The Political Nature of Modern Fiction, Poetry, and Drama covers writing ranging from the beginning of the 20th century to the present, with special emphasis on works written in English. The content of the some 150 alphabetically arranged entries is ideal for high school students working on assignments involving literature to explore such current yet historically ongoing social issues as censorship and propaganda. This book is appropriate for public libraries where it will serve to support student research and to help general readers learn more about enduring political concerns through literary works. Academic libraries will find this reference a valuable guide for undergraduates studying literature, history, political science, law, and other disciplines.

WhenThe Grapes of Wrathwas published in 1939, it had an explosive effect on the public, calling attention to the problems of migrant farm workers during the Great Depression. This casebook provides a rich source of primary materials on the period and the plight of the migrant farm worker that brings to life the problems Steinbeck immortalized in the novel. Included are interviews with eyewitnesses to the Dust Bowl, firsthand accounts and investigative reports of the causes and effects of the Great Depression, letters to Eleanor Roosevelt and Labor Secretary Frances Perkins, diaries and autobiographies of migrant farm workers in the 1930s, newspaper articles and editorials of the period, congressional testimony, a Wobbly song, affidavits by union activists, and other unique materials, many of which have never before appeared in print. All these materials can be used in literature, American history, and interdisciplinary classes to enrich the study of this novel and its times. Following a literary analysis of the novel, six chapters present primary documents on the following topics related to the novel: the financial causes and results of the Great Depression; the history of farming in the early twentieth century and the growth of agribusiness in California; working and living conditions of migrant farm workers in 1930s California; attempts to unionize farm workers and major strikes of the period; lawlessness among law enforcement officers in dealing with union members; the legacy of the 1930s—Cesar Chavez and the United Farm Workers, and working and living conditions of farm workers long after the publication of the novel. Each chapter is followed by study questions, topics for research papers and class discussion, and suggestions of further reading.

This handbook aims to provide an overview of knowledge about age and ageing in ‘Western’ societies at the beginning of the 21st century, which is intended to be equally suitable for research and practice. It focuses on relevant contributions from the social and behavioural sciences and their access to selected aspects of age and ageing. Its main topics can be described as quintessential core subjects, e.g. theories of ageing, socio-economic situation and inequalities, mental and physical health, social networks and social participation. These are supplemented by contributions on often marginalised topics and ‘emerging topics’ such as very old age, experiences of violence and delinquency, sexuality, and the spirituality and ethics of ageing. Finally, a series of topics relevant to everyday life and research practice (e.g. age and technology and data collection among the elderly) form a third central component of the book. With contributions by Heike Baranzke | Hermann Brandenburg | Susanne Brose | Josef Ehmer | Yvonne Eisenmann | Lea Ellwardt | Marcel Erlinghagen | Uwe Fachinger | Luise Geithner | Thomas Görgen | Bernadette Groebe | Helen Güther | Hans Gutzmann | Karsten Hank | Peter Häussermann | Rolf G. Heinze | Kira Hower | Anna Janhsen | Roman Kaspar | Daniela Klaus | Lars-Oliver Klotz | Franziska Kunz | Lisa Luft | Katharina Mahne | Michael Neise | Frank Oswald | Johannes Pantel | Susanne Penger | Holger Pfaff | M. Christina Polidori | Christian Rietz | Charlotte Şahin | Anna Schlomann | Holger Schmidt | Laura Schmidt | Wiebke Schmitz | Katrin Schneiders | Frank Schulz-Nieswandt | Andreas Simm | Julia Simonson | Anja Steinbach | Stephanie Stock | Julia Strupp | Clemens Tesch-Römer | Claudia Vogel | Raymond Voltz | Michael Wagner | Hans-Werner Wahl | Inka Wilhelm | Christiane Woopen | Susanne Zank

Social theatre and politically engaged theatre are two designations that gained acceptance amid a lively debate that went on throughout the late 19th century and consolidated in the 20th century. Its turning point lay in the structure of the relations between theatre and politics or even between theatre and propaganda. This text addresses what resistance and political-cultural protest meant to Grupo Teatro Moderno de Lisboa (TML), from Lisbon/Portugal, in the 1960s, based on the interviews and discourses about their collective creation processes, theoretical research, and social intervention. According to many interpreters, the Group broke with the theater establishment of 1960 and came out as one generation's great movement. It only lasted for 4 years, from 1961 to 1965. During this time, TML staged theatrical texts by Carlos Muniz, Dostoyevsky, Miguel Mihura, John Steinbeck, Luiz Francisco Rebello, William Shakespeare, and José Carlos Pires. These artists made up and remade different universes according to their purposes and wishes. By reading the above authors' texts in the 1960s, these Portuguese artists gave new meanings to the present and to the past itself – recalling here Brecht's "past and present in one". The political and aesthetic issues in the plays were updated through debates between the theater group and the audience —quite a difficult task in a period when a political-cultural protest against the "Estado Novo" dictatorship was increasingly strong and constant, and in which official censorship, always vigilant against heterodox artistic manifestations, was stifling. Being active in the politically engaged theater then meant looking for different staging places and other points of view on the years of lead. Utilizing its actions, it is a ground principle, and its practices, TML would sow the seeds of the independent theatre group movement, having taken the first steps in the pathway toward an intervention theater that, later on, these groups took upon themselves to continue with. Despite adversities, theatrical experiments that go against the grain of prevailing thoughts are still tenaciously current on the agenda. Doing theater amid commercial pressure is, undoubtedly, a form of provocation, of insubordination to the "hit parade" market, to which Comuna – Teatro Pesquisa, Teatro da Cornucópia, O Bando, Casa da Comédia, A Barraca, the Évora Culture Center and SeivaTrupestill resort.

Abstract Throughout the twentieth century, a large number of studies and authors have confirmed that access, quality of care, and years of healthy living showed a significant relationship to race, ethnicity, income, and social class under the traditional fee-for-service system prevalent in the United States (Abe-Kim & Takeuchi, 1996; Ayanian, 1994; Center for Health Economics Research, 1993; Clinton, 1998; Cole & Pilisuk, 1976; Council on Ethical and Judicial Affairs, 1989; Garretson, 1993; Gaston, Barrett et al., 1998; Hadley, Steinberg et al., 1991; Hawkins & Rosenbaum, 1993; Jang, Lee et al., 1998; Jones & Gray, 1986; Livingston, 1994; Moy & Bartman, 1995; Mutchler & Burr, 1991; McWhorter & Moyer, 1987; Rice & Winn, 1990; Peterson, Wright et al., 1994; Weiss, 1997). These articles and studies show that under the American fee-for-service system the health and mental health problems of low-income people of color were misdiagnosed frequently, diagnosed more severely than the symptoms warranted, but treated less frequently with current medical procedures than were whites, even when there were no differences in ability to pay for services (Mutchler & Burr, 1991; Peterson, Wright et al., 1994).