The metabolism of estrogen

Dissertation (Ph.D)--Boston University, 1944. This item was digitized by the Internet Archive

Structural and Functional Organization of Macroarthropod Communities in a Mined Versus a Pristine Stream in the Cumberland Mountains of Eastern Tennessee

The effects of surface mining coal on the structural and functional organization of macroarthropod communities as a result of changes in the physical structure of small streams was investigated. Two first order streams in the Cumberland Mountains of eastern Tennessee, a pristine reference stream and a stream mined approximately 15 years earlier, were compared for particulate organic matter (POM) dynamics, structural and functional group composition, and productivity of their mecroarthropod communities. POM dynamics of the two streams were compared by measuring their input, standing stock, and processing in each stream. Macroinvertebrates were sampled with standard Surber samplers. The community structure of the two streams was compared in terms of taxonomic composition, abundance, species richness, and Shannon diversity. Functional group composition of the macroarthropod communities were compared using the functional group classification of Merritt and Cummins (1984). Productivity of the dominant taxa was calculated by the size-frequency method. The total productivity and productivity within functional feeding groups were then compared. Input and standing stock of POM in the two streams was similar. Faster rates of POM processing in the mined stream resulted from greater macroarthropod shredder densities. Differences in POM processing, macroarthropod functional group composition, and productivity within functional groups between the two streams suggest that their macroarthropod communities are functionally different. The lower abundance, species richness, and diversity were typical of the structural differences reported for other macroarthropod communities in mined streams of this region. Overall productivity of the surface mined stream was similar to the reference stream, although it was disturbed differently between functional groups. The results indicated that analysis of the functional group organization of mined streams reveals important differences in their ecology which could be underestimated or overlooked by conventional indices of community structure. Taxonomic surveys and diversity indices provide useful tools for monitoring and detection of environmental degradation. However, additional understanding of the causal relationships between environmental disturbance and biological change can be obtained from a functional approach which can identify its effects on specific biological processes in the stream community

E5501: phase II study of topotecan sequenced with etoposide/cisplatin, and irinotecan/cisplatin sequenced with etoposide for extensive-stage small-cell lung cancer.

PURPOSE: Sequence-dependent improved efficacy of topoisomerase I followed by topoisomerase 2 inhibitors was assessed in a randomized phase II study in extensive-stage small-cell lung cancer (SCLC). METHODS: Patients with previously untreated extensive-stage SCLC with measurable disease, ECOG performance status of 0-3 and stable brain metastases were eligible. Arm A consisted of topotecan (0.75 mg/m(2)) on days 1, 2 and 3, etoposide (70 mg/m(2)) and cisplatin (20 mg/m(2)) (PET) on days 8, 9 and 10 in a 3-week cycle. Arm B consisted of irinotecan (50 mg/m(2)) and cisplatin (20 mg/m(2)) on days 1 and 8 followed by etoposide (85 mg/m(2) PO bid) on days 3 and 10 (PIE) in a 3-week cycle. RESULTS: We enrolled 140 patients and randomized 66 eligible patients to each arm. Only 54.5 % of all patients completed the planned maximum 6 cycles. There were grade ≥3 treatment-related adverse events in approximately 70 % of the patients on both arms including 6 treatment-related grade 5 events. The overall response rates (CR + PR) were 69.7 % (90 % CI 59.1-78.9, 95 % CI 57.1-80.4 %) for arm A and 57.6 % (90 % CI 46.7-67.9, 95 % CI 44.8-69.7 %) for arm B. The median progression-free survival and overall survival were 6.4 months (95 % CI 5.4-7.5 months) and 11.9 months (95 % CI 9.6-13.7 months) for arm A and 6.0 months (95 % CI 5.4-7.0 months) and 11.0 months (95 % CI 8.6-13.1 months) for arm B. CONCLUSION: Sequential administration of topoisomerase inhibitors did not improve on the historical efficacy of standard platinum-doublet chemotherapy for extensive-stage SCLC

Characteristics of multi-institutional health sciences education research: a systematic review

Objectives: Multi-institutional research increases the generalizability of research findings. However, little is known about characteristics of collaborations across institutions in health sciences education research. Using a systematic review process, the authors describe characteristics of published, peer-reviewed multi-institutional health sciences education research to inform educators who are considering such projects. Methods: Two medical librarians searched MEDLINE, the Education Resources Information Center (ERIC), EMBASE, and CINAHL databases for English-language studies published between 2004 and 2013 using keyword terms related to multi-institutional systems and health sciences education. Teams of two authors reviewed each study and resolved coding discrepancies through consensus. Collected data points included funding, research network involvement, author characteristics, learner characteristics, and research methods. Data were analyzed using descriptive statistics. Results: One hundred eighteen of 310 articles met inclusion criteria. Sixty-three (53%) studies received external and/or internal financial support (87% listed external funding, 37% listed internal funding). Forty-five funded studies involved graduate medical education programs. Twenty (17%) studies involved a research or education network. Eighty-five (89%) publications listed an author with a master’s degree or doctoral degree. Ninety-two (78%) studies were descriptive, whereas 26 studies (22%) were experimental. The reported study outcomes were changes in student attitude (38%; n=44), knowledge (26%; n=31), or skill assessment (23%; n=27), as well as patient outcomes (9%; n=11). Conclusions: Multi-institutional descriptive studies reporting knowledge or attitude outcomes are highly published. Our findings indicate that funding resources are not essential to successfully undertake multi-institutional projects. Funded studies were more likely to originate from graduate medical or nursing programs

A Phase 1 study of intravenous infusions of tigecycline in patients with acute myeloid leukemia.

Acute myeloid leukemia (AML) cells meet the higher energy, metabolic, and signaling demands of the cell by increasing mitochondrial biogenesis and mitochondrial protein translation. Blocking mitochondrial protein synthesis through genetic and chemical approaches kills human AML cells at all stages of development in vitro and in vivo. Tigecycline is an antimicrobial that we found inhibits mitochondrial protein synthesis in AML cells. Therefore, we conducted a phase 1 dose-escalation study of tigecycline administered intravenously daily 5 of 7 days for 2 weeks to patients with AML. A total of 27 adult patients with relapsed and refractory AML were enrolled in this study with 42 cycles being administered over seven dose levels (50-350 mg/day). Two patients experienced DLTs related to tigecycline at the 350 mg/day level resulting in a maximal tolerated dose of tigecycline of 300 mg as a once daily infusion. Pharmacokinetic experiments showed that tigecycline had a markedly shorter half-life in these patients than reported for noncancer patients. No significant pharmacodynamic changes or clinical responses were observed. Thus, we have defined the safety of once daily tigecycline in patients with refractory AML. Future studies should focus on schedules of the drug that permit more sustained target inhibition

Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study.

BackgroundInternal tandem duplication mutations in FLT3 are common in acute myeloid leukaemia and are associated with rapid relapse and short overall survival. The clinical benefit of FLT3 inhibitors in patients with acute myeloid leukaemia has been limited by rapid generation of resistance mutations, particularly in codon Asp835 (D835). We aimed to assess the highly selective oral FLT3 inhibitor gilteritinib in patients with relapsed or refractory acute myeloid leukaemia.MethodsIn this phase 1-2 trial, we enrolled patients aged 18 years or older with acute myeloid leukaemia who either were refractory to induction therapy or had relapsed after achieving remission with previous treatment. Patients were enrolled into one of seven dose-escalation or dose-expansion cohorts assigned to receive once-daily doses of oral gilteritinib (20 mg, 40 mg, 80 mg, 120 mg, 200 mg, 300 mg, or 450 mg). Cohort expansion was based on safety and tolerability, FLT3 inhibition in correlative assays, and antileukaemic activity. Although the presence of an FLT3 mutation was not an inclusion criterion, we required ten or more patients with locally confirmed FLT3 mutations (FLT3mut+) to be enrolled in expansion cohorts at each dose level. On the basis of emerging findings, we further expanded the 120 mg and 200 mg dose cohorts to include FLT3mut+ patients only. The primary endpoints were the safety, tolerability, and pharmacokinetics of gilteritinib. Safety and tolerability were assessed in the safety analysis set (all patients who received at least one dose of gilteritinib). Responses were assessed in the full analysis set (all patients who received at least one dose of study drug and who had at least one datapoint post-treatment). Pharmacokinetics were assessed in a subset of the safety analysis set for which sufficient data for concentrations of gilteritinib in plasma were available to enable derivation of one or more pharmacokinetic variables. This study is registered with ClinicalTrials.gov, number NCT02014558, and is ongoing.FindingsBetween Oct 15, 2013, and Aug 27, 2015, 252 adults with relapsed or refractory acute myeloid leukaemia received oral gilteritinib once daily in one of seven dose-escalation (n=23) or dose-expansion (n=229) cohorts. Gilteritinib was well tolerated; the maximum tolerated dose was established as 300 mg/day when two of three patients enrolled in the 450 mg dose-escalation cohort had two dose-limiting toxicities (grade 3 diarrhoea and grade 3 elevated aspartate aminotransferase). The most common grade 3-4 adverse events irrespective of relation to treatment were febrile neutropenia (97 [39%] of 252), anaemia (61 [24%]), thrombocytopenia (33 [13%]), sepsis (28 [11%]), and pneumonia (27 [11%]). Commonly reported treatment-related adverse events were diarrhoea (92 [37%] of 252]), anaemia (86 [34%]), fatigue (83 [33%]), elevated aspartate aminotransferase (65 [26%]), and increased alanine aminotransferase (47 [19%]). Serious adverse events occurring in 5% or more of patients were febrile neutropenia (98 [39%] of 252; five related to treatment), progressive disease (43 [17%]), sepsis (36 [14%]; two related to treatment), pneumonia (27 [11%]), acute renal failure (25 [10%]; five related to treatment), pyrexia (21 [8%]; three related to treatment), bacteraemia (14 [6%]; one related to treatment), and respiratory failure (14 [6%]). 95 people died in the safety analysis set, of which seven deaths were judged possibly or probably related to treatment (pulmonary embolism [200 mg/day], respiratory failure [120 mg/day], haemoptysis [80 mg/day], intracranial haemorrhage [20 mg/day], ventricular fibrillation [120 mg/day], septic shock [80 mg/day], and neutropenia [120 mg/day]). An exposure-related increase in inhibition of FLT3 phosphorylation was noted with increasing concentrations in plasma of gilteritinib. In-vivo inhibition of FLT3 phosphorylation occurred at all dose levels. At least 90% of FLT3 phosphorylation inhibition was seen by day 8 in most patients receiving a daily dose of 80 mg or higher. 100 (40%) of 249 patients in the full analysis set achieved a response, with 19 (8%) achieving complete remission, ten (4%) complete remission with incomplete platelet recovery, 46 (18%) complete remission with incomplete haematological recovery, and 25 (10%) partial remission INTERPRETATION: Gilteritinib had a favourable safety profile and showed consistent FLT3 inhibition in patients with relapsed or refractory acute myeloid leukaemia. These findings confirm that FLT3 is a high-value target for treatment of relapsed or refractory acute myeloid leukaemia; based on activity data, gilteritinib at 120 mg/day is being tested in phase 3 trials.FundingAstellas Pharma, National Cancer Institute (Leukemia Specialized Program of Research Excellence grant), Associazione Italiana Ricerca sul Cancro

Evaluating visible derivative spectroscopy by varimax-rotated, principal component analysis of aerial hyperspectral images from the western basin of Lake Erie

The Kent State University (KSU) spectral decomposition method provides information about the spectral signals present in multispectral and hyperspectral images. Pre-processing steps that enhance signal to noise ratio (SNR) by 7.37–19.04 times, enables extraction of the environmental signals captured by the National Aeronautics and Space Administration (NASA) Glenn Research Center\u27s, second generation, Hyperspectral imager (HSI2) into multiple, independent components. We have accomplished this by pre-processing of Level 1 HSI2 data to remove stripes from the scene, followed by a combination of spectral and spatial smoothing to further increase the SNR and remove non-Lambertian features, such as waves. On average, the residual stochastic noise removed from the HSI2 images by this method is 5.43 ± 1.42%. The method also enables removal of a spectrally coherent residual atmospheric bias of 4.28 ± 0.48%, ascribed to incomplete atmospheric correction. The total noise isolated from signal by the method is thu