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Leukemia stem cells utilize cell adhesion molecules like CXCR4/CXCL12 to home to bone marrow stromal niches where they are maintained in a dormant, protected state. Dociparstat sodium (DSTAT, CX-01) is a low anticoagulant heparin with multiple mechanisms of action, including inhibition of the CXCR4/CXCL12 axis, blocking HMGB1, and binding platelet factor 4 (PF-4). We conducted a pilot study adding DSTAT to azacitidine for patients with AML or MDS unresponsive to or relapsed after prior hypomethylating agent therapy, hypothesizing that DSTAT may improve response rates. Twenty patients were enrolled, with a median of 2 prior lines of therapy and 6 cycles of prior hypomethylating agents. Among fifteen patients evaluable for response, there was 1 complete remission, and 3 marrow complete remissions, for a response rate of 27 % among evaluable patients (20 % overall). Hematologic improvement was observed in 5 additional patients. The median overall survival for all enrolled patients was 205 days (95 % CI 119-302). While cytopenias and infections were common, these were not out of proportion to what would be expected in this population of patients undergoing treatment with azacitidine alone. In summary, this trial demonstrated the feasibility of combining DSTAT with azacitidine, with several responses observed, suggesting this combination warrants further study., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Spatial resource subsidies can alter bottom-up and top-down forces of community regulation across ecosystem boundaries. Most subsidies are temporally variable, and recent theory has suggested that consumer-resource dynamics can be stabilized if the peak timing of a subsidy is desynchronized with that of prey productivity in the recipient ecosystem. However, magnitude of consumer responses per se could depend on the subsidy timing, which may be a critical component for community dynamics and ecosystem processes. The aim of this study was to test (i) whether a recipient consumer (cutthroat trout) responds differently to a resource subsidy occurring early in its growing season than to a subsidy occurring late in the season and, if this is the case, (ii) whether the timing-dependent consumer response has cascading effects on communities and ecosystem functions in streams. To test those hypotheses, we conducted a large-scale field experiment, in which we directly manipulated the timing of augmentation of the terrestrial invertebrates that enter stream (i.e. peak timing of June-August vs. August-October), keeping constant the total amounts of the invertebrates entered. We found large increases in the individual growth rate and population biomass of the cutthroat trout, in response to the early resource pulse, but not to the late pulse. This timing-dependent consumer response cascaded down to reduce benthic invertebrates and leaf breakdown rate, and increased water nutrient concentrations. Furthermore, the early resource pulse resulted in higher maturity rate of the cutthroat trout in the following spring, demonstrating the importance of the subsidy timing on long-term community dynamics via the consumer's numerical response. Our results emphasize the need to acknowledge timing-dependent consumer responses in understanding the effects of subsidies on communities and ecosystem processes. Elucidating the mechanisms by which consumers effectively exploit pulsed subsidies is an important avenue to better understand community dynamics in spatially coupled ecosystems., (© 2016 The Authors. Journal of Animal Ecology © 2016 British Ecological Society.)

Purpose: The aim of this study was to estimate the contribution of deleterious mutations in the RAD51B, RAD51C, and RAD51D genes to invasive epithelial ovarian cancer (EOC) in the population and in a screening trial of individuals at high risk of ovarian cancer., Patients and Methods: The coding sequence and splice site boundaries of the three RAD51 genes were sequenced and analyzed in germline DNA from a case-control study of 3,429 patients with invasive EOC and 2,772 controls as well as in 2,000 unaffected women who were BRCA1/BRCA2 negative from the United Kingdom Familial Ovarian Cancer Screening Study (UK&#95;FOCSS) after quality-control analysis., Results: In the case-control study, we identified predicted deleterious mutations in 28 EOC cases (0.82%) compared with three controls (0.11%; P < .001). Mutations in EOC cases were more frequent in RAD51C (14 occurrences, 0.41%) and RAD51D (12 occurrences, 0.35%) than in RAD51B (two occurrences, 0.06%). RAD51C mutations were associated with an odds ratio of 5.2 (95% CI, 1.1 to 24; P = .035), and RAD51D mutations conferred an odds ratio of 12 (95% CI, 1.5 to 90; P = .019). We identified 13 RAD51 mutations (0.65%) in unaffected UK&#95;FOCSS participants (RAD51C, n = 7; RAD51D, n = 5; and RAD51B, n = 1), which was a significantly greater rate than in controls (P < .001); furthermore, RAD51 mutation carriers were more likely than noncarriers to have a family history of ovarian cancer (P < .001)., Conclusion: These results confirm that RAD51C and RAD51D are moderate ovarian cancer susceptibility genes and suggest that they confer levels of risk of EOC that may warrant their use alongside BRCA1 and BRCA2 in routine clinical genetic testing., (© 2015 by American Society of Clinical Oncology.)

Background: Thyrotoxicosis is common in the Australian community and is frequently encountered in general practice. Graves disease, toxic multinodular goitre, toxic adenoma and thyroiditis account for most presentations of thyrotoxicosis., Objective: This article outlines the clinical presentation and evaluation of a patient with thyrotoxicosis. Management of Graves disease, the most frequent cause of thyrotoxicosis, is discussed in further detail., Discussion: The classic clinical manifestations of thyrotoxicosis are often easily recognised by general practitioners. However, the presenting symptoms of thyrotoxicosis are varied, with atypical presentations common in the elderly. Following biochemical confirmation of thyrotoxicosis, a radionuclide thyroid scan is the most useful investigation in diagnosing the underlying cause. The selection of treatment differs according to the cause of thyrotoxicosis and the wishes of the individual patient. The preferred treatment for Graves disease is usually antithyroid drug therapy, almost always carbimazole. The primary treatment of a toxic multinodular goitre or toxic adenoma is usually radioactive iodine therapy. Specific therapy is usually not warranted in cases of thyroiditis, however, treatment directed at symptoms may be required. Referral to an endocrinologist is recommended if thyroiditis is unlikely or has been excluded.

Context: Recent case reports detail the successful use of temozolomide in the management of aggressive pituitary tumours. O(6)-methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein that counteracts the effect of temozolomide., Objective: To study MGMT expression in pituitary tumours and consider whether MGMT expression is associated with response to temozolomide therapy in aggressive pituitary tumours., Patients: We report two patients with aggressive pituitary tumours treated with temozolomide, one who responded to temozolomide and the other who did not. MGMT expression was assessed in a further 88 archived pituitary tumour samples., Design: MGMT expression was assessed by immunohistochemistry. MGMT promoter methylation was studied by methylation-specific polymerase chain reaction (MSP), sequencing of MGMT was performed and loss of heterozygosity (LOH) analysis undertaken., Results: Low MGMT expression and MGMT promoter methylation were found in the pituitary tumour of the patient who responded to temozolomide. Conversely, high MGMT expression was seen in the patient demonstrating a poor response to temozolomide. Eleven out of 88 archived tumour samples (13%) had low MGMT expression. Prolactinomas were more likely to have low MGMT expression compared with other pituitary tumour subtypes (P < 0.001). There was no significant difference in MGMT expression between invasive and noninvasive tumours, or between recurrent and nonrecurrent tumours. A significant inverse correlation was found between MGMT expression and promoter methylation (P = 0.012)., Conclusion: MGMT expression as assessed by immunohistochemistry may predict response to temozolomide therapy in patients with aggressive pituitary tumours. MGMT promoter methylation is likely to explain low MGMT expression in some, but not all, pituitary tumours.

Given high rates of smoking among cancer patients, smoking cessation treatment is crucial; yet limited data exist to guide integration of such trials into the oncologic context. In order to determine the feasibility of conducting smoking cessation clinical trials with cancer patients, screening and baseline data from a large randomized placebo-controlled pharmacotherapy trial were analyzed. Descriptive statistics and regression analyses were used to compare enrollees to decliners, describe program enrollees, and assess correlates of confidence in quitting smoking. Out of 14,514 screened patients, 263 (<2%) were eligible; 43 (16%) refused enrollment. Among the eligible patients, 220 (84%) enrolled. Enrollment barriers included smoking rate, medical history/contraindicated medication, lack of interest, and language. Compared to enrollees, decliners were more likely to have advanced cancer. The trial enrolled a sample of 67 (>30%) African Americans; participants had extensive smoking histories; many were highly nicotine dependent; and participants consumed about seven alcoholic beverages/week on average. Head and neck and breast cancer were the most common tumors. About 52 (25%) reported depressive symptoms. A higher level of confidence to quit smoking was related to lower depression and lower tumor stage. Integrating a smoking cessation clinical trial into the oncologic setting is challenging, yet feasible. Recruitment strategies are needed for patients with advanced disease and specific cancers. Once enrolled, addressing participant's depressive symptoms is critical for promoting cessation.