Citations

Abstract IFN regulatory factor 4 (IRF4) is a key transcription factor that promotes effector CD8+ T cell differentiation and expansion. The roles of IRF4 in regulating the CD8+ T cell response to cytokines have not been explored. In this article, we show that IL-2 and IL-15 signaling and STAT5 activation regulate IRF4 expression in CD8+ T cells. Gene-expression profile analysis has also revealed that IRF4 is required for expression of the receptors of IL-2 family cytokines CD122 and CD127. We found that IRF4 binds directly to CD122 and CD127 gene loci, indicating that it may directly promote CD122 and CD127 gene transcription. As a consequence, IRF4-deficient CD8+ T cells show diminished sensitivity to IL-2, IL-15, and IL-7 treatment in vitro. Furthermore, we found that IRF4-deficient CD8+ T cells had lower expression of CD122 and CD127 in vivo during influenza virus infection. These data suggest that IRF4 regulates the sensitivity of CD8+ T cells to IL-2 family cytokines, which correlates with the diminished effector and memory CD8+ T cell responses in IRF4-deficient CD8+ T cells.

AbstractPurposeThe purpose of this guideline is to provide a list of critical performance tests in order to assist the Qualified Medical Physicist (QMP) in establishing and maintaining a safe and effective quality assurance (QA) program. The performance tests on a linear accelerator (linac) should be selected to fit the clinical patterns of use of the accelerator and care should be given to perform tests which are relevant to detecting errors related to the specific use of the accelerator.MethodsA risk assessment was performed on tests from current task group reports on linac QA to highlight those tests that are most effective at maintaining safety and quality for the patient. Recommendations are made on the acquisition of reference or baseline data, the establishment of machine isocenter on a routine basis, basing performance tests on clinical use of the linac, working with vendors to establish QA tests and performing tests after maintenance.ResultsThe recommended tests proposed in this guideline were chosen based on the results from the risk analysis and the consensus of the guideline's committee. The tests are grouped together by class of test (e.g., dosimetry, mechanical, etc.) and clinical parameter tested. Implementation notes are included for each test so that the QMP can understand the overall goal of each test.ConclusionThis guideline will assist the QMP in developing a comprehensive QA program for linacs in the external beam radiation therapy setting. The committee sought to prioritize tests by their implication on quality and patient safety. The QMP is ultimately responsible for implementing appropriate tests. In the spirit of the report from American Association of Physicists in Medicine Task Group 100, individual institutions are encouraged to analyze the risks involved in their own clinical practice and determine which performance tests are relevant in their own radiotherapy clinics.

Objectives: Delirium severity is independently associated with longer hospital stays, nursing home placement, and death in patients outside the ICU. Delirium severity in the ICU is not routinely measured because the available instruments are difficult to complete in critically ill patients. We designed our study to assess the reliability and validity of a new ICU delirium severity tool, the Confusion Assessment Method for the ICU-7 delirium severity scale. Design: Observational cohort study. Setting: Medical, surgical, and progressive ICUs of three academic hospitals. Patients: Five hundred eighteen adult (≥ 18 yr) patients. Interventions: None. Measurements and Main Results: Patients received the Confusion Assessment Method for the ICU, Richmond Agitation-Sedation Scale, and Delirium Rating Scale-Revised-98 assessments. A 7-point scale (0–7) was derived from responses to the Confusion Assessment Method for the ICU and Richmond Agitation-Sedation Scale items. Confusion Assessment Method for the ICU-7 showed high internal consistency (Cronbach’s α = 0.85) and good correlation with Delirium Rating Scale-Revised-98 scores (correlation coefficient = 0.64). Known-groups validity was supported by the separation of mechanically ventilated and nonventilated assessments. Median Confusion Assessment Method for the ICU-7 scores demonstrated good predictive validity with higher odds (odds ratio = 1.47; 95% CI = 1.30–1.66) of in-hospital mortality and lower odds (odds ratio = 0.8; 95% CI = 0.72–0.9) of being discharged home after adjusting for age, race, gender, severity of illness, and chronic comorbidities. Higher Confusion Assessment Method for the ICU-7 scores were also associated with increased length of ICU stay (p = 0.001). Conclusions: Our results suggest that Confusion Assessment Method for the ICU-7 is a valid and reliable delirium severity measure among ICU patients. Further research comparing it to other delirium severity measures, its use in delirium efficacy trials, and real-life implementation is needed to determine its role in research and clinical practice.

OBJECTIVE Defects in the apoptotic machinery and augmented survival signals contribute to drug resistance in glioblastoma (GBM). Moreover, another complexity related to GBM treatment is the concept that GBM development and recurrence may arise from the expression of GBM stem cells (GSCs). Therefore, the use of a multifaceted approach or multitargeted agents that affect specific tumor cell characteristics will likely be necessary to successfully eradicate GBM. The objective of this study was to investigate the usefulness of sulforaphane (SFN)—a constituent of cruciferous vegetables with a multitargeted effect—as a therapeutic agent for GBM. METHODS The inhibitory effects of SFN on established cell lines, early primary cultures, CD133-positive GSCs, GSC-derived spheroids, and GBM xenografts were evaluated using various methods, including GSC isolation and the sphere-forming assay, analysis of reactive oxygen species (ROS) and apoptosis, cell growth inhibition assay, comet assays for assessing SFN-triggered DNA damage, confocal microscopy, Western blot analysis, and the determination of in vivo efficacy as assessed in human GBM xenograft models. RESULTS SFN triggered the significant inhibition of cell survival and induced apoptotic cell death, which was associated with caspase 3 and caspase 7 activation. Moreover, SFN triggered the formation of mitochondrial ROS, and SFN-triggered cell death was ROS dependent. Comet assays revealed that SFN increased single- and double-strand DNA breaks in GBM. Compared with the vehicle control cells, a significantly higher amount of γ-H2AX foci correlated with an increase in DNA double-strand breaks in the SFN-treated samples. Furthermore, SFN robustly inhibited the growth of GBM cell–induced cell death in established cell cultures and early-passage primary cultures and, most importantly, was effective in eliminating GSCs, which play a major role in drug resistance and disease recurrence. In vivo studies revealed that SFN administration at 100 mg/kg for 5-day cycles repeated for 3 weeks significantly decreased the growth of ectopic xenografts that were established from the early passage of primary cultures of GBM10. CONCLUSIONS These results suggest that SFN is a potent anti-GBM agent that targets several apoptosis and cell survival pathways and further preclinical and clinical studies may prove that SFN alone or in combination with other therapies may be potentially useful for GBM therapy.

IgA nephropathy frequently leads to progressive CKD. Although interest surrounds use of immunosuppressive agents added to standard therapy, several recent studies have questioned efficacy of these agents. Depleting antibody–producing B cells potentially offers a new therapy. In this open label, multicenter study conducted over 1-year follow-up, we randomized 34 adult patients with biopsy–proven IgA nephropathy and proteinuria >1 g/d, maintained on angiotensin–converting enzyme inhibitors or angiotensin receptor blockers with well controlled BP and eGFR<90 ml/min per 1.73 m 2 , to receive standard therapy or rituximab with standard therapy. Primary outcome measures included change in proteinuria and change in eGFR. Median baseline serum creatinine level (range) was 1.4 (0.8–2.4) mg/dl, and proteinuria was 2.1 (0.6–5.3) g/d. Treatment with rituximab depleted B cells and was well tolerated. eGFR did not change in either group. Rituximab did not alter the level of proteinuria compared with that at baseline or in the control group; three patients in each group had ≥50% reduction in level of proteinuria. Serum levels of galactose-deficient IgA1 or antibodies against galactose-deficient IgA1 did not change. In this trial, rituximab therapy did not significantly improve renal function or proteinuria assessed over 1 year. Although rituximab effectively depleted B cells, it failed to reduce serum levels of galactose-deficient IgA1 and antigalactose–deficient IgA1 antibodies. Lack of efficacy of rituximab, at least at this stage and severity of IgA nephropathy, may reflect a failure of rituximab to reduce levels of specific antibodies assigned salient pathogenetic roles in IgA nephropathy.

Medical care providers recognize nonadjustable examination tables in clinics as a barrier to comprehensively and safely providing routine healthcare for disabled, elderly and obese patients. The aim of this study was to understand how the availability of the adjustable examination table may affect the medical care provider’s perception of the quality of care provided to patients who need physical assistance. Fifty providers answered questionnaires to report their perceptions of two different examination tables’ usability. The first one is a mid-century industrial designed table and the other adjustable and ADA compliant, as used in a community health clinic. Before implementation of the new adjustable examination table, 34 medical care providers provided feedback on their experiences with nonadjustable examination tables. A second survey was administered approximately six months after implementation of the new adjustable examination tables to 16 medical care providers (with 2 indicating participation in the prior-to-implementation survey) for their feedback on experiences with the new adjustable examination tables. Providers reported significantly (p<0.05) more comfort in getting typical patients (27%), bariatric patients (50%), and geriatric patients (30%) into a sitting position when they used the adjustable examination table compared to the nonadjustable examination table. Providers considered the adjustable examination tables to have a more ideal width (60%) and length (64%) to accommodate a wider variety of patients than the nonadjustable examination tables. Providers also considered the adjustable table (33%) easier to use and preferable to the nonadjustable table. This research showed how the adjustable examination table improves healthcare provider experience to provide access to healthcare for patients with disabilities with better ergonomics and greater safety for both patients and providers.