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Supplementary Figure 1 from Methylation-Independent Silencing of the Tumor Suppressor INK4b (p15) by CBFβ-SMMHC in Acute Myelogenous Leukemia with inv(16)

Supplementary Figure 1 Legend from Methylation-Independent Silencing of the Tumor Suppressor INK4b (p15) by CBFβ-SMMHC in Acute Myelogenous Leukemia with inv(16)

Supplementary Tables 1-2 from Methylation-Independent Silencing of the Tumor Suppressor INK4b (p15) by CBFβ-SMMHC in Acute Myelogenous Leukemia with inv(16)

Important biological and pathologic properties are often conserved across species. Although several mouse leukemia models have been well established, the genes deregulated in both human and murine leukemia cells have not been studied systematically. We performed a serial analysis of gene expression in both human and murine MLL-ELL or MLL-ENL leukemia cells and identified 88 genes that seemed to be significantly deregulated in both types of leukemia cells, including 57 genes not reported previously as being deregulated in MLL-associated leukemias. These changes were validated by quantitative PCR. The most up-regulated genes include several HOX genes (e.g., HOX A5, HOXA9, and HOXA10) and MEIS1, which are the typical hallmark of MLL rearrangement leukemia. The most down-regulated genes include LTF, LCN2, MMP9, S100A8, S100A9, PADI4, TGFBI, and CYBB. Notably, the up-regulated genes are enriched in gene ontology terms, such as gene expression and transcription, whereas the down-regulated genes are enriched in signal transduction and apoptosis. We showed that the CpG islands of the down-regulated genes are hypermethylated. We also showed that seven individual microRNAs (miRNA) from the mir-17-92 cluster, which are overexpressed in human MLL rearrangement leukemias, are also consistently overexpressed in mouse MLL rearrangement leukemia cells. Nineteen possible targets of these miRNAs were identified, and two of them (i.e., APP and RASSF2) were confirmed further by luciferase reporter and mutagenesis assays. The identification and validation of consistent changes of gene expression in human and murine MLL rearrangement leukemias provide important insights into the genetic base for MLL-associated leukemogenesis. [Cancer Res 2009;69(3):OF1109–16]

Supplementary Tables 5-8 from Consistent Deregulation of Gene Expression between Human and Murine MLL Rearrangement Leukemias

The tumor suppressor gene INK4b (p15) is silenced by CpG island hypermethylation in most acute myelogenous leukemias (AML), and this epigenetic phenomenon can be reversed by treatment with hypomethylating agents. Thus far, it was not investigated whether INK4b is hypermethylated in all cytogenetic subtypes of AML. A comparison of levels of INK4b methylation in AML with the three most common cytogenetic alterations, inv(16), t(8;21), and t(15;17), revealed a strikingly low level of methylation in all leukemias with inv(16) compared with the other types. Surprisingly, the expression level of INK4b in inv(16)+ AML samples was low and comparable with that of the other subtypes. An investigation into an alternative mechanism of INK4b silencing determined that the loss of INK4b expression was caused by inv(16)-encoded core binding factor β-smooth muscle myosin heavy chain (CBFβ-SMMHC). The silencing was manifested in an inability to activate the normal expression of INK4b RNA as shown in vitamin D3–treated U937 cells expressing CBFβ-SMMHC. CBFβ-SMMHC was shown to displace RUNX1 from a newly determined CBF site in the promoter of INK4b. Importantly, this study (a) establishes that the gene encoding the tumor suppressor p15INK4b is a target of CBFβ-SMMHC, a finding relevant to the leukemogenesis process, and (b) indicates that, in patients with inv(16)-containing AML, reexpression from the INK4b locus in the leukemia would not be predicted to occur using hypomethylating drugs. [Cancer Res 2007;67(3):992–1000]

Supplementary Tables 1-4 from Consistent Deregulation of Gene Expression between Human and Murine MLL Rearrangement Leukemias

Age-related changes of intracortical myelin in bipolar disorder (BD) have been observed to deviate from the quadratic age curve observed in healthy controls (HC), but it is unclear if this holds at varying cortical depths. From BD (n = 44; age range = 17.6–45.5 years) and HC (n = 60; age range = 17.1–45.8 years) participants, we collected 3T T1-weighted (T1w) images with strong intracortical contrast. Signal values were sampled from 3 equivolume cortical depths. Linear mixed models were used to compare age-related changes in the T1w signal between depths and between groups at each depth. In HC, the age-related changes were significantly different between the superficial one-fourth depth and the deeper depths in the right ventral somatosensory (t = −4.63; FDRp = 0.00025), left dorsomedial somatosensory (t = −3.16; FDRp = 0.028), left rostral ventral premotor (t = −3.16; FDRp = 0.028), and right ventral inferior parietal cortex (t = −3.29; FDRp = 0.028). BD participants exhibited no differences in the age-related T1w signal between depths. Illness duration was negatively correlated with the T1w signal at the one-fourth depth in the right anterior cingulate cortex (rACC; rho = −0.50; FDRp = 0.029). Physiological age-related and depth-specific variation in the T1w signal were not observed in BD. The T1w signal in the rACC may reflect lifetime disease burden in the disorder.

Cancer patients often want information from "peers" with the same diagnosis or treatment. To increase access to this valuable resource, we developed a website to deliver written peer support to cancer patients undergoing stem cell transplant. Because little evidence describes how to optimize benefits or reduce potential harms of written peer support, we gathered multiple forms of stakeholder feedback to inform the website's ethical approach, personalization, design, function, and content: a Community Advisory Board; a longitudinal study of patients' written peer support needs and motivations; focus groups; semi-structured interviews; and usability testing. Findings provide a rich foundation for website development.

Hematopoietic stem cell transplantation (HSCT) is an effective treatment for most hematological malignancies. Autologous HSCT targets malignancies in a dose-responsive manner, but regimen-related toxicities limit the intensity of the treatment regimen that can be given. Autologous HSCT may serve as a platform for subsequent therapies. Allogeneic HSCT offers a form of immunotherapy against malignancies, as demonstrated by a powerful graft-versus-tumor (GvT) effect in some malignancies. Allogeneic HSCT, however, has a higher incidence of morbidity and mortality from the similar graft-versus-host disease (GvHD), and maintaining a fine balance between GvT and GvHD is a continuing area of evolution, expertise, and research. The subtle nuances of donor selection, degree of human leukocyte antigen (HLA) disparity, type of conditioning regimen, and the choice of stem cell source all influence the outcome of allogeneic HSCT. Relapse is the most common cause of failure of autologous and allogeneic HSCT, and the use of immunotherapy during and/or after HSCT is the focus of research in this decade.

Southwest Utah contains what may be the largest landslide complex on land in the world. This complex includes three ancient side-by-side gigantic slides that cover an area roughly the size of Yellowstone National Park with a volume of slide debris that would nearly fill the Grand Canyon to its rim. Geologists call it the Marysvale gravity slide complex— “Marysvale” for the namesake volcanic field that partly failed catastrophically three separate times, and “gravity slide” to call attention to a special class of extremely large and geologically complex landslides several tens to thousands of square miles in extent. Here we refer to them simply as mega-landslides or slides—they are larger and far more interesting than geologists could ever have imagined.

PURPOSE In this work, we propose that Δ B1+ -induced errors in magnetization transfer (MT) saturation (MTsat ) maps can be corrected with use of an R1 and B1+ map and through numerical simulations of the sequence. THEORY AND METHODS One healthy subject was scanned at 3.0T using a partial quantitative MT protocol to estimate the relationship between observed R1 (R1,obs ) and apparent bound pool size ( M0,appB ) in the brain. MTsat values were simulated for a range of B1+ , R1,obs , and M0,appB . An equation was fit to the simulated MTsat , then a linear relationship between R1,obs and M0,appB was generated. These results were used to generate correction factor maps for the MTsat acquired from single-point data. The proposed correction was compared to an empirical correction factor with different MT-preparation schemes. RESULTS M0,appB was highly correlated with R1,obs (r > 0.96), permitting the use of R1,obs to estimate M0,appB for B1+ correction. All B1+ corrected MTsat maps displayed a decreased correlation with B1+ compared to uncorrected MTsat and MTsat corrected with an empirical factor in the corpus callosum. There was good agreement between the proposed approach and the empirical correction with radiofrequency saturation at 2 kHz, with larger deviations seen when using saturation pulses further off-resonance and in inhomogeneous (ih) MTsat maps. CONCLUSION The proposed correction decreases the dependence of MTsat on B1+ inhomogeneities. Furthermore, this flexible framework permits the use of different saturation protocols, making it useful for correcting B1+ inhomogeneities in ihMT.

PURPOSE: Cancer survivors frequently describe wanting to learn from others who have had similar diagnoses or treatments (peer support). We conducted focus groups to investigate hematopoietic stem cell transplant survivors’ attitudes and preferences regarding accessing written peer support through a website. Although written peer support does not allow for interpersonal interactions with peers, it could increase transplant recipients’ access to evidence-based benefits of informational and emotional peer support. METHODS: We conducted four videoconference focus groups with 34 adult transplant survivors who were diverse in their medical and sociodemographic characteristics and geographic location. Discussions were recorded, transcribed, and content analyzed. RESULTS: Many participants reported need for information about transplant beyond what they received from their healthcare providers. Needs varied across participants, as did preferences for characteristics and timing of information optimally provided through peer support. Participants were enthusiastic about the value of written peer support but emphasized that it should be delivered in a way that accommodates variation in transplant experiences, underscores its trustworthiness, and pairs it with useful psychoeducational content. CONCLUSIONS: Findings provide guidance for making written peer support an accessible, supportive resource for transplant survivors. Future research should evaluate personalized online delivery of written peer support paired with psychoeducational content that enhances its benefits. IMPLICATIONS FOR CANCER SURVIVORS: Written peer support delivered online could be a useful, valued resource for transplant survivors.

We evaluated standard-of-care (SOC) treatment with or without midostaurin to prevent relapse following allogeneic hematopoietic stem cell transplant (alloHSCT) in patients with acute myeloid leukemia (AML) harboring internal tandem duplication (ITD) in FLT3. Adults (aged 18–70 years) who received alloHSCT in first complete remission, had achieved hematologic recovery, and were transfusion independent were randomized to receive SOC with or without midostaurin (50 mg twice daily) continuously in twelve 4-week cycles. The primary endpoint was relapse-free survival (RFS) 18 months post-alloHSCT. Sixty patients were randomized (30/arm); 30 completed all 12 cycles (midostaurin + SOC, n = 16; SOC, n = 14). The estimated 18-month RFS (95% CI) was 89% (69–96%) in the midostaurin arm and 76% (54–88%) in the SOC arm (hazard ratio, 0.46 [95% CI, 0.12–1.86]; P = 0.27); estimated relapse rates were 11% and 24%, respectively. Inhibition of FLT3 phosphorylation to FLT3-ITD AML. (ClinicalTrials.gov identifier: NCT01883362).

Background: As the global outbreak of COVID-19 continues to ravage the world, it is important to understand how frontline clinicians manage ventilatory support and the various limiting factors. / Methods: An online survey composed of 32 questions was developed and validated by an international expert panel. / Results: Overall, 502 respondents from 40 countries across six continents completed the survey. The mean number (±SD) of ICU beds was 64 ± 84. The most popular initial diagnostic tools used for treatment initiation were arterial blood gas (48%) and clinical presentation (37.5%), while the national COVID-19 guidelines were the most used (61.2%). High flow nasal cannula (HFNC) (53.8%), non-invasive ventilation (NIV) (47%), and invasive mechanical ventilation (IMV) (92%) were mostly used for mild, moderate, and severe COVID-19 cases, respectively. However, only 38.8%, 56.6% and 82.9% of the respondents had standard protocols for HFNC, NIV, and IMV, respectively. The most frequently used modes of IMV and NIV were volume control (VC) (36.1%) and continuous positive airway pressure/pressure support (CPAP/PS) (40.6%). About 54% of the respondents did not adhere to the recommended, regular ventilator check interval. The majority of the respondents (85.7%) used proning with IMV, with 48.4% using it for 12– 16 hours, and 46.2% had tried awake proning in combination with HFNC or NIV. Increased staff workload (45.02%), lack of trained staff (44.22%) and shortage of personal protective equipment (PPE) (42.63%) were the main barriers to COVID-19 management. / Conclusion: Our results show that general clinical practices involving ventilatory support were highly heterogeneous, with limited use of standard protocols and most frontline clinicians depending on isolated and varied management guidelines. We found increased staff workload, lack of trained staff and shortage of PPE to be the main limiting factors affecting global COVID-19 ventilatory support management.

Psychosocial functioning in bipolar disorder (BD) persists even during euthymia and has repeatedly been associated with illness progression and cognitive function. Its neurobiological correlates remain largely unexplored. Using a structural covariance approach, we explored whole cortex intracortical myelin (ICM) and psychosocial functioning in 39 BD type I and 58 matched controls.TIn BD only, psychosocial functioning was associated with global efficiency (β = -0.312, pThese results uncovered a novel brain-behaviour relationship between intracortical myelin signal changes and psychosocial functioning in BD.

Noise pollution can reduce the quality and even the length of our lives, causing around 12,000 early deaths in Europe each year. Devices called resonators can be used to reduce unwanted noise from engines and fans, by cancelling out sound waves. However, the sound waves of low-pitched noises are difficult to cancel because they are very big: sometimes as long as 17 m! To cancel such large sound waves would require an impractically large resonator. One solution to this problem is to make the resonator from a special class of material called a metamaterial. Metamaterials have specially designed structures that give them properties that are not found in ordinary materials. This article explains how we used mathematics to design a metamaterial that slows down sound waves. Slowing the sound allows us to use smaller resonators, so we can cancel lower-pitched noises than we can with ordinary materials.

Patients with high-risk multiple myeloma (hrMM) relapse after autologous stem cell transplantation (ASCT) with a median progression free survival (PFS) of 8-14 months without lenalidomide maintenance and 24-39 months with lenalidomide maintenance. We hypothesized that Pembro-Rd will prolong PFS post-ASCT in patients with hrMM compared to historical controls. This Phase II study enrolled hrMM patients with primary objective to assess the efficacy of the combination of Pembro-Rd for a total of 2 cycles and then an additional 2 cycles without dexamethasone. There were 12 evaluable subjects, as enrollment was stopped after an FDA hold. With a median follow-up of 50.7 months, the median PFS was 27.7 months. The PFS rates at years 1 and 2 are 90.9% and 63.6%, respectively. The most common adverse events were neutropenia (grade 1-3), cough, diarrhea and constipation, all grade 1 or 2. The PFS rate with fixed duration therapy was comparable to that seen with continuous dose lenalidomide, potentially offering a new post-ASCT therapeutic strategy. This article is protected by copyright. All rights reserved.

Cedar Breaks National Monument straddles the western rim of the Markagunt Plateau, and, at over 10,000 feet (3050 m) in elevation, offers spectacular views westward into the adjacent Great Basin. The heart of the monument consists of a series of overlooks along a beautiful, 4-mile-long (6 km), west-facing amphitheater that is eroded into the plateau’s margin. These overlooks are adorned with a fantastic variety of hoodoos and sculpted fins eroded from alternating resistant and soft, jointed and fractured layers of the Claron Formation. Of these overlooks, the North View Overlook encapsulates the entire geologic story preserved at Cedar Breaks—a history not only of the enigmatic Claron Formation, but also of the demise of its depositional basin and eventual burial by volcanic sediments of the Brian Head Formation.

Exercise has been shown to counteract age-related volume decreases in the human brain, and in this imaging study, we ask whether the same holds true for the microstructure of the cortex. Healthy older adults (n = 47, 65-90 years old) either exercised three times a week on a stationary bike or maintained their usual physical routine over a 12-week period. Quantitative longitudinal relaxation rate (R1 ) magnetic resonance imaging (MRI) maps were made at baseline and after the 12-week intervention. R1 is commonly taken to reflect cortical myelin density. The change in R1 (ΔR1 ) was significantly increased in a region of interest (ROI) in the primary motor cortex containing motor outputs to the leg musculature in the exercise group relative to the control group (p = .04). The change in R1 in this ROI correlated with an increase in oxygen consumption at the first ventilatory threshold (VT1) (p = .04), a marker of improvement in submaximal aerobic performance. An exploratory analysis across the cortex suggested that the correlation was predominately confined to the leg representation in the motor cortex. This study suggests that microstructural declines in the cortex of older adults may be staved off by exercise.