Myeloid cell subsets that express latency-associated peptide promote cancer growth by modulating T cells.

Myeloid suppressor cells promote tumor growth by a variety of mechanisms which are not fully characterized. We identified myeloid cells (MCs) expressing the latency-associated peptide (LAP) of TGF-ß on their surface and LAPHi MCs that stimulate Foxp3+ Tregs while inhibiting effector T cell proliferation and function. Blocking TGF-ß inhibits the tolerogenic ability of LAPHi MCs. Furthermore, adoptive transfer of LAPHi MCs promotes Treg accumulation and tumor growth in vivo. Conversely, anti-LAP antibody, which reduces LAPHi MCs, slows cancer progression. Single-cell RNA-Seq analysis on tumor-derived immune cells revealed LAPHi dominated cell subsets with distinct immunosuppressive signatures, including those with high levels of MHCII and PD-L1 genes. Analogous to mice, LAP is expressed on myeloid suppressor cells in humans, and these cells are increased in glioma patients. Thus, our results identify a previously unknown function by which LAPHi MCs promote tumor growth and offer therapeutic intervention to target these cells in cancer.

Myeloablative Versus Reduced Intensity Conditioning Regimens for Allogeneic Hematopoietic Stem Cell Transplant for Acute Myeloid Leukemia and Myelodysplastic Syndrome: A Retrospective Analysis.

The conditioning regimens used for the allo-HSCT include either myeloablative conditioning (MAC) or reduced intensity conditioning (RIC) regimens based on the age, performance status and co-morbidities. Studies comparing the survival outcomes of RIC and MAC allo-HSCT in AML and MDS patients have reported contradictory results. We therefore retrospectively analyzed our data of AML and MDS patients who received MAC and RIC allo-HSCT at our center and compared the long term outcome of the two conditioning regimens. One hundred twenty six consecutive patients were evaluated, 32 (25.4%) underwent MAC allo-HSCT and 94 (74.6%) underwent RIC allo-HSCT. The most common MAC regimen used was busulfan plus cyclophosphamide and the most common RIC regimen used was fludarabine plus melphalan. The median age was higher in RIC group (44 years, range 4-75 years) compared to MAC group (31 yrs, range 6-51 yrs, p = 0.001). There was no significant difference in terms of overall survival (p = 0.498), relapse-free survival (p = 0.791) and non-relapse mortality (p = 0.366) between the two groups. In multivariate analysis, only chronic graft-versus-host disease resulted in decreased risk of relapse and improved overall survival irrespective of the conditioning regimens used.

Polysomnography in children with obstructive sleep apnoea and neurocognitive disorders.

OBJECTIVE: The neurocognitive associations in paediatric obstructive sleep apnoea (OSA) are well known; however, whether polysomnographic features can predict these associations is unknown. Therefore, the primary objective of this study was to compare common polysomnographic parameters in children with OSA in the presence and absence of neurocognitive dysfunction. METHODS: Polysomnography data for children ages 3-6 years with mild-moderate OSA who as defined by AHI between 5 and 10 were analysed from a single sleep centre at a tertiary paediatric hospital from January 2016 to December 2018. The following parameters were identified: arousals per hour, percentage of time asleep, apnoea-hypopnoea index (AHI), oxygen desaturation nadir during sleeps, baseline oxygen saturation during sleep, time spent with SpO2 less than 90%, maximum transcutaneous CO2, per cent of the total sleep time spent with TcCO2 greater than 50 mmHg, age, body mass index (BMI), gender and type of disability in the neurocognitive dysfunction group. Neurocognitive diagnoses were recorded. Those with syndromic comorbidities were excluded. The study cohort was then compared to a cohort of 200 subjects with OSA and no neurocognitive disorders matched for age, gender and BMI. A paired column analysis by chi-squared analysis was then undertaken between the two groups. RESULTS: A total of 200 children were identified (126 males and 74 females) in the neurocognitive dysfunction group (OSA with neurocognitive dysfunction) and compared with 200 children in the control group (OSA without neurocognitive dysfunction) (113 males and 87 females). There were no statistical differences between groups. CONCLUSION: Commonly used polysomnographic indices are not predictive of neurocognitive dysfunction in paediatric OSA.

Imaging Features of Spindle Cell Breast Lesions.

OBJECTIVE: The purpose of our study is to review the clinical presentation, multimodality appearance, and management of the most common benign and malignant spindle cell lesions of the breast. CONCLUSION: Spindle cell lesions of the breast exhibit characteristic features at mammography, ultrasound, and MRI. Although a definitive diagnosis of these lesions cannot be made with diagnostic imaging alone, knowledge of their characteristic imaging features can assist in refining the differential diagnosis and guiding appropriate management.

Prevalence and risk factors of nonalcoholic fatty liver disease in HIV-monoinfection.

OBJECTIVE: To identify the prevalence and risk factors of nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH) and fibrosis in HIV-monoinfected patients. DESIGN: Systematic review and meta-analysis. METHODS: We searched Medline and Embase and included studies that enrolled HIV-monoinfected patients with NAFLD defined by imaging and/or liver histology. Data on prevalence and risk factors for NAFLD, NASH and fibrosis were collected for meta-analysis using random effects models. RESULTS: Ten studies were included from the United States of America (n = 4), Canada (n = 1), France (n = 2), Italy (n = 1), Japan (n = 1) and China (n = 1). The prevalence of NAFLD (Imaging studies), NASH and fibrosis (biopsied populations) were 35% [95% confidence interval (CI) 29-42], 42% (95% CI 22-64) and 22% (95% CI 13-34), respectively. Meta-analysis of risk factors showed that high BMI, waist circumference, type 2 diabetes, hypertension, triglycerides and high CD4 cell count were associated with NAFLD, whereas HIV viral load, duration of HIV infection, duration of antiretroviral therapy and CD4 cell count nadir were not. Patients with high BMI [mean difference (MD) 1.38, 95% CI 0.04-2.71 P = 0.04], fasting glucose (MD 0.80, 95% CI 0.47-1.13 P < 0.00001) and AST level (MD 13.00, 95% CI 4.34-21.65 P = 0.003) were at increased risk of significant liver fibrosis. CONCLUSION: NAFLD is frequently observed in HIV-monoinfected patients, and NASH is a common cause of unexplained abnormal liver function in patients selected for liver biopsy. Metabolic disorders are key risk factors independently of HIV parameters. Future trials on pharmacological interventions in NASH with fibrosis should include patients with HIV.

A Pilot Study of the Pediatric Oral Medications Screener (POMS).

OBJECTIVE: Oral medications are commonly used to treat acute and chronic conditions, but formal evaluation of a child's pill-swallowing ability rarely occurs. In this pilot study, the Pediatric Oral Medication Screener (POMS) was used to physically assess a child's pill swallowing ability and identify children who would benefit from a targeted intervention. METHODS: We identified children 3 to 17 years old admitted to a general pediatric service over a 3-month period in 2014. Patients were asked to swallow several different-sized placebo formulations. If subjects did not meet age-based goals, they were referred for pill swallowing interventions (POMS+). Follow-up parental surveys were performed for patients completing the intervention. RESULTS: The prospective pilot study recruited 34 patients. Twenty-eight patients (82%) passed the screening, and a majority of this group started or continued taking pill medications. Six did not pass the screen. Three of the 6 completed the intervention, improved their pill swallowing ability, and were taking oral pill medications at discharge. Parent prediction of pill swallowing was accurate only 56% of the time. Follow-up survey of the 3 families who completed POMS+ reported satisfaction with the program, and 2 of the patients had continued success with swallowing pills 5 months later. CONCLUSIONS: The POMS was effective at identifying children who could benefit from an intervention to improve pill-swallowing ability. Our analysis demonstrated that POMS has the potential to improve patient satisfaction and discharge planning.

Association between right ventricular dysfunction and restrictive lung disease in childhood cancer survivors as measured by quantitative echocardiography.

BACKGROUND: Restrictive lung disease is a complication in childhood cancer survivors who received lung-toxic chemotherapy and/or thoracic radiation. Left ventricular dysfunction is documented in these survivors, but less is known about right ventricular (RV) function. Quantitative echocardiography may help detect subclinical RV dysfunction. The aim of this study was to assess RV function quantitatively in childhood cancer survivors after lung-toxic therapy. PROCEDURES: We identified records of 33 childhood cancer survivors who (1) were treated with lung-toxic therapy and/or radiation, (2) were cancer-free for ≥ one year after therapy, and (3) had pulmonary function tests and echocardiograms from their most recent follow-up visit. RESULTS: Participants' mean age was 11.6 ± 4.5 years at cancer diagnosis and 23 ± 8.6 years at evaluation. The most common diagnosis was lymphoma/leukemia (n = 27). Twenty-nine subjects had anthracycline exposure. Eleven of the 33 subjects demonstrated restrictive pulmonary impairment (total lung capacity 3.69 ± 1.5 L [69.3 ± 22.4% predicted]). Among quantitative measures of RV function, isovolumetric acceleration (IVA), a measure of contractility, was significantly lower in the group with restrictive lung disease (2.42 ± 0.56 vs. 1.83 ± 0.78 m/sec(2); P < 0.05). There was a trend towards lower tissue Doppler derived S' and tricuspid annular plane systolic excursion in the group with restrictive lung disease. Subjects with restrictive lung disease were found to have ≥ 2 abnormal parameters (P < 0.01). CONCLUSION: IVA may detect early RV dysfunction in childhood cancer survivors with restrictive lung disease. Our findings require confirmation in a larger study population and validation by cardiac MRI.

PAK1 mediates resistance to PI3K inhibition in lymphomas.

PURPOSE: The phosphoinositide 3-kinase (PI3K) pathway is known to play an active role in many malignancies. The role of PI3K inhibition in the treatment of lymphomas has not been fully delineated. We sought to identify a role for therapeutic PI3K inhibition across a range of B-cell lymphomas. EXPERIMENTAL DESIGN: We selected three small molecule inhibitors to test in a panel of 60 cell lines that comprised diverse lymphoma types. We tested the selective PI3K inhibitor BKM120 and the dual PI3K/mTOR inhibitors BEZ235 and BGT226 in these cell lines. We applied gene expression profiling to better understand the molecular mechanisms associated with responsiveness to these drugs. RESULTS: We found that higher expression of the PAK1 gene was significantly associated with resistance to all three PI3K inhibitors. Through RNA-interference-mediated knockdown of the PAK1 gene, we showed a dramatic increase in the sensitivity to PI3K inhibition. We further tested a small-molecule inhibitor of PAK1 and found significant synergy between PI3K and PAK1 inhibition. CONCLUSION: Thus, we show that PI3K inhibition is broadly effective in lymphomas and PAK1 is a key modulator of resistance to PI3K inhibition.

An ATM/Chk2-mediated DNA damage-responsive signaling pathway suppresses Epstein-Barr virus transformation of primary human B cells.

Epstein-Barr virus (EBV), an oncogenic herpesvirus that causes human malignancies, infects and immortalizes primary human B cells in vitro into indefinitely proliferating lymphoblastoid cell lines, which represent a model for EBV-induced tumorigenesis. The immortalization efficiency is very low, suggesting that an innate tumor suppressor mechanism is operative. We identify the DNA damage response (DDR) as a major component of the underlying tumor suppressor mechanism. EBV-induced DDR activation was not due to lytic viral replication, nor did the DDR marks colocalize with latent episomes. Rather, a transient period of EBV-induced hyperproliferation correlated with DDR activation. Inhibition of the DDR kinases ATM and Chk2 markedly increased transformation efficiency of primary B cells. Further, the viral latent oncoprotein EBNA3C was required to attenuate the EBV-induced DDR. We propose that heightened oncogenic activity in early cell divisions activates a growth-suppressive DDR that is attenuated by viral latency products to induce cell immortalization.

Deep sequencing of the small RNA transcriptome of normal and malignant human B cells identifies hundreds of novel microRNAs.

A role for microRNA (miRNA) has been recognized in nearly every biologic system examined thus far. A complete delineation of their role must be preceded by the identification of all miRNAs present in any system. We elucidated the complete small RNA transcriptome of normal and malignant B cells through deep sequencing of 31 normal and malignant human B-cell samples that comprise the spectrum of B-cell differentiation and common malignant phenotypes. We identified the expression of 333 known miRNAs, which is more than twice the number previously recognized in any tissue type. We further identified the expression of 286 candidate novel miRNAs in normal and malignant B cells. These miRNAs were validated at a high rate (92%) using quantitative polymerase chain reaction, and we demonstrated their application in the distinction of clinically relevant subgroups of lymphoma. We further demonstrated that a novel miRNA cluster, previously annotated as a hypothetical gene LOC100130622, contains 6 novel miRNAs that regulate the transforming growth factor-ß pathway. Thus, our work suggests that more than a third of the miRNAs present in most cellular types are currently unknown and that these miRNAs may regulate important cellular functions.

Recent advances in uterine fibroid embolization.

PURPOSE OF REVIEW: To summarize the literature on uterine embolization for fibroids published in 2004 and 2005. RECENT FINDINGS: During the last two years, our understanding of the outcome of uterine fibroid embolization has increased. The outcomes are comparable to those that occur after hysterectomy. Health-related quality-of-life studies have confirmed the positive impact of the procedure. Improvement in menorrhagia has been quantified using the alkaline hematin method, objectively confirming the outcome. Recovery is also better understood and quantified, with most patients experiencing only moderate pain over the first few days after embolization. In two pregnancy-outcome studies, an increased frequency of cesarean section occurred and possibly a greater likelihood of abnormal placentation, although the data are too few to draw conclusions at this time. Contrast-enhanced magnetic resonance imaging (MRI) has emerged as the primary tool for assessing the potential of complications following the procedure, and our understanding of vaginal discharge and uterine infarction has been increased as a result of its use. SUMMARY: Within the last few years, uterine embolization has become an accepted therapy for uterine fibroids. The increase in understanding gained in recent years has helped to confirm the effectiveness and relative tolerability of this therapy.