Increased Frequency of Clonal Hematopoiesis of Indeterminate Potential in Bloom Syndrome Probands and Carriers.

Background: Bloom Syndrome (BSyn) is an autosomal recessive disorder caused by biallelic germline variants in BLM, which functions to maintain genomic stability. BSyn patients have poor growth, immune defects, insulin resistance, and a significantly increased risk of malignancies, most commonly hematologic. The malignancy risk in carriers of pathogenic variants in BLM (BLM variant carriers) remains understudied. Clonal hematopoiesis of indeterminate potential (CHIP) is defined by presence of somatic mutations in leukemia-related genes in blood of individuals without leukemia and is associated with increased risk of leukemia. We hypothesize that somatic mutations driving clonal expansion may be an underlying mechanism leading to increased cancer risk in BSyn patients and BLM variant carriers. Methods: To determine whether de novo or somatic variation is increased in BSyn patients or carriers, we performed and analyzed exome sequencing on BSyn and control trios. Results: We discovered that both BSyn patients and carriers had increased numbers of low-frequency, putative somatic variants in CHIP genes compared to controls. Furthermore, BLM variant carriers had increased numbers of somatic variants in DNA methylation genes compared to controls. There was no statistical difference in the numbers of de novo variants in BSyn probands compared to control probands. Conclusion: Our findings of increased CHIP in BSyn probands and carriers suggest that one or two germline pathogenic variants in BLM could be sufficient to increase the risk of clonal hematopoiesis. These findings warrant further studies in larger cohorts to determine the significance of CHIP as a potential biomarker of aging, cancer, cardiovascular disease, morbidity and mortality.

A comparison of clinical development pathways to advance tuberculosis regimen development.

BACKGROUND: Current tuberculosis (TB) regimen development pathways are slow and in urgent need of innovation. We investigated novel phase IIc and seamless phase II/III trials utilizing multi-arm multi-stage and Bayesian response adaptive randomization trial designs to select promising combination regimens in a platform adaptive trial. METHODS: Clinical trial simulation tools were built using predictive and validated parametric survival models of time to culture conversion (intermediate endpoint) and time to TB-related unfavorable outcome (final endpoint). This integrative clinical trial simulation tool was used to explore and optimize design parameters for aforementioned trial designs. RESULTS: Both multi-arm multi-stage and Bayesian response adaptive randomization designs were able to reliably graduate desirable regimens in ≥ 95% of trial simulations and reliably stop suboptimal regimens in ≥ 90% of trial simulations. Overall, adaptive phase IIc designs reduced patient enrollment by 17% and 25% with multi-arm multi-stage and Bayesian response adaptive randomization designs respectively compared to the conventional sequential approach, while seamless designs reduced study duration by 2.6 and 3.5 years respectively (typically ≥ 8.5 years for standard sequential approach). CONCLUSIONS: In this study, we demonstrate that adaptive trial designs are suitable for TB regimen development, and we provide plausible design parameters for a platform adaptive trial. Ultimately trial design and specification of design parameters will depend on clinical trial objectives. To support decision-making for clinical trial designs in contemporary TB regimen development, we provide a flexible clinical trial simulation tool that can be used to explore and optimize design features and parameters.

Comprehensive Analysis of Stromal and Serum Markers in Gastric Cancer.

A comprehensive analysis of the cell phenotype of the inflammatory infiltrate of the tumor stroma represents a promising area of molecular oncology. The study of not only soluble forms of various immunoregulatory molecules, but also their membrane-bound forms is also considered highly relevant. We performed a comprehensive analysis of tissue and circulating forms of the PD-1 and PD-L1 proteins, as well as macrophage and B-cell markers in the tumor stroma of gastric cancer, to assess their clinical and prognostic significance. The tumor and blood plasma samples from 63 gastric cancer patients were studied using ELISA and immunohistochemistry. Malignant gastric tumors were shown to be strongly infiltrated by B-cells, and their number was comparable to that of macrophages. For PU.1 expression, an association with tumor size was observed; i.e., larger tumors were characterized by fewer PU.1+ infiltrating cells (p = 0.005). No clinical significance was found for CD20 and CD163, but their numbers were higher at earlier stages of the disease and in the absence of metastases. It was also demonstrated that the PD-L1 content in tumor cells was not associated with the clinical and morphological characteristics of GC. At the same time, PD-L1 expression in tumor stromal cells was associated with the presence of distant metastases. The analysis of the prognostic significance of all the markers studied demonstrated that CD163 was statistically significantly associated with a poor prognosis for the disease (p = 0.019). In addition, PD-L1 expression in tumor cells tended to indicate a favorable prognosis (p = 0.122). The results obtained in this work indicate that the study of soluble and tissue markers of tumor stroma is promising in prognosticating the course of GC. The search for combinations of markers seems to be highly promising, with their comprehensive analysis capable of helping personalize advanced antitumor therapy.

Prognostic significance of soluble forms of immune checkpoint PD-1/PDL1 receptor and ligand in blood plasma of gastric cancer patients.

Analysis of long-term treatment results of 101 primary gastric cancer patients at various stages of the tumor process followed during 1 - 41 months (median - 6,4 months) from the onset of specific treatment are presented depending on the levels of soluble forms (s) of PD-1 receptor and its ligand PD-L1 in blood plasma. Overall survival assessed by Kaplan-Meyer analysis and with the help of Cox multiparametric regression model was applied as the criterion of prognostic value. It was found that at high (≥ 35 pg/ml) sPD-L1 levels in blood plasma, the overall survival of patients with gastric cancer was statistically significantly lower than at the marker's levels below 35 pg / ml (p <0.045): 1-year survival comprised 78 and 96%, 2-year - 52 and 78%; 3-year - 40 and 61% at high and low sPD-L1 respectively. Median survival of patients with high plasma sPD-L1 comprised 29 months, of those with low sPD-L1 was not achieved during the whole follow-up period. This trend was observed not only in the total group of stage I-IV gastric cancer patients, but also in patients at the early stages of the disease, though sPD-L1 did not show an independent prognostic value in multiparametric model. At the same time, the overall survival of patients with gastric cancer did not depend on the baseline levels sPD-1 in blood plasma. Thus, soluble ligand sPD-L1 can be considered as a potentially valuable factor for prognosis of gastric cancer patients' survival, and, probably, of anti-PD-1/PD-L1 treatment efficiency, but further studies and patients' monitoring are required to prove this statement.

[The content of the soluble forms PD-1 and PD-L1 in blood serum of patients with gastric cancer and their relationship with clinical and morphological characteristics of the disease.]

Results of comparative ELISA investigation of pretreatment sPD-1 and sPD-L1 content in blood plasma of 100 gastric cancer patients at various disease stages aged 25 to 81 years are presented. Control group included 60 practically healthy donors aged 18 - 68 years. Plasma sPD-L1 concentrations did not differ between gastric cancer patients and control group, and sPD-1 levels were statistically significantly lower in patients than in healthy donors (p<0.0001). Positive correlation (R=0.38; p=0.003) was revealed between plasma sPD-1 и sPD-L1 levels in control group and negative (R= -0.26; p=0,009) - in gastric cancer patients. ROC curve revealed the best sPD-1 cut-off level (< 21 pg/ml) with 77% sensitivity and 63.3% specificity, which is not sufficient for its application as diagnostic marker. Statistically significant increase of plasma sPD-L1 from stage I to stage IIIC (R=0.50; p=0.000011) was found. Analysis of associations between the evaluated markers' levels and indices of gastric cancer expansion according to TNM system revealed statistically significant positive associations of plasma sPD -L1 levels with T (tumor invasiondepth) and N (number of affected lymph nodes) indices: R=0.33; p=0.00093, and R=0.27; p=0.0099 respectively. sPD-L1 level was significantly increased in patients with low differentiated adenocarcinoma and cricoid-cell cancer as compared to highly differentiated adenocarcinoma (p=0.02 and p=0.004 respectively); in patients with cricoid-cell cancer it was also higher than in those with moderately differentiated adenocarcinoma (p=0.043) and undifferentiated cancer (p=0.049). Plasma sPD-1 level did not depend on disease stage, TNM system indices and tumor histological structure. Thus, soluble ligand sPD-L1, but not its receptor sPD-1, plasma level is increased in patients with unfavorable clinical and morphological characteristics, may be regarded as potentially valuable prognostic factor for gastric cancer patients' survival, and probably as a predictor of anti - PD-1/PD-L1 treatment efficiency.

Review: Recent advances in the understanding of the pathophysiology of neuromyelitis optica spectrum disorder.

Neuromyelitis optica is an autoimmune inflammatory disorder of the central nervous system that preferentially targets the spinal cord and optic nerve. Following the discovery of circulating antibodies against the astrocytic aquaporin 4 (AQP4) water channel protein, recent studies have expanded our knowledge of the unique complexities of the pathogenesis of neuromyelitis optica and its relationship with the immune response. This review describes and summarizes the recent advances in our understanding of the molecular mechanisms underlying neuromyelitis optica disease pathology and examines their potential as therapeutic targets. Additionally, we update the most recent research by proposing major unanswered questions regarding how peripheral AQP4 antibodies are produced and their entry into the central nervous system, the causes of AQP4-IgG-seronegative disease, why peripheral AQP4-expressing organs are spared from damage, and the impact of this disease on pregnancy.

Clinical Significance of Matrix Metalloproteinases in Blood Plasma of Patients with Gastric Cancer.

Plasma levels of MMP-2, MMP-7, and MMP-9 and their tissue inhibitor TIMP-2 were measured in 89 patients with gastric cancer and the relationship between these parameters and the main clinical morphological characteristics of the disease was analyzed. Plasma levels of the proteins were measured using standard direct ELISA kits. The level of MMP-7 in patients with gastric cancer was significantly higher than in the control group (medians 2.7 and 1.2 ng/ml, respectively; p<0.01), but only in 51% patients this parameter surpassed the upper threshold normal value (2.35 ng/ml; 95% percentile of control). The level of MMP-9 in gastric cancer patients was lower than in control group by 1.6 times (medians 167 and 267 ng/ml, respectively; p<0.01). Plasma levels of MMP-2 and TIMP-2 in patients with gastric cancer and healthy subjects were similar. No appreciable associations of plasma matrixins and TIMP-2 with the main clinical morphological characteristics of the disease were detected. The patients were followed up for 8 to 85 months (median 70.8 months). Low level of MMP-2 and high level of MMP-7 in the plasma proved to be unfavorable prognostic factors for overall survival. At MMP-2<268 ng/ml, the 5-year overall survival was 32% vs. 60% for patients with the marker level higher than this threshold value (p=0.016). The differences in overall survival in relation to their MMP-7 levels for 5-year observation did not surpass 16% (39% at marker level >2.7 ng/ml and 55% at lower level; p=0.048). Plasma levels of MMP-2 and TIMP-2 were not significantly associated with overall survival. Multivariate analysis showed that only T index (p=0.034) and plasma MMP-7 level (p=0.007) were essential for overall survival. The increase in plasma or serum MMP-7 levels is a universal phenomenon in tumors of different histogenesis, which precluded the use of this parameter as a specific diagnostic marker of gastric cancer. At the same time, it could be useful for monitoring the treatment efficiency and detection of relapses. In addition, high plasma level of MMP-7 remained an independent factor of unfavorable prognosis for overall survival of patients with gastric cancer.

The modified Memorial Symptom Assessment Scale Short Form: a modified response format and rational scoring rules.

PURPOSE: The Memorial Symptom Assessment Scale Short Form (MSAS-SF) is a widely used symptom assessment instrument. Patients who self-complete the MSAS-SF have difficulty following the two-part response format, resulting in incorrectly completed responses. We describe modifications to the response format to improve useability, and rational scoring rules for incorrectly completed items. METHODS: The modified MSAS-SF was completed by 311 women in our Peer and Nurse support Trial to Assist women in Gynaecological Oncology; the PeNTAGOn study. Descriptive statistics were used to summarise completion of the modified MSAS-SF, and provide symptom statistics before and after applying the rational scoring rules. Spearman's correlations with the Functional Assessment for Cancer Therapy-General (FACT-G) and Hospital Anxiety and Depression Scale (HADS) were assessed. RESULTS: Correct completion of the modified MSAS-SF items ranged from 91.5 to 98.7%. The rational scoring rules increased the percentage of useable responses on average 4% across all symptoms. MSAS-SF item statistics were similar with and without the scoring rules. The pattern of correlations with FACT-G and HADS was compatible with prior research. CONCLUSION: The modified MSAS-SF was useable for self-completion and responses demonstrated validity. The rational scoring rules can minimise loss of data from incorrectly completed responses. Further investigation is recommended.

Birth weight, early life weight gain and age at menarche: a systematic review of longitudinal studies.

BACKGROUND AND OBJECTIVE: Adiposity in pre- and postnatal life may influence menarcheal age. Existing evidence is primarily cross-sectional, failing to address temporality, for which the role of adiposity in early life remains unclear. The current study sought to systematically review longitudinal studies evaluating the associations between birth weight and infant/childhood weight status/weight gain in relation to menarcheal age. METHODS: PubMed, EMBASE, Web of Science, Global Health (Ovid) and CINAHL were systematically searched. Selected studies were limited to English-language articles presenting multi-variable analyses. Seventeen studies reporting risk estimates for birth weight (n = 3), infant/childhood weight gain/weight status (n = 4) or both (n = 10), in relation to menarcheal age were included. RESULTS: Lower vs. higher birth weight was associated with earlier menarche in nine studies and later menarche in one study, while three studies reported a null association. Greater BMI or weight gain over time and greater childhood weight were significantly associated with earlier menarche in nine of nine and six of seven studies, respectively. CONCLUSIONS: Studies suggested that lower birth weight and higher body weight and weight gain in infancy and childhood may increase the risk of early menarche. The pre- and postnatal period may thus be an opportune time for weight control interventions to prevent early menarche, and its subsequent consequences.

KLF10 loss in the pancreas provokes activation of SDF-1 and induces distant metastases of pancreatic ductal adenocarcinoma in the KrasG12D p53flox/flox model.

Krüppel-like transcription factor 10 (KLF10), also named as TIEG1, plays essential roles in mediating transforming growth factor beta (TGFß) signaling and has been shown to function as a tumor suppressor in multiple cancer types. However, its roles in mediating cancer progression in vivo have yet to be fully characterized. Here, we have employed two well-characterized Pdx-1CreLSL-KrasG12D and Pdx-1CreLSL-KrasG12Dp53L/L pancreatic cancer models to ablate KLF10 expression and determine the impact of KLF10 deletion on tumor development and progression. We show that loss of KLF10 cooperates with KrasG12D leading to an invasive and widely metastatic phenotype of pancreatic ductal adenocarcinoma (PDAC). Mechanistically, loss of KLF10 in PDAC is shown to increase distant metastases and cancer stemness through activation of SDF-1/CXCR4 and AP-1 pathways. Furthermore, we demonstrate that targeting the SDF-1/CXCR4 pathway in the context of KLF10 deletion substantially suppresses PDAC progression suggesting that inhibition of this pathway represents a novel therapeutic strategy for PDAC treatment.

Self-organizing actin patterns shape membrane architecture but not cell mechanics.

Cell-free studies have demonstrated how collective action of actin-associated proteins can organize actin filaments into dynamic patterns, such as vortices, asters and stars. Using complementary microscopic techniques, we here show evidence of such self-organization of the actin cortex in living HeLa cells. During cell adhesion, an active multistage process naturally leads to pattern transitions from actin vortices over stars into asters. This process is primarily driven by Arp2/3 complex nucleation, but not by myosin motors, which is in contrast to what has been theoretically predicted and observed in vitro. Concomitant measurements of mechanics and plasma membrane fluidity demonstrate that changes in actin patterning alter membrane architecture but occur functionally independent of macroscopic cortex elasticity. Consequently, tuning the activity of the Arp2/3 complex to alter filament assembly may thus be a mechanism allowing cells to adjust their membrane architecture without affecting their macroscopic mechanical properties.

Thermal comfort, perceived air quality, and cognitive performance when personally controlled air movement is used by tropically acclimatized persons.

In a warm and humid climate, increasing the temperature set point offers considerable energy benefits with low first costs. Elevated air movement generated by a personally controlled fan can compensate for the negative effects caused by an increased temperature set point. Fifty-six tropically acclimatized persons in common Singaporean office attire (0.7 clo) were exposed for 90 minutes to each of five conditions: 23, 26, and 29°C and in the latter two cases with and without occupant-controlled air movement. Relative humidity was maintained at 60%. We tested thermal comfort, perceived air quality, sick building syndrome symptoms, and cognitive performance. We found that thermal comfort, perceived air quality, and sick building syndrome symptoms are equal or better at 26°C and 29°C than at the common set point of 23°C if a personally controlled fan is available for use. The best cognitive performance (as indicated by task speed) was obtained at 26°C; at 29°C, the availability of an occupant-controlled fan partially mitigated the negative effect of the elevated temperature. The typical Singaporean indoor air temperature set point of 23°C yielded the lowest cognitive performance. An elevated set point in air-conditioned buildings augmented with personally controlled fans might yield benefits for reduced energy use and improved indoor environmental quality in tropical climates.

Influence of moisturizer and relative humidity on human emissions of fluorescent biological aerosol particles.

Utilizing the ultraviolet light-induced fluorescence (UV-LIF) measurement technique as embodied in the Waveband Integrated Bioaerosol Sensor (WIBS-4A), we evaluated the fluorescent particle emissions associated with human shedding while walking in a chamber. The mean emission rates of supermicron (1-10 µm) fluorescent particles were in the range 6.8-7.5 million particles per person-h (~0.3 mg per person-h) across three participants, for conditions when the relative humidity was 60%-70% and no moisturizer was applied after showering. The fluorescent particles displayed a lognormal distribution with the geometric mean diameter in the range 2.5-4 µm and exhibited asymmetry factors that increased with particle size. Use of moisturizer was associated with changes in number and mass emission rates, size distribution, and particle shape. Emission rates were lower when the relative humidity was reduced, but these differences were not statistically significant.

Ecological succession of the microbial communities of an air-conditioning cooling coil in the tropics.

Air-conditioning systems harbor microorganisms, potentially spreading them to indoor environments. While air and surfaces in air-conditioning systems are periodically sampled as potential sources of indoor microbes, little is known about the dynamics of cooling coil-associated communities and their effect on the downstream airflow. Here, we conducted a 4-week time series sampling to characterize the succession of an air-conditioning duct and cooling coil after cleaning. Using an universal primer pair targeting hypervariable regions of the 16S/18S ribosomal RNA, we observed a community succession for the condensed water, with the most abundant airborne taxon Agaricomycetes fungi dominating the initial phase and Sphingomonas bacteria becoming the most prevalent taxa toward the end of the experiment. Duplicate air samples collected upstream and downstream of the coil suggest that the system does not act as ecological filter or source/sink for specific microbial taxa during the duration of the experiment.

Epigallocatechin-3-Gallate Upregulates miR-221 to Inhibit Osteopontin-Dependent Hepatic Fibrosis.

Osteopontin (OPN) promotes hepatic fibrosis, and developing therapies targeting OPN expression in settings of hepatic injury holds promise. The polyphenol epigallocatechin-3-gallate (EGCG), found in high concentrations in green tea, downregulates OPN expression through OPN mRNA degradation, but the mechanism is unknown. Previous work has shown that microRNAs can decrease OPN mRNA levels, and other studies have shown that EGCG modulates the expression of multiple microRNAs. In our study, we first demonstrated that OPN induces hepatic stellate cells to transform into an activated state. We then identified three microRNAs which target OPN mRNA: miR-181a, miR-10b, and miR-221. In vitro results show that EGCG upregulates all three microRNAs, and all three microRNAs are capable of down regulating OPN mRNA when administered alone. Interestingly, only miR-221 is necessary for EGCG-mediated OPN mRNA degradation and miR-221 inhibition reduces the effects of EGCG on cell function. In vivo experiments show that thioacetamide (TAA)-induced cell cytotoxicity upregulates OPN expression; treatment with EGCG blocks the effects of TAA. Furthermore, chronic treatment of EGCG in vivo upregulates all three microRNAs equally, suggesting that in more chronic treatment all three microRNAs are involved in modulating OPN expression. We conclude that in in vitro and in vivo models of TAA-induced hepatic fibrosis, EGCG inhibits OPN-dependent injury and fibrosis. EGCG works primarily by upregulating miR-221 to accelerate OPN degradation. EGCG may therefore have utility as a protective agent in settings of liver injury.

Fall-related injuries among Canadian seniors, 2005-2013: an analysis of the Canadian Community Health Survey.

INTRODUCTION: We describe the epidemiology and trends of fall-related injuries among Canadian seniors aged 65 years and older by sex and age, as well as the circumstances and consequences of their injuries. METHODS: We analyzed nationally representative data from the 2005, 2009/2010 and 2013 samples of the Canadian Community Health Survey to calculate the number and rates of fall-related injuries for each survey year. Where possible, we combined data from two or more samples to estimate the proportion of fall-related injuries by type of injury, part of body injured, type of activity and type of treatment. RESULTS: The rate of fall-related injuries among seniors increased from 49.4 to 58.8 per 1000 population between 2005 and 2013, during which the number of fall-related injuries increased by 54% overall. Women had consistently higher rates than men across all survey years, while rates increased with advancing age. The upward trend in fall-related injury rates was more prominent among women and younger age groups. The most common type of injury was broken or fractured bones (37%), and the shoulder or upper arm (16%) was the most commonly injured body part. Many fall-related injuries occurred while walking on a surface other than snow or ice (45%). Over 70% of seniors seeking treatment for their injuries visited a hospital emergency department. CONCLUSION: Given the increase in both the number and rates of fall-related injuries over time, there is a need to continue monitoring trends and injury patterns associated with falls.

TITRE: Blessures liées à une chute chez les aînés canadiens entre 2005 et 2013 : une analyse de l'Enquête sur la santé dans les collectivités canadiennes. INTRODUCTION: Nous décrivons l'épidémiologie et les tendances des blessures liées à une chute chez les aînés canadiens de 65 ans et plus selon le sexe et l'âge, ainsi que les circonstances et les conséquences de ces blessures. MÉTHODOLOGIE: Nous avons utilisé des données représentatives tirées des échantillons de 2005, de 2009-2010 et de 2013 de l'Enquête sur la santé dans les collectivités canadiennes afin de calculer le nombre et les taux de blessures liées à une chute pour chaque année d'enquête. Nous avons combiné, dans la mesure du possible, les données d'au moins deux échantillons afin d'estimer la proportion de blessures liées à une chute par type de blessure, partie du corps affectée, type d'activité et type de traitement. RÉSULTATS: Le taux de blessures liées à une chute chez les aînés est passé de 49,4 à 58,8 pour 1 000 personnes entre 2005 et 2013, période durant laquelle le nombre de blessures liées à une chute a de façon générale augmenté de 54 %. Les femmes ont présenté des taux plus élevés que les hommes pour toutes les années d'enquête, ces taux augmentant avec l'âge. La tendance à la hausse dans les taux de blessures liées à une chute était plus marquée chez les femmes et les plus jeunes. Les cassures et les fractures (37 %) ont été les blessures les plus courantes, et l'épaule et le bras (16 %) ont été les parties du corps les plus couramment affectées. Plusieurs blessures liées à une chute se sont produites alors que la personne marchait sur une surface non enneigée ou glacée (45 %). Plus de 70 % des aînés qui ont cherché à obtenir des soins médicaux pour leur blessure se sont rendus au service d'urgence d'un hôpital. CONCLUSION: Compte tenu de l'augmentation du nombre et des taux de blessures liées à une chute au fil du temps, la surveillance des tendances et des profils de ces dernières demeure nécessaire.

Therapeutic implications of activation of the host gene (Dleu2) promoter for miR-15a/16-1 in chronic lymphocytic leukemia.

Genetic lesions and other regulatory events lead to silencing of the 13q14 locus in a majority of chronic lymphocytic leukemia (CLL) patients. This locus encodes a pair of critical proapoptotic microRNAs, miR-15a/16-1. Decreased levels of miR-15a/16-1 are critical for the increased survival exhibited by CLL cells. Similarly, in a de novo murine model of CLL, the NZB strain, germline-encoded regulation of the syntenic region resulted in decreased miR-15a/16-1. In this paper, we have identified additional molecular mechanisms regulating miR-15a/16-1 levels and have shown that the transcription factor BSAP (B-cell-specific activator protein) directly interacts with Dleu2, the host gene containing the miR-15a/16-1 loci, and by negative regulation of the Dleu2 promoter, results in repression of miR-15a/16-1 expression. CLL patient B-cell expression levels of BSAP were increased compared with control sources of B cells. With the use of small interfering RNA-mediated repression, the levels of BSAP were decreased in vitro in the NZB-derived malignant B-1 cell line, LNC, and in ex vivo CLL patient peripheral blood mononuclear cells (PBMCs). BSAP knockdown led to an increase in the expression of miR-15a/16-1 and an increase in apoptosis, and a cell cycle arrest in both the cell line and patient PBMCs. Moreover, using Dleu2 promoter analysis by chromatin immunoprecipitation assay, we have shown that BSAP directly interacts with the Dleu2 promoter. Derepression of the Dleu2 promoter via inhibition of histone deacetylation combined with BSAP knockdown increased miR-15a/16-1 expression, and also increased malignant B-cell death. In summary, therapy targeting enhanced host gene Dleu2 transcription may augment CLL therapy.

Controversies in the management of cervical spondylotic myelopathy.

AIM: Cervical spondylotic myelopathy (CSM) is a common clinical entity that can be a significant cause of disability in the adult population. Although our CSM knowledge has markedly grown in recent years, a variety of controversies exist regarding the optimal treatment strategies. The goal of this paper is to review and discuss current areas of controversy in the management of CSM patients. METHODS: Topics addressed in this manuscript include: operative versus nonoperative management for patients with mild CSM, optimal surgical approaches for CSM, the utility of intraoperative monitoring, and radiographical prognostic indicators for outcome following surgery for CSM. RESULTS: A current review reveals several areas where Class I evidence exists regarding these controversies. However, many other studies consist contain Class III or weaker data, thereby making it difficult to draw any definitive conclusions. Despite the lack of a consensus in some areas, it appears that CSM patients can often achieve satisfactory treatment through a variety of different options. CONCLUSION: CSM remains a challenging clinical problem where several areas of controversy still exist. Large, multi-center, randomized prospective trials will be required to help resolve some of the controversies.

Employment outcomes among survivors of common cancers: the Symptom Outcomes and Practice Patterns (SOAPP) study.

INTRODUCTION: Risk factors for employment difficulties after cancer diagnosis are incompletely understood, and interventions to improve post-cancer employment remain few. New targets for intervention are needed. METHODS: We assessed a cohort of 530 nonmetastatic cancer patients (aged ≤ 65 years, >6 months from diagnosis, off chemo- or radiotherapy) from the observational multi-site Symptom Outcomes and Practice Patterns study. Participants reported employment change, current employment, and symptoms. Groups were based on employment at survey (working full- or part-time versus not working) and whether there had been a change due to illness (yes versus no). The predictive power of symptom interference with work was evaluated for employment group (working stably versus no longer working). Race/ethnicity, gender, cancer type, therapy, and time since diagnosis were also assessed. Association between employment group and specific symptoms was examined. RESULTS: The cohort was largely non-Hispanic white (76 %), female (85 %), and diagnosed with breast cancer (75 %); 24 % reported a change in employment. On multivariable analysis, participants with at least moderate symptom interference were more likely to report no longer working than their less effected counterparts (odds ratio (OR) = 8.0, 95 % CI, 4.2-15.4), as were minority participants compared with their non-Hispanic white counterparts (OR = 3.2, 95 % CI, 1.8-5.6). Results from the multiple regression model indicated the combination of fatigue (OR = 2.3, 95 % CI, 1.1-4.7), distress (OR = 3.9, 95 % CI, 1.7-9.0), and dry mouth (OR = 2.6, 95 % CI, 1.1-6.2) together with race/ethnicity and time since diagnosis adequately accounted for employment group. CONCLUSIONS: Our findings support the hypothesis that residual symptom burden is related to post-cancer employment: Residual symptoms may be targets for intervention to improve work outcomes among cancer survivors. IMPLICATIONS FOR CANCER SURVIVORS: This analysis examines whether increased symptom burden is associated with a change to not working following a cancer diagnosis. We also examined individual symptoms to assess which symptoms were most strongly associated with not working after a cancer diagnosis. Our hope is that we will be able to use this information to both screen survivors post-active treatment as well as target high-risk symptoms for further and more aggressive intervention, in an attempt to improve post-cancer work outcomes.

Comparison of cardiac and pulmonary-specific quality-of-life measures in pulmonary arterial hypertension.

Studies systematically comparing the performance of health-related quality-of-life (HRQoL) instruments in pulmonary arterial hypertension (PAH) are lacking. We sought to address this by comparing cardiac and respiratory-specific measures of HRQoL in PAH. We prospectively assessed HRQoL in 128 patients with catheterisation-confirmed PAH at baseline and at 6, 12 and post-24 month follow-up visits. Cardiac-specific HRQoL was assessed using the Minnesota Living with Heart Failure Questionnaire (LHFQ); respiratory-specific HRQoL was assessed using the Airways Questionnaire 20 (AQ20); and general health status was assessed using the 36-item Short Form physical component summary (SF-36 PCS). The LHFQ and AQ20 were highly intercorrelated. Both demonstrated strong internal consistency and converged with the SF-36 PCS. Both discriminated patients based on World Health Organization (WHO) functional class, 6-min walking distance (6MWD) and Borg dyspnoea index (BDI), with the exception of a potential floor effect associated with low 6MWD. The LHFQ was more responsive than the AQ20 to changes over time in WHO functional class, 6MWD and BDI. In multivariate analyses, the LHFQ and AQ20 were each longitudinal predictors of general health status, independent of functional class, 6MWD and BDI. In conclusion, both cardiac-specific and respiratory-specific measures appropriately assess HRQoL in most patients with PAH. Overall, the LHFQ demonstrates stronger performance characteristics than the AQ20.