Interfaces of Malignant and Immunologic Clonal Dynamics in Ovarian Cancer.

High-grade serous ovarian cancer (HGSC) exhibits extensive malignant clonal diversity with widespread but non-random patterns of disease dissemination. We investigated whether local immune microenvironment factors shape tumor progression properties at the interface of tumor-infiltrating lymphocytes (TILs) and cancer cells. Through multi-region study of 212 samples from 38 patients with whole-genome sequencing, immunohistochemistry, histologic image analysis, gene expression profiling, and T and B cell receptor sequencing, we identified three immunologic subtypes across samples and extensive within-patient diversity. Epithelial CD8+ TILs negatively associated with malignant diversity, reflecting immunological pruning of tumor clones inferred by neoantigen depletion, HLA I loss of heterozygosity, and spatial tracking between T cell and tumor clones. In addition, combinatorial prognostic effects of mutational processes and immune properties were observed, illuminating how specific genomic aberration types associate with immune response and impact survival. We conclude that within-patient spatial immune microenvironment variation shapes intraperitoneal malignant spread, provoking new evolutionary perspectives on HGSC clonal dispersion.

Comparison of passive drool and cotton-based collection methods for salivary C-reactive protein measurement.

Saliva collection and handling procedures for salivary C-reactive protein (CRP) can be challenging due to a lack of standardized protocols. This study compared two collection methods used to quantify salivary CRP. Twenty-two Chinese adults provided two unstimulated whole saliva samples using passive drool and cotton-based collection devices in two consecutive mornings at baseline and 1 month later. The effects of various factors on CRP levels were analyzed using linear mixed models. Salivary CRP levels were significantly affected by collection time and method, but not day or wave. The CRP peaked upon awakening and declined 45 min later. CRP levels were significantly higher in the passive drool than in the cotton-based method. The Bland-Altman plot revealed relative and proportional biases. The difference in the CRP levels between the methods decreased as the CRP levels increased. Results suggest that passive drool and cotton-based collection methods should not be used interchangeably for measuring low levels of salivary CRP.

Psychometric properties of the Chinese version of Five Facet Mindfulness Questionnaire-short form in cancer patients: a Bayesian structural equation modeling approach.

BACKGROUND: Mindfulness has emerged as an important correlate of well-being in various clinical populations. The present study evaluated the psychometric properties of the 20-item short form of the Five Facet Mindfulness Questionnaire (FFMQ-SF) in the Chinese context. METHODS: The study sample was 127 Chinese colorectal cancer patients who completed the FFMQ-SF and validated physical and mental health measures. Factorial validity of the FFMQ-SF was assessed using Bayesian structural equation modeling (BSEM) via informative priors on cross-loadings and residual covariances. Linear regression analysis examined its convergent validity with the health measures on imputed datasets. RESULTS: The five-factor BSEM model with approximate zero cross-loadings and one residual covariance provided an adequate model fit (PPP = 0.07, RMSEA = 0.06, CFI = 0.95). Satisfactory reliability (ω = 0.77-0.85) was found in four of the five facets (except nonjudging). Acting with awareness predicted lower levels of perceived stress, negative affect, anxiety, depression, and illness symptoms (ß = - 0.37 to - 0.42) and better quality of life (ß = 0.29-0.32). Observing, nonjudging, and nonreacting did not show any significant associations (p > .05) with health measures. Acting with awareness was not significantly correlated (r < 0.15) with the other four facets. CONCLUSION: The present findings provide partial support for the psychometric properties of the FFMQ-SF in colorectal cancer patients. The nonjudging facet showed questionable validity and reliability in the present sample. Further studies with larger sample sizes are needed to elucidate the viability of FFMQ-SF as a measure of mindfulness facets in cancer patients.

Dynamics of genomic clones in breast cancer patient xenografts at single-cell resolution.

Human cancers, including breast cancers, comprise clones differing in mutation content. Clones evolve dynamically in space and time following principles of Darwinian evolution, underpinning important emergent features such as drug resistance and metastasis. Human breast cancer xenoengraftment is used as a means of capturing and studying tumour biology, and breast tumour xenografts are generally assumed to be reasonable models of the originating tumours. However, the consequences and reproducibility of engraftment and propagation on the genomic clonal architecture of tumours have not been systematically examined at single-cell resolution. Here we show, using deep-genome and single-cell sequencing methods, the clonal dynamics of initial engraftment and subsequent serial propagation of primary and metastatic human breast cancers in immunodeficient mice. In all 15 cases examined, clonal selection on engraftment was observed in both primary and metastatic breast tumours, varying in degree from extreme selective engraftment of minor (<5% of starting population) clones to moderate, polyclonal engraftment. Furthermore, ongoing clonal dynamics during serial passaging is a feature of tumours experiencing modest initial selection. Through single-cell sequencing, we show that major mutation clusters estimated from tumour population sequencing relate predictably to the most abundant clonal genotypes, even in clonally complex and rapidly evolving cases. Finally, we show that similar clonal expansion patterns can emerge in independent grafts of the same starting tumour population, indicating that genomic aberrations can be reproducible determinants of evolutionary trajectories. Our results show that measurement of genomically defined clonal population dynamics will be highly informative for functional studies using patient-derived breast cancer xenoengraftment.

Clonal genotype and population structure inference from single-cell tumor sequencing.

Single-cell DNA sequencing has great potential to reveal the clonal genotypes and population structure of human cancers. However, single-cell data suffer from missing values and biased allelic counts as well as false genotype measurements owing to the sequencing of multiple cells. We describe the Single Cell Genotyper (https://bitbucket.org/aroth85/scg), an open-source software based on a statistical model coupled with a mean-field variational inference method, which can be used to address these problems and robustly infer clonal genotypes.

Stress and psychosomatic symptoms in Chinese adults with sleep complaints: mediation effect of self-compassion.

Although stress has been widely acknowledged to link to psychosomatic dysfunctioning, the underlying mechanism that transmits the impact is not adequately investigated. This study examined self-compassion as a potential mediator that may explain the pathway from stress to depressive and somatic symptoms. Data in the present study were drawn from a baseline survey of 998 Chinese participants who enrolled in an intervention study on sleep disturbance in Hong Kong. Participants completed measures of perceived stress, self-compassion, depressive symptoms, and somatic symptoms. The results showed that stress was associated with depressive symptoms (r = .79, p < .01) and somatic symptoms (r = .47, p < .01). The path analyses showed that low levels of self-compassion mediated the association between stress and psychosomatic symptoms. Our findings provide insight into the pathway how stress affects psychosomatic symptoms. The intervention programs for stress management to improve psychological and physical functioning are recommended to consider self-compassion as a promising component in practice.

PyClone: statistical inference of clonal population structure in cancer.

We introduce PyClone, a statistical model for inference of clonal population structures in cancers. PyClone is a Bayesian clustering method for grouping sets of deeply sequenced somatic mutations into putative clonal clusters while estimating their cellular prevalences and accounting for allelic imbalances introduced by segmental copy-number changes and normal-cell contamination. Single-cell sequencing validation demonstrates PyClone's accuracy.

Study protocol on comparative effectiveness of mindfulness meditation and qigong on psychophysiological outcomes for patients with colorectal cancer: a randomized controlled trial.

BACKGROUND: Colorectal cancer imposes threats to patients' well-being. Although most physical symptoms can be managed by medication, psychosocial stressors may complicate survival and hamper quality of life. Mindfulness and Qigong, two kinds of mind-body exercise rooted in Eastern health philosophy, has been found effective in symptoms management, improving mental health, and reducing stress. With these potential benefits, a randomized controlled trial (RCT) is planned to investigate the comparative effectiveness of mindfulness and Baduanjin intervention on the bio-psychosocial wellbeing of people with colorectal cancer. METHODS/ DESIGN: A 3-arm RCT with waitlist control design will be used in this study. One hundred eighty-nine participants will be randomized into (i) Mindfulness, (ii) Baduanjin, or (iii) waitlist control groups. Participants in both the Baduanjin and mindfulness groups will receive 8-weeks of specific intervention. All three groups will undergo four assessment phases: (i) at baseline, (ii) at 4-week, (iii) at 8-week (post-intervention), and 6-month post-intervention (maintenance). All participants will be assessed in terms of cancer-related symptoms and symptom distress, mental health status, quality of life, stress level based on physiological marker. DISCUSSION: Based on prior research studies, participants in both the mindfulness and Baduanjn intervention group are expected to have better symptoms management, lower stress level, better mental health, and higher level of quality of life than the control group. This study contributes to better understanding on the common and unique effectiveness of mindfulness and Baduanjin qigong, as such patients and qualified healthcare professionals can select or provide practices which will produce maximum benefits, satisfaction, adherence, and sustainability. TRIAL REGISTRATION: The trial has been registered in the Clinical Trials Centre of the University of Hong Kong ( HKCTR-2198 ) on 08 March 2017.

Toward a Holistic Approach to Spiritual Health Care for People With Schizophrenia.

Medical and behavioral treatments are the predominant types of rehabilitation services for people with schizophrenia. Spirituality in people with schizophrenia remains poorly conceptualized, thereby limiting knowledge advancement in the area of spiritual health care services. To provide a framework for better clinical and research practices, we advocate a holistic approach to investigating spirituality and its application in spiritual health care services of people with schizophrenia.

A co-culture genome-wide RNAi screen with mammary epithelial cells reveals transmembrane signals required for growth and differentiation.

INTRODUCTION: The extracellular signals regulating mammary epithelial cell growth are of relevance to understanding the pathophysiology of mammary epithelia, yet they remain poorly characterized. In this study, we applied an unbiased approach to understanding the functional role of signalling molecules in several models of normal physiological growth and translated these results to the biological understanding of breast cancer subtypes. METHODS: We developed and utilized a cytogenetically normal clonal line of hTERT immortalized human mammary epithelial cells in a fibroblast-enhanced co-culture assay to conduct a genome-wide small interfering RNA (siRNA) screen for evaluation of the functional effect of silencing each gene. Our selected endpoint was inhibition of growth. In rigorous postscreen validation processes, including quantitative RT-PCR, to ensure on-target silencing, deconvolution of pooled siRNAs and independent confirmation of effects with lentiviral short-hairpin RNA constructs, we identified a subset of genes required for mammary epithelial cell growth. Using three-dimensional Matrigel growth and differentiation assays and primary human mammary epithelial cell colony assays, we confirmed that these growth effects were not limited to the 184-hTERT cell line. We utilized the METABRIC dataset of 1,998 breast cancer patients to evaluate both the differential expression of these genes across breast cancer subtypes and their prognostic significance. RESULTS: We identified 47 genes that are critically important for fibroblast-enhanced mammary epithelial cell growth. This group was enriched for several axonal guidance molecules and G protein-coupled receptors, as well as for the endothelin receptor PROCR. The majority of genes (43 of 47) identified in two dimensions were also required for three-dimensional growth, with HSD17B2, SNN and PROCR showing greater than tenfold reductions in acinar formation. Several genes, including PROCR and the neuronal pathfinding molecules EFNA4 and NTN1, were also required for proper differentiation and polarization in three-dimensional cultures. The 47 genes identified showed a significant nonrandom enrichment for differential expression among 10 molecular subtypes of breast cancer sampled from 1,998 patients. CD79A, SERPINH1, KCNJ5 and TMEM14C exhibited breast cancer subtype-independent overall survival differences. CONCLUSION: Diverse transmembrane signals are required for mammary epithelial cell growth in two-dimensional and three-dimensional conditions. Strikingly, we define novel roles for axonal pathfinding receptors and ligands and the endothelin receptor in both growth and differentiation.

Recurrent somatic DICER1 mutations in nonepithelial ovarian cancers.

BACKGROUND: Germline truncating mutations in DICER1, an endoribonuclease in the RNase III family that is essential for processing microRNAs, have been observed in families with the pleuropulmonary blastoma-family tumor and dysplasia syndrome. Mutation carriers are at risk for nonepithelial ovarian tumors, notably sex cord-stromal tumors. METHODS: We sequenced the whole transcriptomes or exomes of 14 nonepithelial ovarian tumors and noted closely clustered mutations in the region of DICER1 encoding the RNase IIIb domain of DICER1 in four samples. We then sequenced this region of DICER1 in additional ovarian tumors and in certain other tumors and queried the effect of the mutations on the enzymatic activity of DICER1 using in vitro RNA cleavage assays. RESULTS: DICER1 mutations in the RNase IIIb domain were found in 30 of 102 nonepithelial ovarian tumors (29%), predominantly in Sertoli-Leydig cell tumors (26 of 43, or 60%), including 4 tumors with additional germline DICER1 mutations. These mutations were restricted to codons encoding metal-binding sites within the RNase IIIb catalytic centers, which are critical for microRNA interaction and cleavage, and were somatic in all 16 samples in which germline DNA was available for testing. We also detected mutations in 1 of 14 nonseminomatous testicular germ-cell tumors, in 2 of 5 embryonal rhabdomyosarcomas, and in 1 of 266 epithelial ovarian and endometrial carcinomas. The mutant DICER1 proteins had reduced RNase IIIb activity but retained RNase IIIa activity. CONCLUSIONS: Somatic missense mutations affecting the RNase IIIb domain of DICER1 are common in nonepithelial ovarian tumors. These mutations do not obliterate DICER1 function but alter it in specific cell types, a novel mechanism through which perturbation of microRNA processing may be oncogenic. (Funded by the Terry Fox Research Institute and others.).

Psychometric validation of the consensus five-factor model of the Positive and Negative Syndrome Scale.

BACKGROUND: The Positive and Negative Syndrome Scale (PANSS) is widely used for clinical assessment of symptoms in schizophrenia. Instead of the traditional pyramidal model, recent literature supports the pentagonal model for the dimensionality of the PANSS. AIM: The present study aimed to validate the consensus five-factor model of the PANSS and evaluate its convergent validity. METHODS: Participants were 146 Chinese chronic schizophrenic patients who completed diagnostic interviews and cognitive assessments. Exploratory structural equation modeling (ESEM) was performed to investigate the dimensionality of the PANSS. Covariates (age, sex, and education level) and concurrent outcomes (perceived stress, memory, daily living functions, and motor deficits) were added in the ESEM model. RESULTS: The results supported the consensus 5-factor underlying structure, which comprised 20 items categorized into positive, negative, excitement, depression, and cognitive factors with acceptable reliability (α=.69-.85) and strong factor loadings (λ=.41-.93). The five factors, especially the cognitive factor, showed evident convergent validity with the covariates and concurrent outcomes. CONCLUSION: The results support the consensus five-factor structure of the PANSS as a robust measure of symptoms in schizophrenia. Future studies could explore the clinical and practical utility of the consensus five-factor model.

The psychophysiological effects of Tai-chi and exercise in residential schizophrenic patients: a 3-arm randomized controlled trial.

BACKGROUND: Patients with schizophrenia are characterized by high prevalence rates and chronicity that often leads to long-term institutionalization. Under the traditional medical model, treatment usually emphasizes the management of psychotic symptoms through medication, even though anti-psychotic drugs are associated with severe side effects, which can diminish patients' physical and psychological well-being. Tai-chi, a mind-body exercise rooted in Eastern health philosophy, emphasizes the motor coordination and relaxation. With these potential benefits, a randomized controlled trial (RCT) is planned to investigate the effects of Tai-chi intervention on the cognitive and motor deficits characteristic of patients with schizophrenia. METHODS/DESIGN: A 3-arm RCT with waitlist control design will be used in this study. One hundred and fifty three participants will be randomized into (i) Tai-chi, (ii) exercise or (iii) waitlist control groups. Participants in both the Tai-chi and exercise groups will receive 12-weeks of specific intervention, in addition to the standard medication and care received by the waitlist control group. The exercise group will serve as a comparison, to delineate any unique benefits of Tai-chi that are independent of moderate aerobic exercise. All three groups will undergo three assessment phases: (i) at baseline, (ii) at 12 weeks (post-intervention), and (iii) at 24 weeks (maintenance). All participants will be assessed in terms of symptom management, motor coordination, memory, daily living function, and stress levels based on self-perceived responses and a physiological marker. DISCUSSION: Based on a promising pilot study conducted prior to this RCT, subjects in the Tai-chi intervention group are expected to be protected against deterioration of motor coordination and interpersonal functioning. They are also expected to have better symptoms management and lower stress level than the other treatment groups. TRIAL REGISTRATION: The trail has been registered in the Clinical Trials Center of the University of Hong Kong (HKCTR-1453).

Ontogeny stage-independent and high-level clonal expansion in vitro of mouse hematopoietic stem cells stimulated by an engineered NUP98-HOX fusion transcription factor.

Achieving high-level expansion of hematopoietic stem cells (HSCs) in vitro will have an important clinical impact in addition to enabling elucidation of their regulation. Here, we couple the ability of engineered NUP98-HOXA10hd expression to stimulate > 1000-fold net expansions of murine HSCs in 10-day cultures initiated with bulk lin(-)Sca-1(+)c-kit(+) cells, with strategies to purify fetal and adult HSCs and analyze their expansion clonally. We find that NUP98-HOXA10hd stimulates comparable expansions of HSCs from both sources at ∼ 60% to 90% unit efficiency in cultures initiated with single cells. Clonally expanded HSCs consistently show balanced long-term contributions to the lymphoid and myeloid lineages without evidence of leukemogenic activity. Although effects on fetal and adult HSCs were indistinguishable, NUP98-HOXA10hd-transduced adult HSCs did not thereby gain a competitive advantage in vivo over freshly isolated fetal HSCs. Live-cell image tracking of single transduced HSCs cultured in a microfluidic device indicates that NUP98-HOXA10hd does not affect their proliferation kinetics, and flow cytometry confirmed the phenotype of normal proliferating HSCs and allowed reisolation of large numbers of expanded HSCs at a purity of 25%. These findings point to the effects of NUP98-HOXA10hd on HSCs in vitro being mediated by promoting self-renewal and set the stage for further dissection of this process.

Start With the Body or the Mind? Differential Benefits of Mindfulness and Qigong Practices for Colorectal Cancer Survivors: A Qualitative Study.

BACKGROUND: Mindfulness and qigong are 2 distinct forms of mind-body practice that have been well-received by cancer survivors. Although there is evidence supporting the effectiveness of mindfulness or qigong in promoting wellness of cancer survivors, little is known about the differential benefits of these common forms of mind-body practices among survivors. OBJECTIVE: To compare the potential biopsychosocial-spiritual impacts of mindfulness and Baduanjin (BDJ) qigong on colorectal cancer survivors. METHODS: Sixty cancer survivors who participated in a mindfulness intervention (n = 38) and BDJ qigong (n = 22) intervention were invited to provide qualitative feedback for their experiences. Content analyses were conducted to identify emerging themes from the data, and χ2 tests were conducted to compare the responses of the mindfulness and BDJ groups in the major categories. RESULTS: Both practices positively influenced psychosocial wellness. The practice of BDJ qigong led to more prominent improvements in physical well-being, whereas mindfulness worked best in enhancing spiritual growth and intrapersonal connectedness. CONCLUSIONS: Survivors of colorectal cancer who are looking for ways to enhance their vitality and rejuvenate their physical body may find the practice of BDJ helpful, whereas survivors who are looking for spiritual comfort or growth may consider practicing mindfulness as an entry point toward mind-body unity. IMPLICATIONS FOR PRACTICE: Mindfulness and BDJ may be helpful for survivors of colorectal cancer to improve their holistic wellness. Oncology nurses can consider prescription of mindfulness and/or BDJ for patients recovering from colorectal cancer.

Protocol for a mixed-methods randomised controlled trial evaluating the effectiveness of a dyadic expressive arts-based intervention in improving the psychosocial well-being of children with intellectual disability in special schools and their mothers.

INTRODUCTION: Mothers of children with intellectual disability (ID) are often distressed because of intensive workloads and difficulties in communicating with their children. Given the interdependence between the psychosocial well-being of such dyads, interventions that promote parent-child relationships and mutual communication would be beneficial. Arts provide alternative avenues for expression and offer an imaginative and playful environment for discovering new communication strategies. Given the lack of studies on arts-based dyadic interventions, this study aims to examine the effectiveness of dyadic expressive arts-based intervention (EXAT) in improving the psychosocial outcomes of children with ID and their mothers and the mother-child relationships. METHODS AND ANALYSIS: This study will adopt a mixed-methods randomised controlled trial design, wherein 154 dyads of children with ID and their mothers will be randomised into either the dyadic EXAT group or the treatment-as-usual waitlist control group. Quantitative data will be collected at four time points: baseline (T0), postintervention (T1), 3-month postintervention (T2) and 6-month postintervention (T3). Qualitative data will be collected from a subset of 30 mothers in the intervention group at T1 and T3 to document their experiences and perceived changes after the intervention. Mixed-effects models and path analysis will be adopted to analyse the quantitative data, whereas thematic analysis will be applied to the qualitative data. Both sets of data will be triangulated for an integrated view of the effectiveness and mechanism of the intervention. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Human Research Ethics Committee of the University of Hong Kong (Ref. no.: EA200329). Written consent forms will be obtained from all recruited participants (mothers, children with ID and teachers/social workers) before data collection. The study findings will be disseminated in international conferences and peer-reviewed academic journals. TRIAL REGISTRATION NUMBER: NCT05214859.

A randomised controlled trial of expressive arts-based intervention for young stroke survivors.

BACKGROUND: Stroke causes lasting brain damage that has numerous impacts on the survivor's physical, psychosocial, and spiritual well-being. Young survivors (< 65 years old) tend to suffer more because of their longer overall survival time. Expressive arts-based intervention is considered a holistic approach for stroke rehabilitation because it allows participants to express their thoughts and emotions through the arts. The group environment also promotes mutual support among participants. The creative art-making process helps expand participants' creativity and imagination as well as promote a sense of aesthetic appreciation. Previous studies have shown the effectiveness of the arts-based intervention in managing stroke and its psychosocial-spiritual comorbidities. Nevertheless, a systematic study has not been conducted, including in young survivors. This trial plans to investigate the effectiveness of an expressive arts-based intervention on bio-psychosocial-spiritual outcomes in young Chinese stroke survivors. METHODS/DESIGN: A single-blind, two-arm cluster randomised control trial with a waitlist control design will be adopted. One hundred and fifty-four stroke survivors, aged 18-64 years with modified Rankin Scale scores of 1-4, will be screened and randomised to either an expressive arts-based intervention group or a treatment-as-usual waitlist control group. The intervention group will receive a 90-min session once a week for a total of 8 weeks. All participants will be assessed three times: at baseline, 8 weeks, and 8 months after the baseline. Study outcomes include measures of depression and anxiety, perceived stress, perceived social support, hope, spiritual well-being, quality of life, salivary cortisol, blood pressure, and heart rate. DISCUSSION: This study is expected to contribute to the current knowledge on the effectiveness of an arts-based intervention on the holistic wellness of young stroke survivors. The findings will help stroke survivors and healthcare professionals make better choices in selecting practices that will yield maximum benefits, satisfaction, adherence, and sustainability. In addition, the examination of the relationships between bio-psychosocial-spiritual variables will help contribute to the development of holistic care for the survivors. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03729648 . Registered 31 October 2018 - Retrospectively registered, (329 words).

Chemogenomic profiling of breast cancer patient-derived xenografts reveals targetable vulnerabilities for difficult-to-treat tumors.

Subsets of breast tumors present major clinical challenges, including triple-negative, metastatic/recurrent disease and rare histologies. Here, we developed 37 patient-derived xenografts (PDX) from these difficult-to-treat cancers to interrogate their molecular composition and functional biology. Whole-genome and transcriptome sequencing and reverse-phase protein arrays revealed that PDXs conserve the molecular landscape of their corresponding patient tumors. Metastatic potential varied between PDXs, where low-penetrance lung micrometastases were most common, though a subset of models displayed high rates of dissemination in organotropic or diffuse patterns consistent with what was observed clinically. Chemosensitivity profiling was performed in vivo with standard-of-care agents, where multi-drug chemoresistance was retained upon xenotransplantation. Consolidating chemogenomic data identified actionable features in the majority of PDXs, and marked regressions were observed in a subset that was evaluated in vivo. Together, this clinically-annotated PDX library with comprehensive molecular and phenotypic profiling serves as a resource for preclinical studies on difficult-to-treat breast tumors.

Linkage of Meis1 leukemogenic activity to multiple downstream effectors including Trib2 and Ccl3.

OBJECTIVE: MEIS1, a HOX cofactor, collaborates with multiple HOX and NUP98-HOX fusion proteins to accelerate the onset of acute myeloid leukemia (AML) through largely unknown molecular mechanisms. MATERIALS AND METHODS: To further resolve these mechanisms, we conducted a structure-function analysis of MEIS1 and gene-expression profiling, in the context of NUP98-HOXD13 (ND13) leukemogenesis. RESULTS: We show, in a murine bone marrow transplantation model, that the PBX-interaction domain, the homeodomain, and the C-terminal domain of MEIS1, are all required for leukemogenic collaboration with ND13. In contrast, the N-terminal domain of MEIS1 is dispensable for collaboration with ND13, but is required for Flt3 upregulation, indicating additional roles for MEIS1 in induction of leukemia independent of alterations in Flt3 expression. Gene-expression profiling of a cloned ND13 preleukemic cell line transduced with wild-type or Meis1 mutant forms revealed deregulation of multiple genes, including a set not previously implicated as MEIS1 targets. Chromatin immunoprecipitation revealed the in vivo occupancy of MEIS1 on regulatory sequences of Trib2, Flt3, Dlk1, Ccl3, Ccl4, Pf4, and Rgs1. Furthermore, engineered overexpression of Trib2 complements ND13 to induce AML while Ccl3 potentiates the repopulating ability of ND13. CONCLUSION: This study shows that Meis1-induced leukemogenesis with ND13 can occur in the absence of Flt3 upregulation and reveals the existence of other pathways activated by MEIS1 to promote leukemia.

Psychiatric symptoms mediate the effects of neurological soft signs on functional outcomes in patients with chronic schizophrenia: A longitudinal path-analytic study.

Neurological soft signs (NSS) in motor coordination and sequencing occur in schizophrenia patients and are an intrinsic sign of the underlying neural dysfunctions. The present longitudinal study explored the relationships among NSS, psychiatric symptoms, and functional outcomes in 151 Chinese patients with chronic schizophrenia across a 6-month period. The participants completed neurological assessments at baseline (Time 1), psychiatric interviews at Time 1 and 3-month follow-up (Time 2), and self-report measures on daily functioning at 6-month follow-up (Time 3). Two possible (combined and cascading) path models were examined on predicting the functional outcomes. Direct and indirect effects of Time 1 NSS on Time 3 functional outcomes via Time 2 psychiatric symptoms were evaluated using path analysis under bootstrapping. Motor coordination and sequencing NSS did not have significant direct effects on functional outcomes. Motor coordination NSS exerted significant and negative indirect effects on functional outcomes via psychiatric symptoms. These results contribute to a better understanding of the determinants of functional outcomes by showing significant indirect pathways from motor coordination NSS to functional outcomes via psychiatric symptoms. That motor sequencing NSS did not affect functional outcomes either directly or indirectly may be explained by their trait marking features.