A gene regulatory network armature for T lymphocyte specification

Choice of a T lymphoid fate by hematopoietic progenitor cells depends on sustained Notch–Delta signaling combined with tightly regulated activities of multiple transcription factors. To dissect the regulatory network connections that mediate this process, we have used high-resolution analysis of regulatory gene expression trajectories from the beginning to the end of specification, tests of the short-term Notch dependence of these gene expression changes, and analyses of the effects of overexpression of two essential transcription factors, namely PU.1 and GATA-3. Quantitative expression measurements of >50 transcription factor and marker genes have been used to derive the principal components of regulatory change through which T cell precursors progress from primitive multipotency to T lineage commitment. Our analyses reveal separate contributions of Notch signaling, GATA-3 activity, and down-regulation of PU.1. Using BioTapestry (www.BioTapestry.org), the results have been assembled into a draft gene regulatory network for the specification of T cell precursors and the choice of T as opposed to myeloid/dendritic or mast-cell fates. This network also accommodates effects of E proteins and mutual repression circuits of Gfi1 against Egr-2 and of TCF-1 against PU.1 as proposed elsewhere, but requires additional functions that remain unidentified. Distinctive features of this network structure include the intense dose dependence of GATA-3 effects, the gene-specific modulation of PU.1 activity based on Notch activity, the lack of direct opposition between PU.1 and GATA-3, and the need for a distinct, late-acting repressive function or functions to extinguish stem and progenitor-derived regulatory gene expression

The effects of booster sessions on self-management interventions for chronic musculoskeletal pain: a systematic review and meta-analysis of randomised controlled trials

Our objective was to investigate the effectiveness of booster sessions after self-management interventions as a means of maintaining self-management behaviours in the treatment of chronic musculoskeletal pain. We searched MEDLINE, EMBASE, Science Citation Index, Cochrane Central Register of Controlled Trials and PsycINFO. Two authors independently identified eligible trials and collected data. We calculated the odds ratio (OR) for the analyses of dichotomous data, and standardised mean differences (SMD) with 95% confidence interval (CI) for continuous variables. Our search identified 14 studies with a total of 1695 patients. All studies were at high risk of bias and provided very low quality evidence. For the primary outcomes, booster sessions had no evidence of an effect on improving patient-reported outcomes on physical function (SMD-0.13, 95%CI -0.32 to -0.06; P=0.18), pain-related disability (SMD-0.16, 95%CI -0.36 to 0.03; P=0.11) and pain self-efficacy (SMD 0.15, 95%CI -0.07 to 0.36; P=0.18). For the secondary outcomes, booster sessions caused a significant reduction in patient-reported pain catastrophising (SMD-0.42, 95%CI -0.64 to -0.19; P=0.0004), and no evidence of an effect on patient-reported pain intensity, depression, coping or treatment adherence. There is currently little evidence that booster sessions are an effective way to prolong positive treatment effects or improve symptoms of long-term musculoskeletal conditions following self-management interventions. However, the studies were few with high heterogeneity, high risk of bias and overall low quality of evidence. Our review argues against including booster sessions routinely to self-management interventions for the purpose of behaviour maintenance

The patient acceptability of a remotely delivered pain management programme for people with persistent musculoskeletal pain: A qualitative evaluation.

INTRODUCTION: Remotely delivered pain management programmes have been offered in place of in-person programmes by many chronic pain services since the onset of the COVID-19 pandemic. There is a lack of evidence regarding the acceptability of these programmes. In this evaluation, we have explored patients' acceptability of a remotely delivered pain management programme for patients with persistent musculoskeletal pain. METHODS: Qualitative data were collected using focus groups with participants who had previously attended the remote pain management programme. Data were analysed using abductive analysis. RESULTS: Three focus groups were conducted with a total of 13 participants. The programmme was either entirely acceptable, had some acceptable components or was not acceptable to patients. Factors leading to the programme being acceptable include learning to manage pain from home, receiving high quality care from home, enhancing the potential of rehabilitation using technology, enabling attendance on a pain management programme from home, overcoming social distancing requirements of COVID-19 using technology, and virtual peer support. Factors leading to the programme not being acceptable include having an inappropriate home environment for virtual therapy, communication challenges with virtual therapy, technological issues and concerns regarding the quality of care. CONCLUSIONS: There is a spectrum of acceptability with respect to the remote programme. The factors that influence this are dynamic, individual and situational. Hybrid programmes have the potential to enhance access to pain management programmes and improve patient experience and programme outcomes in the future

Patient perspectives on the unwanted effects of multidisciplinary pain management programmes: A qualitative study

Objective This study aimed to understand the impact of pain management programmes, focusing on the unwanted effects and their influence on patients’ long-term use of self-management strategies. Design Qualitative study. Setting Specialist musculoskeletal hospital in North London, England. Participants Patients with chronic musculoskeletal pain that have completed a pain management programme. Intervention Multidisciplinary pain management programmes. Main measures Data were collected regarding patients’ experiences and unwanted effects from the pain management programme using semi-structured interviews. Data were analysed using thematic analysis. Results Fourteen participant interviews were included in the analysis (median age 54 years, 12 females). Four themes were generated from the data: Benefits and burdens, Pain management programme and real life, Social support and Healthcare interventions. Unwanted effects included heightened anxiety related to negative interactions with peers, being in a new environment, worries about ability to cope with the programme, social anxiety from being in a group, the strain on families due to participants being away from home and a sense of abandonment at end of the programme. Burdens associated with implementing pain management strategies were identified, including the emotional burden of imposing their self-management on close family and competing demands with time and energy spent on self-management at the expense of work or home commitments. Conclusions Pain management programmes have an important role in helping patients to learn how to self-manage chronic pain. Their unwanted effects and the treatment burdens associated with long-term self-management may be an important consideration in improving the longevity of their beneficial effects

Patient perspectives on the unwanted effects of multidisciplinary pain management programmes: A qualitative study.

OBJECTIVE: This study aimed to understand the impact of pain management programmes, focusing on the unwanted effects and their influence on patients' long-term use of self-management strategies. DESIGN: Qualitative study. SETTING: Specialist musculoskeletal hospital in North London, England. PARTICIPANTS: Patients with chronic musculoskeletal pain that have completed a pain management programme. INTERVENTION: Multidisciplinary pain management programmes. MAIN MEASURES: Data were collected regarding patients' experiences and unwanted effects from the pain management programme using semi-structured interviews. Data were analysed using thematic analysis. RESULTS: Fourteen participant interviews were included in the analysis (median age 54 years, 12 females). Four themes were generated from the data: Benefits and burdens, Pain management programme and real life, Social support and Healthcare interventions. Unwanted effects included heightened anxiety related to negative interactions with peers, being in a new environment, worries about ability to cope with the programme, social anxiety from being in a group, the strain on families due to participants being away from home and a sense of abandonment at end of the programme. Burdens associated with implementing pain management strategies were identified, including the emotional burden of imposing their self-management on close family and competing demands with time and energy spent on self-management at the expense of work or home commitments. CONCLUSIONS: Pain management programmes have an important role in helping patients to learn how to self-manage chronic pain. Their unwanted effects and the treatment burdens associated with long-term self-management may be an important consideration in improving the longevity of their beneficial effects

Nuclear factor κB-inducing kinase activation as a mechanism of pancreatic β cell failure in obesity

The nuclear factor κB (NF-κB) pathway is a master regulator of inflammatory processes and is implicated in insulin resistance and pancreatic β cell dysfunction in the metabolic syndrome. Whereas canonical NF-κB signaling is well studied, there is little information on the divergent noncanonical NF-κB pathway in the context of pancreatic islet dysfunction. Here, we demonstrate that pharmacological activation of the noncanonical NF-κB-inducing kinase (NIK) disrupts glucose homeostasis in zebrafish in vivo. We identify NIK as a critical negative regulator of β cell function, as pharmacological NIK activation results in impaired glucose-stimulated insulin secretion in mouse and human islets. NIK levels are elevated in pancreatic islets isolated from diet-induced obese (DIO) mice, which exhibit increased processing of noncanonical NF-κB components p100 to p52, and accumulation of RelB. TNF and receptor activator of NF-κB ligand (RANKL), two ligands associated with diabetes, induce NIK in islets. Mice with constitutive β cell-intrinsic NIK activation present impaired insulin secretion with DIO. NIK activation triggers the noncanonical NF-κB transcriptional network to induce genes identified in human type 2 diabetes genome-wide association studies linked to β cell failure. These studies reveal that NIK contributes a central mechanism for β cell failure in diet-induced obesity

Hepatocyte Growth Factor Modulates Interleukin-6 Production in Bone Marrow Derived Macrophages: Implications for Inflammatory Mediated Diseases

The generation of the pro-inflammatory cytokines IL-6, TNF-α, and IL-1β fuel the acute phase response (APR). To maintain body homeostasis, the increase of inflammatory proteins is resolved by acute phase proteins via presently unknown mechanisms. Hepatocyte growth factor (HGF) is transcribed in response to IL-6. Since IL-6 production promotes the generation of HGF and induces the APR, we posited that accumulating HGF might be a likely candidate for quelling excess inflammation under non-pathological conditions. We sought to assess the role of HGF and how it influences the regulation of inflammation utilizing a well-defined model of inflammatory activation, lipopolysaccharide (LPS)-stimulation of bone marrow derived macrophages (BMM). BMM were isolated from C57BL6 mice and were stimulated with LPS in the presence or absence of HGF. When HGF was present, there was a decrease in production of the pro-inflammatory cytokine IL-6, along with an increase in the anti-inflammatory cytokine IL-10. Altered cytokine production correlated with an increase in phosphorylated GSK3β, increased retention of the phosphorylated NFκB p65 subunit in the cytoplasm, and an enhanced interaction between CBP and phospho-CREB. These changes were a direct result of signaling through the HGF receptor, MET, as effects were reversed in the presence of a selective inhibitor of MET (SU11274) or when using BMM from macrophage-specific conditional MET knockout mice. Combined, these data provide compelling evidence that under normal circumstances, HGF acts to suppress the inflammatory response

HGF/SF and its receptor c-MET play a minor role in the dissemination of human B-lymphoma cells in SCID mice

The MET protooncogene, c-MET, encodes a cell surface tyrosine kinase receptor. The ligand for c-MET is hepatocyte growth factor (HGF), also known as scatter factor (SF), which is known to affect proliferation and motility of primarily epithelial cells. Recently, HGF/SF was also shown to affect haemopoiesis. Studies with epithelial and transfected NIH3T3 cells indicated that the HGF/SF–c-MET interaction promotes invasion in vitro and in vivo. We previously demonstrated that HGF/SF induces adhesion of c-MET-positive B-lymphoma cells to extracellular matrix molecules, and promoted migration and invasion in in vitro assays. Here, the effect of HGF/SF on tumorigenicity of c-MET-positive and c-MET-negative human B-lymphoma cell lines was studied in C.B-17 scid/scid (severe combined immune deficient) mice. Intravenously (i.v.) injected c-MET-positive (BJAB) as well as c-MET-negative (Daudi and Ramos cells) B-lymphoma cells formed tumours in SCID mice. The B-lymphoma cells invaded different organs, such as liver, kidney, lymph nodes, lung, gonads and the central nervous system. We assessed the effect of human HGF/SF on the dissemination of the B-lymphoma cells and found that administration of 5 μg HGF/SF to mice, injected (i.v.) with c-MET-positive lymphoma cells, significantly (P = 0.018) increased the number of metastases in lung, liver and lymph nodes. In addition, HGF/SF did not significantly influence dissemination of c-MET-negative lymphoma cells (P = 0.350 with Daudi cells and P = 0.353 with Ramos cells). Thus the effect of administration of HGF/SF on invasion of lymphoma cells is not an indirect one, e.g. via an effect on endothelial cells. Finally, we investigated the effect of HGF/SF on dissemination of c-MET-transduced Ramos cells. In response to HGF/SF, c-MET-transduced Ramos cells showed an increased migration through Matrigel in Boyden chambers compared to wild-type and control-transduced Ramos cells. The dissemination pattern of c-MET-transduced cells did not differ from control cells in in vivo experiments using SCID mice. Also no effect of HGF/SF administration could be documented, in contrast to the in vitro experiments. From our experiments can be concluded that the HGF/SF–c-MET interaction only plays a minor role in the dissemination of human B-lymphoma cells. © 1999 Cancer Research Campaig