An Improved System to Measure Leaf Gas Exchange on Adaxial and Abaxial Surfaces.

Measurement of leaf carbon gain and water loss (gas exchange) in planta is a standard procedure in plant science research for attempting to understand physiological traits related to water use and photosynthesis. Leaves carry out gas exchange through the upper (adaxial) and lower (abaxial) surfaces at different magnitudes, depending on the stomatal density, stomatal aperture, cuticular permeability, etc., of each surface, which we account for in gas exchange parameters such as stomatal conductance. Most commercial devices measure leaf gas exchange by combining the adaxial and abaxial fluxes and calculating bulk gas exchange parameters, missing details of the plant's physiological response on each side. Additionally, the widely used equations to estimate gas exchange parameters neglect the contribution of small fluxes such as cuticular conductance, adding extra uncertainties to measurements performed in water-stress or low-light conditions. Accounting for the gas exchange fluxes from each side of the leaf allows us to better describe plants' physiological traits under different environmental conditions and account for genetic variability. Here, apparatus and materials are presented for adapting two LI-6800 Portable Photosynthesis Systems to work as one gas exchange system to measure adaxial and abaxial gas exchange simultaneously. The modification includes a template script with the equations to account for small fluxes. Instructions are provided for incorporating the add-on script into the device's computational sequence, display, variables, and spreadsheet results. We explain the method to obtain an equation to estimate boundary layer conductance to water for the new setup and how to embed this equation in the devices' calculations using the provided add-on script. The apparatus, methods, and protocols presented here provide a simple adaptation combining two LI-6800s to obtain an improved system to measure leaf gas exchange on adaxial and abaxial surfaces. Graphical overview Figure 1.Diagram of the connection of two LI-6800s.Figure adapted from Márquez et al. (2021).

ADAM9 Mediates Triple-Negative Breast Cancer Progression via AKT/NF-κB Pathway.

Upregulation of a disintegrin and metalloprotease 9 (ADAM9) is correlated with progression of cancers, such as prostate, bladder, and pancreatic cancers. However, its role in triple-negative breast cancer (TNBC) is still unclear. Our study aimed to investigate whether ADAM9 is upregulated and promoted the aggressiveness in TNBC. Breast cancer cell lines and patient specimens were used to evaluate the ADAM9 expression by western blotting and immunohistochemistry staining, respectively. Compared with the non-TNBC, ADAM9 expression was significantly increased in TNBC cells and TNBC patient specimens. Based on the data acquired from public databases, the correlation between ADAM9 expression and breast cancer patient survival was analyzed by Kaplan-Meier method. It was shown that ADAM9 overexpression was significantly correlated with poorer survival in patients with TNBC. Furthermore, ADAM9 in TNBC cells was knocked down by small interference RNA and then studied by the MTT/colony formation assay, wound healing assay and transwell invasion assay on the cell proliferation, migration, and invasion, respectively. We found that inhibiting ADAM9 expression suppressed TNBC cell proliferation, migration, and invasion by lowering the activation of AKT/NF-κB pathway. Our results demonstrated that ADAM9 is an important molecule in mediating TNBC aggressiveness and may be a potential useful therapeutic target in TNBC treatment.

Systematic review of the effects of bisphosphonates on bone density and fracture incidence in childhood acute lymphoblastic leukaemia.

Skeletal fragility is a common complication of childhood acute lymphoblastic leukaemia (ALL) but the impact of bisphosphonate therapy on bone mass and fracture is unclear. We aim to conduct a systematic review to evaluate the effects of bisphosphonates on bone mineral density (BMD) and fracture incidence in children with ALL. METHODS: EMBASE, Medline and the Cochrane Library were thoroughly searched by two researchers. Inclusion criteria was any child under the age of 18 years with a diagnosis of ALL, who had received any bisphosphonate treatment and had serial measurements of bone density performed thereafter. All primary research studies of any study design, excluding case reports, were included. RESULTS: Ten full text papers were identified with two exclusively meeting the inclusion criteria. Both studies administered bisphosphonates to children receiving maintenance chemotherapy for varying durations. Bone density was assessed at regular intervals by dual x-ray absorptiometry (DXA). The majority of participants had an improvement in bone density at the end of each study. However, no size adjustment of DXA data was performed. Limited information on fracture occurrence was provided by one study but did not include routine screening for vertebral fractures. CONCLUSIONS: This systematic review identified that there is insufficient evidence to support routine use of prophylactic bisphosphonate therapy in childhood ALL for prevention of fracture and improvement of bone mass. Future well-designed clinical trials in those at highest risk of fractures in ALL are now needed.

Non-invasive Potential Circulating mRNA Markers for Colorectal Adenoma Using Targeted Sequencing.

We have developed an optimized protocol for plasma targeted mRNA sequencing in our previous study. Here, we performed plasma targeted mRNA sequencing for 40 colorectal adenoma patients and 39 colonoscopy-proven normal controls in order to find potential circulating mRNA markers for colorectal adenoma. Results showed that GSK3A and RHOA were differential expressed genes identified by a cut-off of fold change >2 and adjusted P value < 0.05. More detailed analysis showed that the expression of both GSK3A (0.01-fold with adjusted P < 1 × 10-6) and RHOA (0.35-fold with adjusted P < 0.01) in adenoma patients was significantly lower than those in normal healthy subjects. Based on the enrichment analysis of biological process for potential markers, we found that the regulation of programmed cell death (GO: 0043067; GO: 0043069), regulation of cell death (GO: 0010941; GO: 0060548) and cell differentiation (GO: 0021861) were the main processes involved in adenoma formation. In summary, this study is a cutting-edge research on the detection of plasma mRNA in colorectal adenoma patients and normal healthy subjects.

Multi-scale representation of proteomic data exhibits distinct microRNA regulatory modules in non-smoking female patients with lung adenocarcinoma.

Adenocarcinoma in female non-smokers is an under-explored subgroup of non-small cell lung cancer (NSCLC), in which the molecular mechanism and genetic risk factors remain unclear. We analyzed the protein profiles of plasma samples of 45 patients in this subgroup and 60 non-cancer subjects using surface-enhanced laser desorption/ionization time-of- flight mass spectrometry. Among 85 peaks of mass spectra, the differential expression analysis identified 15 markers based on False Discovery Rate control and the Discrete Wavelet Transforms further selected a cluster of 6 markers that were consistently observed at multiple scales of mass-charge ratios. This marker cluster, corresponding to 7 unique proteins, was able to distinguish the female non-smokers with adenocarcinoma from non-cancer subjects with a value of accuracy of 87.6%. We also predicted the role of competing endogenous RNAs (ceRNAs) in 3 out of these 7 proteins. Other studies reported that these ceRNAs and their targeting microRNAs, miR-206 and miR-613, were significantly associated with NSCLC. This study paves a crucial path for further investigating the genetic markers and molecular mechanism of this special NSCLC subgroup.

Prospective evaluation of plasma Epstein-Barr virus DNA clearance and fluorodeoxyglucose positron emission scan in assessing early response to chemotherapy in patients with advanced or recurrent nasopharyngeal carcinoma.

BACKGROUND: Plasma Epstein-Barr virus (pEBV) DNA and fluorodeoxyglucose positron emission (PET) reflect tumour burden in advanced NPC. This study hypothesised that a dual endpoint based on assessing pEBV DNA clearance and PET response could predict early drug response. METHODS: Eligible patients underwent a computed tomography (CT) scan and dual PET-CT at baseline, a PET-CT at 4 weeks, and then a CT scan at 10 weeks after starting palliative or induction chemotherapy. Plasma EBV DNA clearance was determined. RESULTS: Fifty-eight out of 70 enrolled patients completed all imaging and 50/58 had falling pEBV DNA level, which allowed calculation of the clearance. At a median follow-up of 29.1 months, the dual endpoint (pEBV DNA clearance ≤ 10 days and > 50% drop in sum of SUVmax of target lesions) was an independent indicator of overall survival (hazard ratio (HR) = 0.135, 95% CI = 0.039 to 0.466, p = 0.0015) and progression-free survival (HR = 0.136, 95% CI = 0.048 to 0.385, p = 0002). This dual endpoint could predict subsequent response by Response Evaluation Criteria In Solid Tumours (RECIST) criteria at 10 weeks after chemotherapy. CONCLUSIONS: Early PET-CT response and pEBV DNA clearance could predict survival and subsequent response. This dual endpoint is an innovative tool for assessing early drug response.

Association Patterns of Ontological Features Signify Electronic Health Records in Liver Cancer.

Electronic Health Record (EHR) system enables clinical decision support. In this study, a set of 112 abdominal computed tomography imaging examination reports, consisting of 59 cases of hepatocellular carcinoma (HCC) or liver metastases (so-called HCC group for simplicity) and 53 cases with no abnormality detected (NAD group), were collected from four hospitals in Hong Kong. We extracted terms related to liver cancer from the reports and mapped them to ontological features using Systematized Nomenclature of Medicine (SNOMED) Clinical Terms (CT). The primary predictor panel was formed by these ontological features. Association levels between every two features in the HCC and NAD groups were quantified using Pearson's correlation coefficient. The HCC group reveals a distinct association pattern that signifies liver cancer and provides clinical decision support for suspected cases, motivating the inclusion of new features to form the augmented predictor panel. Logistic regression analysis with stepwise forward procedure was applied to the primary and augmented predictor sets, respectively. The obtained model with the new features attained 84.7% sensitivity and 88.4% overall accuracy in distinguishing HCC from NAD cases, which were significantly improved when compared with that without the new features.

Checkpoint blockade immunotherapy reshapes the high-dimensional phenotypic heterogeneity of murine intratumoural neoantigen-specific CD8+ T cells.

The analysis of neoantigen-specific CD8+ T cells in tumour-bearing individuals is challenging due to the small pool of tumour antigen-specific T cells. Here we show that mass cytometry with multiplex combinatorial tetramer staining can identify and characterize neoantigen-specific CD8+ T cells in mice bearing T3 methylcholanthrene-induced sarcomas that are susceptible to checkpoint blockade immunotherapy. Among 81 candidate antigens tested, we identify T cells restricted to two known neoantigens simultaneously in tumours, spleens and lymph nodes in tumour-bearing mice. High-dimensional phenotypic profiling reveals that antigen-specific, tumour-infiltrating T cells are highly heterogeneous. We further show that neoantigen-specific T cells display a different phenotypic profile in mice treated with anti-CTLA-4 or anti-PD-1 immunotherapy, whereas their peripheral counterparts are not affected by the treatments. Our results provide insights into the nature of neoantigen-specific T cells and the effects of checkpoint blockade immunotherapy.Immune checkpoint blockade (ICB) therapies can unleash anti-tumour T-cell responses. Here the authors show, by integrating MHC tetramer multiplexing, mass cytometry and high-dimensional analyses, that neoantigen-specific, tumour-infiltrating T cells are highly heterogeneous and are subjected to ICB modulations.

Identifying an early indicator of drug efficacy in patients with metastatic colorectal cancer-a prospective evaluation of circulating tumor cells, 18F-fluorodeoxyglucose positron-emission tomography and the RECIST criteria.

BACKGROUND: This study investigated the predictive and prognostic significance of assessing early drug response with both positron-emission computerized tomography (PET-CT) and circulating tumor cells (CTCs) in patients receiving first-line chemotherapy for metastatic colorectal cancer. PATIENTS AND METHODS: Eligible patients had PET-CT and CTC analysis at baseline and 4-6 weeks after starting chemotherapy, and then a CT scan at 10-12 weeks to assess the Response Evaluation Criteria In Solid Tumors (RECIST) response. Early response was defined as achieving a dual-endpoint consisting of PET-CT (30% drop in the sum of maximum standard uptake values-SUVmax-of target lesions) and CTC response (CTC < 3 cells/7.5 ml blood) at 4-6 weeks after starting chemotherapy. RESULTS: About 84 patients were enrolled with a median follow-up of 32.9 months (95% confidence interval, CI, 24.5 months-not reached, NR), and 70 patients (84.3%) completed all assessments. Achieving an early response based on the dual-endpoint was independently associated with progression-free survival (hazard ratio, HR = 0.452, 95% CI 0.267-0.765). The median progression-free survival of early responders was 7.41 months (95% CI, 6.05-9.11) compared with 5.37 months (95% CI, 4.68-6.24) in non-responders (log-rank, P = 0.0167). RECIST response at 10 weeks was independently associated with overall survival (OS) (HR = 0.484, 95% CI, 0.275-0.852). Early response based on the dual-endpoint could predict the subsequent RECIST response with a sensitivity, specificity and positive predictive value of 64%, 70% and 74%, respectively. CONCLUSIONS: Early response based on both PET-CT and CTC analysis has prognostic and probably predictive significance in patients undergoing first-line chemotherapy for metastatic colorectal cancer. Its utility as a new tool for assessing early drug response should be further validated.

Ear health and hearing surveillance in girls and women with Turner's syndrome: recommendations from the Turner's Syndrome Support Society.

BACKGROUND: Turner's syndrome (TS) is a common chromosomal disorder, affecting one in 2000 newborn girls, in which part or all of one X chromosome is missing. Ear and hearing problems are very common in girls and women with TS. The aim of this review was to review the published literature to suggest recommendations for otological health surveillance. METHOD: A keyword search of Ovid Medline was performed for published literature on the subject and evidence rated according to the GRADE criteria. RESULTS: Middle ear disorders are very common and persistent in girls and women with TS as are progressive sensorineural hearing loss and balance disorders. CONCLUSIONS: Otolaryngologists should be aware of the high prevalence and challenging nature of all forms of ear disease in individuals with TS. Early intervention may offer benefits to health and education, and we advocate routine lifelong annual hearing screening in this group.

MiR-30a-5p Overexpression May Overcome EGFR-Inhibitor Resistance through Regulating PI3K/AKT Signaling Pathway in Non-small Cell Lung Cancer Cell Lines.

Lung cancer is one of the most common deadly diseases worldwide, most of which is non-small cell lung cancer (NSCLC). The epidermal growth factor receptor (EGFR) mutant NSCLCs frequently respond to the EGFR tyrosine kinase inhibitors (EGFR-TKIs) treatment, such as Gefitinib and Erlotinib, but the development of acquired resistance limits the utility. Multiple resistance mechanisms have been explored, e.g., the activation of alternative tyrosine kinase receptors (TKRs) sharing similar downstream pathways to EGFR. MicroRNAs (miRNAs) are short, endogenous and non-coding RNA molecules, regulating the target gene expression. In this study, we explored the potential of miR-30a-5p in targeting the EGFR and insulin-like growth factor receptor-1 (IGF-1R) signaling pathways to overcome the drug resistance. IGF-1R is one of the tyrosine kinase receptors that share the same EGFR downstream molecules, including phosphatidylinositol 3 kinase (PI3K) and protein kinase B (AKT). In this work, an in vitro study was designed using EGFR inhibitor (Gefitinib), IGF-1R inhibitor (NVP-AEW541), and miRNA mimics in two Gefitinib-resistant NSCLC cell lines, H460 and H1975. We found that the combination of EGFR and IGF-1R inhibitors significantly decreased the phosphorylated AKT (p-AKT) expression levels compared to the control group in these two cell lines. Knockdown of phosphoinositide-3-kinase regulatory subunit 2 (PIK3R2) had the same effect with the dual inhibition of EGFR and IGF-1R to reduce the expression of p-AKT in the signaling pathway. Overexpression of miR-30a-5p significantly reduced the expression of the PI3K regulatory subunit (PIK3R2) to further induce cell apoptosis, and inhibit cell invasion and migration properties. Hence, miR-30a-5p may play vital roles in overcoming the acquired resistance to EGFR-TKIs, and provide useful information for establishing novel cancer treatment.

Circulating Plasma MicroRNAs As Diagnostic Markers for NSCLC.

Lung cancer is the most common cause of cancer deaths all over the world, in which non-small cell lung cancer (NSCLC) accounts for ~85% of cases. It is well known that microRNAs (miRNAs) play a critical role in various cellular processes, mediating post-transcriptional silencing either by mRNA degradation through binding the 3' UTR of target mRNA or by translational inhibition of the protein. In the past decade, miRNAs have also been increasingly identified in biological fluids such as human serum or plasma known as circulating or cell-free miRNAs, and may function as non-invasive diagnostic markers for various cancer types including NSCLC. Circulating tumor cells (CTCs) are those cells that are shed from solid tumors and then migrate into the circulation. However, reports concerning the roles of CTCs are quite rare, which may be attributed to the difficulties in the enrichment and detection of CTCs in the circulation. Although, there have been reassuring advances in identifying circulating miRNA-panels, which are assumed to be of diagnostic value in NSCLC early stage, some issues remain concerning the reliability of using miRNA panels as a diagnostic tool for NSCLC. In the current review, we are aiming at providing insights into the miRNAs biology, the mechanisms of miRNAs release into the bloodstream, cell-free miRNAs as the diagnostic markers for NSCLC and the current limitations of CTCs as diagnostic markers in NSCLC.

Associations of mRNA:microRNA for the Shared Downstream Molecules of EGFR and Alternative Tyrosine Kinase Receptors in Non-small Cell Lung Cancer.

Lung cancer is the top cancer killer worldwide with high mortality rate. Majority belong to non-small cell lung cancers (NSCLCs). The epidermal growth factor receptor (EGFR) has been broadly explored as a drug target for therapy. However, the drug responses are not durable due to the acquired resistance. MicroRNAs (miRNAs) are small non-coding and endogenous molecules that can inhibit mRNA translation initiation and degrade mRNAs. We wonder if some downstream molecules shared by EGFR and the other tyrosine kinase receptors (TKRs) further transduce the signals alternatively, and some miRNAs play the key roles in affecting the expression of these downstream molecules. In this study, we investigated the mRNA:miRNA associations for the direct EGFR downstream molecules in the EGFR signaling pathway shared with the other TKRs, including c-MET (hepatocyte growth factor receptor), Ron (a protein tyrosine kinase related to c-MET), PDGFR (platelet-derived growth factor receptor), and IGF-1R (insulin-like growth factor receptor-1). The multiple linear regression and support vector regression (SVR) models were used to discover the statistically significant and the best weighted miRNAs regulating the mRNAs of these downstream molecules. These two models revealed the similar mRNA:miRNA associations. It was found that the miRNAs significantly affecting the mRNA expressions in the multiple regression model were also those with the largest weights in the SVR model. To conclude, we effectively identified a list of meaningful mRNA:miRNA associations: phospholipase C, gamma 1 (PLCG1) with miR-34a, phosphoinositide-3-kinase, regulatory subunit 2 (PIK3R2) with miR-30a-5p, growth factor receptor-bound protein 2 (GRB2) with miR-27a, and Janus kinase 1 (JAK1) with miR-302b and miR-520e. These associations could make great contributions to explore new mechanism in NSCLCs. These candidate miRNAs may be regarded as the potential drug targets for treating NSCLCs with acquired drug resistance.

Implications of MicroRNAs in the Treatment of Gefitinib-Resistant Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) represents about 85% of the reported cases of lung cancer. Acquired resistance to targeted therapy with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, is not uncommon. It is thus vital to explore novel strategies to restore sensitivity to gefitinib. Provided that microRNAs (miRNAs) negatively regulate their gene targets at the transcriptional level, it is speculated that miRNA mimetics may reduce the expression, activity and signal transduction of EGFR so that sensitization of tumour sites to gefitinib-induced cytotoxicity can be achieved. Indeed, a growing body of evidence has shown that the manipulation of endogenous levels of miRNA not only attenuates the EGFR/PI3K/Akt phosphorylation cascade, but also restores apoptotic cell death in in vitro models of experimentally-induced gefitinib resistance and provoked tumour regression/shrinkage in xenograft models. These data are in concordant with the clinical data showing that the differential expression profiles of miRNA in tumour tissues and blood associate strongly with drug response and overall survival. Furthermore, another line of studies indicate that the chemopreventive effects of a variety of natural compounds may involve miRNAs. The present review aims to discuss the therapeutic capacity of miRNAs in relation to recent discoveries on EGFR-TKI resistance, including chronic drug exposure and mutations.

Growth and the Growth Hormone-Insulin Like Growth Factor 1 Axis in Children With Chronic Inflammation: Current Evidence, Gaps in Knowledge, and Future Directions.

Growth failure is frequently encountered in children with chronic inflammatory conditions like juvenile idiopathic arthritis, inflammatory bowel disease, and cystic fibrosis. Delayed puberty and attenuated pubertal growth spurt are often seen during adolescence. The underlying inflammatory state mediated by proinflammatory cytokines, prolonged use of glucocorticoid, and suboptimal nutrition contribute to growth failure and pubertal abnormalities. These factors can impair growth by their effects on the GH-IGF axis and also directly at the level of the growth plate via alterations in chondrogenesis and local growth factor signaling. Recent studies on the impact of cytokines and glucocorticoid on the growth plate further advanced our understanding of growth failure in chronic disease and provided a biological rationale of growth promotion. Targeting cytokines using biological therapy may lead to improvement of growth in some of these children, but approximately one-third continue to grow slowly. There is increasing evidence that the use of relatively high-dose recombinant human GH may lead to partial catch-up growth in chronic inflammatory conditions, although long-term follow-up data are currently limited. In this review, we comprehensively review the growth abnormalities in children with juvenile idiopathic arthritis, inflammatory bowel disease, and cystic fibrosis, systemic abnormalities of the GH-IGF axis, and growth plate perturbations. We also systematically reviewed all the current published studies of recombinant human GH in these conditions and discussed the role of recombinant human IGF-1.

Novel structural co-expression analysis linking the NPM1-associated ribosomal biogenesis network to chronic myelogenous leukemia.

Co-expression analysis reveals useful dysregulation patterns of gene cooperativeness for understanding cancer biology and identifying new targets for treatment. We developed a structural strategy to identify co-expressed gene networks that are important for chronic myelogenous leukemia (CML). This strategy compared the distributions of expressional correlations between CML and normal states, and it identified a data-driven threshold to classify strongly co-expressed networks that had the best coherence with CML. Using this strategy, we found a transcriptome-wide reduction of co-expression connectivity in CML, reflecting potentially loosened molecular regulation. Conversely, when we focused on nucleophosmin 1 (NPM1) associated networks, NPM1 established more co-expression linkages with BCR-ABL pathways and ribosomal protein networks in CML than normal. This finding implicates a new role of NPM1 in conveying tumorigenic signals from the BCR-ABL oncoprotein to ribosome biogenesis, affecting cellular growth. Transcription factors may be regulators of the differential co-expression patterns between CML and normal.

PubMed-supported clinical term weighting approach for improving inter-patient similarity measure in diagnosis prediction.

BACKGROUND: Similarity-based retrieval of Electronic Health Records (EHRs) from large clinical information systems provides physicians the evidence support in making diagnoses or referring examinations for the suspected cases. Clinical Terms in EHRs represent high-level conceptual information and the similarity measure established based on these terms reflects the chance of inter-patient disease co-occurrence. The assumption that clinical terms are equally relevant to a disease is unrealistic, reducing the prediction accuracy. Here we propose a term weighting approach supported by PubMed search engine to address this issue. METHODS: We collected and studied 112 abdominal computed tomography imaging examination reports from four hospitals in Hong Kong. Clinical terms, which are the image findings related to hepatocellular carcinoma (HCC), were extracted from the reports. Through two systematic PubMed search methods, the generic and specific term weightings were established by estimating the conditional probabilities of clinical terms given HCC. Each report was characterized by an ontological feature vector and there were totally 6216 vector pairs. We optimized the modified direction cosine (mDC) with respect to a regularization constant embedded into the feature vector. Equal, generic and specific term weighting approaches were applied to measure the similarity of each pair and their performances for predicting inter-patient co-occurrence of HCC diagnoses were compared by using Receiver Operating Characteristics (ROC) analysis. RESULTS: The Areas under the curves (AUROCs) of similarity scores based on equal, generic and specific term weighting approaches were 0.735, 0.728 and 0.743 respectively (p < 0.01). In comparison with equal term weighting, the performance was significantly improved by specific term weighting (p < 0.01) but not by generic term weighting. The clinical terms "Dysplastic nodule", "nodule of liver" and "equal density (isodense) lesion" were found the top three image findings associated with HCC in PubMed. CONCLUSIONS: Our findings suggest that the optimized similarity measure with specific term weighting to EHRs can improve significantly the accuracy for predicting the inter-patient co-occurrence of diagnosis when compared with equal and generic term weighting approaches.

Coexpression Pattern Analysis of NPM1-Associated Genes in Chronic Myelogenous Leukemia.

BACKGROUND: Nucleophosmin 1 (NPM1) plays an important role in ribosomal synthesis and malignancies, but NPM1 mutations occur rarely in the blast-crisis and chronic-phase chronic myelogenous leukemia (CML) patients. The NPM1-associated gene set (GCM_NPM1), in total 116 genes including NPM1, was chosen as the candidate gene set for the coexpression analysis. We wonder if NPM1-associated genes can affect the ribosomal synthesis and translation process in CML. RESULTS: We presented a distribution-based approach for gene pair classification by identifying a disease-specific cutoff point that classified the coexpressed gene pairs into strong and weak coexpression structures. The differences in the coexpression patterns between the normal and the CML groups were reflected from the overall structure by performing two-sample Kolmogorov-Smirnov test. Our developed method effectively identified the coexpression pattern differences from the overall structure: P value = 1.71 × 10(-22) < 0.05 for the maximum deviation D = 0.109. Moreover, we found that genes involved in the ribosomal synthesis and translation process tended to be coexpressed in the CML group. CONCLUSION: Our developed method can identify the coexpression difference between two different groups. Dysregulation of ribosomal synthesis and translation process may be related to the CML disease. Our significant findings may provide useful information for the novel CML mechanism exploration and cancer treatment.

The inflammatory milieu and the insulin like growth factor axis in children with inflammatory bowel disease following recombinant human growth hormone treatment.

It is unclear whether recombinant human growth hormone (rhGH) in inflammatory bowel disease (IBD) alters cytokine profile. The objective of this study is to evaluate changes in cytokines and systemic markers of the insulin growth factor axis following 6 months of rhGH treatment in children with IBD. In a six-month randomised control trial in children with IBD treated with rhGH at 0.067 mg/kg/day and controls (11 in each group), we measured pro-, anti-inflammatory cytokines and systemic markers of the IGF axis (total IGF-1, free IGF-1, total IGFBP-3, ALS, IGFBP-2) at baseline (T+0), and six months (T+6). Results expressed as median (range). In the rhGH group, TNFα was 3.1pg/ml (2.9, 100.6) and 3.6pg/ml (3.1, 5.3) at T+0 and T+6, respectively (p=0.85), whereas in the controls this was 3.3pg/ ml (2.7, 4.0) and 3.1pg/m l (2.7, 4.7), respectively (p=0.79). In the rhGH group, IL1ß was 18.0pg/ml (5.0,716.7) and 18.0pg/ml (1.7, 52.2) at T+0 and T+6 respectively(p=0.90), whereas in the controls this was 19.8pg/ml (4.1, 27.1) and 19.1pg/ml (2.4,77.3), respectively (p=0.65). None of the twenty-eight other cytokines analysed was different at T+6 in either group. Despite increase in total IGF1 in the rhGH group (p=0.03), free IGF1, IGFBP3, ALS and IGFBP2 did not change in either group at T+6. Percentage change in IGFBP3, was significantly associated with percentage change in IL2 (r=0.77, p=0.009) and IL4 (r=0.58, p=0.01). Percentage change in ALS was significantly associated with percentage change in IL2 (r=0.90, p less than 0.0001) and IL4 (r=0.63, p=0.04). Although changes in markers of the GH/IGF-1 axis do show an association with cytokines (IL-2, IL-4) in pediatric IBD, six months of rhGH treatment was not associated with any significant changes in levels of a range of pro and anti-inflammatory cytokine. Careful evaluation of disease process is required in future trials of rhGH in paediatric IBD.