Genetic Characteristics of Systematic Juvenile Idiopathic Arthritis and The Bioinformatics Basis for Treatment

Abstract Objective Systemic Juvenile Idiopathic Arthritis (sJIA) is a distinctive subtype of Juvenile Idiopathic Arthritis (JIA). The pathogenesis of sJIA is still unclear with the treatment options limited. Although previous bioinformatics analyses have identified some genetic factors underlying sJIA, these studies were mostly single center with a small sample size and the results were often inconsistent. Herein, we combined two datasets of GSE20307 and GSE21521 and select the matrix of patients diagnosed as sJIA in it for further analysis. Methods The GSE20307 and GSE21521 matrixs downloaded from the Gene Expression Omnibus (GEO) were analyzed using online-tool GEO2R, Venny, Metascape, STRING, and Cytoscape to identify differentially expressed genes (DEGs), enrichment pathways, protein-protein interaction (PPI), main Module and hub genes between sJIA individuals and healthy controls. Results A total of 289 overlapping genes (consisting of 41 downregulated genes and 248 upregulated genes) were identified. Hub genes were primarily related to erythropoiesis. And the KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis of overlapping DEGs were maily involved in Malaria and non-small cell lung cancer. Besides, DEGs in main module were involved in ubiquitin mediated proteolysis. Conclusions our study suggests that the erythropoiesis signature indeed exists in sJIA similar to previous reports. And combining previous research and our results, we provide a basis for the application of proteasome inhibitors, hydroxychloroquine and kinase inhibitors in patients with sJIA from the perspective of bioinformatics.

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Application of Weighted Gene Coexpression Network Analysis to Identify Key Modules and Hub Genes in Systemic Juvenile Idiopathic Arthritis

BioMed Research International ◽

10.1155/2021/9957569 ◽

2021 ◽

Vol 2021 ◽

pp. 1-13

Author(s):

Mi Zhou ◽

Ruru Guo ◽

Yong-Fei Wang ◽

Wanling Yang ◽

Rongxiu Li ◽

...

Keyword(s):

Juvenile Idiopathic Arthritis ◽

Network Analysis ◽

Immune Responses ◽

Systemic Juvenile Idiopathic Arthritis ◽

Functional Enrichment ◽

Coexpression Network ◽

Gene Coexpression Network ◽

Hub Genes ◽

Gene Coexpression ◽

Coexpression Network Analysis

Systemic juvenile idiopathic arthritis (sJIA) is a severe autoinflammatory disorder with a still not clearly defined molecular mechanism. To better understand the disease, we used scattered datasets from public domains and performed a weighted gene coexpression network analysis (WGCNA) to identify key modules and hub genes underlying sJIA pathogenesis. Two gene expression datasets, GSE7753 and GSE13501, were used to construct the WGCNA. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were applied to the genes and hub genes in the sJIA modules. Cytoscape was used to screen and visualize the hub genes. We further compared the hub genes with the genome-wide association study (GWAS) genes and used a consensus WGCNA to verify that our conclusions were conservative and reproducible across multiple independent datasets. A total of 5,414 genes were obtained for WGCNA, from which highly correlated genes were divided into 17 modules. The red module demonstrated the highest correlation with the sJIA module ( r = 0.8 , p = 3 e − 29 ), whereas the green-yellow module was found to be closely related to the non-sJIA module ( r = 0.62 , p = 1 e − 14 ). Functional enrichment analysis demonstrated that the red module was mostly enriched in the activation of immune responses, infection, nucleosomes, and erythrocytes, and the green-yellow module was mostly enriched in immune responses and inflammation. Additionally, the hub genes in the red module were highly enriched in erythrocyte differentiation, including ALAS2, AHSP, TRIM10, TRIM58, and KLF1. The hub genes from the green-yellow module were mainly associated with immune responses, as exemplified by the genes KLRB1, KLRF1, CD160, and KIRs. We identified sJIA-related modules and several hub genes that might be associated with the development of sJIA. Particularly, the modules may help understand the mechanisms of sJIA, and the hub genes may become biomarkers and therapeutic targets of sJIA in the future.

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An Electronic Teaching Module for Improving Knowledge of Self-Management of Vaso-Occlusive Pain Crises in Patients With Sickle Cell Disease: Pilot Questionnaire Study (Preprint)

10.2196/preprints.13501 ◽

2019 ◽

Author(s):

Tammie Tam ◽

Maria R Baer ◽

Lewis L Hsu ◽

Jennie Y Law

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Small Sample Size ◽

Treatment Options ◽

Small Sample ◽

Self Management ◽

Cell Disease ◽

Teaching Module ◽

Baseline Knowledge ◽

Electronic Teaching

BACKGROUND For patients with sickle cell disease (SCD), effective management of vaso-occlusive crises (VOCs) is integral to provision of care, as nearly all affected individuals will suffer from VOCs in their lifetime. A recent systematic review of technological interventions to improve self-management in the care of SCD concluded that electronic health has the potential to improve the care of individuals with SCD. OBJECTIVE The aim of this study was to assess the value of an electronic teaching module (ETM) provided by Emmi Solutions for educating adult SCD patients on VOC self-management and treatment options for SCD. METHODS A pretest assessed adults with SCD for baseline knowledge with regard to self-management of VOCs. Participants then watched the 35-min ETM and completed a posttest and survey on the ETM. RESULTS A total of 20 adults enrolled. Their knowledge scores improved (pretest median 66.5% and posttest median 85%; P<.001). In total, 18 participants (18/20, 90%) agreed that they “learned a lot” or “learned something” from the ETM. The most common topic about which they reported learning was hydroxyurea. A total of 12 participants (12/20, 60%) agreed with the statement that they “would recommend the module to a friend or family member with sickle cell disease.” CONCLUSIONS The ETM is associated with an increase in knowledge in patients with SCD. Limitations of the study include small sample size, no assessment of knowledge before premodule questionnaire completion, and no longitudinal follow-up. Identifying patients with SCD who demonstrate affinity for self-education via an ETM may further enhance utility of this tool to educate and empower patients.

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Recurrence after pituitary surgery in adult Cushing’s disease: a systematic review on diagnosis and treatment

Endocrine ◽

10.1007/s12020-020-02432-z ◽

2020 ◽

Vol 70 (2) ◽

pp. 218-231

Author(s):

Leah T. Braun ◽

German Rubinstein ◽

Stephanie Zopp ◽

Frederick Vogel ◽

Christine Schmid-Tannwald ◽

...

Keyword(s):

Medical Therapy ◽

Cushing’S Disease ◽

Small Sample Size ◽

Case Reports ◽

Treatment Options ◽

Pituitary Surgery ◽

Small Sample ◽

Bilateral Adrenalectomy ◽

Cushing's Disease ◽

Success Rates

Abstract Purpose Recurrence after pituitary surgery in Cushing’s disease (CD) is a common problem ranging from 5% (minimum) to 50% (maximum) after initially successful surgery, respectively. In this review, we give an overview of the current literature regarding prevalence, diagnosis, and therapeutic options of recurrent CD. Methods We systematically screened the literature regarding recurrent and persistent Cushing’s disease using the MESH term Cushing’s disease and recurrence. Of 717 results in PubMed, all manuscripts in English and German published between 1980 and April 2020 were screened. Case reports, comments, publications focusing on pediatric CD or CD in veterinary disciplines or studies with very small sample size (patient number < 10) were excluded. Also, papers on CD in pregnancy were not included in this review. Results and conclusions Because of the high incidence of recurrence in CD, annual clinical and biochemical follow-up is paramount. 50% of recurrences occur during the first 50 months after first surgery. In case of recurrence, treatment options include second surgery, pituitary radiation, targeted medical therapy to control hypercortisolism, and bilateral adrenalectomy. Success rates of all these treatment options vary between 25 (some of the medical therapy) and 100% (bilateral adrenalectomy). All treatment options have specific advantages, limitations, and side effects. Therefore, treatment decisions have to be individualized according to the specific needs of the patient.

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Current Treatment Options for Metastatic Hormone-Sensitive Prostate Cancer.

Cancers ◽

10.3390/cancers11091355 ◽

2019 ◽

Vol 11 (9) ◽

pp. 1355 ◽

Cited By ~ 14

Author(s):

Cattrini ◽

Castro ◽

Lozano ◽

Zanardi ◽

Rubagotti ◽

...

Keyword(s):

Prostate Cancer ◽

Small Sample Size ◽

Treatment Options ◽

Current Treatment ◽

Abiraterone Acetate ◽

Small Sample ◽

Phase 3 ◽

Tumor Patient ◽

Randomized Controlled ◽

Hormone Sensitive

The possible treatments options for metastatic hormone-sensitive prostate cancer (mHSPC) have dramatically increased during the last years. The old backbone, which androgen-deprivation therapy (ADT) is the exclusive approach for hormone-naïve patients, has been disrupted. Despite the fact that several high-quality, randomized, controlled phase 3 trials have been conducted in this setting, no direct comparison is currently available among the different strategies. Inadequate power, absence of preplanning and small sample size frequently affect the subgroup analyses according to disease volume or patient’s risk. The choice between ADT alone and ADT combined with docetaxel, abiraterone acetate, enzalutamide, apalutamide or radiotherapy to the primary tumor remains challenging. Factors that are related to the tumor, patient or drug side effects, currently guide these clinical decisions. This comprehensive review aims to indirectly compare the phase 3 trials in the mHSPC setting, in order to extrapolate data useful for treatment selection, providing also perspectives on future biomarkers.

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Outcome of rapid disease progression in the treatment break following cytoreductive nephrectomy (CN) after presurgical sunitinib in patients with primary metastatic renal cell carcinoma (RCC).

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.4611 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 4611-4611

Author(s):

Axel Bex ◽

Thomas Powles ◽

Christian U. Blank ◽

Simon Chowdhury ◽

Simon Horenblas ◽

...

Keyword(s):

Disease Progression ◽

Kinase Inhibitors ◽

Small Sample Size ◽

Recovery Period ◽

Significant Proportion ◽

Disease Stabilisation ◽

Small Sample ◽

Phase Ii Trials ◽

Exact Test ◽

Poor Risk

4611 Background: There is concern that interruption of tyrosine kinase inhibitors (TKI) triggers disease progression (PD) and metastasis. This is based on preclinical models and observation of rapid PD in the postsurgical treatment break in patients pretreated with TKI. Little is known about the frequency of PD during postsurgical TKI interruption and its outcome. These data may have implications for neoadjuvant or presurgical treatment concepts. Methods: Of 66 patients from two closed phase II trials investigating 2-3 months presurgical sunitinib for primary metastatic clear-cell RCC, 45 were evaluated in this retrospective analysis because they had absence of PD prior to planned surgery and underwent CN (35 [78%] MSKCC intermediate and 10 [22%] poor risk). Patients had CT scans at the end of pretreatment and at 4 weeks post-nephrectomy before restarting sunitinib. In patients with postsurgical RECIST PD at 4 weeks when compared to the preoperative CT scan overall survival (OS) was measured from the time of nephrectomy and compared to patients without treatment break PD. Results: Median OS of 45 patients from the time of surgery was 22 months (13.0-31.5 months). Overall 14 patients progressed during treatment break (31%), with new sites of disease in 5/14 (35%). Reintroduction of sunitinib resulted in disease stabilisation or better in 13. Patients with poor risk were represented in the progressors (n=4[28%]) and non-progressors (n=6 [19%]) (p=0.7 fishers exact test). The hazard ratio (HR) for death associated with PD during treatment break was 1.90 (95% CI 0.89-4.08). OS for non-progressors was 25 months (15-NA) and 13 months (6-27) for progressors. Conclusions: A significant proportion of patients develop PD upon sunitinib withdrawal in a 4 week recovery period following CN. In view of the small sample size these data suggest a strong trend toward treatment break PD being associated with a poor outcome. It is not clear whether this PD is related to interruption of TKI, surgery or a combination of factors. The EORTC SURTIME trial investigates treatment break PD after immediate CN and CN after sunitinib and may answer this question.

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Phenotype-Genotype Correlation in Colorectal Cancer: A Real-Life Study

GE Portuguese Journal of Gastroenterology ◽

10.1159/000516009 ◽

2021 ◽

pp. 1-9

Author(s):

Catarina Frias-Gomes ◽

Ana Carla Sousa ◽

Inês Rolim ◽

Ana Raquel Henriques ◽

Francisco Branco ◽

...

Keyword(s):

Colorectal Cancer ◽

Mismatch Repair ◽

Early Stage ◽

Small Sample Size ◽

Real Life ◽

Disease Free Survival ◽

Small Sample ◽

Stage I ◽

Curative Surgery ◽

Genetic Characteristics

Background and Aims: Colorectal cancer (CRC) is a heterogeneous disease with distinctive genetic pathways, such as chromosomal instability, microsatellite instability and methylator pathway. Our aim was to correlate clinical and genetic characteristics of CRC patients in order to understand clinical implications of tumour genotype. Methods: Single-institution retrospective cohort of patients who underwent curative surgery for CRC, from 2012 to 2014. RAS and BRAF mutations were evaluated with the real-time PCR technique Idylla®. Mismatch repair deficiency (dMMR) was characterized by absence of MLH1, MSH6, MSH2 and/or PMS2 expression, evaluated by tissue microarrays. Overall survival (OS) and disease-free survival (DFS) were assessed using survival analysis. Results: Overall, 242 patients were included (males 57.4%, age 69.3 ± 12.9 years; median follow-up 49 months). RAS-mutated tumours were associated with reduced DFS (p = 0.02) and OS (p = 0.045) in stage I–III CRC. BRAF-mutated tumours were more predominant in females and in the right colon, similarly to dMMR tumours. BRAF status did not influence OS (4 years)/DFS (3.5 years) in stage I–III disease. However, after relapse, length of survival was 3.5 months in BRAF-mutated tumours in contrast to 18.6 months in BRAF wild-type tumours (p = NS). No germline mutations in mismatch repair genes were so far identified in the patients with dMMR tumours. Molecular phenotype (RAS, BRAF and MMR) did not influence OS in metastatic patients. Our small sample size may be a limitation of the study. Conclusion: In our cohort, RAS-mutated tumours were associated with worse DFS and OS in early-stage CRC, whereas the remaining molecular variables had no prognostic influence.

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Predictive Factors of Efficacy of Sunitinib Therapy in Gastrointestinal Stromal Tumours

European Oncology & Haematology ◽

10.17925/eoh.2012.08.3.167 ◽

2012 ◽

Vol 08 (03) ◽

pp. 167

Author(s):

Piotr Rutkowski ◽

Monika Jurkowska ◽

◽

Keyword(s):

Patient Outcomes ◽

Kinase Inhibitors ◽

Treatment Options ◽

Growth Factor Receptor ◽

Gastrointestinal Stromal Tumours ◽

Genetic Characteristics ◽

Sunitinib Malate ◽

Factor Receptor Alpha ◽

Substantial Heterogeneity ◽

Mesenchymal Tumours

Until the introduction of tyrosine kinase inhibitors, only limited treatment options were available for advanced/inoperable gastrointestinal stromal tumours (GISTs), the most common mesenchymal tumours of the gastrointestinal tract. Initially, it was imatinib mesylate that revolutionised patient outcomes in advanced cases, followed by sunitinib malate when the activity of imatinib turned out to be time-limited. There is substantial heterogeneity between GISTs in terms of response to targeted therapy. As was the case for imatinib, the efficacy of sunitinib depends on the primary tumour’sKIT/PDGFRA(platelet-derived growth factor receptor-alpha) genotype and on secondary mutations emerging during treatment. Interestingly, sunitinib-related adverse effects, such as arterial hypertension, may serve as biomarkers of the antitumour efficacy of the drug. Here we discuss possible mechanisms underlying these phenomena as well as data from our recently published study – the first to investigate the clinicopathologic and genetic characteristics associated with the results of sunitinib therapy in a large group of patients treated in routine clinical practice.

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Comparing Treatment Options for Large Talar Osteochondral Lesions

Foot & Ankle Orthopaedics ◽

10.1177/2473011417s000135 ◽

2017 ◽

Vol 2 (3) ◽

pp. 2473011417S0001

Author(s):

Kenneth Chin ◽

John T. Campbell ◽

Rebecca Cerrato ◽

Clifford Jeng ◽

Tyler Rutherford

Keyword(s):

Revision Surgery ◽

Short Form ◽

Small Sample Size ◽

Treatment Options ◽

Return To Sport ◽

Postoperative Outcome ◽

Functional Results ◽

Small Sample ◽

Osteochondral Lesions ◽

Physical And Mental Health

Category: Ankle, Arthroscopy, Sports Introduction/Purpose: The surgical treatment of large or revision osteochondral (OCD) lesions of the talus remain challenging. Currently, there are several treatment options for these patients, including: osteochondral autograft (OATS), allograft cartilage extracellular matrix (Arthrex BioCartilage), and particulated juvenile articular cartilage allograft (Zimmer DeNovo). Due to the relative rarity of these procedures, the literature comparing these three modalities is scarce. The aim of this study was to assess midterm clinical outcomes after these surgical treatments for large or revision talar OCD lesions. Methods: Hospital IRB approval was obtained. We reviewed surgical case logs and identified 78 total patients between 2003- 2015 for inclusion in this retrospective study. Thirty-three patients were excluded due to incomplete preoperative or postoperative outcome scoring data, and 23 patients are pending followup, leaving a cohort of N = 22 patients (5 OATS, 5 DeNovo, 12 BioCartilage). Functional outcomes preoperatively and postoperatively were evaluated using Short Form 12-item Physical and Mental Health Survey (SF12 M and SF12P) and Foot Function Index (FFI) scores, ability to return to sport or work, and the need to return to the OR for revision surgery. Data were compared using paired student’s t-test and a one way ANOVA. Results: Mean age was 38y with mean followup of 4.3y (range 1.1-12.5). Of 22 patients, three were revisions. Mean lesion size was (12.6x9.1x6.5 mm). All groups showed significant improvements in FFI (p < 0.05) compared to preoperative baseline. Only the BioCartilage group showed significant improvement in SF12P (37.6 vs 47.8, p<0.05). The OATS and DeNovo groups did not show a significant increase in SF12P, and none of the groups demonstrated significant improvement in SF12 M. All patients returned to work, and 8/11 (73%) athletes returned to sport. There were no significant differences between groups when comparing SF12, FFI, and return to sport/work. Revision surgery was necessary in 6/22 (28%) patients. Post-hoc power analysis revealed limited power (0.23), and effect size (f=0.32) may be due to small sample size. Conclusion: All three treatment methods resulted in good medium-term functional results for the treatment of large or revision talar OCD lesions. However, we were unable to distinguish significant differences between OATS, Biocartilage, and Denovo, likely due to small cohort numbers and low power. Further study is warranted with increased patient numbers to improve power and differentiate among the three treatment options, as well as provide longer clinical and radiographic follow-up.

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0755 Pitolisant (Wakix) is an Effective Anti-Cataplexy Agent in Narcolepsy Type 1

SLEEP ◽

10.1093/sleep/zsaa056.751 ◽

2020 ◽

Vol 43 (Supplement_1) ◽

pp. A287-A287

Author(s):

G J Meskill

Keyword(s):

Clinical Judgment ◽

Small Sample Size ◽

Treatment Options ◽

Standard Of Care ◽

The United States ◽

Substantial Improvement ◽

Small Sample ◽

Adult Patients

Abstract Introduction Harmony Biosciences initiated the Pitolisant Expanded Access Clinical Evaluation (PEACE) program to allow treatment with pitolisant in adult patients with narcolepsy while pitolisant was an investigational medication in the United States. Starting in March 2019, Comprehensive Sleep Medicine Associates (CSMA) offered enrollment to patients who met the inclusion/exclusion criteria and who were deemed appropriate based on clinical judgment. All patients who enrolled were taking at least one standard-of-care agent for narcolepsy at enrollment. Many of the enrolled patients had refractory/challenging cases of narcolepsy. On August 14, 2019, Wakix received FDA approval for the treatment of excessive daytime sleepiness in adult patients with narcolepsy, which contrasts with the European label that states that Wakix is indicated for the treatment of narcolepsy in adults with or without cataplexy. Methods CSMA enrolled 21 patients in the PEACE program. The charts for all 10 narcolepsy type 1 (NT1) patients were reviewed. The 2 patients who did not have follow up after starting pitolisant were excluded. Results Of the 8 NT1 patients who had at least one follow up visit after initiating pitolisant, 6 reported substantial improvement or complete resolution of cataplexy compared to baseline. For example, one patient’s wife stated, “I forgot my husband was funny because he would avoid telling jokes until he started pitolisant.” Another stated, “I have not had an episode of cataplexy since starting pitolisant.” 5 of these patients were taking an anti-cataplectic agent at the time of starting pitolisant (sodium oxybate 3, venlafaxine 2). Conclusion While a relatively small sample size, these results demonstrate that in a “real world” uncontrolled population of refractory/challenging NT1 patients, pitolisant is an effective anti-cataplectic agent. As there are relatively few treatment options for NT1, clinicians should consider use of pitolisant for patients with cataplexy, and further consideration for adding an indication for pitolisant to treat cataplexy is warranted. Support Harmony Biosciences (PEACE trial)

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Do Differing Levels of Boldness Influence the Success of Translocation? A Pilot Study on Red Squirrels (Sciurus vulgaris)

Animals ◽

10.3390/ani10101748 ◽

2020 ◽

Vol 10 (10) ◽

pp. 1748

Author(s):

Jack A. Bamber ◽

Craig M. Shuttleworth ◽

Matt W. Hayward

Keyword(s):

Population Distribution ◽

Small Sample Size ◽

Release Site ◽

Small Sample ◽

Video Data ◽

Personality Testing ◽

Red Squirrels ◽

Genetic Characteristics ◽

Video Data Collection ◽

Population Restoration

Conservation translocations, including reintroductions, are practices that are vital to restoring biodiversity and ecosystem function within conservation schemes globally. Sadly, population translocations have had a poor success rate historically. At a time where biodiversity is constantly decreasing, improving translocation success is vital for future conservation schemes. Often, to improve success, the selection of individuals is based on genetic characteristics and behaviours linked directly to survival. Further development to improve selection is proposed within this paper using animal personality. The study took place opportunistically to test how personality, in particular an animal’s boldness/timidness, may influence a population restoration of red squirrels into the Ogwen Valley, North Wales. Despite frequent translocations, data on how boldness and timidness may affect the establishment of this species are low. Testing was performed on key survival behaviours and boldness/timidness pre-release. This was performed via video data collection and identification of key behaviours that could be used to identify boldness or behaviours that could be linked to reduced fitness once released. Encounters at different distance intervals were monitored post-release via camera trapping to identify if boldness/timidness may change the furthest encounter distance of focal animals away from their release site. Relationships between the period for an individual to reappear post-threat was significantly linked to boldness, with other behavioural results and the encounter distance also showing trends of a potential relationship. Our results indicate that bolder individuals have a higher chance of expressing behavioural traits that will increase exposure to risks and, therefore, reduce the likelihood of successfully establishing populations. However, the small sample size of this study means that further research is needed. We suggest that during early stages of conservation translocation programmes, personality testing for boldness should become common practice, and we recommend selecting timid individuals for an initial release to improve population establishment, with bolder individuals utilised later to expand population distribution.

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