A Novel Anti-CD38 Monoclonal Antibody for Treating Immune Thrombocytopenia.

BACKGROUND: Immune thrombocytopenia (ITP) is an autoimmune disease characterized by autoantibody-mediated platelet destruction. Treatment with CM313, a novel anti-CD38 monoclonal antibody, can result in targeted clearance of CD38-positive cells, including plasma cells. METHODS: We conducted a phase 1-2, open-label study to evaluate the safety and efficacy of CM313 in adult patients with ITP. CM313 was administered intravenously at a dose of 16 mg per kilogram of body weight every week for 8 weeks, followed by a 16-week follow-up period. The primary outcomes were adverse events and documentation of two or more consecutive platelet counts of at least 50×109 per liter within 8 weeks after the first dose of CM313. The status of peripheral-blood immune cells in patients and changes in the mononuclear phagocytic system in passive mouse models of ITP receiving anti-CD38 therapy were monitored. RESULTS: Of the 22 patients included in the study, 21 (95%) had two consecutive platelet counts of at least 50×109 per liter during the treatment period, with a median cumulative response duration of 23 weeks (interquartile range, 17 to 24). The median time to the first platelet count of at least 50×109 per liter was 1 week (range, 1 to 3). The most common adverse events that occurred during the study were infusion-related reaction (in 32% of the patients) and upper respiratory tract infection (in 32%). After CD38-targeted therapy, the percentage of CD56dimCD16+ natural killer cells, the expression of CD32b on monocytes in peripheral blood, and the number of macrophages in the spleen of the passive mouse models of ITP all decreased. CONCLUSIONS: In this study, anti-CD38 targeted therapy rapidly boosted platelet levels by inhibiting antibody-dependent cell-mediated cytotoxicity on platelets, maintained long-term efficacy by clearing plasma cells, and was associated with mainly low-grade toxic effects. (Funded by the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences and others; ClinicalTrials.gov number, NCT05694767).

Proteomics landscape and machine learning prediction of long-term response to splenectomy in primary immune thrombocytopenia.

This study aimed to identify key proteomic analytes correlated with response to splenectomy in primary immune thrombocytopenia (ITP). Thirty-four patients were retrospectively collected in the training cohort and 26 were prospectively enrolled as validation cohort. Bone marrow biopsy samples of all participants were collected prior to the splenectomy. A total of 12 modules of proteins were identified by weighted gene co-expression network analysis (WGCNA) method in the developed cohort. The tan module positively correlated with megakaryocyte counts before splenectomy (r = 0.38, p = 0.027), and time to peak platelet level after splenectomy (r = 0.47, p = 0.005). The blue module significantly correlated with response to splenectomy (r = 0.37, p = 0.0031). KEGG pathways analysis found that the PI3K-Akt signalling pathway was predominantly enriched in the tan module, while ribosomal and spliceosome pathways were enriched in the blue module. Machine learning algorithm identified the optimal combination of biomarkers from the blue module in the training cohort, and importantly, cofilin-1 (CFL1) was independently confirmed in the validation cohort. The C-index of CFL1 was >0.7 in both cohorts. Our results highlight the use of bone marrow proteomics analysis for deriving key analytes that predict the response to splenectomy, warranting further exploration of plasma proteomics in this patient population.

Single-dose rituximab plus glucocorticoid versus cyclophosphamide plus glucocorticoid in patients with newly diagnosed acquired hemophilia A: A multicenter, open-label, randomized noninferiority trial.

Acquired hemophilia A (AHA) is a rare but serious bleeding disorder. Randomized controlled trial (RCT) comparing the efficacy of immunosuppression therapy for AHA lacks. We conducted the first multicenter RCT aiming to establish whether the single-dose rituximab combination regimen was noninferior to the cyclophosphamide combination regimen. From 2017 to 2022, 63 patients with newly diagnosed AHA from five centers were randomly assigned 1:1 to receive glucocorticoid (methylprednisolone 0.8 mg/kg per day for the first 3 weeks and then tapered) plus single-dose rituximab (375 mg/m2 ; n = 31) or plus cyclophosphamide (2 mg/kg per day until inhibitor becomes negative, for a maximum of 5 weeks; n = 32). The primary outcome was complete remission (CR, defined as FVIII activity ≥50 IU/dL, FVIII inhibitor undetectable, immunosuppression tapered and no bleeding for 24 h without bypassing agents) rate measured within 8 weeks. The noninferiority margin was an absolute difference of 20%. Twenty-four (77.4%) patients in the rituximab group and 22 (68.8%) patients in the cyclophosphamide group achieved CR, which showed the noninferiority of the single-dose rituximab-based regimen (absolute difference = -8.67%, lower limit of the 95% confidence interval = -13.11%; Pnoninferiority = 0.005). No difference was found in the incidence of treatment-related adverse events. Single-dose rituximab plus glucocorticoid regimen showed similar efficacy and safety, without a reported risk of secondary malignancies or reproductive toxicity seen in cyclophosphamide, it might be recommended as a first-line therapy for AHA, especially in China where there is a young age trend in AHA patients. This trial was registered at ClinicalTrials.gov as #NCT03384277.

Prognostic value of EBV DNA and platelet-to-lymphocyte ratio in patients with non-metastatic nasopharyngeal carcinoma: a retrospective study.

PURPOSE: Analyzing the prognostic value of Epstein-Barr virus (EBV) DNA load and platelet-to-lymphocyte ratio (PLR) in non-metastatic nasopharyngeal carcinoma (NPC) patients, thereby developing a reliable and effective marker. METHODS: We compared survival rates among different groups using the Kaplan-Meier method and the Log-rank test. The factors affecting the prognosis of NPC patients were determined using univariate and multivariate cox regression analysis. Receiver operating characteristic (ROC) curves were used to identify the cutoff-value and discriminant performance of the model. RESULTS: The ROC curve indicated a cut-off value of 775 copies/ml for EBV DNA and 203.3 for PLR. Kaplan-Meier and Log-rank tests showed that 3-year overall survival (OS), local recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS) of NPC patients in high risk group (HRG) were significantly poorer than those in medium risk group (MRG) and low risk group (LRG). The 3-year OS of NPC patients was significantly correlated with age, N stage and EBV DNA-PLR. The 3-year LRFS were significantly correlated with sex, N stage, histology type, and EBV DNA-PLR. The 3-year DMFS were correlated with histology type. The ROC curve showed that area under the curve (AUC) values of EBV DNA-PLR of 3-year OS, LRFS and DMFS in NPC were higher than those of PLR and EBV DNA. CONCLUSION: EBV DNA-PLR is an independent risk factor for the prognosis of NPC. Compared with PLR or EBV DNA alone, the combination of EBV DNA and PLR may be more accurate in predicting the prognosis of NPC patients.

Clinical features and current treatment status of essential thrombocythemia in older adults: a multicenter real-world study in China.

Approximately half of patients diagnosed with essential thrombocythemia (ET) are older adults (aged ≥ 60 years), but to date, little is known about the clinical and molecular characteristics of older patients diagnosed according to the 2016 World Health Organization criteria. We retrospectively collected clinical and molecular data from 282 older (≥ 60 years) and 621 younger ET patients (18-59 years) in China from March 1, 2012 to November 1, 2021 and summarized the clinical characteristics and treatment of these older ET patients. Compared to younger patients, older patients had a higher incidence of the JAK2V617F mutation (P = 0.001), a lower incidence of CALR mutations (P = 0.033) and a higher rate of epigenetic mutations (P < 0.001), TP53 mutations (P = 0.005), and RNA splicing mutations (P < 0.001). Older patients had not only a higher incidence of thrombosis but also a higher incidence of bleeding events. Furthermore, older patients had a significantly higher mortality rate after disease progression (P = 0.050) or after thrombotic events (P = 0.013). Risk factors for thrombosis or prognosis were significantly different between older patients and the entire ET cohort. In older patients, non-driver mutations contributed significantly to thrombotic complications and a poor prognosis, while the JAK2V617F mutation was a risk factor for overall survival but not for thrombotic events. The application of interferon in older ET patients was not inferior to that of hydroxyurea in terms of efficacy and safety. Older patients presented unique characteristics different from those of younger patients, which could provide new information for formulating more appropriate treatment and follow-up strategies.

Machine learning analyses constructed a novel model to predict recurrent thrombosis in adults with essential thrombocythemia.

The current study involving 318 essential thrombocythemia (ET) patients with prior thrombosis was designed to identify risk factors that were predictive of recurrent thrombosis. The whole cohort was randomly split into derivation and validation cohorts. The random forest method, support vector machine with built-in recursive feature elimination model, and logistic multivariable analysis were performed in the derivation cohort, and cardiovascular risk factor (CVF) and RBC distribution width with standard deviation (RDW-SD) were finally selected as independent predictors. Subsequently we devise a 3-tiered model (low risk: 0 points; intermediate risk: 1-1.5 points; and high risk: 2.5 points) and it showed good discrimination in all cohorts. Moreover, the model was significantly correlated with rethrombosis-free survival (rTFS) (p = 0.0007 in the derivation cohort; p = 0.0019 in the validation cohort). In the whole cohort, cytoreductive therapy was more effective than antiplatelet agents alone for 10-year rTFS (p = 0.0336). No significant difference in 10-year rTFS was observed among interferon (IFN), hydroxyurea (HU), and IFN + HU therapy (p = 0.444). The present study helps identify individuals who need close monitoring and provides valuable risk signals for recurrence in ET patients with prior thrombosis.

Time Perspective, Dietary Behavior, and Glycemic Control in Patients With Type 2 Diabetes.

BACKGROUND: Dietary behavior is a key component in the self-management of patients with Type 2 diabetes (T2DM), as it is essential for glycemic control and preventing diabetic complications. However, it is challenging for patients with diabetes to make sustainable dietary behavior changes and achieve long-term optimal glycemic control. OBJECTIVES: Dietary behavior changes involve present efforts to achieve future benefits. The primary aim of this study was to investigate the relationships among time perspective, dietary behaviors, and health outcomes in patients with T2DM. Based on the temporal self-regulation theory and previous research, the secondary aim of the study was to explore how time perspective influences dietary behaviors. METHODS: Following convenient sampling ( N = 329), a cross-sectional study was conducted in patients with T2DM between November 2021 and October 2022. Data were collected using self-reported questionnaires and the retrieval of clinical information from medical records. Hierarchical regression and path analysis were used to explore the relationships among study variables. RESULTS: Our analyses showed that a future-oriented time perspective was associated with better dietary behavior but was not significantly related to hemoglobin A1c. Hierarchical regression analysis also demonstrated that having a more future-oriented time perspective was associated with healthier dietary behavior after controlling covariates. Based on the theory and path analysis, there was an indirect effect of future time perspective on dietary behavior through self-control capacity and intention. DISCUSSION: The study reveals that a future-oriented time perspective can promote healthier dietary behavior when providing care for patients with T2DM. As a theoretical framework, the temporal self-regulation theory offers references for researchers and clinicians to take into consideration patients' time perspectives and their intentions and self-control capacity when developing interventional programs to improve dietary behaviors.

Lifestyle changes are burdensome with my body broken by pain and obesity: patients' perspectives after pain rehabilitation.

BACKGROUND: Despite the existing evidence regarding the interrelated relationship between pain and obesity, knowledge about patients' perspectives of this relationship is scarce, especially from patients with chronic pain and obesity after completing Interdisciplinary Pain Rehabilitation Program (IPRP). AIMS: This qualitative study expands the understanding of patients' perspectives on how chronic pain and obesity influence each other and how the two conditions affect the ability to make lifestyle changes. METHOD: A purposive sample of patients with Body Mass Index (BMI) ≥ 30 kg/m2 and who had completed an IPRP were recruited for individual semi-structured interviews. The transcribed interviews were analysed using latent content analysis and a pattern of theme and categories was constructed based on the participants' perspectives. RESULTS: Sixteen patients (aged 28-63 years, 11 female, BMI 30-43 kg/m2) shared their experiences of chronic pain, obesity and lifestyle changes after IPRP. The analysis revealed one overall theme (lifestyle changes are burdensome with a body broken by both pain and obesity) and four categories (pain disturbing days and nights worsens weight control, pain-related stress makes lifestyle changes harder, a painful and obese body intertwined with negative emotions and the overlooked impact of obesity on chronic pain). Most participants perceived that their pain negatively impacted their obesity, but they were uncertain whether their obesity negatively impacted their pain. Nevertheless, the participants desired and struggled to make lifestyle changes. CONCLUSION: After IPRP, patients with chronic pain and obesity perceived difficulties with self-management and struggles with lifestyle changes. They experienced a combined burden of the two conditions. Their perspective on the unilateral relationship between pain and obesity differed from the existing evidence. Future tailored IPRPs should integrate nutritional interventions and address the knowledge gaps as well.

The anatomical growth of the thoracic cage in adolescents with specific reference to axial growth comparing the right and left hemithorax.

This study has demonstrated the changing volume of both the anterior and posterior thorax in normal adolescents (without spinal or thoracic deformity), differentiating for both sex and age, to further understand how the thorax grows, along with the differences in growth between the anterior and posterior thorax. The thorax was measured on axial CT slices at every vertebral level from T3 to T12 in a series of scans previous taken for routine clinical care. Measurements taken were the anteroposterior thoracic distance and the area of the anterior and posterior rib prominences on either side of the thorax. Data was analyzed per vertebral level, differentiating for age and sex. There were 486 CT scans analyzed (257 males and 229 females) between the ages of 8 and 18 years. The analysis identified that for the anterior thorax, there are three phases of growth with an initial slow increase in volume, followed by a stabilization of little growth, followed by another phase of a more rapid increase in volume. For the posterior thorax, there was a gradual increase in area with increasing age. This study demonstrates that the shape of the thorax is age and sex dependent, with males having both a greater width and depth of thorax compared to females. Of particular note is the difference in patterns of growth between the anterior and posterior thorax. This information will add to the understanding of normal growth, which will aid in the management of conditions where that growth is disturbed.

Repeat revision TKR for failed management of peri-prosthetic infection has long-term success but often require multiple operations: a case control study.

BACKGROUND: Prosthetic joint infection (PJI) is associated with poor outcomes and catastrophic complications. The aim of this study was to present the outcomes of re-revision surgery for PJI of the knee following previous failed two-stage exchange arthroplasty. MATERIALS AND METHODS: A retrospective analysis was performed of 32 patients who underwent re-revision knee arthroplasty, having already undergone at least one previous two-stage exchange for PJI with a minimum follow-up of two-years for alive patients. Outcomes were compared to a matched control of two-stage revisions for PJI of a primary knee replacement also containing 32 patients. Outcomes investigated were eradication of infection, re-operation, mortality and limb-salvage rate. RESULTS: Successful eradication of infection was achieved in 50% of patients following re-revision surgery, compared with 91% following two-stage exchange of primary knee replacement for PJI (p < 0.001). Fourteen (44%) patients required further re-operation compared with three (9%) patients in the primary group (p = 0.006). Amputation was performed in one case (3%) with thirteen patients (92%) who had infection controlled by debridement, antibiotics and implant retention (DAIR), further revision surgery or arthrodesis. Two patients died with infection (6%) and the long-term rate for infection control was 91%. The mean number of procedures following surgery for the re-revision group was 2.8 (0-9) compared with 0.13 (0-1) for the primary two-stage group (p < 0.001). Five-year patient survival was 90.6% (95% CI 77.1-100). The limb-salvage rate for the re-revision cohort was 97%. CONCLUSION: Outcomes for re-revision knee arthroplasty for PJI have higher re-operation and failure rates, but no worse mortality than in revisions of primary knee replacements. Failures can successfully be managed by further operation.

[Research progress in gut-skin axis and its association with traditional Chinese medicine theory].

Currently, the gut-organ axis has become a hot research topic. As increasing attention has been paid to the role of gut microbiota in the health of organs, the complex and integrated dialogue mechanism between the gastrointestinal tract and the associated microbiota has been demonstrated in more and more studies. Skin as the largest organ in the human body serves as the primary barrier protecting the human body from damage. The proposal of the gut-skin axis has established a bidirectional link between the gut and the skin. The disturbance of gut microbiota can lead to the occurrence of skin diseases, the mechanism of which is complex and may involve multiple pathways in immunity, metabolism, and internal secretion. According to the theory of traditional Chinese medicine(TCM), the connection between the intestine and the skin can be established through the lung, and the interior disorders will definitely cause symptoms on the exterior. This paper reviews the research progress in the gut-skin axis and its correlation with TCM theory and provides ideas and a basis for cli-nical treatment and drug development of skin and intestinal diseases.

Sunflower Leaf Structure Affects Chlorophyll a Fluorescence Induction Kinetics In Vivo.

Chlorophyll a fluorescence induction kinetics (CFI) is an important tool that reflects the photosynthetic function of leaves, but it remains unclear whether it is affected by leaf structure. Therefore, in this study, the leaf structure and CFI curves of sunflower and sorghum seedlings were analyzed. Results revealed that there was a significant difference between the structures of palisade and spongy tissues in sunflower leaves. Their CFI curves, measured on both the adaxial and abaxial sides, also differed significantly. However, the differences in the leaf structures and CFI curves between both sides of sorghum leaves were not significant. Further analysis revealed that the differences in the CFI curves between the adaxial and abaxial sides of sunflower leaves almost disappeared due to reduced incident light scattering and refraction in the leaf tissues; more importantly, changes in the CFI curves of the abaxial side were greater than the adaxial side. Compared to leaves grown under full sunlight, weak light led to decreased differences in the CFI curves between the adaxial and abaxial sides of sunflower leaves; of these, changes in the CFI curves and palisade tissue structure on the adaxial side were more obvious than on the abaxial side. Therefore, it appears that large differences in sunflower leaf structures may affect the shape of CFI curves. These findings lay a foundation for enhancing our understanding of CFI from a new perspective.

ARHGAP10 inhibits the epithelial-mesenchymal transition of non-small cell lung cancer by inactivating PI3K/Akt/GSK3ß signaling pathway.

BACKGROUND: Rho GTPase activating protein 10 (ARHGAP10) has been implicated as an essential element in multiple cellular process, including cell migration, adhesion and actin cytoskeleton dynamic reorganization. However, the correlation of ARHGAP10 expression with epithelial-mesenchymal transition (EMT) in lung cancer cells is unclear and remains to be elucidated. Herein, we investigated the relationship between the trait of ARHGAP10 and non-small cell lung cancer (NSCLC) pathological process. METHODS: Immunohistochemistry was conducted to evaluate the expression of ARHGAP10 in NSCLC tissues. CCK-8 assays, Transwell assays, scratch assays were applied to assess cell proliferation, invasion and migration. The expression levels of EMT biomarkers and active molecules involved in PI3K/Akt/GSK3ß signaling pathway were examined through immunofluorescence and Western blot. RESULTS: ARHGAP10 was detected to be lower expression in NSCLC tissues compared with normal tissues from individuals. Moreover, overexpression of ARHGAP10 inhibited migratory and invasive potentials of A549 and NCI-H1299 cells. In addition, ARHGAP10 directly mediated the process of EMT via PI3K/Akt/GSK3ß pathway. Meanwhile, activation of the signaling pathway of insulin-like growth factors-1 (IGF-1) reversed ARHGAP10 overexpression regulated EMT in NSCLC cells. CONCLUSION: ARHGAP10 inhibits the epithelial-mesenchymal transition in NSCLC via PI3K/Akt/GSK3ß signaling pathway, suggesting agonist of ARHGAP10 may be an optional remedy for NSCLC patients than traditional opioids.

Overexpression of CENPF is associated with progression and poor prognosis of lung adenocarcinoma.

Background and aim: The molecular signatures of lung adenocarcinoma (LUAD) are not well understood. Centromere protein F (CENPF) has been shown to promote oncogenesis in many cancers; however, its role in LUAD has not been illustrated. We explored the role of CENPF in LUAD. Methods: CENPF expression level was investigated in public online database firstly, the prognosis of CENPF in LUAD were also assessed by Kaplan-Meier analysis. Then quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was performed using 13 matched pairs of clinical LUAD tissue samples. Subsequently, the impact of CENPF expression on cell proliferation, cell cycle, apoptosis, colony formation was investigated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), flow cytometric analysis and colony formation assay, respectively. Finally, experimental xenograft lung cancer model of nude mice armpit of right forelimb to determine the effect of CENPF on LUAD tumorigenesis. Results: CENPF mRNA expression was significantly elevated in LUAD tissues compared with adjacent non-tumor lung tissues in Gene Expression Profiling Interactive Analysis (GEPIA) (P < 0.001). Up-regulated CENPF was remarkably positively associated with pathological stage, relapse free survival (RFS) as well as overall survival (OS) of LUAD patients. Besides, CENPF knockdown greatly suppressed A549 cell proliferation, induced S phase arrest, promoted apoptosis and decreased colony numbers of LUAD cells. Furthermore, knockdown of CENPF significantly inhibited the tumor growth of the LUAD cells in an experimental xenograft lung cancer model of nude mice armpit of right forelimb. Conclusion: Taken together, these results demonstrated that CENPF may serve as a potential biomarker of prognostic relevance and a potential therapeutic target for LUAD.

OSchol: an online consensus survival web server for cholangiocarcinoma prognosis analysis.

BACKGROUND: As the most common biliary ducts, cholangiocarcinoma (CHOL) is an aggressive malignancy with complex pathological context, high mortality and relapse rate. The current therapy of CHOL is mainly performed with surgery followed by chemoradiotherapy. Due to the high metastasis and relapse rate of CHOL, the prognosis of CHOL is still poor, and the molecular prognostic system is to be constructed. METHODS: In this study, we have established an online prognostic analysis web server named OSchol to evaluate the correlation between candidate genes and survival for CHOL. RESULTS: The prognostic values of previous published biomarkers in OSchol, including ITIH4, PTEN and DACH1, have been validated by OSchol. In addition, we have identified novel potential prognostic biomarker for CHOL using OSchol, that E2F1 has significant prognostic ability in OSchol (both TCGA and GSE107943 cohorts). CONCLUSION: Our study provides a platform for researchers and clinicians to screen, develop and validate their genes of interest to be potential prognostic biomarkers for CHOL and may also help guide the targeted therapies for CHOL.

Decreased Cephalosporin Susceptibility of Oropharyngeal Neisseria Species in Antibiotic-using Men Who Have Sex With Men in Hanoi, Vietnam.

BACKGROUND: Neisseria gonorrhoeae (NG) infections are a global health burden. NG resistance to cephalosporins, which is increasingly reported, is an imminent threat to public health. Many hypothesize that commensal Neisseria species are an important reservoir for genetic material conferring antimicrobial resistance in NG; however, clinical data are lacking. METHODS: Men who have sex with men (MSM) in Hanoi, Vietnam, completed a questionnaire regarding antibiotic use. We collected pharyngeal specimens, cultured Neisseria species, and measured minimum inhibitory concentrations (MICs) to ciprofloxacin, cefixime, ceftriaxone, and cefpodoxime. Using MIC criteria for antimicrobial susceptibility in NG, we categorized the Neisseria species and compared mean MIC levels between different antibiotic user groups. RESULTS: Of 207 participants, 38% used at least 1 antibiotic in the past 6 months; 52% without a prescription. A median of 1 Neisseria species was cultured from each participant (range, 1-4) with 10 different Neisseria species identified overall. The proportion of Neisseria with reduced susceptibility to ciprofloxacin was 93%, cefpodoxime 84%, cefixime 31%, and ceftriaxone 28%. Antibiotic use within the past month was strongly associated with Neisseria species having increased MICs to cefixime, ceftriaxone, and cefpodoxime (mean MIC ratios of 6.27, 4.11, and 7.70, respectively), compared with those who used antibiotics between 1 and 6 months prior (P < .05, all comparisons). CONCLUSIONS: MSM in our study often used antibiotics without a prescription. At least 1 commensal Neisseria species colonized all men. Recent use of any antibiotics may select for oropharyngeal Neisseria species with antimicrobial resistance. The normal flora of the oropharynx may be an important source of antimicrobial resistance in Neisseria gonorrhoeae.

OSpaad: An online tool to perform survival analysis by integrating gene expression profiling and long-term follow-up data of 1319 pancreatic carcinoma patients.

Pancreatic carcinoma (PC) is a type of highly lethal malignant tumor that has unfavorable outcomes. One major challenge in improving clinical outcomes is to identify novel biomarkers for prognosis. In this study, we developed an online consensus survival tool for pancreatic adenocarcinoma (OSpaad), which allows researchers and clinicians to analyze the prognostic value of selected genes in PC. OSpaad contains 1319 unique PC cases that have both gene expression data and correspondent clinical data from seven individual cohorts and provides four survival terms including overall survival, disease-specific survival, disease-free interval, progression-free interval for prognosis evaluation. To meet the different research needs, OSpaad allows users to limit survival analysis in subgroups by selecting different terms of clinical confounding factors such as TNM stage, sex, smoking time, lymph invasion, and race. Moreover, we showed that 97% (116 out of 120) previously reported prognostic biomarkers, including ERBB2, TP53, EGFR and so forth, were validated and confirmed their prognostic significance in OSpaad, demonstrating the well performance of survival analysis in OSpaad. OSpaad is a user-friendly online tool with a straightforward interface allowing clinicians and basic research scientists with even a limited bioinformatics background to easily screen and evaluate the prognostic value of genes in a large PC cohort. This online tool can be accessed at http://bioinfo.henu.edu.cn/PAAD/PAADList.jsp.

OSuvm: An interactive online consensus survival tool for uveal melanoma prognosis analysis.

Uveal melanoma (UM) is a rare, aggressive, but the most frequent primary intraocular malignancy in adults, and up to 50% of patients develop a tendency of liver metastases. Great efforts have been made to develop biomarkers that facilitate diagnosis, prediction of the risk, and response to treatment of UM. However, a biologically informative and highly accurate gold standard system for prognostic evaluation of UM remains to be established. To facilitate assessment of the prognosis of UM patients, we established a user-friendly Online consensus Survival tool for uveal melanoma, named OSuvm, by which users can easily estimate the prognostic values of genes of interest by the Kaplan-Meier survival plot with hazard ratio and log-rank test. OSuvm comprises four independent cohorts including 229 patients with both gene expression profiles and relevant clinical follow-up information, and it has shown great performance in evaluating the prognostic roles of previously reported biomarkers. Using OSuvm enables researchers and clinicians to rapidly and conveniently explore the prognostic value of genes of interest and develop new potential molecular biomarkers for UM. OSuvm can be accessed at http://bioinfo.henu.edu.cn/UVM/UVMList.jsp.

Multilevel defects in the hematopoietic niche in essential thrombocythemia.

The role of the bone marrow niche in essential thrombocythemia (ET) remains unclear. Here, we observed multilevel defects in the hematopoietic niche of patients with JAK2V617F-positive ET, including functional deficiency in mesenchymal stromal cells (MSC), immune imbalance, and sympathetic-nerve damage. Mesenchymal stromal cells from patients with JAK2V617F-positive essential thrombocythemia had a transformed transcriptome. In parallel, they showed enhanced proliferation, decreased apoptosis and senescence, attenuated ability to differentiate into adipocytes and osteocytes, and insufficient support for normal hematopoiesis. Additionally, they were inefficient in suppressing immune responses. For instance, they poorly inhibited proliferation and activation of CD4-positive T cells and the secretion of the inflammatory factor soluble CD40-ligand. They also poorly induced formation of mostly immunosuppressive T-helper 2 cells (Th2) and the secretion of the anti-inflammatory factor interleukin-4 (IL-4). Furthermore, we identified WDR4 as a potent protein with low expression and which was correlated with increased proliferation, reduced senescence and differentiation, and insufficient support for normal hematopoiesis in MSC from patients with JAK2V617F-positive ET. We also observed that loss of WDR4 in MSC cells downregulated the interleukin-6 (IL-6) level through the ERK-GSK3ß-CREB signaling based on our in vitro studies. Altogether, our results show that multilevel changes occur in the bone marrow niche of patients with JAK2V617F-positive ET, and low expression of WDR4 in MSC may be critical for inducing hematopoietic related changes.

Clinically useful prediction of hospital admissions in an older population.

BACKGROUND: The healthcare for older adults is insufficient in many countries, not designed to meet their needs and is often described as disorganized and reactive. Prediction of older persons at risk of admission to hospital may be one important way for the future healthcare system to act proactively when meeting increasing needs for care. Therefore, we wanted to develop and test a clinically useful model for predicting hospital admissions of older persons based on routine healthcare data. METHODS: We used the healthcare data on 40,728 persons, 75-109 years of age to predict hospital in-ward care in a prospective cohort. Multivariable logistic regression was used to identify significant factors predictive of unplanned hospital admission. Model fitting was accomplished using forward selection. The accuracy of the prediction model was expressed as area under the receiver operating characteristic (ROC) curve, AUC. RESULTS: The prediction model consisting of 38 variables exhibited a good discriminative accuracy for unplanned hospital admissions over the following 12 months (AUC 0.69 [95% confidence interval, CI 0.68-0.70]) and was validated on external datasets. Clinically relevant proportions of predicted cases of 40 or 45% resulted in sensitivities of 62 and 66%, respectively. The corresponding positive predicted values (PPV) was 31 and 29%, respectively. CONCLUSION: A prediction model based on routine administrative healthcare data from older persons can be used to find patients at risk of admission to hospital. Identifying the risk population can enable proactive intervention for older patients with as-yet unknown needs for healthcare.