Development of a Novel Prognostic Model of Glioblastoma Based on m6A-Associated Immune Genes and Identification of a New Biomarker.

Background: Accumulating evidence shows that m6A regulates oncogene and tumor suppressor gene expression, thus playing a dual role in cancer. Likewise, there is a close relationship between the immune system and tumor development and progression. However, for glioblastoma, m6A-associated immunological markers remain to be identified. Methods: We obtained gene expression, mutation, and clinical data on glioblastoma from The Cancer Genome Atlas and Chinese Glioma Genome Atlas databases. Next, we performed univariate COX-least absolute shrinkage and selection operator (LASSO)-multivariate COX regression analyses to establish a prognostic gene signature and develop a corresponding dynamic nomogram application. We then carried out a clustering analysis twice to categorize all samples according to their m6A-regulating and m6A-associated immune gene expression levels (high, medium, and low) and calculated their m6A score. Finally, we performed quantitative reverse transcription-polymerase chain reaction, cell counting kit-8, cell stemness detection, cell migration, and apoptosis detection in vitro assays to determine the biological role of CD81 in glioblastoma cells. Results: Our glioblastoma risk score model had extremely high prediction efficacy, with the area under the receiver operating characteristic curve reaching 0.9. The web version of the dynamic nomogram application allows rapid and accurate calculation of patients' survival odds. Survival curves and Sankey diagrams indicated that the high-m6A score group corresponded to the groups expressing medium and low m6A-regulating gene levels and high m6A-associated prognostic immune gene levels. Moreover, these groups displayed lower survival rates and higher immune infiltration. Based on the gene set enrichment analysis, the pathophysiological mechanism may be related to the activation of the immunosuppressive function and related signaling pathways. Moreover, the risk score model allowed us to perform immunotherapy benefit assessment. Finally, silencing CD81 in vitro significantly suppressed proliferation, stemness, and migration and facilitated apoptosis in glioblastoma cells. Conclusion: We developed an accurate and efficient prognostic model. Furthermore, the correlation analysis of different stratification methods with tumor microenvironment provided a basis for further pathophysiological mechanism exploration. Finally, CD81 may serve as a diagnostic and prognostic biomarker in glioblastoma.

Impact of optical noises on unipolar-coded Brillouin optical time-domain analyzers.

Noise models for both single-pulse and coded Brillouin optical time-domain analyzers (BOTDA) are established to quantify the actual signal-to-noise ratio (SNR) enhancement provided by pulse coding at any fiber position and in any operating condition. Simulation and experimental results show that the polarization noise and spontaneous Brillouin scattering (SpBS) to signal beating noise could highly penalize the performance of coded-BOTDA, depending on the code type and the interrogated fiber position. The models also serve as a useful tool to optimize the SNR improvement by trading off the accumulated Brillouin gain and optical noises.

Genetic-optimised aperiodic code for distributed optical fibre sensors.

Distributed optical fibre sensors deliver a map of a physical quantity along an optical fibre, providing a unique solution for health monitoring of targeted structures. Considerable developments over recent years have pushed conventional distributed sensors towards their ultimate performance, while any significant improvement demands a substantial hardware overhead. Here, a technique is proposed, encoding the interrogating light signal by a single-sequence aperiodic code and spatially resolving the fibre information through a fast post-processing. The code sequence is once forever computed by a specifically developed genetic algorithm, enabling a performance enhancement using an unmodified conventional configuration for the sensor. The proposed approach is experimentally demonstrated in Brillouin and Raman based sensors, both outperforming the state-of-the-art. This methodological breakthrough can be readily implemented in existing instruments by only modifying the software, offering a simple and cost-effective upgrade towards higher performance for distributed fibre sensing.

Frequency shift estimation technique near the hotspot in BOTDA sensor.

When studying the spatial resolution and Brillouin frequency shift (BFS) uncertainty in Brillouin optical time domain analysis (BOTDA) system with a hotspot, people usually focuses on the point with best performance in the hotspot and neglect the huge error around it. The error is caused by the Brillouin gain spectrum (BGS) contributed by both the hotspot and the ambient segment, which is distorted from standard Lorentzian curve. Due to the distortion of BGS, the estimated BFS near the hotspot is shifted from the actual value and results in BFS error along the fiber. The distorted BGS can be double-peak or single-peak curve that is dependent on both the length of the hotspot that contributes to BGS and the BFS difference between the hotspot and the ambient segment. A fitting technique considering the combined contributions of hotspot and ambient segment is proposed to recover the distorted BGS near the hotspot and evaluate BFS. It is demonstrated that BFS error around hotspot is greatly reduced compare to the conventional Lorentzian fitting and dual Lorentzian fitting schemes.

The role of WASp in T cells and B cells.

Wiskott-Aldrich syndrome (WAS) is a form of primary immunodeficiency (PIDs) resulting from mutations of the gene that encodes Wiskott-Aldrich syndrome protein (WASp). WASp is the first identified and most widely studied protein belonging to the actin nucleation-promoting factor family and plays significant role in integrating and transforming signals from critical receptors on the cell surface to actin remodeling. WASp functions in immune defense and homeostasis through the regulation of actin cytoskeleton-dependent cellular processes as well as processes uncoupled with actin polymerization like nuclear transcription programs. In this article, we review the mechanisms of WASp activation through an understanding of its structure. We further discuss the role of WASp in adaptive immunity, paying special attention to some recent findings on the crucial role of WASp in the formation of immunological synapse, the regulation of T follicular helper (Tfh) cells and in the prevention of autoimmunity.

The regulators of BCR signaling during B cell activation.

B lymphocytes produce antibodies under the stimulation of specific antigens, thereby exerting an immune effect. B cells identify antigens by their surface B cell receptor (BCR), which upon stimulation, directs the cell to activate and differentiate into antibody generating plasma cells. Activation of B cells via their BCRs involves signaling pathways that are tightly controlled by various regulators. In this review, we will discuss three major BCR mediated signaling pathways (the PLC-γ2 pathway, PI3K pathway and MAPK pathway) and related regulators, which were roughly divided into positive, negative and mutual-balanced regulators, and the specific regulators of the specific signaling pathway based on regulatory effects.

The Coordination Between B Cell Receptor Signaling and the Actin Cytoskeleton During B Cell Activation.

B-cell activation plays a crucial part in the immune system and is initiated via interaction between the B cell receptor (BCR) and specific antigens. In recent years with the help of modern imaging techniques, it was found that the cortical actin cytoskeleton changes dramatically during B-cell activation. In this review, we discuss how actin-cytoskeleton reorganization regulates BCR signaling in different stages of B-cell activation, specifically when stimulated by antigens, and also how this reorganization is mediated by BCR signaling molecules. Abnormal BCR signaling is associated with the progression of lymphoma and immunological diseases including autoimmune disorders, and recent studies have proved that impaired actin cytoskeleton can devastate the normal activation of B cells. Therefore, to figure out the coordination between the actin cytoskeleton and BCR signaling may reveal an underlying mechanism of B-cell activation, which has potential for new treatments for B-cell associated diseases.

Characterization of a "low-risk" cohort of grade group 2 prostate cancer patients: Results from the Shared Equal Access Regional Cancer Hospital database.

OBJECTIVES: To examine if there is a subset of men with grade group 2 prostate cancer who could be potential candidates for active surveillance. METHODS: We used the Shared Equal Access Regional Cancer Hospital database to identify 776 men undergoing radical prostatectomy from 2006 to 2015 with >8 biopsy cores obtained and complete information. We compared men who fulfilled low-risk disease criteria (clinical stage T1c/T2a; grade group 1; prostate-specific antigen ≤10 ng/mL) with the exception of grade group 2 versus men who met all three low-risk criteria. Logistic regression was used to test the association between grade group and radical prostatectomy pathological features. Biochemical recurrence was examined using Cox models. To examine whether there was a subset of men with low-volume grade group 2 with comparable outcomes to low-risk men, we repeated all analyses limiting the percentage of positive cores in the grade group 2 group to ≤33%, and positive cores to ≤4, ≤3 or ≤2. RESULTS: Grade group 2 low-risk men had increased risk of pathological grade group 3 or higher (P < 0.001), extraprostatic extension (P < 0.001), seminal vesicle invasion (P < 0.001) and higher risk of biochemical recurrence (hazard ratio = 1.76, P = 0.006). Using increasingly strict definitions of low-volume disease, at ≤2 positive cores there was no difference in adverse pathology between groups (all P > 0.2), except higher pathological grade group (P = 0.006). Biochemical recurrence was similar in men in grade group 1 and grade group 2 (hazard ratio = 1.24; P = 0.529). CONCLUSIONS: Among men with prostate-specific antigen ≤10 ng/mL and clinical stage T1c/T2a, those in grade group 2 with ≤2 total positive cores have similar rates of adverse pathology and biochemical recurrence as men with grade group 1.

Efficacy of iron-supplement bars to reduce anemia in urban Indian women: a cluster-randomized controlled trial.

Background: India's high prevalence of iron-deficiency anemia has largely been attributed to the local diet consisting of nonheme iron, which has lower absorption than that of heme iron.Objective: We assessed the efficacy of the consumption of iron-supplement bars in raising hemoglobin concentrations and hematocrit percentages in anemic (hemoglobin concentration <12 g/dL) Indian women of reproductive age.Design: The Let's be Well Red study was a 90-d, pair-matched, cluster-randomized controlled trial. A total of 361 nonpregnant women (age 18-35 y) were recruited from 10 sites within Mumbai and Navi Mumbai, India. All participants received anemia education and a complete blood count (CBC). Random assignment of anemic participants to intervention and control arms occurred within 5 matched site-pairs. Intervention participants received 1 iron-supplement bar (containing 14 mg Fe)/d for 90 d, whereas control subjects received nothing. CBC tests were given at days 15, 45, and 90. Primary outcomes were 90-d changes from baseline in hemoglobin concentrations and hematocrit percentages. Linear mixed models and generalized estimating equations were used to model continuous and binary outcomes, respectively.Results: Of 179 anemic participants, 136 (76.0%) completed all follow-up assessments (65 intervention and 71 control participants). Baseline characteristics were comparable by arm. Mean hemoglobin and hematocrit increases after 90 d were greater for intervention than for control participants [1.4 g/dL (95% CI: 1.3, 1.6 g/dL) and 2.7% (95% CI: 2.2%, 3.2%), respectively]. The anemia prevalence at 90 d was lower for intervention (29.2%) than for control participants (98.6%) (OR: 0.007; 95% CI: 0.001, 0.04).Conclusions: The daily consumption of an iron-supplement bar leads to increased hemoglobin concentrations and hematocrit percentages and to a lower anemia prevalence in the target population with no reported side effects. This intervention is an attractive option to combat anemia in India. This trial was registered at clinicaltrials.gov as NCT02032615.

Utilization and impact of surgical technique on the performance of pelvic lymph node dissection at radical prostatectomy: Results from the Shared Equal Access Regional Cancer Hospital database.

OBJECTIVE: To evaluate performance of pelvic lymph node dissection during radical prostatectomy within an equal access care setting over a period of time, and stratified by prostate cancer risk group and surgical technique. METHODS: We identified men in the Shared Equal Access Regional Cancer Hospital database who had open or robotic-assisted radical prostatectomy from 2006 to 2013. Univariable logistic regression was used to test the association between age, race, body mass index, total biopsy cores, number of positive biopsy cores, risk group, year, center, surgical volume and surgical technique on pelvic lymph node dissection use. Multivariable logistic analysis was used to examine surgical technique and pelvic lymph node dissection performance. Spearman's correlation examined temporal changes in pelvic lymph node dissection utilization stratified by risk group and surgical technique. RESULTS: A total of 1425 men met inclusion criteria; 67% of them underwent pelvic lymph node dissection. On multivariable analysis, robotic-assisted radical prostatectomy was associated with an 92% decreased use of pelvic lymph node dissection in low-risk, 84% decreased in intermediate-risk and 91% decreased in high-risk men (all P < 0.001). In robotic-assisted radical prostatectomy, there was a trend for increased pelvic lymph node dissection utilization over time in high-risk men (Spearman; P = 0.077) reaching ~85% in 2012-2013, which was accompanied by increased use in low-risk men (P = 0.016). For open radical prostatectomy, fewer pelvic lymph node dissections were carried out in low-risk men over time, decreasing to ~35% (P = 0.047) in 2012-2013, whereas rates remained high for high-risk men throughout (~95%; P = 0.621). CONCLUSION: Regardless of risk group, pelvic lymph node dissection is carried out significantly less during robotic-assisted radical prostatectomy. For robotic-assisted radical prostatectomy, pelvic lymph node dissection utilization increased over time for high-risk men, but rates also increased for low-risk men. Further attention to the discrepancy between provided and guideline recommended pelvic lymph node dissection performance is required to improve prostate cancer care.

Metformin use and risk of prostate cancer: results from the REDUCE study.

The role of metformin in prostate cancer chemoprevention remains unclear. REDUCE, which followed biopsy-negative men with protocol-dictated PSA-independent biopsies at 2- and 4-years, provides an opportunity to evaluate the link between metformin use and prostate cancer diagnosis with minimal confounding from screening biases. In diabetic men from REDUCE, we tested the association between metformin use, use of other antidiabetic medications, versus no antidiabetic medication use, and prostate cancer diagnosis as well as prostate cancer grade (low-grade Gleason 4-6 and high-grade Gleason 7-10) using logistic regression. Of the 540 diabetic men with complete data, 205 (38%) did not report use of any antidiabetic medications, 141 (26%) reported use of at least one antidiabetic medication other than metformin, and 194 (36%) reported use of metformin. During the 4-year study, 122 men (23%) were diagnosed with prostate cancer. After adjusting for various clinical and demographic characteristics, we found that metformin use was not significantly associated with total (OR, 1.19; P = 0.50), low- (OR, 1.01; P = 0.96), or high-grade (OR, 1.83; P = 0.19) prostate cancer diagnosis. Likewise, there was no significant association between the use of non-metformin antidiabetic medications and prostate cancer risk in both crude (OR, 1.02; P = 0.95) and multivariable analysis (OR, 0.85; P = 0.56). Furthermore, the interactions between antidiabetic medication use and BMI, geographic location, coronary artery disease, smoking, and treatment group were not significant (all P > 0.05). Among diabetic men with a negative prestudy biopsy who all underwent biopsies largely independent of PSA, metformin use was not associated with reduced risk of prostate cancer diagnosis.