Overcoming the therapeutic limitations of EZH2 inhibitors in Burkitt’s lymphoma: a comprehensive study on the combined effects of MS1943 and Ibrutinib

Enhancer of zeste homolog 2 (EZH2) and Bruton’s tyrosine kinase (BTK) are both key factors involved in the development and progression of hematological malignancies. Clinical studies have demonstrated the potential of various EZH2 inhibitors, which target the methyltransferase activity of EZH2, for the treatment of lymphomas. However, despite their ability to effectively reduce the H3K27me3 levels, these inhibitors have shown limited efficacy in blocking the proliferation of lymphoma cells. To overcome this challenge, we employed a hydrophobic tagging approach utilizing MS1943, a selective EZH2 degrader. In this study, we investigated the inhibitory effects of two drugs, the FDA-approved EZH2 inhibitor Tazemetostat, currently undergoing clinical trials, and the novel drug MS1943, on Burkitt’s lymphoma. Furthermore, we assessed the potential synergistic effect of combining these drugs with the BTK inhibitor Ibrutinib. In this study, we evaluated the effects of combination therapy with MS1943 and Ibrutinib on the proliferation of three Burkitt’s lymphoma cell lines, namely RPMI1788, Ramos, and Daudi cells. Our results demonstrated that the combination of MS1943 and Ibrutinib significantly suppressed cell proliferation to a greater extent compared to the combination of Tazemetostat and Ibrutinib. Additionally, we investigated the underlying mechanisms of action and found that the combination therapy of MS1943 and Ibrutinib led to the upregulation of miR29B-mediated p53-upregulated modulator of apoptosis PUMA, BAX, cleaved PARP, and cleaved caspase-3 in Burkitt’s lymphoma cells. These findings highlight the potential of this innovative therapeutic strategy as an alternative to traditional EZH2 inhibitors, offering promising prospects for improving treatment outcomes in Burkitt’s lymphoma

Machine Learning-Based Genome-Wide Salivary DNA Methylation Analysis for Identification of Noninvasive Biomarkers in Oral Cancer Diagnosis

This study aims to examine the feasibility of ML-assisted salivary-liquid-biopsy platforms using genome-wide methylation analysis at the base-pair and regional resolution for delineating oral squamous cell carcinoma (OSCC) and oral potentially malignant disorders (OPMDs). A nested cohort of patients with OSCC and OPMDs was randomly selected from among patients with oral mucosal diseases. Saliva samples were collected, and DNA extracted from cell pellets was processed for reduced-representation bisulfite sequencing. Reads with a minimum of 10× coverage were used to identify differentially methylated CpG sites (DMCs) and 100 bp regions (DMRs). The performance of eight ML models and three feature-selection methods (ANOVA, MRMR, and LASSO) were then compared to determine the optimal biomarker models based on DMCs and DMRs. A total of 1745 DMCs and 105 DMRs were identified for detecting OSCC. The proportion of hypomethylated and hypermethylated DMCs was similar (51% vs. 49%), while most DMRs were hypermethylated (62.9%). Furthermore, more DMRs than DMCs were annotated to promoter regions (36% vs. 16%) and more DMCs than DMRs were annotated to intergenic regions (50% vs. 36%). Of all the ML models compared, the linear SVM model based on 11 optimal DMRs selected by LASSO had a perfect AUC, recall, specificity, and calibration (1.00) for OSCC detection. Overall, genome-wide DNA methylation techniques can be applied directly to saliva samples for biomarker discovery and ML-based platforms may be useful in stratifying OSCC during disease screening and monitoring

Real-time bladder volume monitoring by the application of a new implantable bladder volume sensor for a small animal model

AbstractAlthough real-time monitoring of bladder volume together with intravesical pressure can provide more information for understanding the functional changes of the urinary bladder, it still entails difficulties in the accurate prediction of real-time bladder volume in urodynamic studies with small animal models. We studied a new implantable bladder volume monitoring device with eight rats. During cystometry, microelectrodes prepared by the microelectromechanical systems process were placed symmetrically on both lateral walls of the bladder, and the expanded bladder volume was calculated. Immunohistological study was done after 1 week and after 4 weeks to evaluate the biocompatibility of the microelectrode. From the point that infused saline volume into the bladder was higher than 0.6mL, estimated bladder volume was statistically correlated with the volume of saline injected (p<0.01). Additionally, the microelectromechanical system microelectrodes used in this study showed reliable biocompatibility. Therefore, the device can be used to evaluate changes in bladder volume in studies with small animals, and it may help to provide more information about functional changes in the bladder in laboratory studies. Furthermore, owing to its biocompatibility, the device could be chronically implanted in conscious ambulating animals, thus allowing a novel longitudinal study to be performed for a specific purpose

Assessing brain function in self-identified individuals suspected of being on the autism spectrum using fMRI: a case study.

Autism Spectrum Disorder（ASD）is a widely recognized neurodevelopmental disorder that has gained recognition among both the general public and professional groups such as physicians and researchers. However, with this increasing awareness, some individuals have begun to suspect that they may be autistic based on their own knowledge and understanding. This suspicion can lead to unnecessary anxiety and other difficulties in one’s life. A simple objective method of assessment prior to formal diagnosis would be beneficial for those who suspect they may have autism. Thus, we posited that measuring brain function would be a viable candidate for this. As a preliminary study, we evaluated the brain function of an individual who suspected he may be autistic using our developed estimator of human characteristics. Additionally, we also compared this individual to a cohort of typical subjects based on functional networks consisting of previously identified ASD-related brain regions. The individual was determined to be typical by our estimator, however, the comparison with the normal group indicated deviation in brain regions such as the precuneus and ventral prefrontal cortex from the normal group. These results suggest that the individual is considered normal, but some brain functions may deviate from the normal group. Brain function measuring may be a good assessment method for those who suspect they may have autism.journal articl

Controllable synthesis of molybdenum tungsten disulfide alloy for vertically composition-controlled multilayer

The effective synthesis of two-dimensional transition metal dichalcogenides alloy is essential for successful application in electronic and optical devices based on a tunable band gap. Here we show a synthesis process for Mo&lt;inf&gt;1-x&lt;/inf&gt;W&lt;inf&gt;x&lt;/inf&gt;S&lt;inf&gt;2&lt;/inf&gt; alloy using sulfurization of super-cycle atomic layer deposition Mo&lt;inf&gt;1-x&lt;/inf&gt;W&lt;inf&gt;x&lt;/inf&gt;O&lt;inf&gt;y&lt;/inf&gt;. Various spectroscopic and microscopic results indicate that the synthesized Mo&lt;inf&gt;1-x&lt;/inf&gt;W&lt;inf&gt;x&lt;/inf&gt;S&lt;inf&gt;2&lt;/inf&gt; alloys have complete mixing of Mo and Watoms and tunable band gap by systematically controlled composition and layer number. Based on this, we synthesize a vertically composition-controlled (VCC) Mo&lt;inf&gt;1-x&lt;/inf&gt;W&lt;inf&gt;x&lt;/inf&gt;S&lt;inf&gt;2&lt;/inf&gt; multilayer using five continuous super-cycles with different cycle ratios for each super-cycle. Angle-resolved X-ray photoemission spectroscopy, Raman and ultraviolet-visible spectrophotometer results reveal that a VCC Mo&lt;inf&gt;1-x&lt;/inf&gt;W&lt;inf&gt;x&lt;/inf&gt;S&lt;inf&gt;2&lt;/inf&gt; multilayer has different vertical composition and broadband light absorption with strong interlayer coupling within a VCC Mo&lt;inf&gt;1-x&lt;/inf&gt;W&lt;inf&gt;x&lt;/inf&gt;S&lt;inf&gt;2&lt;/inf&gt; multilayer. Further, we demonstrate that a VCC Mo&lt;inf&gt;1-x&lt;/inf&gt;W&lt;inf&gt;x&lt;/inf&gt;S&lt;inf&gt;2&lt;/inf&gt; multilayer photodetector generates three to four times greater photocurrent than MoS&lt;inf&gt;2&lt;/inf&gt;-and WS&lt;inf&gt;2&lt;/inf&gt;-based devices, owing to the broadband light absorption. &amp;#169; 2015 Macmillan Publishers Limitedopen1

Current Antimicrobial Usage for the Management of Neutropenic Fever in Korea: A Nationwide Survey

A nationwide questionnaire-based survey was performed to evaluate the current clinical practices for the management of neutropenic fever in hematology units and hematopoietic stem cell transplantation (HSCT) centers throughout Korea. A 86.9% response rate was obtained from a total of 46 doctors and practical policies of the 33 sites were analysed. Approximately 42.4% and 84.8% of the sites responded that they used oral fluoroquinolone as prophylaxis for neutropenic patients receiving chemotherapy and HSCT, respectively. Additionally, 42.4% of the sites responded that they used antifungal prophylaxis in the chemotherapy groups whereas 90.9% of the sites responded that they used antifungal prophylaxis in HSCT recipients. Approximately half of the responding sites prescribed combination regimen with 3rd or 4th cephalosporin plus aminoglycoside as a first-line therapy. Most of the sites considered persistent fever for 2-4 days or aggravated clinical symptoms for 1-2 days as failure of the first-line regimen, and they changed antibiotics to second-line regimens that varied widely among the sites. Twenty-seven sites (84.4%) responded that they considered adding an antifungal agent when fever persisted for 5-7 days despite antibacterial therapy. Amphotericin B deoxycholate was preferred as a first-line antifungal, which was probably due to the limitations of the national health insurance system. The role of oral antibiotics in the management of neutropenic fever still accounted for a small portion. To the best of our knowledge, this survey is the first report to examine the practical policies currently in place for the management of neutropenic fever in Korea and the results of this survey may help to establish a Korean guideline in the future

DeepParcellation: A novel deep learning method for robust brain magnetic resonance imaging parcellation in older East Asians

Accurate parcellation of cortical regions is crucial for distinguishing morphometric changes in aged brains, particularly in degenerative brain diseases. Normal aging and neurodegeneration precipitate brain structural changes, leading to distinct tissue contrast and shape in people aged &gt;60 years. Manual parcellation by trained radiologists can yield a highly accurate outline of the brain; however, analyzing large datasets is laborious and expensive. Alternatively, newly-developed computational models can quickly and accurately conduct brain parcellation, although thus far only for the brains of Caucasian individuals. To develop a computational model for the brain parcellation of older East Asians, we trained magnetic resonance images of dimensions 256 × 256 × 256 on 5,035 brains of older East Asians (Gwangju Alzheimer’s and Related Dementia) and 2,535 brains of Caucasians. The novel N-way strategy combining three memory reduction techniques inception blocks, dilated convolutions, and attention gates was adopted for our model to overcome the intrinsic memory requirement problem. Our method proved to be compatible with the commonly used parcellation model for Caucasians and showed higher similarity and robust reliability in older aged and East Asian groups. In addition, several brain regions showing the superiority of the parcellation suggest that DeepParcellation has a great potential for applications in neurodegenerative diseases such as Alzheimer’s disease