Sarcopenic obesity in nursing home residents: a multi-center study on diagnostic methods and their association with instrumental activities of daily living.

BACKGROUND: Sarcopenic obesity (SO) in nursing home residents is rarely studied. We aimed to evaluate and compare the prevalence and consistency of different SO diagnostic methods and to investigate which criterion demonstrated a stronger association with instrumental activities of daily living (IADL) disability. METHODS: We consecutively recruited older adults aged ≥ 60 years, residing in 15 nursing homes in Zigong City, China. Sarcopenia obesity was defined according to the European Society for Clinical Nutrition and Metabolism (ESPEN) and the European Association for the Study of Obesity criteria (SOESPEN), recommending skeletal muscle mass (SMM) adjusted by body weight (SMM/W) to identify low muscle mass. Further, we adapted ESPEN criteria (SOESPEN-M) by employing SMM adjusted by body mass index (SMM/BMI). RESULTS: We included 832 participants (median age 73.0 years, 296 women). The prevalence of SOESPEN and SOESPEN-M was 43.5% and 45.3%, respectively. SOESPEN showed good consistency with SOESPEN-M (Cohen's kappa = 0.759). More than one-third of participants in the normal weight group were diagnosed with SOESPEN or SOESPEN-M. Even within the underweight group, the prevalence of SOESPEN and SOESPEN-M was 8.9% and 22.2%, respectively. Participants with IADL disability had significantly lower SMM/W and SMM/BMI, but higher fat mass percentage of body weight (FM%) than participants without IADL disability. After full adjustment for potential confounders, SOESPEN-M (OR 1.68, 95% CI 1.21 to 2.32), but not SOESPEN (OR 1.28, 95% CI 0.93 to 1.75), remained significantly associated with IADL disability. CONCLUSIONS: Both SOESPEN and SOESPEN-M showed a high prevalence among nursing home residents, even among individuals with underweight or normal weight. While SOESPEN had a good consistency with SOESPEN-M, only SOESPEN-M was independently associated with IADL disability. Screening and diagnosis of SO should be conducted in nursing home residents irrespective of BMI.

Mitochondrial transplantation as a novel therapeutic strategy for cardiovascular diseases.

Cardiovascular disease (CVD) is the leading cause of noncommunicable disease-related death worldwide, and effective therapeutic strategies against CVD are urgently needed. Mitochondria dysfunction involves in the onset and development of CVD. Nowadays, mitochondrial transplantation, an alternative treatment aimed at increasing mitochondrial number and improving mitochondrial function, has been emerged with great therapeutic potential. Substantial evidence indicates that mitochondrial transplantation improves cardiac function and outcomes in patients with CVD. Therefore, mitochondrial transplantation has profound implications in the prevention and treatment of CVD. Here, we review the mitochondrial abnormalities that occur in CVD and summarize the therapeutic strategies of mitochondrial transplantation for CVD.

EZH2 regulates pancreatic cancer cells through E2F1, GLI1, CDK3, and Mcm4.

Pancreatic cancer (PC) is one of the most common malignant tumors in digestive tract. To explore the role of epigenetic factor EZH2 in the malignant proliferation of PC, so as to provide effective medical help in PC. Sixty paraffin sections of PC were collected and the expression of EZH2 in PC tissues was detected by immunohistochemical assay. Three normal pancreas tissue samples were used as controls. The regulation of EZH2 gene on proliferation and migration of normal pancreatic cell and PC cell were determined by MTS, colony forming, Ki-67 antibody, scratch and Transwell assays. Through differential gene annotation and differential gene signaling pathway analysis, differentially expressed genes related to cell proliferation were selected and verified by RT-qPCR. EZH2 is mainly expressed in the nuclei of pancreatic tumor cells, but not in normal pancreatic cells. The results of cell function experiments showed that EZH2 overexpression could enhance the proliferation and migration ability of PC cell BXPC-3. Cell proliferation ability increased by 38% compared to the control group. EZH2 knockdown resulted in reduced proliferation and migration ability of cells. Compared with control, proliferation ability of cells reduced by 16%-40%. The results of bioinformatics analysis of transcriptome data and RT-qPCR demonstrated that EZH2 could regulate the expression of E2F1, GLI1, CDK3 and Mcm4 in normal and PC cells. The results revealed that EZH2 might regulate the proliferation of normal pancreatic cell and PC cell through E2F1, GLI1, CDK3 and Mcm4.

The frequency and clinical implication of mismatch repair protein deficiency in Chinese patients with ovarian clear cell carcinoma.

BACKGROUND: The aim of the present study was to assess the prevalence of deficient mismatch repair (MMR) in Chinese ovarian clear cell carcinoma (CCC) patients and its association with clinicopathologic features. METHODS: Immunohistochemistry with four antibodies against MLH1, PMS2, MSH2 and MSH6 was performed on whole section slides, and the results were correlated with clinicopathologic variables. RESULTS: A total of 108 cases were included in the present study with a median age of 52 years at first diagnosis. Early-stage disease and platinum-sensitive recurrence accounted for 62.3 and 69.6%, respectively, of the total cases. Overall, the estimated 5-year overall survival was 70.3 and 20.7% in patients with early- and late-stage tumors, respectively. Deficient MMR was identified in 5.6% (6/108) of the cohort and included MSH2/MSH6 (n = 4) and MLH1/PMS2 (n = 2). The average age of the six patients with deficient MMR was 45.6 years, and the rate of MMR-deficient tumors in women ≤50 years was relatively higher than that in women over 50 years (10.0% vs. 2.9%; P = 0.266). Half of the patients with deficient MMR were diagnosed with synchronous (endometrial or colorectal) and metachronous (endometrial) cancer, which was significantly more than their intact counterparts (P = 0.002). All six patients with deficient MMR had early-stage tumors, and the majority (83.3%) were platinum sensitive. The median progression-free survival was slightly higher in patients with defective MMR expression than in their intact counterparts (30 months vs. 27 months), but significance was not achieved (P = 0.471). CONCLUSIONS: Young ovarian CCC patients with concurrent diagnosis of endometrial and colorectal cancer are more likely to have MMR-deficient tumors, thereby warranting additional studies to determine whether patients harboring MMR abnormalities have a favorable prognosis.

Efficacy of Individualized Preventive Treatment of Patients with Severe Hemophilia A Guided by Multiple Clinical Parameters and Pharmacokinetics.

OBJECTIVE: The objective of the study was to investigate the effect of multiple clinical parameters (age, weight, blood types, and bleeding types) on FVIII pharmacokinetic parameters (PK parameters) in adult patients with severe hemophilia A (SHA), draw up individualized preventive treatment plans, and observe clinical efficacy. METHODS: Forty SHA patients treated in our hospital from January 2018 to May 2019 were enrolled, with their age, weight, blood types, bleeding types, and PK parameters measured to analyze the effects of clinical parameters on PK parameters. Individualized preventive treatment was developed, and patients were followed up for 1 year. The annual bleeding rate (ABR), annual joint bleeding rate (AJBR), and annual FVIII dosage were observed and compared before and after treatment. RESULTS: Weight, blood types, and bleeding types could affect the PK parameters of FVIII. A prophylaxis plan was formulated under the guidance of FVIII half-life. After 1 year of follow-up, the mean ABR dropped from 36.54 to 4.06, decreased by 88.9%, the mean AJBR dropped from 28.36 to 2.75, decreased by 90%, and annual FVIII dosage increased by 47%. The dosage of FVIII in 8 patients after was less than that before prophylaxis, and the average half-life time of these 8 patients was 13.32 h. CONCLUSIONS: (1) Weight, blood types, and bleeding types of adult SHA patients could affect FVIII half-life. As body mass index increased, FVIII half-life was significantly prolonged. The FVIII half-life of patients with type O blood was significantly shorter than those with other blood types, and the FVIII half-life of knee joint bleeding was conspicuously shorter than those of elbow joint bleeding. (2) Individualized preventive treatment could markedly reduce the number of bleeds. For patients with a long half-life period, the total annual FVIII dosage could be reduced to achieve bleeding prevention.

Design, synthesis, and evaluation of novel pyridone derivatives as potent BRD4 inhibitors for the potential treatment of prostate cancer.

Since androgen receptor (AR) can bind to BRD4 protein and this binding can be blocked by BRD4 inhibitors, targeting BRD4 has emerged as a promising approach for the treatment of prostate cancer (PC). Herein, we designed and synthesized a series of 5-(1-benzyl-1H-indazol-6-yl)-4-ethoxy-1-methylpyridin-2(1H)-one derivatives as novel BRD4 inhibitors for prostate cancer. Among them, compound 13 displayed the most robust BRD4 inhibitory activity with an IC50 value of 18 nM. Furthermore, 13 showed potent anti-proliferative activity against enzalutamide-resistant 22RV1 cells. The mechanism of action studies demonstrated that 13 induced cell apoptosis by regulating Bcl-2/Bax proteins and activating caspase-3 signaling pathway. In addition, the c-Myc level was significantly reduced in 22RV1 cells on the western blot assay. These findings collectively suggested that compound 13 might find potential use for the treatment of prostate cancer.

Establishment of a typing model for diffuse large B-cell lymphoma based on B-cell receptor repertoire sequencing.

BACKGROUND: The purpose of this study was to construct a new typing model for diffuse large B-cell lymphoma (DLBCL) patients based on the B-cell receptor (BCR) and explore its potential molecular mechanism. METHODS: BCR repertoire sequencing and whole-exome sequencing were performed on formalin-fixed paraffin-embedded samples from 12 DLBCL patients. Subsequently, a typing model was built with cluster analysis, and prognostic indicators between the two groups were compared to verify the typing model. Then, mutation and bioinformatics analyses were conducted to investigate the potential biomarkers of prognostic differences between the two groups. RESULTS: Based on BCR sequencing data, we divided patients into two clusters (cluster 1 and cluster 2); this classification differed from the traditional typing method (GCB and non-GCB), in which cluster 1 included some non-GCB patients. The progression-free survival (PFS), overall survival (OS), metastasis and Shannon diversity index of IGH V-J and survival after chemotherapy were significantly different (P < 0.05) between the two clusters, but no statistical significance was found between the GCB and non-GCB groups. The mutation status of 248 genes was significantly different between cluster 1 and cluster 2. Among them, FTSJ3, MAGED2, and ODF3L2 were the specific mutated genes in all patients in cluster 2, and these genes could be considered critical to the different prognoses of the two clusters of DLBCL patients. CONCLUSION: We constructed a new typing model of DLBCL based on BCR repertoire sequencing that can better predict the survival time after chemotherapy. FTSJ3, MAGED2, and ODF3L2 may represent key genes for the difference in prognosis between the two clusters.

Molecular Subtyping of Triple-Negative Breast Cancers by Immunohistochemistry: Molecular Basis and Clinical Relevance.

BACKGROUND: Molecular subtyping of triple-negative breast cancers (TNBCs) via gene expression profiling is essential for understanding the molecular essence of this heterogeneous disease and for guiding individualized treatment. We aim to devise a clinically practical method based on immunohistochemistry (IHC) for the molecular subtyping of TNBCs. MATERIALS AND METHODS: By analyzing the RNA sequencing data on TNBCs from Fudan University Shanghai Cancer Center (FUSCC) (n = 360) and The Cancer Genome Atlas data set (n = 158), we determined markers that can identify specific molecular subtypes. We performed immunohistochemical staining on tumor sections of 210 TNBCs from FUSCC, established an IHC-based classifier, and applied it to another two cohorts (n = 183 and 214). RESULTS: We selected androgen receptor (AR), CD8, FOXC1, and DCLK1 as immunohistochemical markers and classified TNBCs into five subtypes based on the staining results: (a) IHC-based luminal androgen receptor (IHC-LAR; AR-positive [+]), (b) IHC-based immunomodulatory (IHC-IM; AR-negative [-], CD8+), (c) IHC-based basal-like immune-suppressed (IHC-BLIS; AR-, CD8-, FOXC1+), (d) IHC-based mesenchymal (IHC-MES; AR-, CD8-, FOXC1-, DCLK1+), and (e) IHC-based unclassifiable (AR-, CD8-, FOXC1-, DCLK1-). The κ statistic indicated substantial agreement between the IHC-based classification and mRNA-based classification. Multivariate survival analysis suggested that our IHC-based classification was an independent prognostic factor for relapse-free survival. Transcriptomic data and pathological observations implied potential treatment strategies for different subtypes. The IHC-LAR subtype showed relative activation of HER2 pathway. The IHC-IM subtype tended to exhibit an immune-inflamed phenotype characterized by the infiltration of CD8+ T cells into tumor parenchyma. The IHC-BLIS subtype showed high expression of a VEGF signature. The IHC-MES subtype displayed activation of JAK/STAT3 signaling pathway. CONCLUSION: We developed an IHC-based approach to classify TNBCs into molecular subtypes. This IHC-based classification can provide additional information for prognostic evaluation. It allows for subgrouping of TNBC patients in clinical trials and evaluating the efficacy of targeted therapies within certain subtypes. IMPLICATIONS FOR PRACTICE: An immunohistochemistry (IHC)-based classification approach was developed for triple-negative breast cancer (TNBC), which exhibited substantial agreement with the mRNA expression-based classification. This IHC-based classification (a) allows for subgrouping of TNBC patients in large clinical trials and evaluating the efficacy of targeted therapies within certain subtypes, (b) will contribute to the practical application of subtype-specific treatment for patients with TNBC, and (c) can provide additional information beyond traditional prognostic factors in relapse prediction.

Heterogeneous programmed death-ligand 1 expression in gastric cancer: comparison of tissue microarrays and whole sections.

BACKGROUND: Programmed death-ligand 1 (PD-L1) expression determines the eligibility for anti-PD-1 treatment in patients with advanced gastric cancer, but evidence indicates that PD-L1 staining is heterogeneous. Patients who are ineligible for radical surgery could be tested for PD-L1 expression with biopsy staining, but it is unclear if a small biopsy is representative of the PD-L1 status of the whole tumor. The aim of our study was to determine how many biopsy specimens are needed to accurately reflect the objective status of PD-L1 expression in whole sections. METHODS: We built tissue microarrays (TMAs) as substitutes for core biopsies, collecting 6 cores per case from 152 gastric cancer specimens. All of the slides and TMAs underwent PD-L1 immunohistochemical staining, and PD-L1 expression in at least 1% of tumor cells or immune cells was defined as positive. RESULTS: It was necessary to randomly select multiple cores from TMAs to reach a suitable agreement rate (> 90%) and Cohen's κ value (> 0.8) between TMAs and whole sections. We defined the PD-L1 staining status from the whole section as the standard. The evaluation of five randomly selected cores from TMAs agreed well with the evaluation of whole sections. The sensitivity, specificity and the area under the curve (AUC) of the receiver-operating characteristic (ROC) were 0.93, 0.92, and 0.922 (95% confidence interval (CI) 0.863-0.982), respectively. CONCLUSIONS: We conclude that PD-L1 expression among TMA samples had different degrees of relevance to the corresponding surgical specimens, which indicates that at least five biopsies might be necessary to characterize patients taking anti-PD-1 treatment.

miR-22 enhances the radiosensitivity of small-cell lung cancer by targeting the WRNIP1.

Small-cell lung cancer (SCLC) is an aggressive malignancy characterized by high cellular proliferation and early distant metastasis. Our study aimed to explore the effect of miR-22-3p (miR-22, for short) on SCLC radiosensitivity and its molecular mechanisms. The expression level of miR-22 was evaluated in a human normal lung epithelial cell line and a human SCLC cell line, and cell apoptosis and migration were detected. The expression of the miR-22 direct target WRNIP1 mRNA and protein were explored. Five differentially expressed genes were detected. The miR-22 expression in NCI-H446 was significantly decreased, and miR-22 overexpression significantly promoted cell apoptosis. miR-22 overexpression could significantly inhibit the cell migration of SCLC cells, and miR-22 had a negative regulatory effect on WRNIP1 mRNA and protein levels. KLK8 was downregulated, and the messenger RNA (mRNA) of four other genes (PC, SCUBE1, STC1, and GPM6A) was upregulated mRNA in cells overexpressing miR-22, which was in accordance with the bioinformatics analysis. miR-22 could enhance the radiosensitivity of SCLC by targeting WRNIP1.

Losses in Ferroelectric Materials.

Ferroelectric materials are the best dielectric and piezoelectric materials known today. Since the discovery of barium titanate in the 1940s, lead zirconate titanate ceramics in the 1950s and relaxor-PT single crystals (such as lead magnesium niobate-lead titanate and lead zinc niobate-lead titanate) in the 1980s and 1990s, perovskite ferroelectric materials have been the dominating piezoelectric materials for electromechanical devices, and are widely used in sensors, actuators and ultrasonic transducers. Energy losses (or energy dissipation) in ferroelectrics are one of the most critical issues for high power devices, such as therapeutic ultrasonic transducers, large displacement actuators, SONAR projectors, and high frequency medical imaging transducers. The losses of ferroelectric materials have three distinct types, i.e., elastic, piezoelectric and dielectric losses. People have been investigating the mechanisms of these losses and are trying hard to control and minimize them so as to reduce performance degradation in electromechanical devices. There are impressive progresses made in the past several decades on this topic, but some confusions still exist. Therefore, a systematic review to define related concepts and clear up confusions is urgently in need. With this objective in mind, we provide here a comprehensive review on the energy losses in ferroelectrics, including related mechanisms, characterization techniques and collections of published data on many ferroelectric materials to provide a useful resource for interested scientists and engineers to design electromechanical devices and to gain a global perspective on the complex physical phenomena involved. More importantly, based on the analysis of available information, we proposed a general theoretical model to describe the inherent relationships among elastic, dielectric, piezoelectric and mechanical losses. For multi-domain ferroelectric single crystals and ceramics, intrinsic and extrinsic energy loss mechanisms are discussed in terms of compositions, crystal structures, temperature, domain configurations, domain sizes and grain boundaries. The intrinsic and extrinsic contributions to the total energy dissipation are quantified. In domain engineered ferroelectric single crystals and ceramics, polarization rotations, domain wall motions and mechanical wave scatterings at grain boundaries are believed to control the mechanical quality factors of piezoelectric resonators. We show that a thorough understanding on the kinetic processes is critical in analyzing energy loss behavior and other time-dependent properties in ferroelectric materials. At the end of the review, existing challenges in the study and control of losses in ferroelectric materials are analyzed, and future perspective in resolving these issues is discussed.

Contamination of Phenylobacterium in several human and murine cell cultures.

OBJECTIVE: To identify and characterize an unknown microorganism causing contamination in several mammalian cell cultures. METHODS: This bacterium was identified by 16S rRNA sequencing and studied by DAPI and DiOC6 (3) staining, Gram staining, acid-fast staining, and electron microscopy. The isolated bacterium was also used to infect host cells to observe antibiotic effectiveness and its relationship with host cells. RESULTS: The 16S rRNA sequence analysis shows that this rod-shaped microorganism belongs to the family Caulobacteraceae, class Alphaproteobacteria, and was most closely related to Phenylobacterium zucineum HLK1T strain. The bacterium collected in the "swimming" stage was Gram staining negative, but Gram staining positive in the "sessile" stage. Under the electron microscope both flagellated and non-flagellated types were found. So far, no antibiotics were effective to inhibit this microorganism. The contamination with this bacterium frequently led to failed resuscitation of thawed cells. We found that the cells resuscitated with the used culture supernatants were increased in number by 3-4 folds as compared to those resuscitated with freshly prepared media. CONCLUSION: Phenylobacterium may have a dimorphic life cycle including a swimming stage and a sessile stalked stage.

Myocardial Metabolic Reprogramming in HFpEF.

Heart failure (HF) caused by structural or functional cardiac abnormalities is a significant cause of morbidity and mortality worldwide. While HF with reduced ejection fraction (HErEF) is well understood, more than half of patients have HF with preserved ejection fraction (HFpEF). Currently, the treatment for HFpEF primarily focuses on symptom alleviation, lacking specific drugs. The stressed heart undergoes metabolic switches in substrate preference, which is a compensatory process involved in cardiac pathological remodeling. Although metabolic reprogramming in HF has gained attention in recent years, its role in HFpEF still requires further elucidation. In this review, we present a summary of cardiac mitochondrial dysfunction and cardiac metabolic reprogramming in HFpEF. Additionally, we emphasize potential therapeutic approaches that target metabolic reprogramming for the treatment of HFpEF.

Prediction of retinopathy progression using deep learning on retinal images within the Scottish screening programme.

BACKGROUND/AIMS: National guidelines of many countries set screening intervals for diabetic retinopathy (DR) based on grading of the last screening retinal images. We explore the potential of deep learning (DL) on images to predict progression to referable DR beyond DR grading, and the potential impact on assigned screening intervals, within the Scottish screening programme. METHODS: We consider 21 346 and 247 233 people with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), respectively, each contributing on average 4.8 and 4.4 screening intervals of which 1339 and 4675 intervals concluded with a referable screening episode. Information extracted from fundus images using DL was used to predict referable status at the end of interval and its predictive value in comparison to screening-assigned DR grade was assessed. RESULTS: The DL predictor increased the area under the receiver operating characteristic curve in comparison to a predictor using current DR grades from 0.809 to 0.87 for T1DM and from 0.825 to 0.87 for T2DM. Expected sojourn time-the time from becoming referable to being rescreened-was found to be 3.4 (T1DM) and 2.7 (T2DM) weeks less for a DL-derived policy compared with the current recall policy. CONCLUSIONS: We showed that, compared with using the current retinopathy grade, DL of fundus images significantly improves the prediction of incident referable retinopathy before the next screening episode. This can impact screening recall interval policy positively, for example, by reducing the expected time with referable disease for a fixed workload-which we show as an exemplar. Additionally, it could be used to optimise workload for a fixed sojourn time.

Melatonin enhanced the cardioprotective effects of HTK solution on Langendorff-perfused mouse hearts subjected to ischemia/reperfusion.

Objectives: Cardiac arrest is a crucial procedure in various cardiac surgeries, during which the heart is subjected to an ischemic state. The occurrence of ischemia/reperfusion (I/R) injury is inevitable due to aortic blockage and opening. The Histidine-tryptophan-ketoglutarate (HTK) solution is commonly used as an organ protection liquid to mitigate cardiac injury during cardiac surgery. Despite its widespread use, there is significant potential for improving its protective efficacy. Materials and Methods: The cardioprotective effect of HTK solution with and without melatonin was evaluated using the isolated Langendorff-perfused mouse heart model. The isolated C57bL/6 mouse hearts were randomly divided into four groups: control, I/R, HTK solution treatment before reperfusion (HTK+I/R), and HTK solution combined with melatonin before reperfusion (HTK+M+I/R). Cardiac function and myocardial injury markers were then measured. AMP-activated protein kinase α2 (AMPKα2) KO mice were used to investigate the underlying mechanism. Results: In our study, we found that melatonin significantly improved the protective effects of HTK solution in an isolated Langendorff-perfused mouse model, mechanistically by reducing mitochondrial damage, improving energy metabolism, inhibiting cardiomyocyte apoptosis, and reducing myocardial infarction size. We also observed that the HTK solution alone was ineffective in inhibiting ER stress, but when melatonin was added, there was a significant reduction in ER stress. Furthermore, melatonin was found to alleviate carbonyl stress during cardiac I/R. Interestingly, our results showed that the cardioprotective properties of melatonin were dependent on AMPKα2. Conclusion: The findings presented in this study offer a valuable empirical foundation for the development of perioperative cardioprotective strategies.

MNDA expression and its value in differential diagnosis of B-cell non-Hodgkin lymphomas: a comprehensive analysis of a large series of 1293 cases.

AIMS: MNDA (myeloid nuclear differentiation antigen) has been considered as a potential diagnostic marker for marginal zone lymphoma (MZL), but its utility in distinguishing MZL from other B-cell non-Hodgkin lymphomas (B-NHLs) and its clinicopathologic relevance in diffuse large B-cell lymphoma (DLBCL) are ambiguous. We comprehensively investigated MNDA expression in a large series of B-NHLs and evaluated its diagnostic value. METHODS: MNDA expression in a cohort of 1293 cases of B-NHLs and 338  cases of reactive lymphoid hyperplasia (RLH) was determined using immunohistochemistry and compared among different types of B-NHL. The clinicopathologic relevance of MNDA in DLBCL was investigated. RESULTS: MNDA was highly expressed in MZLs (437/663, 65.9%), compared with the confined staining in marginal zone B-cells in RLH; whereas neoplastic cells with plasmacytic differentiation lost MNDA expression. MNDA expression was significantly higher in mantle cell lymphoma (MCL, 79.6%, p = 0.006), whereas lower in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL, 44.8%, p = 0.001) and lymphoplasmacytic lymphoma (LPL, 25%, p = 0.016), and dramatically lower in follicular lymphoma (FL, 5.2%, p < 0.001), compared with MZL. 29.6% (63/213) of DLBCLs were positive for MNDA. The cases in non-GCB group exhibited a higher rate of MNDA positivity (39.8%) compared to those in GCB group (16.3%) (p < 0.001), and MNDA staining was more frequently observed in DLBCLs with BCL2/MYC double-expression (50%) than those without BCL2/MYC double-expression (24.8%) (p = 0.001). Furthermore, there was a significant correlation between MNDA and CD5 expression in DLBCL (p = 0.036). CONCLUSIONS: MNDA was highly expressed in MZL with a potential utility in differential diagnosis between MZL and RLH as well as FL, whereas its value in distinguishing MZL from MCL, CLL/SLL is limited. In addition, MNDA expression in DLBCL was more frequently seen in the non-GCB group and the BCL2/MYC double-expression group, and demonstrated a correlation with CD5, which deserves further investigation. The clinical relevance of MNDA and its correlation with the prognosis of these lymphomas also warrant to be fully elucidated.

Discovery of Novel Phenoxyaryl Pyridones as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with High Selectivity for the Second Bromodomain (BD2) to Potentially Treat Acute Myeloid Leukemia.

Bromodomain-selective BET inhibition has emerged as a promising strategy to improve the safety profiles of pan-BET inhibitors. Herein, we report the discovery of potent phenoxyaryl pyridones as highly BD2-selective BET inhibitors. Compound 23 (IC50 = 2.9 nM) exhibited a comparable BRD4 BD2 inhibitory activity relative to 10 (IC50 = 1.0 nM) and remarkably improved selectivity over BRD4 BD1 (23: 2583-fold; 10: 344-fold). This lead compound significantly inhibited the proliferation of acute myeloid leukemia (AML) cell lines through induction of G0/G1 arrest and apoptosis in vitro. Excellent in vivo antitumor efficacy with 23 was achieved in an MV;411 mouse xenograft model. Pleasingly, compound 23 (hERG IC50 > 30 µM) mitigated the inhibition of the human ether-à-go-go-related gene (hERG) ion channel compared with 10 (hERG IC50 = 2.8 µM). This work provides a promising BD2-selective lead for the development of more effective and safe BET inhibitors as anticancer agents.

Structural basis for the functional roles of critical residues in human cytochrome p450 aromatase.

Cytochrome P450 aromatase (CYP19A1) is the only enzyme known to catalyze the biosynthesis of estrogens from androgens. The crystal structure of human placental aromatase (pArom) has paved the way toward understanding the structure-function relationships of this remarkable enzyme. Using an amino terminus-truncated recombinant human aromatase (rArom) construct, we investigate the roles of key amino acids in the active site, at the intermolecular interface, inside the access channel, and at the lipid-protein boundary for their roles in enzyme function and higher-order organization. Replacing the active site residue D309 with an N yields an inactive enzyme, consistent with its proposed involvement in aromatization. Mutation of R192 at the lipid interface, pivotal to the proton relay network in the access channel, results in the loss of enzyme activity. In addition to the distal catalytic residues, we show that mutation of K440 and Y361 of the heme-proximal region critically interferes with substrate binding, enzyme activity, and heme stability. The D-E loop deletion mutant Del7 that disrupts the intermolecular interaction significantly reduces enzyme activity. However, the less drastic Del4 and point mutants E181A and E181K do not. Furthermore, native gel electrophoresis, size-exclusion chromatography, and analytical ultracentrifugation are used to show that mutations in the intermolecular interface alter the quaternary organization of the enzyme in solution. As a validation for interpretation of the mutational results in the context of the innate molecule, we determine the crystal structure of rArom to show that the active site, tertiary, and quaternary structures are identical to those of pArom.

Joint analysis of binary and quantitative traits with data sharing and outcome-dependent sampling.

We study the analysis of a joint association between a genetic marker with both binary (case-control) and quantitative (continuous) traits, where the quantitative trait values are only available for the cases due to data sharing and outcome-dependent sampling. Data sharing becomes common in genetic association studies, and the outcome-dependent sampling is the consequence of data sharing, under which a phenotype of interest is not measured for some subgroup. The trend test (or Pearson's test) and F-test are often, respectively, used to analyze the binary and quantitative traits. Because of the outcome-dependent sampling, the usual F-test can be applied using the subgroup with the observed quantitative traits. We propose a modified F-test by also incorporating the genotype frequencies of the subgroup whose traits are not observed. Further, a combination of this modified F-test and Pearson's test is proposed by Fisher's combination of their P-values as a joint analysis. Because of the correlation of the two analyses, we propose to use a Gamma (scaled chi-squared) distribution to fit the asymptotic null distribution for the joint analysis. The proposed modified F-test and the joint analysis can also be applied to test single trait association (either binary or quantitative trait). Through simulations, we identify the situations under which the proposed tests are more powerful than the existing ones. Application to a real dataset of rheumatoid arthritis is presented.

The battle between the innate immune cGAS-STING signaling pathway and human herpesvirus infection.

The incidence of human herpesvirus (HHVs) is gradually increasing and has affected a wide range of population. HHVs can result in serious consequences such as tumors, neonatal malformations, sexually transmitted diseases, as well as pose an immense threat to the human health. The cGAS-STING pathway is one of the innate immune pattern-recognition receptors discovered recently. This article discusses the role of the cGAS-STING pathway in human diseases, especially in human herpesvirus infections, as well as highlights how these viruses act on this pathway to evade the host immunity. Moreover, the author provides a comprehensive overview of modulators of the cGAS-STING pathway. By focusing on the small molecule compounds based on the cGAS-STING pathway, novel targets and concepts have been proposed for the development of antiviral drugs and vaccines, while also providing a reference for the investigation of disease models related to the cGAS-STING pathway. HHV is a double-stranded DNA virus that can trigger the activation of intracellular DNA sensor cGAS, after which the host cells initiate a cascade of reactions that culminate in the secretion of type I interferon to restrict the viral replication. Meanwhile, the viral protein can interact with various molecules in the cGAS-STING pathway. Viruses can evade immune surveillance and maintain their replication by inhibiting the enzyme activity of cGAS and reducing the phosphorylation levels of STING, TBK1 and IRF3 and suppressing the interferon gene activation. Activators and inhibitors of the cGAS-STING pathway have yielded numerous promising research findings in vitro and in vivo pertaining to cGAS/STING-related disease models. However, there remains a dearth of small molecule modulators that have been successfully translated into clinical applications, which serves as a hurdle to be overcome in the future.