CEP120-mediated KIAA0753 recruitment onto centrioles is required for timely neuronal differentiation and germinal zone exit in the developing cerebellum.

Joubert syndrome (JS) is a recessive ciliopathy in which all affected individuals have congenital cerebellar vermis hypoplasia. Here, we report that CEP120, a JS-associated protein involved in centriole biogenesis and cilia assembly, regulates timely neuronal differentiation and the departure of granule neuron progenitors (GNPs) from their germinal zone during cerebellar development. Our results show that depletion of Cep120 perturbs GNP cell cycle progression, resulting in a delay of cell cycle exit in vivo. To dissect the potential mechanism, we investigated the association between CEP120 interactome and the JS database and identified KIAA0753 (a JS-associated protein) as a CEP120-interacting protein. Surprisingly, we found that CEP120 recruits KIAA0753 to centrioles, and that loss of this interaction induces accumulation of GNPs in the germinal zone and impairs neuronal differentiation. Importantly, the replenishment of wild-type CEP120 rescues the above defects, whereas expression of JS-associated CEP120 mutants, which hinder KIAA0753 recruitment, does not. Together, our data reveal a close interplay between CEP120 and KIAA0753 for the germinal zone exit and timely neuronal differentiation of GNPs during cerebellar development, and mutations in CEP120 and KIAA0753 may participate in the heterotopia and cerebellar hypoplasia observed in JS patients.

Hydrogen Spillover Induced PtCo/CoOx Interfaces with Enhanced Catalytic Activity for CO Oxidation at Low Temperatures in Humid Conditions.

The development of catalysts with abundant active interfaces for superior low-temperature catalytic CO oxidation is critical to meet increasingly rigorous emission requirements, yet still challenging. Herein, this work reports a PtCo/CoOx/Al2O3 catalyst with PtCo clusters and enriched Pt─O─Co interfaces induced by hydrogen spillover from the Pt sites and self-oxidation process in air, exhibiting excellent performance for CO oxidation at low temperatures and humid conditions. The combination of structural characterizations and in situ Fourier transform infrared spectroscopy reveals that the PtCo cluster effectively prevents CO saturation/poisoning on the Pt surface. Additionally, the presence of Pt─O─Co interfaces in the PtCo/CoOx/Al2O3 catalyst provides a significant number of active sites for oxygen activation and ─OH formation. This facilitates efficient generation of CO2 at ambient temperature by coupling with nearby adsorbed CO molecules, resulting in superior low-temperature activity and long-term stability for CO oxidation under humid conditions. This work provides a facile route toward rationalizing the design of catalysts with more active interfaces for superior low-temperature CO oxidation under humid conditions for practical applications.

Ultrashort channel MoSe2transistors with selenium atoms replaced at the interface: first-principles quantum-transport study.

Realizing n- and p-type transition metal dichalcogenide (TMD)-based field-effect transistors for nanoscale complementary metal oxide semiconductor (CMOS) applications remains challenging owing to undesirable contact resistance. Quantumtransport calculations were performed by replacing single-sided Se atoms of TMD near the interface with As or Br atoms to further improve the contact resistance. Here, partial selenium replacement produced a novel interface with a segment of metamaterial MoSeX (Pt/MoSeX/MoSe2; X = As, Br). Such stable metamaterials exhibit semi-metallicity, and the contact resistance can be thus lowered. Our findings provide insights into the potential of MoSe2-based nano-CMOS logic devices.

Mediating Effect of Heart Rate Variability on the Relationship Between Anxiety Symptoms and Blood Pressure in Patients with Primary Hypertension.

Patients with hypertension (HTN) are at increased risk of developing cardiovascular disease, which can be reduced with blood pressure (BP) control. Anxiety can contribute to high BP and low heart rate variability (HRV). Although relationships between social support, self-rated health-status (SRHS), anxiety and measures of HRV and BP have been suggested, they have not been clearly established. This cross-sectional correlational study aimed to 1) examine relationships between social support, SRHS, and anxiety; and 2) examine if HRV mediated relationships between anxiety symptoms and BP. Patients with primary HTN were recruited from a cardiovascular outpatient clinic using convenience sampling (N = 300). Data included scale scores for SRHS, social support, and anxiety (Hospital Anxiety and Depression Scale). A handheld limb-lead electrocardiogram monitor measured HRV, using the ratio of low-frequency bands to high-frequency bands; an automatic sphygmomanometer measured systolic and diastolic blood pressure (SBP and DBP, respectively). Path analysis of structural equation models examined relationships between variables; the bootstrap method examined the mediating effects of HRV. Analysis showed scores for SRHS and social support had a direct effect on anxiety scores. Scores for anxiety directly affected HRV and BP. HRV also had a direct effect on BP. Bootstrapping indicated HRV mediated the relationship between anxiety symptoms and BP. The final model indicated SRHS, social support, and anxiety symptoms together explained 80% of SBP and 33% of DBP. These findings suggest HRV could be used to measure the effectiveness of strategies aimed at reducing anxiety and improving control of BP.

Translation, adaptation, and validation of a Chinese version of the Hypertension Self-Care Activity Level effects (H-SCALE) for patients with hypertension.

BACKGROUND: Lifestyle modification is an essential component of prevention and management of hypertension. Existing instruments in Taiwan focus on assessing lifestyle modifications by evaluating medication adherence or confidence in controlling blood pressure. However, other self-care activities, such as diet, physical activity, weight management, smoking, and alcohol consumption are also important. The Hypertension Self-Care Activity Level Effects (H-SCALE) is one such instrument, but there are no similar tools available in Taiwan. AIM: This study aimed to translate the H-SCALE into Chinese and test its validity, and reliability in a sample of adults with hypertension. METHODS: The English version of the 31-item H-SCALE was translated into Chinese using the forward-backward method. The content validity index (CVI) of the translated scale was determined by five experts in hypertension. Item analysis was conducted with a pilot sample of 20 patients with hypertension. Cronbach's α was used to establish the internal consistency reliability for the Chinese version of the H-SCALE (H-SCALE-C). Exploratory factor analysis (EFA) explored the structure of the H-SCALE-C. Additionally, construct validity was examined with confirmatory factor analysis (CFA). Patients with hypertension were recruited by convenience sampling from a cardiovascular outpatient clinic of a medical center in northern Taiwan. A total of 318 patients met the inclusion criteria and participated in factor analysis in the study. RESULTS: Pilot testing of the scale items indicated most patients could not accurately estimate the number of days of alcohol consumption for the previous week. Therefore, three alcohol-related items were removed. The adaptation resulted in a 28-item H-SCALE-C. EFA revealed a 4-factor solution with 13 items that explained 63.93% of the total variance. CFA indicated a good fit for a 4-factor model and construct validity was acceptable. Internal consistency reliability was acceptable (Cronbach's alpha for the four subscales ranged from 0.65 to 0.94). Convergent validity was acceptable, and discriminant validity was significant. CONCLUSIONS: The H-SCALE-C is a valid, reliable tool for promptly assessing life-style activities for patients with hypertension in Taiwan. The instrument is suitable for assisting healthcare providers in evaluating self-care activities, which could be used to facilitate lifestyle modifications for patients with hypertension.

Enhancingß-Ga2O3-film ultraviolet detectors via RF magnetron sputtering with seed layer insertion onc-plane sapphire substrate.

Gallium oxide (Ga2O3) possesses a band gap of approximately 4.9 eV, aligning its detection wavelength within the solar-blind region, making it an ideal semiconductor material for solar-blind photodetectors. This study aims to enhance the performance of Ga2O3ultraviolet (UV) detectors by pre-depositing a Ga2O3seed layer on ac-plane sapphire substrate. The x-ray diffraction and x-ray photoelectron spectroscopy analyses validated that the deposited films, following high-temperature annealing, comprisedß-Ga2O3. Comparing samples with and without a 20 nm seed layer, it was found that the former exhibited fewer oxygen defects and substantially improved crystal quality. The incorporation of the seed layer led to the realization of detectors with remarkably low dark current (≤15.3 fA). Moreover, the photo-to-dark current ratio was enhanced by 30% (surpassing 1.3 × 104) and the response/recovery time reduced to 0.9 s/0.01 s, indicating faster performance. Furthermore, these detectors demonstrated higher responsivity (4.8 mA W-1), improved detectivity (2.49 × 1016Jones), and excellent solar-blind characteristics. This study serves as a foundational stepping toward achieving high-qualityß-Ga2O3thin film and UV detector arrays.

Quenching-Induced Defect-Rich Platinum/Metal Oxide Catalysts Promote Catalytic Oxidation.

Enhancing oxygen activation through defect engineering is an effective strategy for boosting catalytic oxidation performance. Herein, we demonstrate that quenching is an effective strategy for preparing defect-rich Pt/metal oxide catalysts with superior catalytic oxidation activity. As a proof of concept, quenching of α-Fe2O3 in aqueous Pt(NO3)2 solution yielded a catalyst containing Pt single atoms and clusters over defect-rich α-Fe2O3 (Pt/Fe2O3-Q), which possessed state-of-the-art activity for toluene oxidation. Structural and spectroscopic analyses established that the quenching process created abundant lattice defects and lattice dislocations in the α-Fe2O3 support, and stronger electronic interactions between Pt species and Fe2O3 promote the generation of higher oxidation Pt species to modulate the adsorption/desorption behavior of reactants. In situ diffuse reflectance infrared Fourier transform spectroscopy (in situ DRIFTS) characterization studies and density functional theory (DFT) calculations determined that molecular oxygen and Fe2O3 lattice oxygen were both activated on the Pt/Fe2O3-Q catalyst. Pt/CoMn2O4, Pt/MnO2, and Pt/LaFeO3 catalysts synthesized by the quenching method also offered superior catalytic activity for toluene oxidation. Results encourage the wider use of quenching for the preparation of highly active oxidation catalysts.

Measuring Frailty Using Patient-Reported Outcomes (PRO) Data: A Feasibility Study in Patients with Multiple Myeloma.

PURPOSE: The objective of this retrospective study was to determine the feasibility of measuring frailty using patient responses to relevant EORTC QLQ-C30 items as proxy criteria for the Fried Frailty Phenotype, in a cohort of patients with Relapsed/Refractory Multiple Myeloma (RRMM). METHODS: Data were pooled from nine Phase III randomized clinical trials submitted to the FDA for regulatory review between 2010 and 2021, for the treatment of RRMM. Baseline EORTC QLQ-C30 responses were used to derive a patient-reported frailty phenotype (PRFP), based on the Fried definition of frailty. PRFP was assessed for internal consistency reliability, structural validity, and known groups validity. RESULTS: This study demonstrated the feasibility of adapting patient responses to relevant EORTC QLQ-C30 items to serve as proxy Fried frailty criteria. Selected items were well correlated with one another and PRFP as a whole demonstrated adequate internal consistency reliability and structural validity. Known groups analysis demonstrated that PRFP could be used to detect distinct comorbidity levels and distinguish between different functional profiles, with frail patients reporting more difficulty in walking about, washing/dressing, and doing usual activities, as compared to their pre-frail and fit counterparts. Among the 4928 patients included in this study, PRFP classified 2729 (55.4%) patients as fit, 1209 (24.5%) as pre-frail, and 990 (20.1%) as frail. CONCLUSION: Constructing a frailty scale from existing PRO items commonly collected in cancer trials may be a patient-centric and practical approach to measuring frailty. Additional psychometric evaluation and research is warranted to further explore the utility of such an approach.

Time to deterioration of symptoms or function using patient-reported outcomes in cancer trials.

Time-to-event endpoints for patient-reported outcomes, such as time to deterioration of symptoms or function, are frequently used in cancer clinical trials. Although time-to-deterioration endpoints might seem familiar to cancer researchers for being similar to survival or disease-progression endpoints, there are unique considerations associated with their use. The complexity of time-to-deterioration endpoints should be weighed against the information that they add to the tumour, survival, and safety data used to inform the risks and benefits of an investigational drug. Here we use the estimand framework to show how analytical decisions answer different clinical questions of interest, some of which might be uninformative. Challenges including the consideration of intercurrent events, the difficulty in maintaining adequate completion rates, and considerable patient and trial burden from long-term, serial, patient-reported outcome measurements render time to deterioration a problematic approach for widespread use. For trials in which a comparative benefit in symptoms or function is an objective, an analysis at pre-specified relevant timepoints could be a better approach.

US Food and Drug Administration Analysis of Patient-Reported Diarrhea and Its Impact on Function and Quality of Life in Patients Receiving Treatment for Breast Cancer.

OBJECTIVES: Many trials conclude "no clinically meaningful detriment" to health-related quality of life (HRQL) or function between arms, even when notable differential toxicity is observed. Mean change from baseline analyses of function or HRQL can possibly obscure important change in subgroups experiencing symptomatic toxicity. We evaluate the impact of diarrhea, a key treatment arm toxicity, on patient-reported HRQL and functioning in clinical trials submitted to US Food and Drug Administration. METHODS: This study used 4 randomized, breast cancer trials (adjuvant to late-line metastatic) as case examples. Diarrhea, physical functioning (PF), and global health status and quality of life (GHS/QoL) from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 were analyzed at baseline and approximately 3 and 6 months. RESULTS: Generally, patients reporting very much diarrhea at months 3 and 6 had worse PF (9-19 points lower) and GHS/QoL (16-19 points lower) than patients reporting no diarrhea regardless of treatment arm. In the change from baseline analysis, patients reporting very much diarrhea also experienced a greater decrease in PF (6-13 points) and GHS/QoL (6-16 points) versus patients reporting no diarrhea in both arms. CONCLUSIONS: In trials with moderate to large differences in symptomatic toxicity by arm, reporting "no meaningful difference in functioning and HRQL between arms" based on mean change from baseline analysis is insufficient and may obscure important impacts on subgroups experiencing symptomatic adverse events. Additional exploratory analyses with simple data visualizations evaluating functioning or HRQL in patient subgroups experiencing expected symptomatic toxicities can further inform the safety and tolerability of an investigational agent.

Nomogram for prognosis of patients with esophageal squamous cell cancer after minimally invasive esophagectomy established based on non-textbook outcome.

BACKGROUND: Non-textbook outcome (non-TO) represents a new prognostic evaluation index for surgical oncology. The present study aimed to develop new nomograms based on non-TO to predict the mortality and recurrence rate in patients with esophageal squamous cell cancer (ESCC) after minimally invasive esophagectomy (MIE). METHODS: The study involved a retrospective analysis of 613 ESCC patients, from the prospectively maintained database from January 2011 to December 2018. All the included ESCC patients underwent MIE, and they were randomly (1:1) assigned to the training cohort (307 patients) and the validation cohort (306 patients). Kaplan-Meier survival analysis was used to analyze the differences recorded between overall survival (OS) and disease-free survival (DFS). In the case of the training cohort, the nomograms based on non-TO were developed using Cox regression, and the performance of these nomograms was calibrated and evaluated in the validation cohort. RESULTS: Significant differences were recorded for 5-year OS and DFS between non-TO and TO groups (p < 0.05). Multivariate cox analysis revealed that non-TO, intraoperative bleeding, T stage, and N stage acted as independent risk factors that affected OS and DFS (p < 0.05). The results for multivariate regression were used to build non-TO-based nomograms to predict OS and DFS of patients with ESCC, the t-AUC curve analysis showed that the nomograms predicting OS and DFS were more accurate as compared to TNM staging, during the follow-up period in the training cohort and validation cohort. Further, the nomogram score was used to divide ESCC patients into low-, middle-, and high-risk groups and significant differences were recorded for OS and DFS between these three groups (p < 0.001). CONCLUSIONS: Non-TO was identified as an independent prognostic factor for ESCC patients. The nomograms based on non-TO could availably predict OS and DFS in ESCC patients after MIE.

Timing is everything: The importance of patient-reported outcome assessment frequency when characterizing symptomatic adverse events.

OBJECTIVE: Although patient-reported symptoms and side effects are increasingly measured in cancer clinical trials, an appropriate assessment frequency has not yet been established. To determine whether differences in assessment frequency affect the apparent incidence and severity of patient-reported symptoms using two well-established patient-reported outcome measures used within the same clinical trial. METHODS: We examined patient-reported outcome results from AURA3 (NCT02151981), a randomized open-label study comparing Tagrisso (osimertinib) with platinum-based chemotherapy in patients with previously treated estimated glomerular filtration rate/T790M mutation-positive metastatic non-small cell lung cancer. The outcome of interest was the proportion of patients in each arm that reported worsening of nausea, vomiting, fatigue, diarrhea, constipation, and appetite loss from baseline measured using the patient-reported outcome-common terminology criteria for adverse event (weekly) or European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (every 6 weeks). RESULTS: Similar trends were observed for all six symptoms investigated. Using nausea in the chemotherapy arm as an example, 76% of patients reported any worsening from baseline based on weekly patient-reported outcome-common terminology criteria for adverse event assessments. When using an every 6-week assessment of Quality of Life Questionnaire Core 30 nausea and restricting analysis to an every 6-week assessment for patient-reported outcome-common terminology criteria for adverse event nausea, the proportion of chemotherapy arm patients reporting any worsening of nausea was 40% for both measures. Across the six patient-reported symptomatic adverse events, we observed differential proportions when comparing frequent versus sparse assessment. CONCLUSION: This analysis demonstrates that more frequent assessment of patient-reported symptomatic adverse events will lead to improved detection, and therefore a more complete understanding of the tolerability of experimental anti-cancer therapies.

Safety and efficacy of pharmacotherapy containing INSTIs and chemotherapy drugs in people living with HIV and concomitant colorectal cancer.

BACKGROUND: Previous clinical data have shown that raltegravir-based antiretroviral therapy (ART) with fewer drug-drug interactions (DDIs) and adverse events (AEs) is a good regimen in patients with HIV infection who need cancer chemotherapy. There are currently few data on ART regimens that include Integrase inhibitors (INSTIs) other than RAL among this patient subgroup. METHODS: We evaluated the safety and efficacy of different kinds of INSTI-based regimens among patients with HIV and concomitant colorectal cancer (CRC) who received antineoplastic agents. RESULTS: From January 2020 to November 2021, 66 patients were enrolled. The patients were divided into three groups: 20 patients treated with dolutegravir (DTG)/lamivudine (3TC)/tenofovir (TDF) (group I), 24 patients treated with DTG/albuvirtide (ABT) (group II), and 22 patients treated with bictegravir (BIC)/tenofovir alafenamide (TAF)/emtricitabine (FTC) (group III). The majority of AEs during treatment were of grade 1-2. Treatment-related AEs of grade 3-4 occurred in 6 patients (9.09%), and no grade 5 AEs occurred. The most common AEs were nausea (100%) and neutrophils (84.85%) attributed to anticancer agents, and there was no significant difference in the incidence of these AEs among the three groups (P > 0.05). Viral load rebound was not observed among pretreated patients during chemotherapy. The viral load of untreated patients who started their ART concomitant with chemotherapy almost decreased to the lower limit of detection 6 months after ART initiation (only one patient in group III had a viral load of 102 copies/ml). At the 6th month, the CD4 count in group I decreased significantly from baseline (P < 0.05). However, the change in CD4 count was not significant in group II (P = 0.457) or group III (P = 0.748). CONCLUSIONS: DTG- or BIC-containing regimens are good options for patients with HIV and concomitant CRC.

A web-based self-care program to promote healthy lifestyles and control blood pressure in patients with primary hypertension: A randomized controlled trial.

BACKGROUND: Hypertension is a major risk factor for cardiovascular diseases, which contributes to the worldwide mortality rate. Successful blood pressure control requires adherence to medications and lifestyle modifications. However, motivating patients with primary hypertension to change and sustain behaviors long-term is challenging. A web-based self-care program centered on self-efficacy theory could provide feedback for effective control of blood pressure. PURPOSE: To examine the effect of a web-based self-care program for patients with primary hypertension on cardiovascular risk-factors (pulse pressure and lipids), self-efficacy, and self-care behaviors (medication adherence and lifestyle). DESIGN: A two-armed randomized controlled trial with 3-month and 6-month follow-ups. SETTING AND PARTICIPANTS: A total of 222 patients with primary hypertension were recruited between February 2017 and August 2018 at a cardiology clinic of a medical center in Taipei, Taiwan. METHODS: Eligible patients were randomized by permuted block randomization into the intervention group (n = 111) and control group (n = 111). Patients in the intervention group received a 6-month web-based self-care program, based on the theory of self-efficacy, while patients in the control group received usual care. Baseline and outcome measures (3 and 6 months) included self-efficacy, evaluated with the Chinese version of the 6-item Self-Efficacy for Managing Chronic Diseases (SEMC6), self-care, using subscales of the Hypertension Self-Care Activity Level Effects Scale (H-SCALE) for lifestyle and medication adherence, and blood pressure and serum lipid data, collected through web-based self-reports and chart review. Generalized estimating equations evaluated the effects of the intervention. FINDINGS: At baseline, the control group had higher scores on the SEMC6, and lower cholesterol (HDL) compared with the intervention group (t = -2.70, p < 0.05; and t = 1.76, p < 0.05, respectively). Pulse pressure decreased significantly (ß = -20.30, 95% CI -23.76, -16.83), and serum triglycerides and low-density lipoprotein cholesterol levels were significantly lower compared with controls at 6 months (all p < 0.001). At 6 months, the intervention group had significantly higher mean scores for the SEMC6 compared with the control group (ß = 21.84, 95% confidence interval [CI] 19.25, 24.42) and H-SCALE subscale for medication adherence, diet, weight management, and physical activity compared with controls at 6 months (all, p < 0.001). CONCLUSIONS AND CLINICAL RELEVANCE: The greatest benefit of this program was allowing participants to immediately consult with the researchers about self-care issues via the website. Lifestyles vary from person to person; therefore, the individuality of each participant was considered when providing feedback. We provided devising interventions for participants that would increase their confidence in self-care for hypertension and ultimately achieve home blood pressure control. We encourage incorporating this program into standard clinical care for patients with hypertension.

A tool for analyzing and visualizing ribo-seq data at the isoform level.

BACKGROUND: Translational regulation is one important aspect of gene expression regulation. Dysregulation of translation results in abnormal cell physiology and leads to diseases. Ribosome profiling (RP), also called ribo-seq, is a powerful experimental technique to study translational regulation. It can capture a snapshot of translation by deep sequencing of ribosome-protected mRNA fragments. Many ribosome profiling data processing tools have been developed. However, almost all tools analyze ribosome profiling data at the gene level. Since different isoforms of a gene may produce different proteins with distinct biological functions, it is advantageous to analyze ribosome profiling data at the isoform level. To meet this need, previously we developed a pipeline to analyze 610 public human ribosome profiling data at the isoform level and constructed HRPDviewer database. RESULTS: To allow other researchers to use our pipeline as well, here we implement our pipeline as an easy-to-use software tool called RPiso. Compared to Ribomap (a widely used tool which provides isoform-level ribosome profiling analyses), our RPiso (1) estimates isoform abundance more accurately, (2) supports analyses on more species, and (3) provides a web-based viewer for interactively visualizing ribosome profiling data on the selected mRNA isoforms. CONCLUSIONS: In this study, we developed RPiso software tool ( http://cosbi7.ee.ncku.edu.tw/RPiso/ ) to provide isoform-level ribosome profiling analyses. RPiso is very easy to install and execute. RPiso also provides a web-based viewer for interactively visualizing ribosome profiling data on the selected mRNA isoforms. We believe that RPiso is a useful tool for researchers to analyze and visualize their own ribosome profiling data at the isoform level.

A novel naphthalimide derivative reduces platelet activation and thrombus formation via suppressing GPVI.

Naphthalimide derivatives have multiple biological activities, including antitumour and anti-inflammatory activities. We previously synthesized several naphthalimide derivatives; of them, compound 5 was found to exert the strongest inhibitory effect on human DNA topoisomerase II activity. However, the effects of naphthalimide derivatives on platelet activation have not yet been investigated. Therefore, the mechanism underlying the antiplatelet activity of compound 5 was determined in this study. The data revealed that compound 5 (5-10 µM) inhibited collagen- and convulxin- but not thrombin- or U46619-mediated platelet aggregation, suggesting that compound 5 is more sensitive to the inhibition of glycoprotein VI (GPVI) signalling. Indeed, compound 5 could inhibit the phosphorylation of signalling molecules downstream of GPVI, followed by the inhibition of calcium mobilization, granule release and GPIIb/IIIa activation. Moreover, compound 5 prevented pulmonary embolism and prolonged the occlusion time, but tended to prolong the bleeding time, indicating that it can prevent thrombus formation but may increase bleeding risk. This study is the first to demonstrate that the naphthalimide derivative compound 5 exerts antiplatelet and antithrombotic effects. Future studies should modify compound 5 to synthesize more potent and efficient antiplatelet agents while minimizing bleeding risk, which may offer a therapeutic potential for cardiovascular diseases.

Septin 7 is a centrosomal protein that ensures S phase entry and microtubule nucleation by maintaining the abundance of p150glued.

Septins play important roles in regulating development and differentiation. Septin 7 (SEPT7) is a crucial component in orchestrating the septin core complex into highly ordered filamentous structures. Here, we showed that genetic depletion of SEPT7 or treatment with forchlorfenuron (FCF; a compound known to affect septin filament assembly) led to reduced the S phase entry in cell models and zebrafish embryos. In addition to colocalizing with actin filaments, SEPT7 resided in the centrosome, and SEPT7 depletion led to aberrant mitotic spindle pole formation. This mitotic defect was rescued in SEPT7-deficient cells by wild-type SEPT7, suggesting that SEPT7 maintained mitotic spindle poles. In addition, we observed disorganized microtubule nucleation and reduced cell migration with SEPT7 depletion. Furthermore, SEPT7 formed a complex with and maintained the abundance of p150glued , the component of centriole subdistal appendages. Depletion of p150glued resulted in a phenotype reminiscent of SEPT7-deficient cells, and overexpression of p150glued reversed the defective phenotypes. Thus, SEPT7 is a centrosomal protein that maintains proper cell proliferation and microtubule array formation via maintaining the abundance of p150glued .

Identification of glomerular lesions and intrinsic glomerular cell types in kidney diseases via deep learning.

Identification of glomerular lesions and structures is a key point for pathological diagnosis, treatment instructions, and prognosis evaluation in kidney diseases. These time-consuming tasks require a more accurate and reproducible quantitative analysis method. We established derivation and validation cohorts composed of 400 Chinese patients with immunoglobulin A nephropathy (IgAN) retrospectively. Deep convolutional neural networks and biomedical image processing algorithms were implemented to locate glomeruli, identify glomerular lesions (global and segmental glomerular sclerosis, crescent, and none of the above), identify and quantify different intrinsic glomerular cells, and assess a network-based mesangial hypercellularity score in periodic acid-Schiff (PAS)-stained slides. Our framework achieved 93.1% average precision and 94.9% average recall for location of glomeruli, and a total Cohen's kappa of 0.912 [95% confidence interval (CI), 0.892-0.932] for glomerular lesion classification. The evaluation of global, segmental glomerular sclerosis, and crescents achieved Cohen's kappa values of 1.0, 0.776, 0.861, and 95% CI of (1.0, 1.0), (0.727, 0.825), (0.824, 0.898), respectively. The well-designed neural network can identify three kinds of intrinsic glomerular cells with 92.2% accuracy, surpassing the about 5-11% average accuracy of junior pathologists. Statistical interpretation shows that there was a significant difference (P value < 0.0001) between this analytic renal pathology system (ARPS) and four junior pathologists for identifying mesangial and endothelial cells, while that for podocytes was similar, with P value = 0.0602. In addition, this study indicated that the ratio of mesangial cells, endothelial cells, and podocytes within glomeruli from IgAN was 0.41:0.36:0.23, and the performance of mesangial score assessment reached a Cohen's kappa of 0.42 and 95% CI (0.18, 0.69). The proposed computer-aided diagnosis system has feasibility for quantitative analysis and auxiliary recognition of glomerular pathological features. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Platycodin D (PD) regulates LncRNA-XIST/miR-335 axis to slow down bladder cancer progression in vitro and in vivo.

Recently, increasing evidences indicated that Platycodin D (PD) served as an effective anti-tumor drug for cancer treatment in clinic. However, the molecular mechanisms are still unclear. In the present study, we proved that PD regulated LncRNA-XIST/miR-335 axis to hamper the development of bladder cancer in vitro and in vivo. Mechanistically, PD inhibited malignant phenotypes, including cell proliferation, invasion, migration and epithelial-mesenchymal transition (EMT), and promoted cell apoptosis in bladder cancer cells in a time- and dose-dependent manner. In addition, the following experiments validated that PD inhibited LncRNA-XIST expressions, while increased miR-335 expression levels in bladder cancer cells. Next, by conducting the dual-luciferase reporter gene system assay and RNA pull-down assay, we validated that LncRNA-XIST inhibited miR-335 expressions through acting as RNA sponges, and the promoting effects of PD stimulation on miR-335 levels were abrogated by upregulating LncRNA-XIST. Interestingly, both silencing LncRNA-XIST and miR-335 overexpression enhanced the inhibiting effects of PD on the malignant phenotypes in bladder cancer cells. Consistently, the xenograft tumor-bearing mice models were established, and the data indicated that PD slowed down tumor growth and inhibited tumorigenesis in vivo, which were also aggravated by downregulating LncRNA-XIST. In general, analysis of data proved that targeting LncRNA-XIST/miR-335 axis was novel to enhance the anti-tumor effects of PD in bladder cancer in vitro and in vivo, and this study provided alternative therapeutic strategies for bladder cancer treatment in clinic.

Minocycline for symptom reduction in patients with multiple myeloma during maintenance therapy: a phase II placebo-controlled randomized trial.

BACKGROUND: Patients with multiple myeloma (MM) experience substantial cancer/treatment-related symptom burden during maintenance therapy. This is a phase II randomized, double-blinded, placebo-controlled clinical trial to examine the effect of minocycline for symptom reduction by its potential anti-inflammatory effect. METHODS: Eligible MM patients for maintenance therapy were randomized to receive minocycline (100 mg twice daily) or placebo. The MD Anderson Symptom Inventory for MM (MDASI-MM) was used to assess multiple symptoms weekly during the trial. Clinician-rated toxicities and blood samples were prospectively collected. The effect size, area under the curve (AUC), and t tests were used to determine the symptom burden between treatment groups and identify the 5 most-severe MDASI-MM symptoms. The longitudinal analysis compared the changes in symptom severity and associated inflammatory markers between groups over time. RESULTS: Sixty-nine evaluable MM patients (33 from the intervention group and 36 from the placebo group) were included. No grade 3+ adverse events related to study medication were noted. The AUCs for the 5 worst MDASI-MM symptoms (fatigue, pain, disturbed sleep numbness/tingling, and drowsiness) were not significantly different between two arms. Regardless of group assignment, pain reduction was positively associated with decreased serum levels of soluble tumor necrosis factor-α receptors 1 and 2 during therapy (all P < 0.05). CONCLUSIONS: This pPhase II randomized study observed no statistically significant positive signal impact from minocycline on symptom reduction or inflammatory markers during maintenance therapy for MM, although using minocycline was feasible and had a low toxicity profile.