Simultaneously improving accuracy and computational cost under parametric constraints in materials property prediction tasks.

Modern data mining techniques using machine learning (ML) and deep learning (DL) algorithms have been shown to excel in the regression-based task of materials property prediction using various materials representations. In an attempt to improve the predictive performance of the deep neural network model, researchers have tried to add more layers as well as develop new architectural components to create sophisticated and deep neural network models that can aid in the training process and improve the predictive ability of the final model. However, usually, these modifications require a lot of computational resources, thereby further increasing the already large model training time, which is often not feasible, thereby limiting usage for most researchers. In this paper, we study and propose a deep neural network framework for regression-based problems comprising of fully connected layers that can work with any numerical vector-based materials representations as model input. We present a novel deep regression neural network, iBRNet, with branched skip connections and multiple schedulers, which can reduce the number of parameters used to construct the model, improve the accuracy, and decrease the training time of the predictive model. We perform the model training using composition-based numerical vectors representing the elemental fractions of the respective materials and compare their performance against other traditional ML and several known DL architectures. Using multiple datasets with varying data sizes for training and testing, We show that the proposed iBRNet models outperform the state-of-the-art ML and DL models for all data sizes. We also show that the branched structure and usage of multiple schedulers lead to fewer parameters and faster model training time with better convergence than other neural networks. Scientific contribution: The combination of multiple callback functions in deep neural networks minimizes training time and maximizes accuracy in a controlled computational environment with parametric constraints for the task of materials property prediction.

Platelet-activating factor antagonist-based intensive antiplatelet strategy in acute ischemic stroke: A propensity score matched with network pharmacology analysis.

BACKGROUND: Diterpene ginkgolides meglumine injection (DGMI) is a platelet-activating factor receptor (PAFR) antagonist that can be used to treat acute ischemic stroke (AIS). This study evaluated the efficacy and safety of an intensive antiplatelet strategy based on PAFR antagonists and explored the underlying mechanisms of PAFR antagonists in AIS treatment. METHODS: This is a retrospective study applying propensity score methods to match AIS patients treated with DGMI to nontreated patients. The primary outcome was functional independence (modified Rankin Scale [mRS] 0-2) at 90 days. The safety outcome was bleeding risk. We used McNemar test to compare the efficacy outcome. Subsequently, the network pharmacology analysis was performed. RESULTS: 161 AIS patients treated with DGMI in the study were matched with 161 untreated patients. Compared with untreated patients, DGMI-treated patients had a significantly higher rate of mRS ranking 0-2 at 90 days (82.0% vs. 75.8%, p < 0.001), without increased risk of bleeding. The gene enrichment analysis showed that the overlap genes of DGMI targeted and AIS-related enriched in thrombosis and inflammatory-related signaling pathways. CONCLUSIONS: An intensive antiplatelet strategy of DGMI plus traditional antiplatelet agents is effective in treating AIS and may work by mediating post-stroke inflammation and thrombosis.

A Novel Study on a Generalized Model Based on Self-Supervised Learning and Sparse Filtering for Intelligent Bearing Fault Diagnosis.

Recently, deep learning has become more and more extensive in the field of fault diagnosis. However, most deep learning methods rely on large amounts of labeled data to train the model, which leads to their poor generalized ability in the application of different scenarios. To overcome this deficiency, this paper proposes a novel generalized model based on self-supervised learning and sparse filtering (GSLSF). The proposed method includes two stages. Firstly (1), considering the representation of samples on fault and working condition information, designing self-supervised learning pretext tasks and pseudo-labels, and establishing a pre-trained model based on sparse filtering. Secondly (2), a knowledge transfer mechanism from the pre-training model to the target task is established, the fault features of the deep representation are extracted based on the sparse filtering model, and softmax regression is applied to distinguish the type of failure. This method can observably enhance the model's diagnostic performance and generalization ability with limited training data. The validity of the method is proved by the fault diagnosis results of two bearing datasets.

Association of Body Mass Index and Waist-to-Hip Ratio With Retinal Microvasculature in Healthy Chinese Adults: An Optical Coherence Tomography Angiography Study.

PURPOSE: To investigate the association of body mass index (BMI) and waist-to-hip ratio (WHR) with macular vessel density (VD) and foveal avascular zone (FAZ), using optical coherence tomography angiography (OCTA), in healthy Chinese adults. DESIGN: Cross-sectional study. METHODS: A total of 1555 Chinese adults aged ≥ 50 years with no history of ocular disease were recruited from communities in Guangzhou, China. The OCTA was performed with a 6 × 6 mm macular angiography model. The FAZ of the superficial capillary plexus (SCP), and VD of SCP and deep capillary plexus (DCP) were calculated. Univariable and multivariable linear regression analyses were used to evaluate the effect of BMI and WHR on VD and FAZ. RESULTS: The VD of the SCP increased as BMI increased, with average measurements of 39.30 ± 2.14 for normal, 39.52 ± 2.07 for overweight, and 39.76 ± 2.03 for obesity (P = .001). The VD of the DCP also increased with increasing BMI (P = .009). Multiple regression models confirmed a positive association between generalized obesity and superficial VD in the whole image (ß = 0.350, P = .008), inner circle (ß = 0.431, P = .032), and outer circle (ß = 0.368, P = .005). After adjusting for confounders, tertile 3 of the WHR level was positively associated with superficial VD (ß = 0.472, P = .033) and deep VD (ß = 0.422, P = .034) only in the inner circle. CONCLUSIONS: Generalized obesity was associated with increased superficial VD, while abdominal obesity was associated with increased superficial and deep VD only in the inner circle. Different manifestations of the retinal microvasculature may reflect distinct roles of body composition on macular vessel alterations and disease occurrence.

Identifying and Targeting Prediction of the PI3K-AKT Signaling Pathway in Drug-Induced Thrombocytopenia in Infected Patients Receiving Linezolid Therapy: A Network Pharmacology-Based Analysis.

The pharmacological mechanisms underlying the adverse effects of linezolid on thrombocytopenia have not been conclusively determined. This network pharmacology study aimed at investigating the potential pharmacological mechanisms of linezolid-induced adverse reactions in thrombocytopenia. In this study, target genes for linezolid and thrombocytopenia were compared and analyzed. Overlapping thrombocytopenia-associated targets and predicted targets of linezolid were imported to establish protein-protein interaction networks. Gene Ontology and the Kyoto Encyclopedia of Genes and Genome pathway enrichment analyses were performed to determine the enriched biological terms and pathways. The mechanisms involved in linezolid-induced thrombocytopenia were established to be associated with various biological processes, including T cell activation, peptidyl serine modification, and peptidyl serine phosphorylation. The top five relevant protein targets were obtained, including ALB, AKT1, EGFR, IL6, and MTOR. Enrichment analysis showed that the targets of linezolid were positively correlated with T cell activation responses. The mechanism of action of linezolid was positively correlated with the PI3K-AKT signaling pathway and negatively correlated with the Ras signaling pathway. We identified the important protein targets and signaling pathways involved in linezolid-induced thrombocytopenia in anti-infection therapy, providing new information for subsequent studies on the pathogenesis of drug-induced thrombocytopenia and potential therapeutic strategies for rational use of linezolid in clinical settings.

Efficacy and Safety of Combination Antifungals as Empirical, Preemptive, and Targeted Therapies for Invasive Fungal Infections in Intensive-Care Units.

Purpose: To determine whether combinations of antifungal drugs are effective and safe for patients in intensive-care units. Methods: This study compared the efficacy and safety of caspofungin (CAS), voriconazole (VOR), amphotericin B liposome (L-AmB), CAS+VOR, and CAS+L-AmB as empirical, preemptive, and targeted therapies for invasive fungal infection (IFI). Results: Comparing the CAS, VOR, and CAS+VOR groups revealed that there were no differences in response rates between all therapy types, IFI-associated death within 90 days was less common in the CAS+VOR group (1.8%) than the VOR group (14.3%), and there were more adverse events in the VOR group than in the CAS group (P < 0.05). For empirical or preemptive therapy, the CAS group had a better response rate (80.0%) than the CAS+VOR group (47.1%), and there were more adverse events in the VOR group than in the CAS group (P < 0.05). For targeted therapy, no differences were found for efficacy and safety. There were no differences among the CAS, L-AmB, and CAS+L-AmB groups in efficacy and safety. Conclusion: Patients who received CAS monotherapy as an empirical or preemptive therapy could achieve good outcomes. Patients who received CAS+VOR or CAS+L-AmB achieved almost the same outcomes when compared with those who received CAS, VOR, and L-AmB monotherapy as targeted therapies, but those who received CAS+VOR had a lower IFI mortality rate than did those who received VOR monotherapy.

Predictive value of longitudinal changes of serum matrix metalloproteinase-9 and brain-derived neurotrophic factor in acute ischemic stroke.

Background: Matrix metalloproteinase-9 (MMP-9) and brain-derived neurotrophic factor (BDNF) have documented roles in the inflammatory injury cascade of neurovascular units following ischemic brain injury. However, their dynamic changes and predictive values after acute ischemic stroke (AIS) have not been well elucidated. Objective: To investigate the temporal profiles of serum MMP-9 and BDNF concentrations and their relationship with the prognosis in patients with AIS. Methods: MMP-9 and BDNF levels were measured in 42 AIS patients in prospectively collected blood samples, which were taken on the first day (Day 1), the second day (Day 2), and the fifth day (Day 5) after admission. Healthy subjects (n = 40) were used as controls. The AIS patients were divided into groups of good functional prognosis (n = 24) and poor prognosis (n = 18) according to their modified Rankin Scale score at 3 months. Longitudinal analysis of MMP-9 and BDNF and their association with neurological prognosis was performed using repeated measurement ANOVA. Results: At baseline (Day 1), the levels of serum MMP-9 and BDNF were significantly higher in the AIS group than in the normal control group (P < 0.01). Repeated measurement ANOVA showed a significant main effect and interaction of MMP-9 between good prognosis and the poor group (P < 0.05). Further simple-effect analysis showed that the MMP-9 level was significantly increased in the poor prognosis group compared with the good prognosis group at T5 (P < 0.05). There were no significant time-dependent or the interaction effect (all P > 0.05), but a main effect (P < 0.05) for BDNF. Compared with the poor prognosis group, the simple-effect results indicated that the BDNF level of the good prognosis group was lower at Day 1, while the same was reversed for expression at Day 5 (P < 0.05). Conclusion: MMP-9 and BDNF are closely related to the prognosis of patients with AIS in a time-dependent manner. The dynamic changes of the two biomarkers are superior to baseline levels in predicting the prognosis of AIS patients. A sustained decrease in MMP-9 and an increase in BDNF levels in AIS patients after several days of treatment implied a favourable prognosis.

Subsequent malaria enhances virus-specific T cell immunity in SIV-infected Chinese rhesus macaques.

BACKGROUND: Coinfection with HIV and Plasmodium parasites is fairly common, but the sequence of infection with these two pathogens and their impact on disease progression are poorly understood. METHODS: A Chinese rhesus macaque HIV and Plasmodium coinfection model was established to compare the impact of pre-existing and subsequent malaria on the progression of SIV infection. RESULTS: We found that a pre-existing malaria caused animals to produce a greater number of CD4+CCR5+ T cells for SIV replication, resulting in higher viral loads. Conversely, subsequent malaria induced a substantially larger proportion of CD4+CD28highCD95high central memory T cells and a stronger SIV-specific T cell response, maintained the repertoire diversity of SIV-specific T cell receptors, and generated new SIV-specific T cell clonotypes to trace SIV antigenic variation, resulting in improved survival of SIV-infected animals. CONCLUSION: The complex outcomes of this study may have important implications for research on human HIV and malaria coinfection. The infection order of the two pathogens (HIV and malaria parasites) should be emphasized. Video abstract.

Differential Effect of Generalized and Abdominal Obesity on the Development and Progression of Diabetic Retinopathy in Chinese Adults With Type 2 Diabetes.

Background: The relationship between obesity and diabetic retinopathy (DR) remains controversial. The aim of this study was to assess the association of generalized obesity [assessed by body mass index (BMI)] and abdominal obesity [assessed by waist to hip ratio (WHR)] with incident DR, and vision-threatening DR (VTDR), and DR progression among Chinese adults with type 2 diabetic mellitus (T2DM). Method: This prospective cohort study was conducted at the Zhongshan Ophthalmic Center, from November 2017 to December 2020. DR was assessed based on the 7-filed fundus photographs using the modified Airlie House Classification. Multivariable logistic regression models were used to evaluate the associations of BMI and WHR with the development and progression of DR after adjusting for age, sex, traditional risk factors, and mutually for BMI and WHR. Results: Among the 1,370 eligible participants, 1,195 (87.2%) had no sign of any DR and 175 (12.8%) had DR at baseline examination. During the 2 years follow-up visit, 342 (28.6%) participants had incident DR, 11 (0.8%) participants developed VTDR, 15 (8.6%) demonstrated DR progression. After adjusting for confounders, the BMI was negatively associated with incident DR [relative risk (RR) =0.31; 95% confidence interval (CI), 0.26-0.38; P < 0.001] and incident VTDR (RR = 0.22; 95%CI, 0.11-0.43; P < 0.001), while WHR was positively associated with incident DR (RR = 1.47; 95% CI, 1.27-1.71; P < 0.001). BMI and WHR level were not significantly associated with 2-year DR progression in multivariate models (all P > 0.05). Conclusions: This study provides longitudinal evidence that generalized obesity confer a protective effect on DR, while abdominal obesity increased the risk of DR onset in Chinese patients, indicating that abdominal obesity is a more clinically relevant risk marker of DR than generalized obesity.

Pharmacokinetic/Pharmacodynamic Target Attainment of Different Antifungal Agents in De-escalation Treatment in Critically Ill Patients: a Step toward Dose Optimization Using Monte Carlo Simulation.

Differences in pharmacokinetics/pharmacodynamics (PK/PD) target attainment are rarely considered when antifungals are switched in critically ill patients. This study intends to explore whether the antifungal de-escalation treatment strategy and the new intermittent dosing strategy of echinocandins in critically ill patients are able to achieve the corresponding PK/PD targets. The published population PK models of antifungals in critically ill patients and a public data set from the MIMIC-III database (n = 662) were employed to evaluate PK/PD target attainment of different dosing regimens of antifungals. Cumulative fraction of response (CFR) was calculated for each dosing regimen. Most guideline-recommended dosing regimens of fluconazole and voriconazole could achieve target exposure as de-escalation treatment in critically ill patients. For initial echinocandin treatment, achievement of the target exposure decreased as body weight increased, and the intermittent dosing strategy had a slightly higher CFR value in most simulations compared to conventional dosing strategy. For Candida albicans and Candida glabrata infection, caspofungin at the lowest dose achieved a CFR of >90%, while micafungin or anidulafungin required almost the highest doses simulated in this study to achieve the same effect. None of the echinocandins other than 150 mg every 24 h (q24h) or 200 mg q48h of caspofungin achieved the target CFR for Candida parapsilosis infection. These findings support the guideline-recommended dose of triazoles for antifungal de-escalation treatment and confirm the insufficient dosage of echinocandins in critically ill patients, indicating that a dosing regimen based on body weight or intermittent dosing of echinocandins may be required.

Baseline Objective Malnutritional Indices as Immune-Nutritional Predictors of Long-Term Recurrence in Patients with Acute Ischemic Stroke.

Background: The controlling nutritional status (CONUT) score and the prognostic nutritional index (PNI) score were designed as indicators of patients' immune-nutritional status. This study aimed to investigate the prognostic impact of the CONUT and PNI scores on long-term recurrent ischemic stroke (RIS) and adverse outcomes for adults with acute ischemic stroke (AIS). Methods: This retrospective study enrolled 991 AIS patients. Multivariable Cox regression models were used to assess the relationships of the malnutritional indices and RIS and major cardiovascular events (MACEs). Results: During a median follow-up at 44 months (IQR 39−49 months), 203 (19.2%) patients had RIS and 261 (26.3%) had MACEs. Compared with normal nutritional status, moderate to severe malnutrition was significantly related to an increased risk of RIS in the CONUT score (adjusted hazard ratio (HR) 3.472, 95% confidence interval (CI) 2.223−5.432, p < 0.001). A higher PNI value tertile (tertile two, adjusted HR 0.295, 95% CI 0.202−0.430; tertile three, adjusted HR 0.445, 95% CI 0.308−0.632, all p < 0.001) was related to a lower risk of RIS. Similar results were found for MACEs. The PNI exhibited nonlinear association with the RIS and both two malnutritional indices improved the model's discrimination when added to the model with other clinical risk factors. Conclusions: This study demonstrated that the CONUT and PNI are promising, straightforward screening indicators to identify AIS patients with impaired immune-nutritional status at higher risk of long-term RIS and MACEs.

Potentially Hazardous Drug-Drug Interactions Associated With Oral Antineoplastic Agents Prescribed in Chinese Tertiary Care Teaching Hospital Settings: A Multicenter Cross-Sectional Study.

Background: Oral administration increases the risk of interactions, because most oral antineoplastic agents (OAAs) are taken on a daily basis. Interactions can increase exposure to antitumoral agents or cause treatment failure. Potential drug-drug interactions (DDIs) are commonly observed in patients with cancer, while the extent to which OAAs related hazardous DDIs remains unclear. Methods: We studied the contraindication patterns between oral antineoplastic agents and other medications among cancer patients in two tertiary care teaching hospitals in China. A total of 20 clinically significant hazardous DDI pairs that involved 30 OAAs were identified based on the predetermined criteria. Patient medications were checked for DDIs by using the US Food and Drug Administration approved labeling. Descriptive statistics and uni- and multivariate logistic regression analyses were carried out. Results: In this study, 13,917 patients were included and a total of 297 DDIs were identified. The results revealed that proton pump inhibitors (PPIs), dexamethasone and fluoroquinolones were the most often involved hazardous DDIs with OAAs. The most prevalent contraindication is the simultaneous use of certain molecular targeted agents and PPIs. In the result of the multivariate analysis, younger age (0-20 group), increasing number of drugs and patient treated with targeted therapy had a higher risk for DDIs. Conclusion: The prevalence of OAAs related hazardous DDIs appears to be low in the cancer patients. However, physicians and clinical pharmacologists should be aware of the potential hazardous DDIs when prescribing OAAs, especially certain pH-dependent molecular targeted agents and potential QTc prolonging drugs.

Effects of residue removal and tillage on greenhouse gas emissions in continuous corn systems as simulated with RZWQM2.

Agricultural production is a major source of carbon dioxide (CO2) and nitrous oxide (N2O) globally. The effects of conservation practices on soil CO2 and N2O emissions remain a high degree of uncertainty. In this study, soil CO2 and N2O emissions under different residue and tillage practices in an irrigated, continuous corn system, were investigated using the Root Zone Water Quality Model (RZWQM2). Combinations of no/high stover removal (NR and HR, respectively) and no-till/conventional tillage (NT and CT, respectively) field experiments were tested over the four crop-years (Apr. 2011-Apr. 2015). The model was calibrated using the NRCT, and validated with other treatments. The simulation results showed that soil volumetric water content (VWC) in the NR treatments (i.e., NRCT and NRNT) was 1.3%-1.9% higher than that in the HR treatments (i.e., HRCT and HRNT) averaged across the four years. A higher amount of CO2 and N2O emissions were simulated in the NRCT across the four years (annual average: 7034 kg C/ha/yr for CO2 and 3.8 kg N/ha/yr for N2O), and lower emissions were in the HRNT (annual average: 6329 kg C/ha/yr and 3.7 kg N/ha/yr for N2O). A long-term simulation (2001-2015) suggested that the CO2 and N2O emissions were closely correlated with the stover removal degree (SRD), tillage, VWC, soil temperature (ST), years in management (Y), and fertilizer application. Stover and tillage practices had cumulative effects on CO2 emissions. The simulated annual CO2 emissions in 1st year from NRCT, NRNT, and HRCT were 7.8%, 0.0%, and 7.7% higher than that from HRNT, respectively; then the emissions in 15th year were 63.6%, 47.7%, and 29.1% higher, respectively. Meanwhile, there were no cumulative effects on N2O emissions. The results also demonstrated that the RZWQM2 is a promising tool for evaluating the long-term effects of CO2 and N2O emissions on different conservation practices.

Interplay between orphan nuclear receptors and androgen receptor-dependent or-independent growth signalings in prostate cancer.

It is well-established that both the initial and advanced growth of prostate cancer depends critically on androgens and thus on the activated androgen receptor (AR) -mediated signaling pathway. The unique hormone-dependent feature of prostate cancer forms the biological basis of hormone or androgen-deprivation therapy (ADT) that aims to suppress the AR signaling by androgen depletion or AR antagonists. ADT still remains the mainstay treatment option for locally advanced or metastatic prostate cancer. However, most patients upon ADT will inevitably develop therapy-resistance and progress to relapse in the form of castration-resistant disease (castration-resistant prostate cancer or CRPC) or even a more aggressive androgen-independent subtype (therapy-related neuroendocrine prostate cancer or NEPC). Recent advances show that besides AR, some ligand-independent members of nuclear receptor superfamily-designated as orphan nuclear receptors (ONRs), as their endogenous physiological ligands are either absent or not yet identified to date, also play significant roles in the growth regulation of prostate cancer via multiple AR-dependent or -independent (AR-bypass) pathways or mechanisms. In this review, we summarize the recent progress in the newly elucidated roles of ONRs in prostate cancer, with a focus on their interplay in the AR-dependent pathways (intratumoral androgen biosynthesis and suppression of AR signaling) and AR-independent pathways or cellular processes (hypoxia, oncogene- or tumor suppressor-induced senescence, apoptosis and regulation of prostate cancer stem cells). These ONRs with their newly characterized roles not only can serve as novel biomarkers but also as potential therapeutic targets for management of advanced prostate cancer.

Correction: Nuclear receptor HNF4α performs a tumor suppressor function in prostate cancer via its induction of p21-driven cellular senescence.

The original version of this Article contained an error in the spelling of the author Chan FL, which was incorrectly given as leung Chan F. This has now been corrected in both the PDF and HTML versions of the Article.

Potential neurotoxicity of 5-hydroxymethylfurfural and its oligomers: widespread substances in carbohydrate-containing foods.

5-Hydroxymethylfurfural (5-HMF) is present in numerous carbohydrate-containing consumer products and is readily converted into two oligomers (II and III) by acid-catalyzed transformations. Previous studies have demonstrated various undesirable effects of 5-HMF at relatively high concentrations. In this study, we demonstrate that 5-HMF and its two oligomers exert neurotoxic effects in vivo and in vitro. All three substances blocked the proliferation of PC12 and HT22 cells at the S or G2-M phase in dose- and time-dependent manners. In addition, [Ca2+]i and reactive oxygen species levels were both significantly increased by treatment with these substances at 100 µM, individually, compared with the control group. Although no motor and cognitive deficits are observed, 5-HMF and III can induce anxiety- and depression-like behavior in adolescent mice at administered doses of 0.15 mg kg-1 and 1.5 mg kg-1in vivo, which are close to or less than the reported 24 h dietary intake of 5-HMF in humans. Together, our findings suggest the need for close monitoring of the content of these substances in food, as well as the need for studies on the effects of long-term exposure to them.

Nuclear receptor ERRα contributes to castration-resistant growth of prostate cancer via its regulation of intratumoral androgen biosynthesis.

Enhanced intratumoral androgen biosynthesis and persistent androgen receptor (AR) signaling are key factors responsible for the relapse growth of castration-resistant prostate cancer (CRPC). Residual intraprostatic androgens can be produced by de novo synthesis of androgens from cholesterol or conversion from adrenal androgens by steroidogenic enzymes expressed in prostate cancer cells via different steroidogenic pathways. However, the dysregulation of androgen biosynthetic enzymes in CRPC still remains poorly understood. This study aims to elucidate the role of the nuclear receptor, estrogen-related receptor alpha (ERRα, ESRRA), in the promotion of androgen biosynthesis in CRPC growth. Methods: ERRα expression in CRPC patients was analyzed using Gene Expression Omnibus (GEO) datasets and validated in established CRPC xenograft model. The roles of ERRα in the promotion of castration-resistant growth were elucidated by overexpression and knockdown studies and the intratumoral androgen levels were measured by UPLC-MS/MS. The effect of suppression of ERRα activity in the potentiation of sensitivity to androgen-deprivation was determined using an ERRα inverse agonist. Results: ERRα exhibited an increased expression in metastatic CRPC and CRPC xenograft model, could act to promote castration-resistant growth via direct transactivation of two key androgen synthesis enzymes CYP11A1 and AKR1C3, and hence enhance intraprostatic production of dihydrotestosterone (DHT) and activation of AR signaling in prostate cancer cells. Notably, inhibition of ERRα activity by an inverse agonist XCT790 could reduce the DHT production and suppress AR signaling in prostate cancer cells. Conclusion: Our study reveals a new role of ERRα in the intratumoral androgen biosynthesis in CRPC via its transcriptional control of steroidogenic enzymes, and also provides a novel insight that targeting ERRα could be a potential androgen-deprivation strategy for the management of CRPC.

CircFOXK2 Promotes Growth and Metastasis of Pancreatic Ductal Adenocarcinoma by Complexing with RNA-Binding Proteins and Sponging MiR-942.

The detailed biological functions of circular RNA (circRNA) are largely unexplored. Using circRNA sequencing, we identified 169 differentially expressed circRNA in pancreatic ductal adenocarcinoma (PDAC) cells compared with nontumor human pancreatic ductal epithelial cells. Among them, circFOXK2 was validated with significant upregulation in PDAC cells and 63% of primary tumors (53 of 84). circFOXK2 promoted cell growth, migration, and invasion and was involved in cell-cycle progression and apoptosis. circFOXK2 contained multiple miRNA binding sites, functioning as a sponge for miR-942, which in turn promoted expression of ANK1, GDNF, and PAX6. A novel and highly specific circRNA-pulldown followed by mass spectrometry analysis identified 94 circFOXK2-interacting proteins, which were involved in cell adhesion, mRNA splicing, and structural molecule activity. Of these, circFOKX2 interactions with YBX1 and hnRNPK enhanced expression of oncogenes NUF2 and PDXK. Knockdown of circFOXK2 reduced binding of YBX1 and hnRNPK to NUF2 and PDXK, in turn decreasing their expression. Collectively, our findings demonstrate that circFOXK2 in complex with YBX1 and hnRNPK promotes expression of oncogenic proteins that contribute to PDAC progression. SIGNIFICANCE: This study reveals a prominent role for the circRNA circFOXK2 in PDAC progression, suggesting that circFOXK2 might be a novel diagnostic marker for PDAC.

Targeting prostate cancer stem-like cells by an immunotherapeutic platform based on immunogenic peptide-sensitized dendritic cells-cytokine-induced killer cells.

BACKGROUND: Autologous cellular immunotherapy or immune enhancement therapy has demonstrated some promising benefits for prostate cancer. T cell-based immunotherapy or sipuleucel-T therapy has yielded certain beneficial responses and a slight improvement on the overall survival of patients with metastatic castration-resistant prostate cancer (mCRPC) as shown in some clinical trials, suggesting that prostate cancer is immunoresponsive. METHODS: In this study, we developed an adaptive cytokine-induced killer cell (CIK)-based immunotherapeutic application targeting the prostate cancer stem-like cells (PCSCs). In this therapeutic platform, dendritic cells (DC) were isolated from the peripheral blood mononuclear cells (PBMCs) and preloaded or sensitized with immunogenic peptides derived from two PCSC-associated cell membrane molecules, CD44 and EpCAM, followed by co-culture with the expanded peripheral blood lymphocyte (PBL)-derived CIK cells. The in vitro cytotoxic activity of DC-activated CIK cells against PCSCs was determined by CCK8 and TUNEL assays, and the in vivo anti-tumor effect of DC-activated CIK cells on prostate cancer xenograft tumors was evaluated in subcutaneous and orthotopic xenograft models. RESULTS: Our results showed that the peptide-sensitized DC-CIK cell preparation manifested significant in vitro cytotoxic activity against the PCSC-enriched prostatospheroids and also in vivo anti-tumor effect against prostate cancer xenografts derived from the PCSC-enriched prostatospheroids. CONCLUSIONS: Together, our established immunogenic peptide-sensitized DC-CIK-based cell preparation platform manifests its potential immunotherapeutic application in targeting the PCSCs and also prostate cancer.

Pharmacokinetic/pharmacodynamic adequacy of polymyxin B against extensively drug-resistant Gram-negative bacteria in critically ill, general ward and cystic fibrosis patient populations.

Dose-limiting nephrotoxicity is a significant side effect of polymyxin B treatment. Only limited clinical studies describe the pharmacodynamics of polymyxin B, with little guidance existing for treatment optimisation against multidrug-resistant Gram-negative bacteria. In this study, differences in the likelihood of achieving efficacious and toxic exposures of polymyxin B for critically ill, general ward and cystic fibrosis (CF) patients were evaluated. The following dosing regimens were tested: maintenance doses of 1, 1.25, 1.5 and 2 mg/kg every 12 h (q12h); and loading doses of 2 mg/kg followed by 1.25 mg/kg q12h and 2.5 mg/kg followed by 1.5 mg/kg q12h. Patient weight notably influenced exposure and the required patient dose. To achieve an optimised exposure with minimal toxicity risk, an empirical polymyxin B dose of 2 mg/kg q12h was required for critically ill patients weighing 50 kg, whereas doses of 1.25 mg/kg q12h and 1 mg/kg q12h were required for those weighing 75 kg and 100 kg, respectively. Conversely, 2 mg/kg q12h was required for general ward patients weighing 75 kg. For general ward and CF patients weighing 50 kg, the target exposure could not be achieved with any regimen. Furthermore, the likelihood of toxicity was always high for bacteria with minimum inhibitory concentrations (MICs) of ≥2 mg/L. These findings support the use of a loading dose to increase the achievement of polymyxin B target exposures. To improve efficacy, doses should be optimised according to the patient population.