PTPRO inhibits LPS-induced apoptosis in alveolar epithelial cells.

Acute lung injury (ALI) and its severe manifestation, acute respiratory distress syndrome (ARDS), represent critical clinical syndromes with multifactorial origins, notably stemming from sepsis within intensive care units (ICUs). Despite their high mortality rates, no selective cure is available beside ventilation support. Apoptosis plays a complex and pivotal role in the pathophysiology of acute lung injury. Excessive apoptosis of alveolar epithelial and microvascular endothelial cells can lead to disruption of lung epithelial barrier integrity, impairing the body's ability to exchange blood and gas. At the same time, apoptosis of damaged or dysfunctional cells, including endothelial and epithelial cells, can help maintain tissue integrity and accelerate recovery from organ pro-inflammatory stress. The balance between pro-survival and pro-apoptotic signals in lung injury determines patient outcomes, making the modulation of apoptosis an area of intense research in the quest for more effective therapies. Here we found that protein tyrosine phosphatase receptor type O (PTPRO), a poorly understood receptor-like protein tyrosine phosphatase, is consistently upregulated in multiple tissue types of mice under septic conditions and in the lung alveolar epithelial cells. PTPRO reduction by its selective short-interfering RNA (siRNA) leads to excessive apoptosis in lung alveolar epithelial cells without affecting cell proliferation. Consistently PTPRO overexpression by a DNA construct attenuates apoptotic signaling induced by LPS. These effects of PTPTO on cellular apoptosis are dependent on an ErbB2/PI3K/Akt/NFκB signaling pathway. Here we revealed a novel regulatory pathway of cellular apoptosis by PTPRO in lung alveolar epithelial cells during sepsis.

Self-Guided DMT: Exploring a Novel Paradigm of Dance Movement Therapy in Mixed Reality for Children with ASD.

Children diagnosed with Autism Spectrum Disorder (ASD) often exhibit motor disorders. Dance Movement Therapy (DMT) has shown great potential for improving the motor control ability of children with ASD. However, traditional DMT methods often lack vividness and are difficult to implement effectively. To address this issue, we propose a Mixed Reality DMT approach, utilizing interactive virtual agents. This approach offers immersive training content and multi-sensory feedback. To improve the training performance of children with ASD, we introduce a novel training paradigm featuring a self-guided mode. This paradigm enables the rapid creation of a virtual twin agent of the child with ASD using a single photo to embody oneself, which can then guide oneself during training. We conducted an experiment with the participation of 24 children diagnosed with ASD (or ASD propensity), recording their training performance under various experimental conditions. Through expert rating, behavior coding of training sessions, and statistical analysis, our findings revealed that the use of the twin agent for self-guidance resulted in noticeable improvements in the training performance of children with ASD. These improvements were particularly evident in terms of enhancing movement quality and refining overall target-related responses. Our study holds clinical potential in the field of medical treatment and rehabilitation for children with ASD.

Design, synthesis and biological evaluation of indole-2-carboxylic acid derivatives as novel HIV-1 integrase strand transfer inhibitors.

Integrase plays an important role in the life cycle of HIV-1, and integrase strand transfer inhibitors (INSTIs) can effectively impair the viral replication. However, drug resistance mutations have been confirmed to decrease the efficacy of INSTI during the antiviral therapy. Herein, indole-2-carboxylic acid (1) was found to inhibit the strand transfer of integrase, and the indole nucleus of compound 1 was observed to chelate with two Mg2+ ions within the active site of integrase. Through optimization of compound 1, a series of indole-2-carboxylic acid derivatives were designed and synthesized, and compound 17a was proved to markedly inhibit the effect of integrase, with IC50 value of 3.11 µM. Binding mode analysis of 17a demonstrated that the introduced C6 halogenated benzene ring could effectively bind with the viral DNA (dC20) through π-π stacking interaction. These results indicated that indole-2-carboxylic acid is a promising scaffold for the development of integrase inhibitors.

The arsenic-lowering effect of inulin-type prebiotics in end-stage renal disease: a randomized crossover trial.

Background: Circulatory imbalance of trace elements is frequent in end-stage renal disease (ESRD), leading to a deficiency of essential elements and excess of toxic elements. The present study aimed to investigate whether inulin-type fructans (ITFs) could ameliorate the circulatory imbalance by modulating gut microbiota and regulating the absorption and elimination of trace elements. Methods: Peritoneal dialysis patients were enrolled in a randomized crossover trial, undergoing interventions with ITFs (10 g d-1) and maltodextrin (placebo) over a 9-month period (with a 3-month washout). The primary outcomes included essential elements Mn, Fe, Co, Cu, Zn, Se, Sr, and Mo and potential toxic elements V, Cr, Ni, As, Cd, Ba, Tl, Pb, Th, and U in plasma. Secondary outcomes included the gut microbiome, short chain fatty acids (SCFAs), bile acids (BAs), and daily removal of trace elements through urine, dialysate and feces. Results: Among the 44 participants initially randomized, 29 completed the prebiotic, placebo or both interventions. The daily dietary intake of macronutrients and trace elements remained consistent throughout the study. The administration of 10 g d-1 ITFs significantly reduced plasma arsenic (As) by 1.03 µg L-1 (95%CI: -1.74, -0.33) (FDR-adjusted P = 0.045) down from the baseline of 3.54 µg L-1 (IQRs: 2.61-4.40) and increased the As clearance rate by urine and dialysis (P = 0.033). Positive changes in gut microbiota were also observed, including an increase in the Firmicutes/Bacteroidetes ratio (P = 0.050), a trend towards higher fecal SCFAs (P = 0.082), and elevated excretion of primary BAs (P = 0.035). However, there were no significant changes in plasma concentrations of other trace elements or their daily removal by urine, dialysis and feces. Conclusions: The daily administration of 10 g d-1 ITFs proved to be effective in reducing the circulating retention of As but demonstrated to be ineffective for other trace elements in ESRD. These sentences are ok to include but as "The clinical trial registry number is ChiCTR-INR-17013739 (https://www.chictr.org.cn/showproj.aspx?proj=21228)".

Dietary Polyphenol Intake and Risk of Hypertension: An 18-y Nationwide Cohort Study in China.

BACKGROUND: Although increasing evidence suggests that polyphenol helps regulate blood pressure (BP), evidence from large-scale and long-term population-based studies is still lacking. OBJECTIVES: This study aimed to investigate the association between dietary polyphenol and hypertension risk in the China Health and Nutrition Survey (N = 11,056). METHODS: Food intake was assessed using 3-d, 24-h dietary recalls and household weighing method; polyphenol intake was calculated by multiplying consumption of each food and its polyphenol content. Hypertension was defined as BP ≥ 140/90 mmHg, physicians' diagnosis, or taking antihypertension medications. HR and 95% CI were estimated using mixed-effects Cox models. RESULTS: During 91,561 person-years of follow-up, a total of 3866 participants developed hypertension (35%). The lowest multivariable-adjusted HR (95% CI) of hypertension risk occurred in the third quartile intake, which was 0.63 (0.57, 0.70) for total polyphenol, 0.61 (0.55, 0.68) for flavonoid, 0.62 (0.56, 0.69) for phenolic acid, 0.46 (0.42, 0.51) for lignan, and 0.58 (0.52, 0.64) for stilbene, compared with the lowest quartile. The polyphenol-hypertension associations were nonlinear (all Pnonlinearity < 0.001), and different patterns were observed. U-shaped relations with hypertension were observed for total polyphenol, flavonoid, and phenolic acid, whereas L-shaped associations were observed for lignan and stilbene. Moreover, higher fiber intake strengthened the polyphenol-hypertension association, especially for lignan (P-interaction = 0.002) and stilbene (P-interaction = 0.004). Polyphenol-containing food, particularly vegetables and fruits rich in lignan and stilbene, were significantly associated with lower hypertension risk. CONCLUSIONS: This study demonstrated an inverse and nonlinear association between dietary polyphenol, especially lignan and stilbene, and hypertension risk. The findings provide implications for hypertension prevention.

[CXCL1 induces the contraction of endothelial cytoskeleton and increases permeability in mouse cerebral endothelium bEND.3 cells by promoting protein kinase B phosphorylation].

Objective To investigate the effects of C-X-C motif chemokine ligand 1 (CXCL1) and its receptor CXCR2 on the cerebral endothelial cytoskeleton rearrangement and permeability in the inflammation of septic encephalopathy. Methods The murine model of septic encephalopathy was established by intraperitoneal injection of LPS (10 mg/kg). The levels of TNF-α and CXCL1 in the whole brain tissue were detected by ELISA. The expression of CXCR2 was detected by Western blot analysis after bEND.3 cells were stimulated with 500 ng/mL LPS and 200 ng/mL TNF-α. After treated with CXCL1(150 ng/mL), the changes of endothelial filamentous actin (F-actin) rearrangement in bEND.3 cells were observed by immuno-fluorescence staining. In the cerebral endothelial permeability test, bEND.3 cells were randomly divided into PBS control group, CXCL1 group, and CXCL1 combined with CXCR2 antagonist SB225002 group. Then endothelial transwell permeability assay kit was used to detect the endothelial permeability changes. After stimulated with CXCL1 in bEND.3 cells, Western blot analysis was used to detect the expression of protein kinase B (AKT) and phosphorylated-AKT (p-AKT). Results Intraperitoneal injection of LPS significantly increased the levels of TNF-α and CXCL1 in the whole brain. LPS and TNF-α both upregulated the expression of CXCR2 protein in bEND.3 cells. CXCL1 stimulation induced the endothelial cytoskeleton contraction, increased paracellular gap formation and elevated endothelial permeability in bEND.3 cells, which was inhibited by the pretreatment with SB225002(CXCR2 antagonist). Furthermore, CXCL1 stimulation also enhanced the phosphorylation of AKT in bEND.3 cells. Conclusion CXCL1 induces the cytoskeleton contraction and increased permeability through AKT phosphorylation in bEND.3 cells, which can be effectively inhibited by CXCR2 antagonist SB225002.

The Effect of Inulin-Type Fructans on Plasma Trimethylamine N-Oxide Levels in Peritoneal Dialysis Patients: A Randomized Crossover Trial.

SCOPE: Trimethylamine N-oxide (TMAO), an important proatherogenic uremic toxin, is oxidized by hepatic-flavin monooxygenases from gut microbiome-generated trimethylamine (TMA). The present study aims to explore whether manipulating the gut microbiota by inulin-type fructans (ITFs) can reduce circulating TMAO levels in peritoneal dialysis patients. METHODS AND RESULTS: This is a randomized, double-blind, placebo-controlled, crossover trial with 10 g day-1 ITFs intervention for 3 months in continuous ambulatory peritoneal dialysis patients. The gut microbiome is measured, and TMA-producing gene clusters are annotated using shotgun metagenomic sequencing. Fecal and plasma TMA, plasma TMAO, and daily urine excretion and dialysis removal of TMAO are measured. Finally, 22 participants complete the trial. The daily intake of macronutrients and TMAO precursors is comparable during the prebiotics, washout, and placebo interventions. The ITFs intervention increases the Firmicutes/Bacteroidetes (F/B) ratio (p = 0.049) of gut microbiome. However, no significant influences are observed on fecal TMA content, circulating TMAO levels, or TMA-producing gene clusters, including choline TMA-lyase (CutC/D), carnitine monooxygenase (CntA/B), and betaine reductase (GrdH). CONCLUSIONS: Intervention with 10 g day-1 of ITFs for 3 months is not sufficient to reduce plasma TMAO levels in peritoneal dialysis patients, but it improves the gut microbiome composition.

[Protein tyrosine phosphatase receptor type O (PTPRO) promotes phagocytic activity of alveolar epithelial cells via activating AKT signal pathway in LPS induced acute lung injury].

Objective To investigate the effect of protein tyrosine phosphatase receptor type O (PTPRO) on the phagocytic activity of alveolar epithelial cells in LPS-induced acute lung injury. Methods Mice were randomly divided into the normal control group and LPS stimulation group. The infiltration of inflammatory cells was detected by HE staining. The cytokine TNF-α level in lung was analyzed by ELISA. Western blotting was performed to detect the effect of LPS on PTPRO protein expression in lung. After the expression of PTPRO in MLE-12 cells was silenced by siRNA in vitro, flow cytometry was used to detect the effects of LPS and PTPRO siRNA on the phagocytic activity of MLE-12 cells, and the effects of LPS and PTPRO siRNA on the expression of PTPRO, AKT and phosphorylated AKT protein were measured by Western blotting. Results After the establishment of murine acute lung injury model by LPS injection(1 mg/kg), the infiltrated polymorphonuclear leukocytes were markedly increased. The level of TNF-α in lung tissue and the expression of PTPRO in MLE-12 cells were both significantly increased after LPS stimulation. However, the activity of MLE-12 cells to phagocytose fluorescent microbeads was evidently decreased after silencing PTPRO. Furthermore, silencing PTPRO induced a remarkable decrease in the phosphorylation of AKT in MLE-12 cells. Conclusion PTPRO can promote phagocytic activity of MLE-12 cells via activating AKT signaling pathway.

Sal synthase induced cytotoxicity of PC12 cells through production of the dopamine metabolites salsolinol and N-methyl-salsolinol.

As a catechol isoquinoline, salsolinol (Sal) is widely distributed in mammalian brains, and is increased in the cerebrospinal fluid (CSF) and urine of Parkinsonian patients. Sal can be metabolized to N-methyl-salsolinol (NM-Sal), an MPP+-like neurotoxin, and impairs the function of dopaminergic neurons, causing the clinical symptoms of Parkinson's disease (PD). Sal synthase, which catalyzes the production of Sal from dopamine and acetaldehyde, may be the important enzyme in the metabolism of catechol isoquinolines (CTIQs). Previously, our work demonstrated the existence of Sal synthase in rat brain and identified its amino acid sequence. However, the biological function of Sal synthase has not been thoroughly explored, especially its role in dopaminergic neuronal degeneration. In this study, we tried to clarify the catalytic role of Sal synthase in the formation of CTIQs which are endogenous neurotoxins in the mammalian brain. Furthermore, the cytotoxicity of Sal synthase was also observed in dopaminergic PC12 cells. The results demonstrated that Sal synthase overexpression can increase the level of Sal and NM-Sal, and ultimately cause mitochondria damage and apoptosis.

Increased risk of modality failure with higher serum uric acid level in continuous ambulatory peritoneal dialysis patients: a prospective cohort study.

BACKGROUND: Peritoneal dialysis (PD) is one of the most important kidney replacement therapies for patients with end-stage kidney disease (ESKD). PD technique failure can lead to an escalated cost and increased infectious and cardiovascular risk, up and including to death. The accumulation of uric acid (UA) was associated with adverse outcomes in ESKD patients. However, the relationship between serum UA and technique failure is little explored. METHODS: Here, a total of 266 continuous ambulatory peritoneal dialysis (CAPD) patients (age, 41.8 ± 12.6 years; 125 males) were enrolled and followed up for 31.7 months. Serum UA levels were examined at baseline and each visit. Subjects were divided into three groups according to their baseline serum UA concentrations. Multivariable Cox regression models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of PD technique failure. RESULTS: The level of serum UA increased gradually as time prolonged. During the follow-up period, 77 (28.9%) patients occurred PD technique failure, of which 56 (21.1%) transferred to hemodialysis (HD) and 21 (7.9%) died. Compared to the lowest UA tertile, after adjusting for potential confounders, HRs of technique failure in tertile 2 and tertile 3 were 1.82 (95% CI: 0.95-3.49) and 2.03 (95% CI: 1.05-3.92), respectively, and p for trend was 0.043. Adjusted HRs of all-cause technique failure, transferring to HD and mortality with each 1 mg/dL increase in serum UA were 1.20 (95% CI: 1.03-1.40, p = 0.019), 1.22 (95% CI: 1.01-1.48, p = 0.039), and 1.25 (95% CI: 0.94-1.67, p = 0.128), respectively. CONCLUSION: Higher serum UA level predicted higher risk of technique failure in CAPD patients.

The Accumulation of Gut Microbiome-derived Indoxyl Sulfate and P-Cresyl Sulfate in Patients With End-stage Renal Disease.

OBJECTIVES: Indoxyl sulfate (IS) and p-cresyl sulfate (pCS) are two important gut microbiota-generated protein-bound uremic toxins. The present study aims to explore the alterations of serum IS and pCS concentrations, their production, and daily removal in end-stage renal disease (ESRD). METHODS: A case-controlled study was conducted based on 11 patients with ESRD and 11 healthy volunteers. The metabolic processes for IS and pCS were compared in these two groups, including gut microbiome, fecal indole and p-cresol, indole-producing bacteria and p-cresol-producing bacteria, serum total IS and pCS concentrations, and their daily removal by urine and spent dialyzate. RESULTS: Compared with healthy controls, patients with ESRD exhibited higher relative abundance of the indole-producing bacteria Escherichia coli (P < .001) and Bacteroides fragilis (P = .010) and p-cresol-producing bacteria Bacteroides fragilis (P = .010) and Bacteroides caccae (P = .047). The predicted functional profiles of gut microbiome based on 16S rRNA gene PhyloChip analysis showed that the microbial tryptophan metabolism pathway (map00380, P = .0006) was significantly enriched in patients with ESRD. However, the fecal precursors indole (P = .332) and p-cresol concentrations (P = .699) were comparable between the two groups. The serum IS (P < .001) and pCS (P < .001) concentrations were far higher in patients with ESRD than those in healthy controls, whereas the daily total removal by urine and dialyzate was much lower for the former than that for the latter (P = .019 for IS, P = .016 for pCS). CONCLUSIONS: The present study showed serious IS and pCS accumulation in patients with ESRD, with significant expansion of indole-producing bacteria and p-cresol-producing bacteria, upregulation of the bacterial tryptophan metabolism pathway, and greatly increased serum IS and pCS concentrations, whereas significant decline of daily IS and pCS removal.

Inulin-type prebiotics reduce serum uric acid levels via gut microbiota modulation: a randomized, controlled crossover trial in peritoneal dialysis patients.

PURPOSE: Increased levels of uric acid (UA), which is mainly excreted through the kidneys, are independently associated with higher mortality in end-stage renal disease (ESRD) patients. The uricolysis of gut microbiota plays an important role in extrarenal excretion of UA. This study aimed to examine the effect of inulin-type prebiotics (a type of fermentable dietary fiber) on intestinal microbiota modulation and serum UA levels in ESRD patients. METHODS: Continuous ambulatory peritoneal dialysis (CAPD) patients were recruited to a randomized, double-blind, placebo-controlled crossover trial of 12-week inulin-type prebiotics. Participants were visited before and after treatment with prebiotics or placebo. Serum UA levels, dietary purine intake, serum xanthine oxidase (XO) activity, daily "renal excretion" of UA, and fecal UA degradation capability were measured at each visit. Fecal metagenomic analysis was conducted to assess microbial composition and function. RESULTS: Sixteen participants (mean age = 37 y; 10 men and 6 women) completed the trial, and 64 specimens were analyzed. The average concentration of serum UA decreased by approximately 10% in the prebiotic intervention group in comparison to the placebo group (p = 0.047) without an increase in daily "renal excretion" of UA via urine and dialysate. There were no significant changes in purine intake or activity of XO. Notably, enhanced fecal UA degradation was observed after prebiotic intervention (p = 0.041), and the ratio of Firmicutes/Bacteroidetes, which was positively associated with fecal UA degradation, increased in the prebiotic period (p = 0.032). Furthermore, prebiotics enriched purine-degrading species in the gut microbiota, including unclassified_o_Clostridiales, Clostridium sp. CAG:7, Clostridium sp. FS41, Clostridium citroniae, Anaerostipes caccae, and Clostridium botulinum. CONCLUSIONS: Inulin-type prebiotics is a promising therapeutic candidate to reduce serum UA levels in renal failure patients, and this urate-lowering effect could possibly be attributed to intestinal microbial degradation of UA. TRIAL REGISTRY: This study was registered at the Chinese Clinical Trials Registry ( http://www.chictr.org.cn/ ), registration ID: ChiCTR-INR-17013739, registration date: 6th Dec 2017.

Nutritional predictors associated with malnutrition in continuous ambulatory peritoneal dialysis patients.

BACKGROUND: Currently in China, out of the total dialysis population, approximately 20% represents continuous ambulatory peritoneal dialysis (CAPD) and almost half of CAPD patients was affected by malnutrition. This study aimed to investigate the association between nutritional predictors and malnutrition with 5.1 years of dialysis according to the subjective global assessment (SGA) in continuous ambulatory peritoneal dialysis (CAPD) patients. METHODS: A cross-sectional study was conducted from April 2013 to May 2018 and included 70 CAPD patients. The relationship between anthropometric and biochemical parameters with malnutrition was assessed by multiple logistic regression analysis. RESULTS: The prevalence of malnutrition in CAPD patients was 52.9%. Our result revealed a 7.05-fold increased odds of malnutrition for patients with protein equivalent of total nitrogen appearance normalized to body weight (nPNA) < 1.0 g/kg per day (d) versus patients with normal nPNA (confidence interval (CI) 1.33-37.34; p < 0.05). Patients whose normalized protein catabolic rate (nPCR) was <1.2 g/(kg/d) had a significant positive association with malnutrition versus patients with normal nPCR (adjusted odds ratio (OR) 7.99; p < 0.05). Patients with dietary protein intake (DPI) < 1.0 g/(kg/d) had a higher likelihood of malnutrition than those with normal DPI (OR 12.73; p < 0.05). CAPD patients with upper arm circumference (UAC) < 23.2 cm had a high risk of malnutrition versus patients with normal UAC (OR 12.99; p < 0.05). CONCLUSIONS: Our study suggested a close association between nPNA, DPI, nPCR, and UAC and malnutrition in CAPD patients. Further studies can be warranted the use of these variables as predictors and a malnutrition consequence among Chinese CAPD patients.

The Association of Feeding Practices and Sociodemographic Factors on Underweight and Wasting in Children in Ethiopia: A Secondary Analysis of Four Health Surveys from 2000 to 2016.

BACKGROUND: Feeding practices highly influence the nutritional status of children between 6 and 23 months of age in developing countries, including Ethiopia. Therefore, this study was conducted to investigate the association of feeding practices and sociodemographic factors on underweight and wasting of children aged 6-23 months in Ethiopia. METHODS: Data on 8003 children 6-23 months of age from four Ethiopia demographic and health surveys (EDHS) from 2000 to 2016 were analyzed using complex sample crosstabs for multivariate analysis. The association of feeding practices and sociodemographic factors on underweight and wasting was assessed via multiple logistic regression analyses adjusting the covariates. The outcomes were reported based on the adjusted odds ratios (ORs) with 95% confidence interval (CI). RESULTS: Male children, very small at birth size children, diarrhea and fever, and short stature mother were risk factors for underweight and wasting (p < 0.05-0.001). Also, minimum dietary diversity, rich and middle-income families, vitamin A in the previous 6 months and antenatal care visits during pregnancy were protective factors for both underweight and wasting (p < 0.05-0.001). Minimum meal frequency was significantly related to lower odds of wasting (p < 0.001). Higher age of the child was significantly associated with underweight (p < 0.05-0.001); however, it was less likely wasted (p < 0.05-0.01). CONCLUSION: The present study depicted that among infant young children feeding core indicators except breastfed, all the other indicators did not met the required standard; however, sociodemographic factors on four health surveys from 2000 to 2016 were associated with underweight and wasting in children in Ethiopia. LAY SUMMARY: • Over the years the prevalence of underweight in children aged 6-23 months in the country has shown a significant improvement from 40.2% in 2000 to 34.7% in 2005, then further reduced to 28.9% and 20.0% in 2011 and 2016 EDHS, respectively.• In the same manner, the prevalence of wasting in children aged 6-23 months in Ethiopia also observed improvement from 18.9% in 2000 to 16.7% in 2005, then further reduced to 15.4% and 13.9% in 2011 and 2016 EDHS, respectively.• Male children, very small at birth size children, diarrhea and fever (for the last 2 weeks), and short stature mother were risk factors for underweight and wasting.• Minimum dietary diversity, rich and middle-income families, vitamin A in the previous 6 months and antenatal care visits during pregnancy were protective factors for both underweight and wasting.• Minimum meal frequency was significantly related to lower odds of wasting.• Higher age of the children was significantly associated with underweight; however, less likely wasted.

Casein Kinase 1 Family Member CK1δ/Hrr25 Is Required for Autophagosome Completion.

Autophagy starts with the initiation and nucleation of isolation membranes, which further expand and seal to form autophagosomes. The regulation of isolation membrane closure remains poorly understood. CK1δ is a member of the casein kinase I family of serine/threonine specific kinases. Although CK1δ is reported to be involved in various cellular processes, its role in autophagy is unknown. Here, we show that CK1δ regulates the progression of autophagy from the formation of isolation membranes to autophagosome closure, and is essential for macroautophagy. CK1δ depletion results in impaired autophagy flux and the accumulation of unsealed isolation membranes. The association of LC3 with ATG9A, ATG14L, and ATG16L1 was found to be increased in CK1δ-depleted cells. The role of CK1δ in autophagosome completion appears to be conserved between yeasts and humans. Our data reveal a key role for CK1δ/Hrr25 in autophagosome completion.

Erratum: Analysis of Tau Protein Expression in Predicting Pathological Complete Response to Neoadjuvant Chemotherapy in Different Molecular Subtypes of Breast Cancer.

[This corrects the article on p. 47 in vol. 23, PMID: 32140269.].

Analysis of Tau Protein Expression in Predicting Pathological Complete Response to Neoadjuvant Chemotherapy in Different Molecular Subtypes of Breast Cancer.

PURPOSE: Tau is a microtubule-associated protein that can be found in both normal and abnormal breast cells. Whether the expression of Tau protein can predict the response to neoadjuvant chemotherapy (NACT) is still unclear. In this study, we assessed the role of Tau protein expression in predicting a pathological complete response (pCR) to NACT for different subtypes of breast cancer. METHODS: Four hundred and sixty-eight eligible patients were retrospectively recruited in our study. The relationship between clinicopathologic factors, including Tau protein expression, and pCR in different subtypes was evaluated using logistic regression analysis. Correlation between Tau and disease-free survival (DFS) and overall survival (OS) was performed using Kaplan-Meier analysis. RESULTS: The expression of Tau protein was negatively correlated with pCR, especially in triple-negative breast cancer (TNBC). No significant difference was observed in the luminal human epidermal growth factor receptor-2 (HER2)-negative subtype and HER2-positive subtype. Patients with pCR were associated with better DFS and OS (p < 0.05). However, Tau protein expression had no association with either DFS or OS (p > 0.05). CONCLUSION: Tau protein expression can predict pCR before NACT in TNBC, but there was no correlation between Tau expression and DFS or OS.

Multiparametric MRI-based radiomics analysis for prediction of breast cancers insensitive to neoadjuvant chemotherapy.

PURPOSE: To evaluate the value of multiparametric magnetic resonance imaging (MRI) in pretreatment prediction of breast cancers insensitive to neoadjuvant chemotherapy (NAC). METHODS: A total of 125 breast cancer patients (63 in the primary cohort and 62 in the validation cohort) who underwent MRI before receiving NAC were enrolled. All patients received surgical resection, and Miller-Payne grading system was applied to assess the response to NAC. Grade 1-2 cases were classified as insensitive to NAC. We extracted 1941 features in the primary cohort. After feature selection, the optimal feature set was used to construct a radiomic signature using machine learning. We built a combined prediction model incorporating the radiomic signature and independent clinical risk factors selected by multivariable logistic regression. The performance of the combined model was assessed with the results of independent validation. RESULTS: Four features were selected for the construction of the radiomic signature based on the primary cohort. Combining with independent clinical factors, the combined prediction model for identifying the Grade 1-2 group reached a better discrimination power than the radiomic signature, with an area under the receiver operating characteristic curve of 0.935 (95% confidence interval 0.848-1) in the validation cohort, and its clinical utility was confirmed by the decision curve analysis. CONCLUSION: The combined model based on radiomics and clinical variables has potential in predicting drug-insensitive breast cancers.

Fatigue in Peritoneal Dialysis Patients and an Exploration of Contributing Factors: A Cross-Sectional Study.

CONTEXT: Fatigue is a common and detrimental symptom in dialysis patients; however, our understanding of it and investigation of its contributing factors is still very limited, especially in peritoneal dialysis (PD) patients. OBJECTIVES: To assess fatigue in PD patients and identify contributing factors. METHODS: One hundred eight PD patients in a comprehensive hospital in China were recruited. The fatigue severity of the participants was assessed using the Chalder Fatigue Scale 11. Demographic factors and results of physiological tests were collected. Quality of sleep, mental health, and social support were assessed with the Pittsburgh Sleep Quality Index, Symptom Checklist 90, and Social Support Rating Scale, respectively. Multiple linear regression models were conducted with candidate variables with a P-value of less than 0.1 on univariate analysis and variables that were clinically relevant to identify contributing factors for fatigue. RESULTS: The fatigue level in PD patients was significantly higher than the community population, and 78.7% of them were suffering from fatigue. The factors that were significantly associated with fatigue were quality of sleep, normalized protein nitrogen appearance, transferrin, alkaline phosphatase, and total cholesterol (adjusted R squared 0.86). Among them, quality of sleep, transferrin, alkaline phosphatase, and total cholesterol were significant contributors for physical fatigue, whereas the quality of sleep and normalized protein nitrogen appearance were contributing factors for mental fatigue. CONCLUSION: Fatigue is a common symptom in PD patients, suggesting that increased awareness of this symptom is required. The identification of correlates by extensive exploration of multidimensional factors in this study may help practitioners to identify patients at higher risk and to develop a multidimensional and targeted intervention plan.

Mammography-based radiomic analysis for predicting benign BI-RADS category 4 calcifications.

PURPOSE: We developed and validated a radiomic model based on mammography and assessed its value for predicting the pathological diagnosis of Breast Imaging Reporting and Data System (BI-RADS) category 4 calcifications. MATERIALS AND METHODS: Patients with a total of 212 eligible calcifications were recruited (159 cases in the primary cohort and 53 cases in the validation cohort). In total, 8286 radiomic features were extracted from the craniocaudal (CC) and mediolateral oblique (MLO) images. Machine learning was used to select features and build a radiomic signature. The clinical risk factors were selected from the independent clinical factors through logistic regression analyses. The radiomic nomogram incorporated the radiomic signature and an independent clinical risk factor. The diagnostic performance of the radiomic model and the radiologists' empirical prediction model was evaluated by the area under the receiver operating characteristic curve (AUC). The differences between the various AUCs were compared with DeLong's test. RESULTS: Six radiomic features and the menopausal state were included in the radiomic nomogram, which discriminated benign calcifications from malignant calcifications with an AUC of 0.80 in the validation cohort. The difference between the classification results of the radiomic nomogram and that of radiologists was significant (p < 0.05). Particularly for patients with calcifications that are negative on ultrasounds but can be detected by mammography (MG+/US- calcifications), the identification ability of the radiomic nomogram was very strong. CONCLUSIONS: The mammography-based radiomic nomogram is a potential tool to distinguish benign calcifications from malignant calcifications.