Clinical value of retinol binding protein, C-reactive protein and urine microalbumin in patients with chronic renal disease and ischemic cerebrovascular disease.

OBJECTIVE: To explore the diagnostic value of retinol binding protein (RBP), C-reactive protein (CRP) and urine microalbumin (UMA) for ischemic cerebrovascular disease (ICD) in patients with chronic kidney disease (CKD). METHODS: In this study, a total of 118 patients with CKD were selected and grouped into two groups: a group of patients who were complicated with ICD (CKD+ICD group, n=58), and a group of patients with CKD only (CKD group, n=60). Then, the patients in the CKD+ICD group were further classified into a good prognosis group and a bad prognosis group according their modified Rankin scale score at sixth months after discharge. Serum RBP, CRP and urine UMA levels were compared between the CKD group and CKD+ICD group. The diagnostic efficiency of serum RBP, CRP and urine UMA levels for ICD in patients with CKD was analyzed. The receiver operating characteristic (ROC) curve was used to assess their prognostic performance. Logistic regression analysis was used to evaluate the risk factors for poor prognosis of patients with CKD and ICD. RESULTS: The levels of RBP, CRP, and UMA in the CKD+ICD group were significantly higher than those in the CKD group (all P<0.05). RBP demonstrated the highest diagnostic accuracy and sensitivity for ICD in CKD patients, while CRP and UMA exhibited equivalent specificity, surpassing that of RBP. ROC curves showed that the areas under the curve (AUCs) of RBP and CRP were significantly greater than that of UMA (P<0.05) and there was no significant difference for AUCs between RBP and CRP. In addition, the levels of RBP, CRP and UMA in the poor prognosis group were significantly higher than those in the good prognosis group (all P<0.05). Logistic regression analysis showed that RBP, CRP and UMA were independent risk factors for the poor prognosis of patients with CKD and ICD (Odds ratios =2.507, 3.677 and 1.919, respectively; all P<0.05). CONCLUSION: The assessment of RBP, CRP and UMA is recommended for diagnosis of ICD in CKD patients. RBP, CRP and UMA are independent risk factors for poor prognosis of CKD patients with ICD.

Dapagliflozin promotes browning of white adipose tissue through the FGFR1-LKB1-AMPK signaling pathway.

BACKGROUND: Obesity is associated with a wide variety of metabolic disorders that impose significant burdens on patients and society. The "browning" phenomenon in white adipose tissue (WAT) has emerged as a promising therapeutic strategy to combat metabolic disturbances. However, though the anti-diabetic drug dapagliflozin (DAPA) is thought to promote "browning," the specific mechanism of this was previously unclear. METHODS: In this study, C57BL/6 J male mice were used to establish an obesity model by high-fat diet feeding, and 3T3-L1 cells were used to induce mature adipocytes and to explore the role and mechanism of DAPA in "browning" through a combination of in vitro and in vivo experiments. RESULTS: The results show that DAPA promotes WAT "browning" and improves metabolic disorders. Furthermore, we discovered that DAPA activated "browning" through the fibroblast growth factor receptors 1-liver kinase B1-adenosine monophosphate-activated protein kinase signaling pathway. CONCLUSION: These findings provide a rational basis for the use of DAPA in treating obesity by promoting the browning of white adipose tissue.

Synthesis of Multisubstituted 1,2,3-Triazoles: Regioselective Formation and Reaction Mechanism.

A synthetically useful approach to functionalized triazoles is described via the reaction of ß-carbonyl phosphonates and azides. 1,4- and 1,5-disubstituted and 1,4,5-trisubstituted triazoles can be regio- and chemoselectively accessed under mild conditions in good to excellent yields (31 examples, up to 99%). A mechanism is proposed that rationalizes the avoidance of the 4-phosphonate byproducts, which is aligned with crystallographic and experimental evidence.

Enhancing tube feeding method for neurosurgery: the application of improved PICC technique.

BACKGROUND AND PURPOSE: Peripherally inserted central catheter (PICC) used in neurosurgical patients requires changes in patients' head positions. However, such changes can worsen pressure on the brain tissue, lead to sudden acute brain herniation and respiratory arrest, resulting in a higher chance of patient death. This paper addresses the aforementioned problems by introducing a new PICC catheterization method. METHOD: In a retrospective study, the records of patients with PICC from April 2020 to April 2023 were reviewed, and they were divided into three groups based on the methods employed. The first group as the conventional group, involved changing patients' body positions during catheterization. The second group, as the intracavitary electrocardiographic (IECG) group, utilized intracavitary electrocardiographic monitoring and involved changing patients' body positions during catheterization. The third group as the intracavitary electrocardiographic with improved body positioning (IECG-IBP) group, catheterization was performed with guidance from intracavitary electrocardiographs and without changing the patients' body positions. The ECG changes among patients undergoing different catheter delivery methods were then compared, as well as the rate of catheter tip misplacement. RESULT: The study encompassed a total of 354 cases. Our findings reveal distinct P wave amplitude percentages among the groups: 0% in the conventional group, 88.46% in the IECG group, and 91.78% in the IECG-IBP group. Furthermore, the following catheter tip misplacement rates were recorded: 11.54% for the conventional group, 5.39% for the IECG group, and 5.47% for the IECG-IBP group. Significantly notable differences were observed in these two key indicators between the conventional group and the IECG-IBP group. Notably, the IECG-IBP group demonstrated a more favorable outcome compared to the IECG group. CONCLUSION: In patients with neurosurgical diseases, especially those with tracheostomy and nuchal stiffness, the IECG-IBP PICC catheter insertion method can effectively reduce the patient's neck resistance, does not increase the patient's headache and dizziness symptoms, and does not reduce the success of one-time catheterization. Rate and does not increase the incidence of jugular venous ectopia.

Classification of autism spectrum disorder using electroencephalography in Chinese children: a cross-sectional retrospective study.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by diverse clinical features. EEG biomarkers such as spectral power and functional connectivity have emerged as potential tools for enhancing early diagnosis and understanding of the neural processes underlying ASD. However, existing studies yield conflicting results, necessitating a comprehensive, data-driven analysis. We conducted a retrospective cross-sectional study involving 246 children with ASD and 42 control children. EEG was collected, and diverse EEG features, including spectral power and spectral coherence were extracted. Statistical inference methods, coupled with machine learning models, were employed to identify differences in EEG features between ASD and control groups and develop classification models for diagnostic purposes. Our analysis revealed statistically significant differences in spectral coherence, particularly in gamma and beta frequency bands, indicating elevated long range functional connectivity between frontal and parietal regions in the ASD group. Machine learning models achieved modest classification performance of ROC-AUC at 0.65. While machine learning approaches offer some discriminative power classifying individuals with ASD from controls, they also indicate the need for further refinement.

Serum binding folate receptor autoantibodies lower in autistic boys and positively-correlated with folate.

Folate receptor autoantibody (FRAA) has caught increasing attention since its discovery in biological fluids of patients with autism spectrum disorder (ASD), but quantification and understanding of its function are still in their infancy. In this study, we aimed to quantify serum binding-FRAA and explore its relation with serum folate, vitamin B12 (VB12) and ferritin. We quantitated serum binding-FRAA in 132 ASD children and 132 typically-developing (TD) children, as well as serum levels of folate, VB12 and ferritin. The results showed that serum binding-FRAA in the ASD group was significantly lower than that in the TD group (p < 0.0001). Further analysis showed that the difference between these two groups was attributed to boys in each group, not girls. There was no statistically significant difference in folate levels between the ASD and TD groups (p > 0.05). However, there was significant difference in boys between these two groups, not girls. Additionally, the combination of nitrite and binding-FRAA showed potential diagnostic value in patients with ASD (AUC > 0.7). Moreover, in the ASD group, the level of folate was consistent with that of binding-FRAA, whereas in the TD group, the binding-FRAA level was high when the folate level was low. Altogether, these differences revealed that the low serum FRAA in autistic children was mediated by multiple factors, which deserves more comprehensive investigation with larger population and mechanistic studies.

Costs and Cardiovascular Benefits of a Fourth-Generation Synchronous Telehealth Program on Mortality and Cardiovascular Outcomes for Patients With Atrial Fibrillation: Retrospective Cohort Study.

BACKGROUND: The prevalence of atrial fibrillation (AF) continues to increase in modern aging society. Patients with AF are at high risk for multiple adverse cardiovascular events, including heart failure, stroke, and mortality. Improved medical care is needed for patients with AF to enhance their quality of life and limit their medical resource utilization. With advances in the internet and technology, telehealth programs are now widely used in medical care. A fourth-generation telehealth program offers synchronous and continuous medical attention in response to physiological parameters measured at home. Although we have previously shown the benefits of this telehealth program for some patients with a high risk of cardiovascular disease, its benefits for patients with AF remains uncertain. OBJECTIVE: This study aims to investigate the benefits of participating in a fourth-generation telehealth program for patients with AF in relation to cardiovascular outcomes. METHODS: This was a retrospective cohort study. We retrospectively searched the medical records database of a tertiary medical center in Northern Taiwan between January 2007 and December 2017. We screened 5062 patients with cardiovascular disease and enrolled 537 patients with AF, of which 279 participated in the telehealth program and 258 did not. Bias was reduced using the inverse probability of treatment weighting adjustment based on the propensity score. Outcomes were collected and analyzed, including all-cause readmission, admission for heart failure, acute coronary syndrome, ischemic stroke, systemic embolism, bleeding events, all-cause mortality, and cardiovascular death within the follow-up period. Total medical expenses and medical costs in different departments were also compared. Subgroup analyses were conducted on ischemic stroke stratified by several subgroup variables. RESULTS: The mean follow-up period was 3.0 (SD 1.7) years for the telehealth group and 3.4 (SD 1.9) years for the control group. After inverse probability of treatment weighting adjustment, the patients in the telehealth program had significantly fewer ischemic strokes (2.0 vs 4.5 events per 100 person-years; subdistribution hazard ratio [SHR] 0.45, 95% CI 0.22-0.92) and cardiovascular deaths (2.5 vs 5.9 events per 100 person-years; SHR 0.43, 95% CI 0.18-0.99) at the follow-up. The telehealth program particularly benefited patients comorbid with vascular disease (SHR 0.11, 95% CI 0.02-0.53 vs SHR 1.16, 95% CI 0.44-3.09; P=.01 for interaction). The total medical expenses during follow-up were similar in the telehealth and control groups. CONCLUSIONS: This study demonstrated the benefits of participating in the fourth-generation telehealth program for patients with AF by significantly reducing their ischemic stroke risk while spending the same amount on medical expenses.

Co-activation of NMDAR and mGluRs controls protein nanoparticle-induced osmotic pressure in neurotoxic edema.

BACKGROUND: Glutamate stimuli and hyperactivation of its receptor are predominant determinants of ischemia-induced cytotoxic cerebral edema, which is closely associated with protein nanoparticle (PN)-induced increases in osmotic pressure. Herein, we investigated the electrochemical and mechanical mechanisms underlying the neuron swelling induced by PNs via the co-activation of N-methyl-D-aspartate receptor subunit (NMDAR) and excitatory metabotropic glutamate receptors (mGluRs). RESULTS: We observed that co-activation of ionic glutamate receptor NMDAR and Group I metabotropic mGluRs promoted alteration of PN-induced membrane potential and increased intracellular osmosis, which was closely associated with calcium and voltage-dependent ion channels. In addition, activation of NMDAR-induced calmodulin (CaM) and mGluR downstream diacylglycerol (DAG)/protein kinase C α (PKCα) were observed to play crucial roles in cytotoxic hyperosmosis. The crosstalk between CaM and PKCα could upregulate the sensitivity and sustained opening of sulfonylurea receptor 1 (SUR1)-transient receptor potential cation channel subfamily M member 4 (TRPM4) and transmembrane protein 16 A (TMEM16A) channels, respectively, maintaining the massive Na+/Cl- influx, and the resultant neuron hyperosmosis and swelling. Intracellular PNs and Na+/Cl- influx were found to be as potential targets for cerebral edema treatment, using the neurocyte osmosis system and a cerebral ischemic rat model. CONCLUSIONS: This study highlights PNs as a key factor in "electrochemistry-tension" signal transduction controlling Na+/Cl- ion channels and increased osmotic pressure in ischemia-induced cytotoxic edema. Moreover, enhanced sensitivity in both Na+ and Cl- ion channels also has a crucial role in cerebral edema.

Correction: Effect of Telehealth Services on Mitral and Tricuspid Regurgitation Progression: Retrospective Study.

[This corrects the article DOI: 10.2196/47947.].

Effect of Telehealth Services on Mitral and Tricuspid Regurgitation Progression: Retrospective Study.

BACKGROUND: Mitral regurgitation (MR) and tricuspid regurgitation (TR) are common cardiac conditions with high mortality risks, which can be improved through early intervention. Telehealth services, which allow for remote monitoring of patient conditions, have been proven to improve the health management of chronic diseases, but the effects on MR and TR progression are unknown. OBJECTIVE: This study aimed to explore whether patients receiving telehealth services have less MR and TR progression compared with a control group. We also aimed to identify the determinants of MR and TR progression. METHODS: This single-center retrospective study conducted at the National Taiwan University Hospital compared MR and TR progression (defined as either progression to moderate or greater MR and TR or MR and TR progression by ≥2 grades during the study period) between the telehealth and control groups. Patients had a minimum of 2 transthoracic echocardiograms at least 6 months apart; baseline mild-moderate MR and TR or lower; and no prior surgeries on the mitral or tricuspid valve. Telehealth patients were defined as those who received telehealth services for at least 28 days within 3 months of baseline. Basic demographics, baseline blood pressure measurements, prescribed medication, and Charlson Comorbidity Index components were obtained for all patients. RESULTS: A total of 1081 patients (n=226 in the telehealth group and n=855 in the control group) were included in the study analyses. The telehealth group showed significantly lower baseline systolic blood pressure (P<.001), higher Charlson Comorbidity Index (P=.02), higher prevalence of prior myocardial infarction (P=.01) and heart failure (P<.001), higher beta-blocker (P=.03) and diuretic (P=.04) use, and lower nitrate use (P=.04). Both groups showed similar cardiac remodeling conditions at baseline. Telehealth was found to be neutral for both MR (hazard ratio 1.10, 95% CI 0.80-1.52; P=.52) and TR (hazard ratio 1.27, 95% CI 0.92-1.74; P=.14) progression. Determinants for moderate or greater MR progression included older age, female sex, diuretic use, larger left atrial dimension, left ventricular end-diastolic dimension, left ventricular end-systolic dimension, and lower left ventricular ejection fraction. Determinants of moderate or greater TR progression included older age, female sex, diuretic use, presence of atrial fibrillation, LA dimension, left ventricular end-systolic dimension, and lower left ventricular ejection fraction; statin use was found to be protective. CONCLUSIONS: This is the first study to assess the association between telehealth services and the progression of MR and TR. Telehealth patients, who had more comorbidities, displayed similar MR and TR progression versus control patients, indicating that telehealth may slow MR and TR progression. Determinants of MR and TR progression included easy-to-measure traditional echo parameters of cardiac function, older age, female sex, and atrial fibrillation, which can be incorporated into a telehealth platform and advanced alert system, improving patient outcomes through personalized care.

Efficacy and safety of thoracic radiotherapy for extensive stage small cell lung cancer after immunotherapy in real world.

The immunotherapy combined chemotherapy has been the standard treatment strategy for extensive-stage small lung cancer (ES-SCLC). The CREST trial reported consolidative thoracic radiotherapy (cTRT) improved overall survival (OS) for ES-SCLC with intrathoracic residual after chemotherapy. In this study, patients with ES-SCLC who received immunotherapy were assigned to receive either TRT or no TRT. TRT significantly improved progression-free survival (PFS), local recurrence-free survival (LRFS) and OS with well tolerated toxicity. Further sub-cohort analysis, TRT significantly improved LRFS in patients with oligo-metastasis and without liver metastasis.

Association between diet quality scores and risk of overweight and obesity in children and adolescents.

BACKGROUND: This study examined the associations of diet quality assessed by Healthy Eating Index 2015 (HEI-2015), Alternative Healthy Eating Index 2010 (AHEI-2010), Mediterranean Diet (MedDiet) and overweight/obesity in children and adolescents. METHODS: This cross-sectional study used data of participants aged 2-19 years from National Health and Nutrition Examination Survey (NHANES) 2005-2018. The weighted logistic regression model was adopted to explore the association between diet quality scores and overweight, obesity in children and adolescents. Subgroup analysis was also performed based on sex. RESULTS: A total of 9,724 participants were included in children group (2-11 years old), and 5,934 were adolescent group (12-19 years old). All participants were divided into based on the BMI-for-age: underweight and normal, overweight and obesity groups. After adjusting for age, race, poverty-income ratio, maternal smoking during pregnancy and total energy, HEI-2015 and MedDiet scores were related to the risk of overweight in children, and only MedDiet scores remained associated with a decreased risk of obesity in children. MedDiet scores were associated with a decreased risk of overweight, obesity in adolescents, respectively, after adjusting age, sex, race, poverty-income ratio, cotinine, total energy and physical activity. The similar results in male participants were also found. CONCLUSION: Higher MedDiet scores were associated with lower the risk of overweight and obesity, respectively, particularly for male children and adolescents. The higher HEI-2015 scores were also related to the risk of overweight in children.

Iron deficiency downregulates ENPEP to promote angiogenesis in liver tumors.

The abnormal iron metabolism in liver cancer leads to iron deficiency in tumor tissues. We previously found that iron deficiency promoted liver cancer metastasis, but the mechanisms were not fully understood. In the present study, we identified that the angiogenesis-associated glutamyl aminopeptidase (ENPEP) was consistently decreased in iron-deficient liver tissues, iron-deficient liver tumors, and iron-deprived liver cancer cells. Interestingly, the lower expression of ENPEP was correlated with the poor prognosis of liver cancer patients, while the biomarkers of angiogenesis, CD31 and CD34, were increased in tumor tissues. In vivo imaging of liver-orthotopically implanted and tail vein-injected liver cancer cells showed that iron deficiency increased the pulmonary metastasis of liver cancer. The angiogenesis in iron-deficient tumors was enhanced, and the expression of ENPEP was decreased. Silencing ENPEP expression increased the migration of liver cancer cells and the proliferation of cocultured HUVECs. By sequence analysis, we found that the transcription factor SP1 possessed abundant binding sites in the ENPEP promoter region. Its combination with ENPEP promoters was verified by chromatin immunoprecipitation. The inhibition of SP1 by mithramycin A effectively restored the expression of ENPEP, which was decreased by iron deficiency. In conclusion, these results revealed that iron deficiency in liver tumors decreased the expression of ENPEP by SP1 and increased the angiogenesis and metastasis of liver tumors, which further explained the mechanism by which iron deficiency promoted liver cancer metastasis.

Exploring a novel therapeutic strategy: the interplay between gut microbiota and high-fat diet in the pathogenesis of metabolic disorders.

In the past two decades, the rapid increase in the incidence of metabolic diseases, including obesity, diabetes, dyslipidemia, non-alcoholic fatty liver disease, hypertension, and hyperuricemia, has been attributed to high-fat diets (HFD) and decreased physical activity levels. Although the phenotypes and pathologies of these metabolic diseases vary, patients with these diseases exhibit disease-specific alterations in the composition and function of their gut microbiota. Studies in germ-free mice have shown that both HFD and gut microbiota can promote the development of metabolic diseases, and HFD can disrupt the balance of gut microbiota. Therefore, investigating the interaction between gut microbiota and HFD in the pathogenesis of metabolic diseases is crucial for identifying novel therapeutic strategies for these diseases. This review takes HFD as the starting point, providing a detailed analysis of the pivotal role of HFD in the development of metabolic disorders. It comprehensively elucidates the impact of HFD on the balance of intestinal microbiota, analyzes the mechanisms underlying gut microbiota dysbiosis leading to metabolic disruptions, and explores the associated genetic factors. Finally, the potential of targeting the gut microbiota as a means to address metabolic disturbances induced by HFD is discussed. In summary, this review offers theoretical support and proposes new research avenues for investigating the role of nutrition-related factors in the pathogenesis of metabolic disorders in the organism.

Population and Conservation Status of the Flying Fox Pteropus dasymallus in Taiwan.

Pteropus dasymallus is widely distributed on islands throughout the western edge of the Pacific Ocean. The Formosan flying fox, P. d. formosus, is an endemic subspecies in Taiwan found mainly on Lyudao; it was previously thought to have been extirpated. Since 2005, intensive surveys have been conducted to investigate the residency, population size and plant resource utilization of P. dasymallus in Taiwan. Interviews were carried out to investigate its former abundance and the causes of population decline. In Taiwan, P. dasymallus is in a state of ongoing oceanic dispersal and colonization and has considerably expanded its geographic range. In addition to remaining in its historic habitat on Lyudao, P. dasymallus has also established colonies on Gueishan Island and in Hualien on Taiwan's main island in the past few decades. The total population size is estimated to be 240 individuals, and this number is on the rise. Approximately three-quarters of the entire population (73.64%) was found on Gueishan Island. The sex ratio was strongly skewed toward males. A total of 40 plant species were recorded as being used by the flying fox for food, roosts or perches. More agricultural and horticultural plant species were used by the flying fox in urban Hualien. According to the interviews, flying foxes were abundant on Lyudao, but their number dramatically declined from the 1970s to the mid-1980s, mainly due to commercial hunting. Maintaining a sufficient population size and genetic variability is fundamental to the long-term survival of the flying fox. Enforcing conservation laws, restoring habitats, controlling invasive species and improving public awareness are the main steps in the recovery and sustainability of the flying fox population.

Integrative genomic analysis of drug resistance in MET exon 14 skipping lung cancer using patient-derived xenograft models.

Background: Non-small cell lung cancer (NSCLC) driven by MET exon 14 skipping (METex14) occurs in 3-4% of NSCLC cases and defines a subset of patients with distinct characteristics. While MET targeted therapy has led to strong clinical results in METex14 patients, acquired drug resistance seemed to be unavoidable during treatment. Limited information is available regarding acquired resistance during MET targeted therapy, nor has there been any report on such patient-derived xenografts (PDXs) model facilitating the research. Methods: We describe a patient case harboring METex14 who exhibited drug resistance after treatment with crizotinib. Subcutaneous xenografts were generated from pretreatment and post-resistance patient specimens. PDX mice were then treated with MET inhibitors (crizotinib and tepotinib) and EGFR-MET bispecific antibodies (EMB-01 and amivantamab) to evaluate their drug response in vivo. DNA and RNA sequencing analysis was performed on patient tumor specimens and matching xenografts. Results: PDXs preserved most of the histological and molecular profiles of the parental tumors. Drug resistance to MET targeted therapy was confirmed in PDX models through in vivo drug analysis. Newly acquired MET D1228H mutations and EGFR amplificated were detected in patient-resistant tumor specimens. Although the mutations were not detected in the PDX, EGFR overexpression was observed in RNA sequencing analysis indicating possible off-target resistance through the EGFR bypass signaling pathway. As expected, EGFR-MET bispecific antibodies overcome drug resistant in the PDX model. Conclusions: We detected a novel MET splice site deletion mutation that could lead to METex14. We also established and characterized a pair of METex14 NSCLC PDXs, including the first crizotinib resistant METex14 PDX. And dual inhibition of MET and EGFR might be a therapeutic strategy for EGFR-driven drug resistance METex14 lung cancer.

Nutrient status regulates MED19a phase separation for ORESARA1-dependent senescence.

The mediator complex is highly conserved in eukgaryotes and is integral for transcriptional responses. Mediator subunits associate with signal-responsive transcription factors (TF) to activate expression of specific signal-responsive genes. As the key TF of Arabidopsis thaliana senescence, ORESARA1 (ORE1) is required for nitrogen deficiency (-N) induced senescence; however, the mediator subunit that associates with ORE1 remains unknown. Here, we show that Arabidopsis MED19a associates with ORE1 to activate -N senescence-responsive genes. Disordered MED19a forms inducible nuclear condensates under -N that is regulated by decreasing MED19a lysine acetylation. MED19a carboxyl terminus (cMED19a) harbors a mixed-charged intrinsically disordered region (MC-IDR) required for ORE1 interaction and liquid-liquid phase separation (LLPS). Plant and human cMED19 are sufficient to form heterotypic condensates with ORE1. Human cMED19 MC-IDR, but not yeast cMED19 IDR, partially complements med19a suggesting functional conservation in evolutionarily distant eukaryotes. Phylogenetic analysis of eukaryotic cMED19 revealed that the MC-IDR could arise through convergent evolution. Our result of MED19 MC-IDR suggests that plant MED19 is regulated by phase separation during stress responses.

Tissue-specific transcriptomic analysis uncovers potential roles of natural antisense transcripts in Arabidopsis heat stress response.

Natural antisense transcripts (NATs) are an important class of non-coding ribonucleic acids (RNAs) that have been shown to regulate gene expression. Using strand-specific RNA sequencing, 36,317 NAT pairs were identified, and 5,536 were specifically expressed under heat stress. We found distinct expression patterns between vegetative and reproductive tissues for both coding genes and genes encoding NATs. Genes for heat-responsive NATs are associated with relatively high levels of H3K4me3 and low levels of H3K27me2/3. On the other hand, small RNAs are significantly enriched in sequence overlapping regions of NAT pairs, and a large number of heat-responsive NATs pairs serve as potential precursors of nat-siRNAs. Collectively, our results suggest epigenetic modifications and small RNAs play important roles in the regulation of NAT expression, and highlight the potential significance of heat-inducible NATs.

Loss of SLC46A1 decreases tumor iron content in hepatocellular carcinoma.

It is interesting that high iron is an independent inducer or cofactor of hepatocellular carcinoma (HCC) while the amount of iron is decreased in the liver tumor tissues. Due to the previous findings that iron deficiency promoted HCC metastasis, it is of significance to identify the underlying mechanism of iron deficiency in HCC. The tumor iron content and expressions of iron-metabolic molecules were observed in the primary liver cancers of rats and mice. The molecules that changed independently of iron were identified by comparing the expression profiles in the human HCC tissues and iron-deprived HCC cells. The downstream effects of these molecules on regulating intracellular iron content were investigated in vitro and further validated in vivo. Both in primary liver cancers of rats and mice, we confirmed the decreased iron content in tumor tissues and the altered expressions of iron-metabolic molecules, including transferrin receptor 1 (TfR1), six-transmembrane epithelial antigen of prostate 3 (STEAP3), divalent metal transporter 1 (DMT1), SLC46A1, ferroportin, hepcidin, and ferritin. Among these, STEAP3, DMT1, and SLC46A1 were altered free of iron deficiency. However, only silence or overexpression of SLC46A1 controlled the intracellular iron content of HCC cells. The interventions of STEAP3 or DMT1 could not change the intracellular iron content. Lentivirus-mediated regain of SLC46A1 expression restored the iron content in orthotopically implanted tumors, with correspondingly changes in the iron-metabolic molecules as iron increasing. Conclusion: Taken together, these results suggest that the loss of SLC46A1 expression leads to iron deficiency in liver tumor tissues, which would be an effective target to manage iron homeostasis in HCC.

Novel chlorpromazine derivatives as anti-endometrial carcinoma agents with reduced extrapyramidal side effects.

As the traditional conservative remedy for endometrial carcinoma (EC), progesterone has great limitations due to its poor performance, and a new strategy is urgently needed. Our previous work revealed that the antipsychotic drug chlorpromazine (CPZ) has stronger antitumor activity on EC than progesterone does, which may provide a promising conservative alternative for EC patients. Unfortunately, the severe extrapyramidal symptoms (EPSs) at concentrations (>5 mg/kg) that are required for anticarcinoma activity limited its repurposing. Therefore, a series of novel CPZ derivatives were designed and synthesized to avoid EPS and retain its antitumor activity. Among them, 11·2HCl and 18 displayed greater inhibitory activity by modulating SOS1. Notably, even at a dose of 100 mg/kg, 11·2HCl/18 had little effect on the extrapyramidal system. In conclusion, 11·2HCl and 18 greatly repressed the malignant features of endometrial carcinoma and decreased extrapyramidal side effects compared with the original drug CPZ.