[Prognostic Factors Affecting Recurrence in Peripheral T-Cell Lymphoma Patients with Different HDAC Levels].

OBJECTIVE: To analyze the distribution characteristics of prognostic factors affecting recurrence in peripheral T-cell lymphoma (PTCL) patients with different levels of histone deacetylase (HDAC) based on latent class analysis. METHODS: 112 PTCL patients who were treated in our hospital from September 2012 to September 2019 were selected and divided into recurrence group and non-recurrence group. The clinical data of the two groups of patients were compared. Multivariate logistic regression was used to analyze the risk factors for recurrence. Latent class analysis was used to compare the distribution characteristics of prognostic factors affecting recurrence between the high-risk group and the low-risk group. RESULTS: There were 87 patients (77.68%) in recurrence group and 25 patients (22.32%) in non-recurrence group. The result of multivariate logistic regression showed that ECOG score ≥2, Ann Arbor stage III-IV, IPI score >2, bone marrow involvement, elevated serum ß2-microglobulin (ß2-MG), short-term efficacy not reaching complete remission (CR) or partial remission (PR), and the high expression of HDAC were all independent risk factors for recurrence in patients with PTCL (P <0.05). The recurrence rate of patients with high HDAC levels was significantly higher than that of patiens with low HDAC levels (P <0.05). The results of cluster analysis showed that the risk of recurrence was obviously clustered, and the patients could be divided into high recurrence risk group (HDAC＞5 points) and low recurrence risk group (HDAC≤5 points). The results of latent class analysis showed that patients with multiple risk factors account for a higher proportion in the high recurrence risk group, compared with the low recurrence risk group (P <0.05). CONCLUSION: There are differences in recurrence rates among PTCL patients with different HDAC levels and in distribution characteristics of risk factors between high recurrence risk and low recurrence risk groups.

Potential Protective Effect of Selenium-Enriched Lactobacillus plantarum on Cadmium-Induced Liver Injury in Mice.

Cadmium (Cd) is a prevalent environmental contaminant that poses a potential hazard to the health of both humans and animals. In this study, biosynthesized selenium-enriched Lactobacillus plantarum and selenium nanoparticles (SeNPs) were developed and evaluated for their protective effects against Cd-induced hepatic injury in mice through oral administration for 4 weeks. Cadmium exposure resulted in severe impairment of liver function, as evidenced by increased levels of serum markers of liver injury and, oxidative stress and significant damage to liver tissue, and a notable decrease in the diversity of the intestinal microbiota. Oral administration of Se-enriched L. plantarum (LS) reduced cadmium accumulation in the liver by 49.5% and, restored other cadmium-induced damage markers to normal levels. A comparison of the effects with those of L. plantarum (L) and SeNPs isolated from LS revealed that LS could more effectively alleviate hepatic oxidative stress and reduce the intrahepatic inflammatory responses of the liver, further protecting against cadmium-induced liver injury. These findings suggest that the development of LS may be effective at protecting the liver and intestinal tract from cadmium-induced damage.

Capsaicin reduces blood glucose and prevents prostate growth by regulating androgen, RAGE/IGF-1/Akt, TGF-ß/Smad signalling pathway and reversing epithelial-mesenchymal transition in streptozotocin-induced diabetic mice.

Type 2 diabetes mellitus (T2DM) is a metabolic disease. Diabetes increases the risk of benign prostatic hyperplasia (BPH). Capsaicin is extracted from chili peppers and possesses many pharmacological properties, including anti-diabetic, pain-relieving, and anti-cancer properties. This study aimed to investigate the effects of capsaicin on glucose metabolism and prostate growth in T2DM mice and uncover the related mechanisms. Mice model of diabetes was established by administering a high-fat diet and streptozotocin. Oral administration of capsaicin for 2 weeks inhibited prostate growth in testosterone propionate (TP)-treated mice. Furthermore, oral administration of capsaicin (5 mg/kg) for 2 weeks decreased fasting blood glucose, prostate weight, and prostate index in diabetic and TP-DM mice. Histopathological alterations were measured using hematoxylin & eosin (H&E) staining. The protein expression of 5α-reductase type II, androgen receptor (AR), and prostate-specific antigen (PSA) were upregulated in diabetic and TP-DM mice, but capsaicin reversed these effects. Capsaicin decreased the protein expression of p-AKT, insulin-like growth factor-1 (IGF-1), IGF-1R, and the receptor for advanced glycation end products (RAGE) in diabetic and TP-DM mice. Capsaicin also regulated epithelial-mesenchymal transition (EMT) and modulated the expression of fibrosis-related proteins, including E-cadherin, N-cadherin, vimentin, fibronectin, α-SMA, TGFBR2, TGF-ß1, and p-Smad in TP-DM mice. In this study, capsaicin alleviated diabetic prostate growth by attenuating EMT. Mechanistically, capsaicin affected EMT by regulating RAGE/IGF-1/AKT, AR, and TGF-ß/Smad signalling pathways. These results provide with new therapeutic approach for treating T2DM or T2DM-induced prostate growth.

Long-term expandable mouse and human-induced nephron progenitor cells enable kidney organoid maturation and modeling of plasticity and disease.

Nephron progenitor cells (NPCs) self-renew and differentiate into nephrons, the functional units of the kidney. Here, manipulation of p38 and YAP activity allowed for long-term clonal expansion of primary mouse and human NPCs and induced NPCs (iNPCs) from human pluripotent stem cells (hPSCs). Molecular analyses demonstrated that cultured iNPCs closely resemble primary human NPCs. iNPCs generated nephron organoids with minimal off-target cell types and enhanced maturation of podocytes relative to published human kidney organoid protocols. Surprisingly, the NPC culture medium uncovered plasticity in human podocyte programs, enabling podocyte reprogramming to an NPC-like state. Scalability and ease of genome editing facilitated genome-wide CRISPR screening in NPC culture, uncovering genes associated with kidney development and disease. Further, NPC-directed modeling of autosomal-dominant polycystic kidney disease (ADPKD) identified a small-molecule inhibitor of cystogenesis. These findings highlight a broad application for the reported iNPC platform in the study of kidney development, disease, plasticity, and regeneration.

CircGPRC5A enhances colorectal cancer progress by stabilizing PPP1CA and inducing YAP dephosphorylation.

BACKGROUND: With the advancements in bioinformatic technology, an increasing number of circular RNAs (circRNAs) have been discovered and their crucial roles in the development and progression of various malignancies have been confirmed through multiple pathways. However, the specific mechanisms involving protein-binding circRNAs in colorectal cancer (CRC) remain largely unexplored. METHODS: Differential circRNA expression was assessed using a human circRNA microarray in five CRC tissue and paired normal samples. CircGPRC5A expression was then confirmed in the CRC tissues and paired normal samples using qRT-PCR. The biological function of circGPRC5A in CRC were studied in vitro and in vivo. Western blotting, fluorescence in situ hybridization, immunofluorescence, RNA pulldown, mass spectrometry, immunoprecipitation, quantitative phosphoproteomics, and RNA-binding protein immunoprecipitation assays were used to study circGPRC5A. RESULTS: Our analysis revealed that circGPRC5A expression was higher in CRC tissues compared to normal tissues and was associated with tumor size, tumor stage and lymph node status. CircGPRC5A promoted CRC cell proliferation, migration, and metastasis in vitro and in vivo. CircGPRC5A could stabilize PPP1CA protein by inhibiting the binding between UBA1 and PPP1CA, and increasing YAP dephosphorylation. CONCLUSIONS: Our study revealed that circGPRC5A plays an essential function in CRC progression by stabilizing PPP1CA protein and enhancing YAP dephosphorylation. CircGPRC5A could act as a novel and potential target for CRC.

Echocardiographic Characteristics of Pulmonary Artery Intimal Sarcoma: Comparison With CTPA.

OBJECTIVES: This study examined the echocardiographic characteristics of patients with pulmonary artery intimal sarcoma (PAIS) and compared the results with those from computed tomographic pulmonary angiography (CTPA). METHOD: Twenty-six (26) patients were diagnosed with PAIS at the current institution during the study period, and 23 were eligible for analysis. Echocardiography and CTPA examinations were performed in all enrolled patients. RESULTS: The echocardiography results showed that most lesions had expansive growth in the left pulmonary artery (PA); the right PA; or a combination of the left PA, right PA, and main PA, with extension to the pulmonary valve and/or right ventricular outflow tract. These lesions also had distinctive sieve-like echogenic signals. Echocardiography also showed that some lesions had lobulated shapes, were nearly round and echolucent or with calcifications, and moved during imaging. The lesion distribution was similar in CTPA and echocardiography (p=0.361), but CTPA was more sensitive in detection of the complete shape (p=0.023). CONCLUSIONS: The unique echocardiographic characteristics of PAIS, especially the "sieve sign", could help in the diagnosis of this cancer. Transthoracic echocardiography is a non-invasive technique that appears effective in detecting PAIS.

Pulmonary artery sarcoma: an unexpected settler in the right ventricular outflow tract.

Pulmonary artery sarcoma (PAS) is a sporadic malignant tumor that mainly originates from the pulmonary arteries. However, PAS may also involve the right ventricular outflow tract (RVOT) and lead to obstruction, syncope, or sudden death. Early diagnosis and complete surgical resection are essential to prolong survival and improve the quality of life of patients with PAS. Herein, we report a case of a young female patient admitted for pulmonary malignancy and acute pulmonary embolism. The patient had a mass in the RVOT, which was detected by transthoracic echocardiography. Computed tomography and magnetic resonance imaging revealed the invasion depth and extent of the lesions. Surgical resection improved hemodynamics, while pathological and immunohistochemical tests confirmed the diagnosis of a pulmonary artery sarcoma. Local recurrence was detected in the adjacent tissues about two months after the surgery. Given the potential risk of reoperation, the patient was suggested to undergo conservative treatment.

Emerging role of ferroptosis-related circular RNA in tumor metastasis.

Tumor metastasis is an important factor that contributes to the poor prognosis of patients with tumors. Therefore, to solve this problem, research on the mechanism of metastasis is essential. Ferroptosis, a new mode of cell death, is characterized by membrane damage due to lipid peroxidation caused by iron overload. Many studies have shown that excessive ferroptosis can affect tumor metastasis and thus inhibit tumor progression. Recently, circular RNA (circRNA), a type of non-coding RNA, has been shown to be associated with the progression of ferroptosis, thus influencing tumor development. However, the specific mechanisms by which circRNAs affect the progression of ferroptosis and their roles in tumor metastasis are not known. In this review, we systematically discuss the role of circRNAs in regulating tumor ferroptosis and their mechanism of action through sponging miRNAS in various tumors, thereby impacting metastasis. This review helps elucidate the relationship and role of ferroptosis-related circRNAs in tumor metastasis and may provide future researchers with new ideas and directions for targeted therapies.

[Evaluation of the effect of Er:YAG laser combined with guided bone regeneration in the treatment of peri-implantitis with osseous defects].

PURPOSE: To evaluate the clinical benefits of Er:YAG laser combined with guided bone regeneration (GBR) in the treatment of peri-implantitis-assocaited osseous defects. METHODS: Twenty-six patients (34 implants in total) who underwent implant restoration in Dental Disease Prevention and Treatment Institute, Jiading District, from 2017 to 2019 and were diagnosed with peri-implantitis with osseous defects, and randomly divided into the experimental group and control group. The two groups of patients received open flap surgery, debridement and GBR treatment. The only difference in the experimental group was the use of Er: YAG laser to modulate and remove inflammatory tissue as well as to decontaminate the implant surface, instead of traditional mechanical treatment in the control group. The probing depth (PD), bleeding on probing (BOP), and plaque index (PI), the height of the bone defect around the implant (reduce of marginal bone level, RBL) were recorded and compared. SPSS 20.0 software package was used to analyze the data. RESULTS: The PD, BOP, PI and RBL of the two groups of patients were significantly improved after treatment with different methods. There was no significant difference in the improvement of PD, BOP and PI between the two groups 6, 12 and 24 months after treatment, while the improvement of RBL in the experimental group was significantly better than that of the control group 12 and 24 months after treatment. CONCLUSIONS: In the treatment of GBR with peri-implantitis and osseous defects, Er: YAG laser therapy is more effective than traditional mechanical methods, and is more conducive to the regeneration of new bone.

Examining the Development of Chronic Thromboembolic Pulmonary Hypertension at the Single-Cell Level.

BACKGROUND: The mechanism of chronic thromboembolic pulmonary hypertension (CTEPH) is known to be multifactorial but remains incompletely understood. METHODS: In this study, single-cell RNA sequencing, which facilitates the identification of molecular profiles of samples on an individual cell level, was applied to investigate individual cell types in pulmonary endarterectomized tissues from 5 patients with CTEPH. The order of single-cell types was then traced along the developmental trajectory of CTEPH by trajectory inference analysis, and intercellular communication was characterized by analysis of ligand-receptor pairs between cell types. Finally, comprehensive bioinformatics tools were used to analyze possible functions of branch-specific cell types and the underlying mechanisms. RESULTS: Eleven cell types were identified, with immune-related cell types (T cells, natural killer cells, macrophages, and mast cells) distributed in the left (early) branch of the pseudotime tree, cancer stem cells, and CRISPLD2+ cells as intermediate cell types, and classic disease-related cell types (fibroblasts, smooth muscle cells, myofibroblasts, and endothelial cells) in the right (later) branch. Ligand-receptor interactions revealed close communication between macrophages and disease-related cell types as well as between smooth muscle cells and fibroblasts or endothelial cells. Moreover, the ligands and receptors were significantly enriched in key pathways such as the PI3K/Akt signaling pathway. Furthermore, highly expressed genes specific to the undefined cell type were significantly enriched in important functions associated with regulation of endoplasmic reticulum stress. CONCLUSIONS: This single-cell RNA sequencing analysis revealed the order of single cells along a developmental trajectory in CTEPH as well as close communication between different cell types in CTEPH pathogenesis.

Cell landscape atlas for patients with chronic thromboembolic pulmonary hypertension after pulmonary endarterectomy constructed using single-cell RNA sequencing.

This study aimed to construct an atlas of the cell landscape and comprehensively characterize the cellular repertoire of the pulmonary endarterectomized tissues of patients with chronic thromboembolic pulmonary hypertension (CTEPH). Five pulmonary endarterectomized tissues were collected. 10× Genomics single-cell RNA sequencing was performed, followed by the identification of cluster marker genes and cell types. Gene Ontology (GO) enrichment analysis was conducted. Seventeen cell clusters were characterized, corresponding to 10,518 marker genes, and then classified into eight cell types, including fibroblast/smooth muscle cell, endothelial cell, T cell/NK cell, macrophage, mast cell, cysteine rich secretory protein LCCL domain containing 2 (CRISPLD2)+ cell, cancer stem cell, and undefined. The specific marker genes of fibroblast/smooth muscle cell, endothelial cell, T cell/NK cell, macrophage, mast cell, and cancer stem cell were significantly enriched for multiple functions associated with muscle cell migration, endothelial cell migration, T cell activation, neutrophil activation, erythrocyte homeostasis, and tissue remodeling, respectively. No functions were significantly enriched for the marker gene of CRISPLD2+ cell. Our study, for the first time, provides an atlas of the cell landscape of the pulmonary endarterectomized tissues of CTEPH patients at single-cell resolution, which may serve as a valuable resource for further elucidation of disease pathophysiology.

Colonic pouch confers better bowel function and similar postoperative outcomes compared to straight anastomosis for low rectal cancer.

BACKGROUND: With advancements in laparoscopic technology and the wide application of linear staplers, sphincter-saving procedures are increasingly performed for low rectal cancer. However, sphincter-saving procedures have led to the emergence of a unique clinical disorder termed anterior rectal resection syndrome. Colonic pouch anastomosis improves the quality of life of patients with rectal cancer > 7 cm from the anal margin. But whether colonic pouch anastomosis can reduce the incidence of rectal resection syndrome in patients with low rectal cancer is unknown. AIM: To compare postoperative and oncological outcomes and bowel function of straight and colonic pouch anal anastomoses after resection of low rectal cancer. METHODS: We conducted a retrospective study of 72 patients with low rectal cancer who underwent sphincter-saving procedures with either straight or colonic pouch anastomoses. Functional evaluations were completed preoperatively and at 1, 6, and 12 mo postoperatively. We also compared perioperative and oncological outcomes between two groups that had undergone low or ultralow anterior rectal resection. RESULTS: There were no significant differences in mean operating time, blood loss, time to first passage of flatus and excrement, and duration of hospital stay between the colonic pouch and straight anastomosis groups. The incidence of anastomotic leakage following colonic pouch construction was lower (11.4% vs 16.2%) but not significantly different than that of straight anastomosis. Patients with colonic pouch construction had lower postoperative low anterior resection syndrome scores than the straight anastomosis group, suggesting better bowel function (preoperative: 4.71 vs 3.89, P = 0.43; 1 mo after surgery: 34.2 vs 34.7, P = 0.59; 6 mo after surgery: 22.70 vs 29.0, P < 0.05; 12 mo after surgery: 15.5 vs 19.5, P = 0.01). The overall recurrence and metastasis rates were similar (4.3% and 11.4%, respectively). CONCLUSION: Colonic pouch anastomosis is a safe and effective procedure for colorectal reconstruction after low and ultralow rectal resections. Moreover, colonic pouch construction may provide better functional outcomes compared to straight anastomosis.

Characteristics, source apportionment and health risks of ambient VOCs during high ozone period at an urban site in central plain, China.

On 3rd to May 24, 2018, volatile organic compound (VOC) samples were collected four times a day by using stainless steel canisters at an urban site in Zhengzhou, China. The concentrations, compositions, sources, ozone (O3) formation potential (OFP), and health risk assessment of VOCs were discussed based on the measurements of 103 VOC species. Results show that the average mixing ratio of VOCs was 29.11 ± 15.33 ppbv, and the dominant components comprised oxygenated VOCs (OVOCs) and alkanes, followed by halocarbons, alkenes, aromatics, and a sulfide. Various groups of VOCs had typical diurnal variation characteristics. Alkenes, alkanes, and aromatics contributed most to the OFP. Five sources identified by the positive matrix factorization model revealed solvent utilization as the largest contributor, followed by industrial production, long-lived and secondary species, vehicular emission, and biogenic emission. Solvent utilization and vehicular emission were important sources to OFP. During O3 episode days, the mixing ratios of alkanes, alkenes, halocarbons, OVOCs, aromatics, and TVOCs decreased to varying degrees; the source contribution of solvent utilization decreased significantly while industrial production showed the opposite trend. VOC species and sources posed no non-carcinogenic risk while five species and all sources except for biogenic emission had carcinogenic risks to exposed population. Industrial emission was the largest contributor to both non-carcinogenic and carcinogenic risks. These results will help to provide some references for O3 pollution research and prevention and control of pollution sources.

Incidental finding of an asymptomatic pulmonary valve papillary fibroelastoma: A case report.

Primary cardiac tumors are rare, but papillary fibroelastoma (PFE) is reportedly the most common form, which usually occurs on the left-side valves of the heart. However, PFE involving the tricuspid and pulmonary valves has also been documented. Although PFE is benign and seldom associated with valvular dysfunction, the associated embolic complications may lead to serious consequences. Most patients with PFE lack specific clinical symptoms and the diagnosis is incidental. Surgical resection is the mainstay treatment for PFE in order to prevent the occurrence of embolic complications. In this report, we present a case of a rare asymptomatic PFE of the pulmonary valve, which was incidentally noted during a routine examination with transthoracic echocardiography (TEE). There was neither valvular dysfunction nor hemodynamic change. The PFE was surgically removed, and the diagnosis was further confirmed with histopathology.

17ß-estradiol preserves right ventricular function in rats with pulmonary arterial hypertension: an echocardiographic and histochemical study.

Pulmonary arterial hypertension (PAH) is more prevalent in females. Paradoxically, female patients have better right ventricular (RV) function and higher survival rates than males. However, the effects of 17ß-estradiol (E2) on RV function in PAH has not been studied. Twenty-four male rats were exposed to monocrotaline (MCT) to induce experimental PAH, while treated with E2 or vehicle respectively. Together with eight control rats, thirty-two rats were examined by echocardiography 4 weeks after drug administration. Echocardiographic measurement of RV function included: tricuspid annular plane systolic excursion (TAPSE), RV index of myocardial performance (RIMP), RV fractional area change (RVFAC) and tricuspid annular systolic velocity (s'). RV free wall longitudinal strain (RVLSFW) and RV longitudinal shortening fraction (RVLSF) were also used to quantify RV function. RV morphology was determined by echocardiographic and histological analysis. TAPSE, RVFAC and s' were reduced, and RIMP was elevated in the MCT-treated group and vehicle-treated group, when compared with control group (P < 0.01). TAPSE, RVFAC and s' in the E2 group were higher, while RIMP was lower than those in the MCT-treated group and vehicle-treated group (P < 0.01). Myocardial functional parameters (RVLSFW and RVLSF) were also higher in the E2 group. Enhanced serum E2 levels were closely correlated with the improvement in RV functional parameters and enhancement of serum BNP levels (P < 0.01 for all groups). RV function decreased significantly in male rats with MCT-induced PAH, while E2 exhibited a protective effect on RV function, suggesting that E2 is a critical modulator of sex differences in PAH.

Association Analysis and Identification of ZmHKT1;5 Variation With Salt-Stress Tolerance.

The high-affinity potassium transporter (HKT) genes are essential for plant salt stress tolerance. However, there were limited studies on HKTs in maize (Zea mays), and it is basically unknown whether natural sequence variations in these genes are associated with the phenotypic variability of salt tolerance. Here, the characterization of ZmHKT1;5 was reported. Under salt stress, ZmHKT1;5 expression increased strongly in salt-tolerant inbred lines, which accompanied a better-balanced Na+/K+ ratio and preferable plant growth. The association between sequence variations in ZmHKT1;5 and salt tolerance was evaluated in a diverse population comprising 54 maize varieties from different maize production regions of China. Two SNPs (A134G and A511G) in the coding region of ZmHKT1;5 were significantly associated with different salt tolerance levels in maize varieties. In addition, the favorable allele of ZmHKT1; 5 identified in salt tolerant maize varieties effectively endowed plant salt tolerance. Transgenic tobacco plants of overexpressing the favorable allele displayed enhanced tolerance to salt stress better than overexpressing the wild type ZmHKT1;5. Our research showed that ZmHKT1;5 expression could effectively enhance salt tolerance by maintaining an optimal Na+/K+ balance and increasing the antioxidant activity that keeps reactive oxygen species (ROS) at a low accumulation level. Especially, the two SNPs in ZmHKT1;5 might be related with new amino acid residues to confer salt tolerance in maize. Key Message: Two SNPs of ZmHKT1;5 related with salt tolerance were identified by association analysis. Overexpressing ZmHKT1;5 in tobaccos showed that the SNPs might enhance its ability to regulating Na+/K+ homeostasis.

Er Shen Wan extract reduces diarrhea and regulates AQP 4 and NHE 3 in a rat model of spleen-kidney Yang deficiency-induced diarrhea.

INTRODUCTION: Er Shen Wan (ESW), a traditional Chinese medicinal formula comprised of Psoraleae Fructus (Babchi seeds, from Psoralea corylifolia Linn.) and Myristicae Semen (Nutmeg, from Myristica fragrans Houtt.), is widely used to treat spleen-kidney Yang deficiency (SKYD)-induced diarrhea. Previous studies have demonstrated preliminarily that the petroleum ether extract of ESW (ESWP) exhibits significant anti-diarrheal activity. The present study aimed to evaluate the anti-diarrhea activity of ESWP and to explore the underlying mechanisms with respect to fluid metabolism in a rat model of SKYD-induced diarrhea. MATERIALS AND METHODS: A high-performance liquid chromatography-diode array detector (HPLC-DAD) approach was developed and validated for qualitative and quantitative analyses of the main constituents of ESWP. SKYD model rats were established and treated with an effective dose (3.5?g/kg) of the extract for two weeks. Anti-diarrheal activity and stool properties were observed. After the experiment, the appearance and histology of the intestines were evaluated. Serum levels of neuropeptide Y (NPY) and vasoactive intestinal peptide (VIP) were also determined. Furthermore, to characterize the regulation of aquaporin-4 (AQP 4) and Na+/H+ exchanger isoform 3 (NHE 3) in the colon, quantitative real-time RT-PCR (qRT-PCR), immunohistochemistry (IHC) and Western blotting (WB) were employed to detect mRNA and protein expression levels. RESULTS: In the rat models, oral ESWP administration significantly reduced the diarrhea score and the number and weight of wet stools. Jejunal and ileac histological damage was impeded, and the histology score decreased. Serum VIP levels were significantly decreased, in contrast to NPY levels. In addition, AQP 4 and NHE 3 expression levels increased significantly. CONCLUSIONS: These results showed that ESWP's anti-diarrheal effect might at least partially involve the regulation of hormones intimately involved in maintaining fluid and electrolyte levels, as well as by increasing AQP 4 and NHE 3 expression levels and enhancing the absorption of Na+ and water.

DNA-binding affinity and transcriptional activity of the RelA homodimer of nuclear factor κB are not correlated.

The nuclear factor κB (NF-κB) transcription factor family regulates genes involved in cell proliferation and inflammation. The promoters of these genes often contain NF-κB-binding sites (κB sites) arranged in tandem. How NF-κB activates transcription through these multiple sites is incompletely understood. We report here an X-ray crystal structure of homodimers comprising the RelA DNA-binding domain containing the Rel homology region (RHR) in NF-κB bound to an E-selectin promoter fragment with tandem κB sites. This structure revealed that two dimers bind asymmetrically to the symmetrically arranged κB sites at which multiple cognate contacts between one dimer to the corresponding DNA are broken. Because simultaneous RelA-RHR dimer binding to tandem sites in solution was anti-cooperative, we inferred that asymmetric RelA-RHR binding with fewer contacts likely indicates a dissociative binding mode. We found that both κB sites are essential for reporter gene activation by full-length RelA homodimer, suggesting that dimers facilitate DNA binding to each other even though their stable co-occupation is not promoted. Promoter variants with altered spacing and orientation of tandem κB sites displayed unexpected reporter activities that were not explained by the solution-binding pattern of RelA-RHR. Remarkably, full-length RelA bound all DNAs with a weaker affinity and specificity. Moreover, the transactivation domain played a negative role in DNA binding. These observations suggest that other nuclear factors influence full-length RelA binding to DNA by neutralizing the transactivation domain negative effect. We propose that DNA binding by NF-κB dimers is highly complex and modulated by facilitated association-dissociation processes.

Bcl3 Phosphorylation by Akt, Erk2, and IKK Is Required for Its Transcriptional Activity.

Unlike prototypical IκB proteins, which are inhibitors of NF-κB RelA, cRel, and RelB dimers, the atypical IκB protein Bcl3 is primarily a transcriptional coregulator of p52 and p50 homodimers. Bcl3 exists as phospho-protein in many cancer cells. Unphosphorylated Bcl3 acts as a classical IκB-like inhibitor and removes p50 and p52 from bound DNA. Neither the phosphorylation site(s) nor the kinase(s) phosphorylating Bcl3 is known. Here we show that Akt, Erk2, and IKK1/2 phosphorylate Bcl3. Phosphorylation of Ser33 by Akt induces switching of K48 ubiquitination to K63 ubiquitination and thus promotes nuclear localization and stabilization of Bcl3. Phosphorylation by Erk2 and IKK1/2 of Ser114 and Ser446 converts Bcl3 into a transcriptional coregulator by facilitating its recruitment to DNA. Cells expressing the S114A/S446A mutant have cellular proliferation and migration defects. This work links Akt and MAPK pathways to NF-κB through Bcl3 and provides mechanistic insight into how Bcl3 functions as an oncoprotein through collaboration with IKK1/2, Akt, and Erk2.

Right atrial cardiac rhabdomyoma with premature foramen ovale restriction: A case report.

Fetal cardiac rhabdomyoma is the most common cardiac tumor in fetuses. However, this benign tumor can cause hemodynamic repercussions and intrauterine fetal mortality. The present study reports a case of rare fetal cardiac rhabdomyoma located in the right atrium, accompanied by premature restriction of the foramen ovale and moderate pericardial effusion, as determined by tomographic ultrasound imaging (TUI). Fetal mortality subsequently occurred late in the second trimester of pregnancy and the diagnosis was confirmed by pathology. The present study discusses the occurrence and diagnosis of this rare abnormality. TUI mode with spatio-temporal image correlation offline imaging provides the physician with clear views of abnormal intracardiac structures in the beating heart. With improvements in sonographic technology, the diagnosis of fetal cardiac rhabdomyoma may be easier and more accurate in the clinical arena.