MitoQ protects against carbon tetrachloride-induced hepatocyte ferroptosis and acute liver injury by suppressing mtROS-mediated ACSL4 upregulation.

Ferroptosis has been shown to be involved in carbon tetrachloride (CCl4)-induced acute liver injury (ALI). The mitochondrion-targeted antioxidant MitoQ can eliminate the production of mitochondrial reactive oxygen species (mtROS). This study investigated the role of MitoQ in CCl4-induced hepatocytic ferroptosis and ALI. MDA and 4HNE were elevated in CCl4-induced mice. In vitro, CCl4 exposure elevated the levels of oxidized lipids in HepG2 cells. Alterations in the mitochondrial ultrastructure of hepatocytes were observed in the livers of CCl4-evoked mice. Ferrostatin-1 (Fer-1) attenuated CCl4-induced hepatic lipid peroxidation, mitochondrial ultrastructure alterations and ALI. Mechanistically, acyl-CoA synthetase long-chain family member 4 (ACSL4) was upregulated in CCl4-exposed human hepatocytes and mouse livers. The ACSL4 inhibitor rosiglitazone alleviated CCl4-induced hepatic lipid peroxidation and ALI. ACSL4 knockdown inhibited oxidized lipids in CCl4-exposed human hepatocytes. Moreover, CCl4 exposure decreased the mitochondrial membrane potential and OXPHOS subunit levels and increased the mtROS level in HepG2 cells. Correspondingly, MitoQ pretreatment inhibited the upregulation of ACSL4 in CCl4-evoked mouse livers and HepG2 cells. MitoQ attenuated lipid peroxidation in vivo and in vitro after CCl4 exposure. Finally, MitoQ pretreatment alleviated CCl4-induced hepatocytic ferroptosis and ALI. These findings suggest that MitoQ protects against hepatocyte ferroptosis in CCl4-induced ALI via the mtROS-ACSL4 pathway.

Mitoquinone protects against acetaminophen-induced liver injury in an FSP1-dependent and GPX4-independent manner.

Mitochondrial oxidative stress has been a crucial mediator in acetaminophen (APAP)-induced hepatotoxicity. MitoQ, an analog of coenzyme Q10, is targeted towards mitochondria and acts as a potent antioxidant. This study aimed to explore the effect of MitoQ on APAP-induced liver injury and its possible mechanisms. To investigate this, CD-1 mice and AML-12 cells were treated with APAP. Hepatic MDA and 4-HNE, two markers of lipid peroxidation (LPO), were elevated as early as 2 h after APAP. Oxidized lipids were rapidly upregulated in APAP-exposed AML-12 cells. Hepatocyte death and mitochondrial ultrastructure alterations were observed in APAP-induced acute liver injury. The in vitro experiments showed that mitochondrial membrane potentials and OXPHOS subunits were downregulated in APAP-exposed hepatocytes. MtROS and oxidized lipids were elevated in APAP-exposed hepatocytes. We discovered that APAP-induced hepatocyte death and liver injury were ameliorated by attenuation of protein nitration and LPO in MitoQ-pretreated mice. Mechanistically, knockdown of GPX4, a key enzyme for LPO defense systems, exacerbated APAP-induced oxidized lipids, but did not influence the protective effect of MitoQ on APAP-induced LPO and hepatocyte death. Whereas knockdown of FSP1, another key enzyme for LPO defense systems, had little effect on APAP-induced lipid oxidation but partially weakened the protection of MitoQ on APAP-induced LPO and hepatocyte death. These results suggest that MitoQ may alleviate APAP-evoked hepatotoxicity by eliminating protein nitration and suppressing hepatic LPO. MitoQ prevents APAP-induced liver injury partially dependent of FSP1 and independent of GPX4.

Infantile hepatic hemangiomas associated with high-output cardiac failure and pulmonary hypertension.

BACKGROUND: Infantile hepatic hemangioma (IHH) is a rare endothelial cell neoplasm, which may be concurrent with severe complications and result in poor outcomes. Moreover, the coexistence of IHH and congenial heart disease is even rarer. CASE PRESENTATION: We present a 10-day-old male born with IHH associated with patent ductus arteriosus (PDA), atrial septal defect (ASD) and pulmonary hypertension. Moreover, we reviewed a series of studies of IHH-associated high-output cardiac failure between 1974 and 2018, and summarized the treatment outcomes. CONCLUSIONS: Infantile hepatic hemangioma (IHH) has been known to induce high-output heart failure. There is no literature to summarize the severity of its impact on heart, which can lead to a high mortality rate. When IHH is detected by ultrasound, the heart should be evaluated to facilitate treatment. The outcomes of IHH associated with heart failure are good.

Isolated metastasis of hepatocellular carcinoma in the right ventricle.

BACKGROUND: Hepatocellular carcinoma (HCC) with right ventricle metastasis without inferior vena cava and right atrium involvement is very rare and the prognosis of HCC with RV metastasis is generally poor. The mass in the cardiac chamber may lead to lethal instability of hemodynamics, however, the initial symptom is probably non-specific, which means that diagnosis timely becomes even harder. CASE PRESENTATION: We present a 63-year-old male with isolated metastasis of HCC in the right ventricle which caused inflow obstruction. Moreover, we reviewed a series of studies of isolated metastasis of hepatocellular carcinoma between 1980 and 2018, and summarized the relative outcomes. CONCLUSIONS: Isolated metastasis of hepatocellular carcinoma in the right ventricle is extraordinarily rare. It may damage cardiac structure and broke hemodynamic balance. Multimodality imaging plays an important in accurate pre-operation assessment. Nowadays, palliative treatments could relieve fatal symptoms to some degree, however, standard treatment has not been well established.

Survival analysis of children with stage II testicular malignant germ cell tumors treated with surgery or surgery combined with adjuvant chemotherapy.

For children with stage II testicular malignant germ cell tumors (MGCT), the survival is good with surgery and adjuvant chemotherapy. However, there is limited data on surgical results for cases in which there was no imaging or pathologic evidence of residual tumor, but in which serum tumor markers either increased or failed to normalize after an appropriate period of half-life time post-surgery. To determine the use of chemotherapy for children with stage II germ cell tumors, we analyzed the outcomes (relapse rate and overall survival) of patients who were treated at the Sun Yat-sen University Cancer Center between January 1990 and May 2013. Twenty-four pediatric patients with a median age of 20 months (range, 4 months to 17 years) were enrolled in this study. In 20 cases (83.3%), the tumors had yolk sac histology. For definitive treatment, 21 patients underwent surgery alone, and 3 patients received surgery and adjuvant chemotherapy. No relapse was observed in the 3 patients who received adjuvant chemotherapy, whereas relapse occurred in 16 of the 21 patients (76.2%) treated with surgery alone. There were a total of 2 deaths. Treatment was stopped for 1 patient, who died 3 months later due to the tumor. The other patient achieved complete response after salvage treatment, but developed lung and pelvic metastases 7 months later and died of the tumor after stopping treatment. For children treated with surgery alone and surgery combined with adjuvant chemotherapy, the 3-year event-free survival rates were 23.8% and 100%, respectively (P = 0.042), and the 3-year overall survival rates were 90.5% and 100%, respectively (P = 0.588). These results suggest that adjuvant chemotherapy can help to reduce the recurrence rate and increase the survival rate for patients with stage II germ cell tumors.

Brain metastasis in children with stage 4 neuroblastoma after multidisciplinary treatment.

INTRODUCTION: Brain metastasis is common in relapsed neuroblastoma patients, but the characteristics of brain metastasis remain largely unknown. This study aimed to investigate the status of brain metastasis with neuroblastoma in South China. METHODS: In this retrospective case-based study, 106 patients with stage 4 neuroblastoma from the Department of Pediatric Oncology in Sun Yat-sen University Cancer Center between January 2004 and May 2013 were included. The incidence, risk factors, and survival status of these patients were reviewed and analyzed. RESULTS: Of the 106 patients, 11 (10.4%) developed brain metastasis, accounting for 20.0% of 55 patients with relapse or progression. The age at initial diagnosis of the 11 patients ranged from 2 to 10 years (median 4 years), which was younger than that of the patients without brain metastasis (median 5 years, range 1-10 years, P=0.073). The male to female ratio of the 11 patients was 8:3, which was not significantly different from that of the patients without brain metastasis (P=0.86). Patients with brain metastasis had higher lactate dehydrogenase levels than those without brain metastasis, but the differences were not significant (P=0.076). Eight patients died, and 3 patients survived. The median interval from the initial diagnosis to the development of brain metastasis was 18 months (range 6-32 months). The median survival was 4 months (range 1 day to 29 months) after the diagnosis of brain metastasis. The median interval from the manifestation of brain metastasis to death was 3 months (range 1 day to 11 months). CONCLUSIONS: High-risk factors for brain metastasis in cases of neuroblastoma include bone marrow involvement and a younger age at initial diagnosis. Nevertheless, multiple treatment modalities can improve disease-free survival.

The clinical characteristics and treatment outcome of 57 children and adolescents with primary central nervous system germ cell tumors.

Primary central nervous system germ cell tumors (CNS-GCTs) in children and adolescents have unique clinical features and methods of treatment compared with those in adults. There is little information about Chinese children and adolescents with CNS-GCTs. Therefore, in this study we retrospectively analyzed the clinical features and treatment outcome of Chinese children and adolescents with primary CNS-GCTs. Between January 2002 and December 2012, 57 untreated patients from a single institution were enrolled. They were diagnosed with CNS-GCTs after pathologic or clinical assessment. Of the 57 patients, 41 were males and 16 were females, with a median age of 12.8 years (range, 2.7 to 18.0 years) at diagnosis; 43 (75.4%) had non-germinomatous germ cell tumors (NGGCTs) and 14 (24.6%) had germinomas; 44 (77.2%) had localized disease and 13 (22.8%) had extensive lesions. Fifty-three patients completed the prescribed treatment, of which 18 underwent monotherapy of surgery, radiotherapy, or chemotherapy, and 35 underwent multimodality therapies that included radiotherapy combined with chemotherapy or surgery combined with chemotherapy and/or radiotherapy. PEB (cisplatin, etoposide, and bleomycin) protocol was the major chemotherapy regimen. The median follow-up time was 32.3 months (range, 1.2 to 139 months). Fourteen patients died of relapse or disease progression. The 3-year event-free survival (EFS) and overall survival rates for all patients were 72.2% and 73.8%, respectively. The 3-year EFS was 92.9% for germinomas and 64.8% for NGGCTs (P = 0.064). The 3-year EFS rates for patients with NGGCTs who underwent monotherapy and multimodality therapies were 50.6% and 73.5%, respectively (P = 0.042). Our results indicate that multimodality therapies including chemotherapy plus radiotherapy were better treatment option for children and adolescents with CNS-GCTs.

Botulinum toxin type A injection combined with biofeedback in the treatment of spastic pelvic floor syndrome.

BACKGROUND: Spastic pelvic floor syndrome (SPFS) is a refractory pelvic floor disease characterized by abnormal (uncoordinated) contractions of the external anal sphincter and puborectalis muscle during defecation, resulting in rectal emptation and obstructive constipation. The clinical manifestations of SPFS are mainly characterized by difficult defecation, often accompanied by a sense of anal blockage and drooping. Manual defecation is usually needed during defecation. From physical examination, it is commonly observed that the patient's anal muscle tension is high, and it is difficult or even impossible to enter with his fingers. AIM: To investigate the characteristics of anorectal pressure and botulinum toxin A injection combined with biofeedback in treating pelvic floor muscle spasm syndrome. METHODS: Retrospective analysis of 50 patients diagnosed with pelvic floor spasm syndrome. All patients underwent pelvic floor surface electromyography assessment, anorectal dynamics examination, botulinum toxin type A injection 100 U intramuscular injection, and two cycles of biofeedback therapy. RESULTS: After the botulinum toxin A injection combined with two cycles of biofeedback therapy, the patient's postoperative resting and systolic blood pressure were significantly lower than before surgery (P < 0.05). Moreover, the electromyography index of the patients in the resting stage and post-resting stages was significantly lower than before surgery (P < 0.05). CONCLUSION: Botulinum toxin A injection combined with biofeedback can significantly reduce pelvic floor muscle tension in treating pelvic floor muscle spasm syndrome. Anorectal manometry is an effective method to evaluate the efficacy of treatment objectively. However, randomized controlled trials are needed.

Synthetic approaches and application of representative clinically approved fluorine-enriched anti-cancer medications.

Fluorine possesses distinctive chemical characteristics, such as its strong electron-withdrawing ability and small atomic size, which render it an invaluable asset in the design and optimization of pharmaceuticals. The utilization of fluorine-enriched medications for combating cancer has emerged as a prominent approach in medicinal chemistry and drug discovery, offering improved clinical outcomes and enhanced pharmacological properties. This comprehensive review explores the synthetic approaches and clinical applications of approved 22 representative fluorinated anti-cancer drugs from 2019 to present, shedding light on their historical development, brand names, drug target activity, mechanism of action, preclinical pharmacodynamics, clinical efficacy, and toxicity. Additionally, the review provides an extensive analysis of the representative synthetic techniques employed. Overall, this review emphasizes the significance of incorporating fluorine chemistry into anti-cancer drug research while highlighting promising future prospects for exploring compounds enriched with fluorine in the battle against cancer.

The impact of high-altitude migration on cardiac structure and function: a 1-year prospective study.

Introduction: The trend of human migration to terrestrial high altitudes (HA) has been increasing over the years. However, no published prospective studies exist with follow-up periods exceeding 1 month to investigate the cardiac change. This prospective study aimed to investigate the changes in cardiac structure and function in healthy young male lowlanders following long-term migration to HA. Methods: A total of 122 Chinese healthy young males were divided into 2 groups: those migrating to altitudes between 3600 m and 4000 m (low HA group, n = 65) and those migrating to altitudes between 4000 m and 4700 m (high HA group, n = 57). Traditional echocardiographic parameters were measured at sea level, 1 month and 1 year after migration to HA. Results: All 4 cardiac chamber dimensions, areas, and volumes decreased after both 1 month and 1 year of HA exposure. This reduction was more pronounced in the high HA group than in the low HA group. Bi-ventricular diastolic function decreased after 1 month of HA exposure, while systolic function decreased after 1 year. Notably, these functional changes were not significantly influenced by altitude differences. Dilation of the pulmonary artery and a progressive increase in pulmonary artery systolic pressure were observed with both increasing exposure time and altitude. Additionally, a decreased diameter of the inferior vena cava and reduced bicuspid and tricuspid blood flow velocity indicated reduced blood flow following migration to the HA. Discussion: 1 year of migration to HA is associated with decreased blood volume and enhanced hypoxic pulmonary vasoconstriction. These factors contribute to reduced cardiac chamber size and slight declines in bi-ventricular function.

Germinal-center type B-cell classification and clinical characteristics of Chinese pediatric diffuse large B-cell lymphoma: a report of 76 cases.

Pediatric diffuse large B-cell lymphoma (DLBCL) is a highly aggressive disease with unique clinical characteristics. This study analyzed the germinal-center type B-cell (GCB) classification and clinical characteristics of Chinese pediatric DLBCL. A total of 76 patients with DLBCL newly diagnosed in Sun Yat-sen University Cancer Center between February 2000 and May 2011, with an age younger than 18 years, were included in the analysis. The male/female ratio was 3.47:1. The median age was 12 years (range, 2 to 18 years), and 47 (61.8%) patients were at least 10 years old. Of the 76 patients, 48 (63.2%) had stage III/IV disease, 9 (11.8%) had bone marrow involvement, 1 (1.3%) had central nervous system (CNS) involvement, and 5 (6.6%) had bone involvement. The GCB classification was assessed in 45 patients: 26 (57.8%) were classified as GCB subtype, and 19 (42.2%) were classified as non-GCB subtype. The modified B-NHL-BFM-90/95 regimen was administered to 50 patients, and the 4-year event-free survival (EFS) rate was 85.8%. Among these 50 patients, 31 were assessed for the GCB classification: 17 (54.8%) were classified as GCB subtype, with a 4-year EFS rate of 88.2%; 14 (45.2%) were classified as non-GCB subtype, with a 4-year EFS rate of 92.9%. Our data indicate that bone marrow involvement and stage III/IV disease are common in Chinese pediatric DLBCL patients, whereas the percentage of patients with the GCB subtype is similar to that of patients with the non-GCB subtype. The modified B-NHL-BFM-90/95 protocol is an active and effective treatment protocol for Chinese pediatric patients with DLBCL.

Safety of in vitro amplified HLA-haploidentical donor immune cell infusions for childhood malignancies.

In vitro amplified human leukocyte antigen (HLA)-haploidentical donor immune cell infusion (HDICI) is not commonly used in children. Therefore, our study sought to evaluate its safety for treating childhood malignancies. Between September 2011 and September 2012, 12 patients with childhood malignancies underwent HDICI in Sun Yat-sen University Cancer Center. The median patient age was 5.1 years (range, 1.7-8.4 years). Of the 12 patients, 9 had high-risk neuroblastoma (NB) [7 showed complete response (CR), 1 showed partial response (PR), and 1 had progressive disease (PD) after multi-modal therapies], and 3 had Epstein-Barr virus (EBV)-positive lymphoproliferative disease (EBV-LPD). The 12 patients underwent a total of 92 HDICIs at a mean dose of 1.6×10(8) immune cells/kg body weight: 71 infusions with natural killer (NK) cells, 8 with cytokine-induced killer (CIK) cells, and 13 with cascade primed immune cells (CAPRIs); 83 infusions with immune cells from the mothers, whereas 9 with cells from the fathers. Twenty cases (21.7%) of fever, including 6 cases (6.5%) accompanied with chills and 1 (1.1%) with febrile convulsion, occurred during infusions and were alleviated after symptomatic treatments. Five cases (5.4%) of mild emotion changes were reported. No other adverse events occurred during and after the completion of HDIDIs. Neither acute nor chronic graft versus host disease (GVHD) was observed following HDICIs. After a median of 5.0 months (range, 1.0-11.5 months) of follow-up, the 2 NB patients with PR and PD developed PD during HDICIs. Of the other 7 NB patients in CR, 2 relapsed in the sixth month of HDICIs, and 5 maintained CR with disease-free survival (DFS) ranging from 4.5 to 11.5 months (median, 7.2 months). One EBV-LPD patient achieved PR, whereas 2 had stable disease (SD). Our results show that HDICI is a safe immunotherapy for childhood malignancies, thus warranting further studies.

[Molecular evolution of the sulphite efflux gene SSU1 in Saccharomyces cerevisiae].

The SSU1 gene encoding a membrane sulfite pump is a main facilitator invovled in sulfite efflux. In Saccharomyce cerevisiae, various range of resistance to sulfite was observed among strains. To explore the evolution traits of SSU1 gene, the population data of S. cerevisiae were collected and analyzed. The phylogenetic analysis indicated that S. cerevisiae population can be classified into three sub-populations, and the positive selection was detected in population by McDonald-Kreitman test. The anaylsis of Ka/Ks ratios further showed that S. cerevisiae sub-population was undergoing positive selection. This finding was also supported by PAML branch model. Nine potential positive selection sites were predicted by branch-site model, and four sites exclusively belong to the sub-population under positive seletion. The data from ssulp protein structure demonstrated that three sites are substitutions between polar and hydrophobic amino acids, and only one site of substitutaion from basic amino acid to basic amino acid (345R/K). Because amino acid pKa values are crucial for sulfite pump to maintain their routine function, positive selection of these amino acid substitutions might affect sulfite efflux efficient.

Pharmacokinetics and Bioequivalence of Abiraterone Acetate Tablets in Healthy Chinese Volunteers: An Open, Randomized, Single-Dose, Three-Period, Three-Sequence Crossover Study.

BACKGROUND AND OBJECTIVE: Abiraterone acetate tablet is an inhibitor of androgen synthesis, primarily for the treatment of metastatic castration-resistant prostate cancer (mCRPC). This study evaluated the bioequivalence and pharmacokinetics of the reference and test formulations of abiraterone acetate tablets in healthy Chinese volunteers. METHODS: A single-center, open, single-dose, randomized, three-period, three-sequence, semi-repeat (only repeated reference formulations), and reference formulation-corrected fasting reference-scaled average bioequivalence test was conducted in 36 healthy volunteers included in this study. Volunteers were randomly assigned to one of three groups in a 1:1:1 ratio. There was a minimum 7-day washout period between each dose. Blood samples were collected at prescribed time intervals, the plasma concentration of abiraterone acetate tablets was determined by liquid chromatography-tandem mass spectrometry, and adverse events were recorded. RESULTS: Under fasting conditions, the maximum plasma concentration (Cmax) was 27.02 ± 14.21 ng/mL, area under the concentration-time curve from time zero to time t (AUCt) was 125.30 ± 82.41 h·ng/mL, and AUC from time zero to infinity (AUC∞) was 133.70 ± 83.99 h·ng/mL. The 90% confidence intervals (CIs) of the geometric mean ratio (GMR) of AUCt and AUC∞ were in the range of 0.8000-1.2500, and the coefficient of variation (CVWR) of Cmax was more than 30%. The Critbound result was - 0.0522, and the GMR was between 0.8000 and 1.2500. CONCLUSION: Both test and reference formulations of abiraterone acetate tablets were bioequivalent in healthy Chinese subjects under fasting conditions. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04863105, registered 26 April 2021-retrospectively registered ( https://register. CLINICALTRIALS: gov/prs/app/action/SelectProtocol?sid=S000ARAA&selectaction=Edit&uid=U00050YQ&ts=2&cx=-vbtjri.

Discovery and Characterization of Intercondylar Transphyseal Complexes and their Oncological Significance in Transphyseal Extension of Pediatric Osteosarcoma.

OBJECTIVE: To explore whether there exist undiscovered transphyseal vasculature-canal compound structures in immature femurs and tibias, and reveal their potential oncological impact. METHODS: This investigation was divided into a morphological study and a clinical study. In the morphological part, a new-identified anatomic structure was investigated by using radiographical, anatomical, and histological methodologies. Twenty-eight 1-mm-slice thickness magnetic resonance images of pediatric knees were generated and 10 pediatric knees were dissected to verify the existence and universality, observe the radiographic and anatomic characteristics, and determined the located region of this structure. Hematoxylin-eosin staining, immunofluorescence, and angiography procedures were performed to illustrate its histological feature, molecular identification, and vascular origination, respectively. In the clinical part, 38 pediatric osteosarcoma patients were enrolled from January 2014 to December 2020. A descriptive clinical study including 13 typical participants was conducted to investigate the oncological significance of this new-identified structure. Meanwhile, the discrepancy in transphyseal osteosarcoma extension between different physeal regions was evaluated in a cross-sectional study. RESULTS: In the morphological study, we discovered a new-found vasculature-canal compound structure, intercondylar transphyseal complex (ITC), which originated from the middle genicular vessels, traversed the whole epiphysis, and breached the intact open physis in the immature proximal tibia or distal femur. The components of ITC included the juxta-articular, epiphyseal, and transphyseal segments of vessels, the canals that traverse the entire epiphysis and physis and enclosed the vessels, vascular foramina on articular facet and foramina-covered synovium. Depending on the location, ITCs can be divided into three types: femoral ITC, anterior tibial ITC, and posterior tibial ITC. Clinically, the ITC may facilitate intercondylar transphyseal sarcomatous dissemination without damaging the adjacent physeal cartilage. Compared to bilateral condylar physes, more osteosarcomas transgressed the open growth plates through intercondylar regions in which ITC was located (P = 0.022). CONCLUSION: As the "gap" on intact open physis, ITC, which is a new-identified compound structure in intercondylar regions of immature femur or tibia, may promote intercondylar transphyseal tumor extension. Moreover, the identification and characterization of ITC subvert some traditional comprehensions about physis and may provide novel perspectives for pediatric osteosarcomas.

Immune-Related LncRNAs as Prognostic Factors for Pediatric Rhabdoid Tumor of the Kidney.

Background: Immune-related long noncoding RNAs (IrlncRNAs) are recognized as important prognostic factors in a variety of cancers, but thus far, their prognostic value in pediatric rhabdoid tumor of the kidney (pRTK) has not been reported. Here, we clarified the associations between IrlncRNAs and overall survival (OS) of pRTK patients and constructed a model to predict their prognosis. Methods: We accessed RNA sequencing data and corresponding clinical data of pRTK from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database. An expression profile of immune-related genes (Irgenes) and lncRNAs of pRTK was extracted from the RNA sequencing data. IrlncRNAs were defined by co-expression analysis of lncRNAs and Irgenes. The limma R package was used to identify differential expression IrlncRNAs. Univariate and multivariate Cox regression analyses were conducted to build a prognostic IrlncRNAs model. The performance of this prognostic model was validated by multimethods, like ROC curve analysis. Results: A total of 1097 IrlncRNAs were defined. Univariate Cox regression analysis identified 7 IrlncRNAs (AC004791.2, AP003068.23, RP11-54O7.14, RP11-680F8.1, TBC1D3P1-DHX40P1, TUNAR, and XXbac-BPG308K3.5) and were significantly associated with OS. Multivariate regression analysis constructed the best prognostic model based on the expression of AC004791.2, AP003068.23, RP11-54O7.14, TBC1D3P1-DHX40P1, and TUNAR. According to the prognostic model, a risk score of each patient was calculated, and patients were divided into high-risk and low-risk groups accordingly. The survival time of low-risk patients was significantly better than high-risk patients (p < 0.001). Univariate (hazard ratio 1.098, 95% confidence interval 1.048-1.149, p value <0.001) and multivariate (hazard ratio 1.095, 95% confidence interval 1.043-1.150, p value <0.001) analyses confirmed that the prognostic model was reliable and independent in prediction of OS. Time-dependent ROC analysis showed that 1-year survival AUC of prognostic model, stage, age, and sex was 0.824, 0.673, 0.531, and 0.495, respectively, which suggested that the prognostic model was the best predictor of survival in pRTK patients. Conclusions: The prognostic model based on 5 IrlncRNAs was robust and could better predict the survival of pRTK than other clinical factors. Additionally, the mechanism of regulation and action of prognosis-associated lncRNAs could provide new avenues for basic research to explore the mechanism of tumor initiation and development in order to prevent and treat pRTK.

Pharmacokinetics and Bioequivalence of Sitagliptin Phosphate/Metformin Hydrochloride Tablets in Healthy Chinese Subjects: A Randomized, Open-Label, Crossover Study.

OBJECTIVE: Our objective was to evaluate the pharmacokinetics and bioequivalence of test and reference (JANUMET®) formulations of sitagliptin phosphate/metformin hydrochloride tablets at a single dose of 50 mg/850 mg. METHODS: The study was a randomized, open-label, two-period, double-crossover trial. Volunteers under fasting (n = 24) and fed (n = 24) conditions were given a single oral dose of test or reference formulations of sitagliptin phosphate/metformin hydrochloride tablets 50 mg/850 mg. We used the liquid chromatography tandem mass spectrometry method to determine the concentrations of sitagliptin and metformin in the plasma of subjects. Pharmacokinetic metrics were calculated using the WinNonlin 7.0 program, and bioequivalence was evaluated using SAS 9.4. RESULTS: Under the fasting condition, the 90% confidence intervals (CIs) of geometric mean ratio for maximum plasma drug concentration (Cmax), area under the plasma concentration-time curve from time zero to time t (AUC0-t), and AUC from time zero to infinity (AUC0-∞) of sitagliptin between the test and reference groups were 101.70-120.62%, 99.81-105.61%, and 100.27-106.12%, respectively; for metformin, they were 90.39-111.48%, 94.76-109.12%, and 95.76-110.38%, respectively. Under the fed condition, they were 102.12-117.31%, 100.80-107.81%, and 100.82-107.78%, respectively, for sitagliptin and 95.53-105.22%, 92.76-103.07%, and 93.40-104.14%, respectively, for metformin. Both were generally well-tolerated. CONCLUSION: The two formulations of sitagliptin phosphate/metformin hydrochloride tablets were bioequivalent under fasting and fed conditions in healthy Chinese subjects.

Cis-cinnamic acid-enhanced 1 gene plays a role in regulation of Arabidopsis bolting.

Cis-cinnamic acid (CA) is one of many cis-phenylpropanoids found in both monocots and dicots. It is produced in planta via sunlight-mediated isomerization of trans-cinnamic acid. This pair of isomers plays a differential role in regulation of plant growth. A functional proteomics approach has been adopted to identify genes of cis/trans-CA mixture-enhanced expression. Out of 1,241 proteins identified by mass spectrometry, 32 were CA-enhanced and 13 repressed. Further analysis with the molecular biology approach revealed 2 cis-CA (Z usammen-CA)-E nhanced genes, named ZCE1 and ZCE2, which encode members of the major latex protein-like (MLPL) gene family. The transcript accumulation of both genes is positively correlated with the amount of cis-CA applied externally, ranging from 1 to 100 µM. ZCE1 transcript accumulation is enhanced largely by cis-CA and slightly by other cis-phenylpropanoids. Treatment of several well-characterized plant growth regulator perception-deficient mutants with cis-CA is able to promote ZCE1 transcript accumulation, suggestive of distinct signaling pathways regulating cis-CA response. The zce1 loss-of-function mutant produced via the RNA-interference technique produces an earlier bolting phenotype in Arabidopsis, suggesting that ZCE1 plays a role in promoting vegetative growth and delay flowering.

Estimation-based approach for underwater image restoration.

For underwater image restoration, modeling of PSF relies on a priori knowledge of the inherent optical properties under water. But full knowledge-based restoration could be corrupted by the complexity and instability of the application environments. Concerned with representation of the backscattering noise of underwater image, this Letter proposes a simplified multilayer transfer model to formulate both the point spread function and the statistics of backscattering noise explicitly. Consequently, the parameters for image restoration are estimated from in situ measurement of the backscattering background without a priori knowledge of the inherent optical properties. The robust Wiener filter is applied to implement the restoration. Experimental results are presented.

Control of Tobacco mosaic virus by PopW as a result of induced resistance in tobacco under greenhouse and field conditions.

In a previous study, we isolated a new harpin protein, PopW, from the bacterium Ralstonia solanacearum ZJ3721 that can induce a hypersensitive response in tobacco, Nicotiana tabacum, leaves. In the current study, we demonstrate that, in a greenhouse experiment, PopW induced tobacco-acquired resistance against the Tobacco mosaic virus (TMV) with a biocontrol efficacy of 80.9 to 97.4% at a concentration as low as 25 µg/ml in both PopW-treated and neighboring leaves. The resistance induced by PopW is systemic acquired resistance mediated by salicylic acid, which was certified by the development of resistance being accompanied by the expression of the pathogenesis-related-1 gene (PR1) 8 h after PopW was sprayed onto the tobacco leaves. In addition, hydrogen peroxide began to accumulate 10 h after PopW spraying, peaking at 24 h with a maximum concentration of 1.97 µM/g fresh weight. The activities of phenylalanine ammonia lyase (EC4.3.1.5), polyphenoloxidase (EC1.14.18.1), and peroxidase (EC1.11.1.7) also increased, peaking at different times in the PopW-treated tobacco leaves. PopW also reduced the level of TMV disease in field trials with a biocontrol efficacy of 45.2%. Furthermore, PopW both increased tobacco yield (by 30.4 more than in control plants) and improved tobacco foliar quality, with an increase of 50.2% in the number of first-class tobacco leaves from treated compared with untreated plants. All of these results indicate that the new harpin protein PopW has the potential to be an effective biocontrol agent against TMV in tobacco.