Whole-exome sequencing reveals causative genetic variants for several overgrowth syndromes in molecularly negative Beckwith-Wiedemann spectrum.

Background Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder caused by (epi)genetic alterations at 11p15. Because approximately 20% of patients test negative via molecular testing of peripheral blood leukocytes, the concept of Beckwith-Wiedemann spectrum (BWSp) was established to encompass a broader cohort with diverse and overlapping phenotypes. The prevalence of other overgrowth syndromes concealed within molecularly negative BWSp remains unexplored. Methods We conducted whole-exome sequencing (WES) on 69 singleton patients exhibiting molecularly negative BWSp. Variants were confirmed by Sanger sequencing or quantitative genomic PCR. We compared BWSp scores and clinical features between groups with classical BWS (cBWS), atypical BWS or isolated lateralised overgrowth (aBWS+ILO) and overgrowth syndromes identified via WES. Results Ten patients, one classified as aBWS and nine as cBWS, showed causative gene variants for Simpson-Golabi-Behmel syndrome (five patients), Sotos syndrome (two), Imagawa-Matsumoto syndrome (one), glycosylphosphatidylinositol biosynthesis defect 11 (one) or 8q duplication/9p deletion (one). BWSp scores did not distinguish between cBWS and other overgrowth syndromes. Birth weight and height in other overgrowth syndromes were significantly larger than in aBWS+ILO and cBWS, with varying intergroup frequencies of clinical features. Conclusion Molecularly negative BWSp encapsulates other syndromes, and considering both WES and clinical features may facilitate accurate diagnosis.

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.

Reciprocal regulation between RACGAP1 and AR contributes to endocrine therapy resistance in prostate cancer.

BACKGROUND: Endocrine resistance driven by sustained activation of androgen receptor (AR) signaling pathway in advanced prostate cancer (PCa) is fatal. Characterization of mechanisms underlying aberrant AR pathway activation to search for potential therapeutic strategy is particularly important. Rac GTPase-activating protein 1 (RACGAP1) is one of the specific GTPase-activating proteins. As a novel tumor proto-oncogene, overexpression of RACGAP1 was related to the occurrence of various tumors. METHODS: Bioinformatics methods were used to analyze the relationship of expression level between RACGAP1 and AR as well as AR pathway activation. qRT-PCR and western blotting assays were performed to assess the expression of AR/AR-V7 and RACGAP1 in PCa cells. Immunoprecipitation and immunofluorescence experiments were conducted to detect the interaction and co-localization between RACGAP1 and AR/AR-V7. Gain- and loss-of-function analyses were conducted to investigate the biological roles of RACGAP1 in PCa cells, using MTS and colony formation assays. In vivo experiments were conducted to evaluate the effect of RACGAP1 inhibition on the tumor growth. RESULTS: RACGAP1 was a gene activated by AR, which was markedly upregulated in PCa patients with CRPC and enzalutamide resistance. AR transcriptionally activated RACGAP1 expression by binding to its promoter region. Reciprocally, nuclear RACGAP1 bound to the N-terminal domain (NTD) of both AR and AR-V7, blocking their interaction with the E3 ubiquitin ligase MDM2. Consequently, this prevented the degradation of AR/AR-V7 in a ubiquitin-proteasome-dependent pathway. Notably, the positive feedback loop between RACGAP1 and AR/AR-V7 contributed to endocrine therapy resistance of CRPC. Combination of enzalutamide and in vivo cholesterol-conjugated RIG-I siRNA drugs targeting RACGAP1 induced potent inhibition of xenograft tumor growth of PCa. CONCLUSION: In summary, our results reveal that reciprocal regulation between RACGAP1 and AR/AR-V7 contributes to the endocrine resistance in PCa. These findings highlight the therapeutic potential of combined RACGAP1 inhibition and enzalutamide in treatment of advanced PCa.

Maize (Zea mays L.) Plants Alter the Fate and Accumulate Nonextractable Residues of Sulfamethoxazole in Farmland Soil.

The fate of sulfonamide antibiotics in farmlands is crucial for food and ecological safety, yet it remains unclear. We used [phenyl-U-14C]-labeled sulfamethoxazole (14C-SMX) to quantitatively investigate the fate of SMX in a soil-maize system for 60 days, based on a six-pool fate model. Formation of nonextractable residues (NERs) was the predominant fate for SMX in unplanted soil, accompanied by minor mineralization. Notably, maize plants significantly increased SMX dissipation (kinetic constant kd = 0.30 day-1 vs 0.17 day-1), while substantially reducing the NER formation (92% vs 58% of initially applied SMX) and accumulating SMX (40%, mostly bound to roots). Significant NERs (maximal 29-42%) were formed via physicochemical entrapment (determined using silylation), which could partially be released and taken up by maize plants. The NERs consisted of a considerable amount of SMX formed via entrapment (1-8%) and alkali-hydrolyzable covalent bonds (2-12%, possibly amide linkage). Six and 10 transformation products were quantified in soil extracts and NERs, respectively, including products of hydroxyl substitution, deamination, and N-acylation, among which N-lactylated SMX was found for the first time. Our findings reveal the composition and instability of SMX-derived NERs in the soil-plant system and underscore the need to study the long-term impacts of reversible NERs.

Reciprocal negative feedback regulation of ATF6α and PTEN promotes prostate cancer progression.

Phosphatase and tensin homolog (PTEN) loss tightly correlates with prostate cancer (PCa) progression and metastasis. Inactivation of PTEN leads to abnormal activation of PI3K/AKT pathway. However, results from clinical trials with AKT inhibitors in PCa have been largely disappointing. Identification of novel regulators of PTEN in PTEN-dysfunctional PCa is urgently needed. Here we demonstrated that the expression level of PTEN is inversely correlated with the signature score of unfolded protein response (UPR) in PCa. Importantly, PTEN suppresses the activity of ATF6α, via interacting to de-phosphorylate ATF6α and consequently inhibiting its nuclear translocation. Conversely, ATF6α promotes the ubiquitination and degradation of PTEN by inducing CHIP expression. Thus, ATF6α and PTEN forms a negative feedback loop during PCa progression. Combination of ATF6α inhibitor with AKT inhibitor suppresses tumor cell proliferation and xenograft growth. Importantly, this study highlighted ATF6α as a therapeutic vulnerability in PTEN dysfunctional PCa.

Alexithymia and negative emotions among nursing students: a moderated mediation model.

Nursing students, who comprise a high percentage of China's college students, experience many psychological problems; however, few studies explored the mechanisms underlying these problems. This cross-sectional study explored the relationships and mechanisms of depression, anxiety, stress, and narrative disorders in senior nursing students. Questionnaires were administered to 380 senior nursing students in Hubei Province using the Sociodemographic Questionnaire, Toronto Alexithymia-20 Scale, Perceived Social Support Scale, 10-Item Connor-Davidson Resilience Scale, and Depression-Anxiety-Stress Scale. After controlling for sociodemographic variables, Hayes' PROCESS macros were used to test how psychological resilience moderates the relationships among narrative disorders, negative affect, and perceived social support. Bootstrap confidence intervals tested for indirect effects. Correlation analyses revealed that alexithymia was correlated significantly positively with depression-anxiety-stress (r = 0.57, 0.56, and 0.58, resp.) and significantly negatively with perceived social support (r = 0-0.46). Psychological resilience was correlated significantly negatively with alexithymia (r=-0.39) and depression-anxiety-stress (r=-0.31, -0.30, and-0.32, resp.) but significantly positively with perceived social support(r = 0.50). Perceived social support was correlated significantly negatively with depression-anxiety-stress (r=-0.33, -0.34, and - 0.42 resp.). Stress was correlated significantly positively with anxiety and depression (r = 0.81 and 0.77, resp.). Psychological resilience was a partial mediator between depression and dysphoria (ß=-0.08, p < 0.05). Dysphoria directly predicted anxiety (ß = 0.31) and stress (ß = 0.37); moreover,alexithymia predicted depression not only directly but also through the mediating effect of psychological resilience. Therefore, educators and clinical administrators must promote and recognise negative emotions among nursing students to help ensure the nursing workforce's stability.

Safety, pharmacokinetics, and pharmacodynamics of SHR7280, an oral gonadotropin-releasing hormone receptor antagonist, in healthy men: a randomized, double-blind, placebo-controlled phase 1 study.

BACKGROUND: Gonadotropin-releasing hormone (GnRH) antagonists are a promising therapeutic approach for treating hormone-dependent prostate cancer. Currently, the mainstream GnRH antagonists are polypeptide agents administered through subcutaneous injection. In this study, we evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of SHR7280, an oral small molecule GnRH antagonist, in healthy men. METHODS: This phase 1 trial was a randomized, double-blind, placebo-controlled, and dose-ascending study. Eligible healthy men were randomized in a 4:1 ratio to receive either oral SHR7280 tablets or placebo twice daily (BID) for 14 consecutive days. The SHR7280 dose was initiated at 100 mg BID and then sequentially increased to 200, 350, 500, 600, 800, and 1000 mg BID. Safety, PK, and PD parameters were assessed. RESULTS: A total of 70 subjects were enrolled and received the assigned drug, including 56 with SHR7280 and 14 with placebo. SHR7280 was well-tolerated. The incidence of adverse events (AEs, 76.8% vs 85.7%) and treatment-related AEs (75.0% vs 85.7%), as well as the severity of AEs (moderate AEs, 1.8% vs 7.1%) were similar between the SHR7280 group and placebo group. SHR7280 was rapidly absorbed in a dose-dependent manner, with a median Tmax of each dose group ranging from 0.8 to 1.0 h on day 14 and a mean t1/2 ranging from 2.8 to 3.4 h. The PD results demonstrated that SHR7280 exhibited a rapid and dose-proportional suppression of hormones, including LH, FSH, and testosterone, with maximum suppression achieved at doses of 800 and 1000 mg BID. CONCLUSIONS: SHR7280 showed an acceptable safety profile, as well as favorable PK and PD profiles within a dose range of 100 to 1000 mg BID. This study proposes a rationale for further investigation of SHR7280 as a potential androgen deprivation therapy. TRIAL REGISTRATION: Clinical trials.gov NCT04554043; registered September 18, 2020.

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.

Treatment outcomes for response-based radiotherapy in children and adolescents with central nervous system germinoma: a prospective study.

PURPOSE: The optimal dose and range of radiotherapy for central nervous system (CNS) germinoma have not yet been established. This study aimed to investigate the effects of individualized radiotherapy on the prognosis of patients with germinoma. METHODS: Based on imaging examination, tumor markers, and pathologic results, patients with germinoma received different radiotherapy strategies, including R1 (24 Gy whole ventricular irradiation + tumor-bed boost to 40 Gy), R2 (24-30 Gy craniospinal irradiation + tumor-bed boost to 54 Gy), R3 (24 Gy craniospinal irradiation + tumor-bed boost to 40 Gy), and R4 (30 Gy craniospinal irradiation + tumor-bed boost to 54 Gy with 45 Gy to spinal metastasis). RESULTS: A total of 77 patients were enrolled in this study between January 2015 and March 2021. The 3-year event-free survival (EFS) and overall survival (OS) of the whole cohort were 94.7% ± 2.6% and 96.0% ± 2.3%, respectively. The 3-year EFS for patients with localized and metastatic disease were 96.6% ± 2.4% and 89.2% ± 7.2%, respectively. The 3-year EFS of patients receiving R1, R2, R3, and R4 radiotherapy were 100%, 94.1% ± 5.7%, 100%, and 86.2% ± 9.1%, respectively. CONCLUSION: Good prognosis was still achieved after reducing dose and extent of radiation for the patients who achieved complete response (CR) after induction chemotherapy or pathological CR after second-look surgery.

Identification of miR-1-3p, miR-143-3p and miR-145-5p association with bone metastasis of Gleason 3+4 prostate cancer and involvement of LASP1 regulation.

Gleason Score (GS) 3 + 4 prostate cancer (PCa) is heterogeneous in clinical course and molecular features. Risk stratification of indolent and aggressive PCa with GS 3 + 4 is critical, especially those with bone metastasis (BM) potential. Microarray-based microRNA(miRNA) profiling with eight PCa cases with or without BM was used to screen the candidate miRNAs associated with BM. Transwell and MTS assays were used to characterize the function of miRNAs and target gene LASP1. RT-qPCR and immunohistochemistry assays were utilized to illustrate the clinical significance of miRNAs and target gene in a cohort of 309 Chinese PCa cases. In the current study, we identified that miR-1-3p, miR-143-3p and miR-145-5p are associated with BM of GS 3 + 4 PCa. Through functional experiments, we show that miR-1-3p/143-3p/145-5p promotes proliferation and migration of PCa in vitro. LASP1 was predicted as the common target of these three miRNAs which was further confirmed by a luciferase assay. Overexpression of LASP1 was correlated with higher GS, higher pathological stage, and the presence of metastasis by immunohistochemistry. siRNA knockdown of LASP1 significantly suppressed proliferation and migration, whereas overexpression of LASP1 promoted it. Bioinformatics analysis revealed the involvement of Wnt signaling pathway in LASP1 mediated function. LASP1 may activate Wnt signaling by interacting with ß-catenin. In all, we suggest that miR-1-3p/143-3p/145-5p are associated with BM of Gleason 3 + 4 PCa. LASP1 is the common target of these miRNAs and may active Wnt signaling by interacting with ß-catenin.

THOC1 deficiency leads to late-onset nonsyndromic hearing loss through p53-mediated hair cell apoptosis.

Apoptosis of cochlear hair cells is a key step towards age-related hearing loss. Although numerous genes have been implicated in the genetic causes of late-onset, progressive hearing loss, few show direct links to the proapoptotic process. By genome-wide linkage analysis and whole exome sequencing, we identified a heterozygous p.L183V variant in THOC1 as the probable cause of the late-onset, progressive, non-syndromic hearing loss in a large family with autosomal dominant inheritance. Thoc1, a member of the conserved multisubunit THO/TREX ribonucleoprotein complex, is highly expressed in mouse and zebrafish hair cells. The thoc1 knockout (thoc1 mutant) zebrafish generated by gRNA-Cas9 system lacks the C-startle response, indicative of the hearing dysfunction. Both Thoc1 mutant and knockdown zebrafish have greatly reduced hair cell numbers, while the latter can be rescued by embryonic microinjection of human wild-type THOC1 mRNA but to significantly lesser degree by the c.547C>G mutant mRNA. The Thoc1 deficiency resulted in marked apoptosis in zebrafish hair cells. Consistently, transcriptome sequencing of the mutants showed significantly increased gene expression in the p53-associated signaling pathway. Depletion of p53 or applying the p53 inhibitor Pifithrin-α significantly rescued the hair cell loss in the Thoc1 knockdown zebrafish. Our results suggested that THOC1 deficiency lead to late-onset, progressive hearing loss through p53-mediated hair cell apoptosis. This is to our knowledge the first human disease associated with THOC1 mutations and may shed light on the molecular mechanism underlying the age-related hearing loss.

Cellulose-Based Cryogel Microspheres with Nanoporous and Controllable Wrinkled Morphologies for Rapid Hemostasis.

First-aid hemostatic agents for acute bleeding can save lives in emergency situations. However, rapid hemostasis remains challenging when uncontrolled hemorrhage occurs on lethal noncompressible and irregular wounds. Herein, cellulose-based cryogel microspheres with deliberately customized micromorphologies for ultrafast water transportation and diffusion, including the shark skin riblet-inspired wrinkled surface with low fluid drag and the hydrophilic nanoporous 3D networks, are developed to deal with the acute noncompressible bleeding within seconds. These cryogel microspheres can rapidly absorb a large amount of blood over 6 times their own weight in 10 s and form a robust barrier to seal a bleeding wound without applying pressure. Remarkably, massive bleeding from a cardiac penetrating hole is effectively stopped using the microspheres within 20 s and no blood leakage is observed after 30 min. Additionally, these microspheres could be readily removed without rebleeding and capillary thrombus, which is highly favorable to rapid hemostasis in emergency rescue.

Roles and Preliminary Mechanism of Tobacco cis-Abienol in Inducing Tomato Resistance against Bacterial Wilt.

Bacterial wilt negatively impacts the yield and quality of tomatoes. cis-Abienol, a labdane diterpenoid abundantly produced in the trichome secretion of Nicotiana spp., can induce bacterial wilt resistance in plants; however, study on its practical application and acting mechanism is very limited. This study established the application conditions of cis-abienol for inducing tomato bacterial wilt resistance by pot-inoculation experiments and investigated the underlying mechanism by determining the physio-biochemical indexes and transcriptomic changes. The results showed that applying cis-abienol to the roots was the most effective approach for inducing tomato bacterial wilt resistance. The optimal concentration was 60 µg/mL, and 2-3 consecutive applications with 3-6 days intervals were sufficient to induce the bacterial wilt resistance of tomato plants. cis-Abienol could enhance the antioxidant enzyme activity and stimulate the defensive signal transduction in tomato roots, leading to the upregulation of genes involved in the mitogen-activated protein kinase cascade. It also upregulated the expression of JAZ genes and increased the content of jasmonic acid (JA) and salicylic acid (SA), which control the expression of flavonoid biosynthetic genes and the content of phytoalexins in tomato roots. cis-Abienol-induced resistance mainly depends on the JA signalling pathway, and the SA signalling pathway is also involved in this process. This study established the feasibility of applying the plant-derived terpenoid cis-abienol to induce plant bacterial wilt resistance, which is of great value for developing eco-friendly bactericides.

Efficacy and safety comparison between R-CHOP and modified NHL-BFM-90 regimens in children and adolescents with diffuse large B-cell lymphoma.

Studies comparing the efficacy and safety of R-CHOP and modified non-Hodgkin lymphoma Berlin-Frankfurt-Münster-90 (NHL-BFM-90) regimens in children and adolescents with diffuse large B-cell lymphoma (DLBCL) are lacking. Thus, we retrospectively analyzed 85 DLBCL patients aged ≤18 years from 2000 to 2020; 74 patients received the modified NHL-BFM-90 regimen, and 11 received the R-CHOP regimen. The 5-year OS and event-free survival (EFS) rates between the modified NHL-BFM-90 and R-CHOP regimens were 91.0% vs. 90.9% (P = 0.466) and 89.8% vs. 68.6% (P = 0.055), respectively. In the stratified analysis, the survival outcome of pediatric patients treated with the modified NHL-BFM-90 regimen was not significantly different from that of adolescent patients. The OS and EFS rates of patients with early-stage disease were both 100%. Patients in the advanced-stage group who were treated with the modified NHL-BFM-90 regimen had superior EFS rates (P < 0.05). The frequency of severe adverse events from the two regimens was similar. There were no treatment-related deaths. We concluded that the modified NHL-BFM-90 regimen has better efficacy than R-CHOP in DLBCL patients with advanced-stage disease. However, the R-CHOP regimen might be an option for early-stage DLBCL. Further prospective studies are needed to guide clinical decisions about treatment.

A randomized, open-label, two-period crossover bridging study on fuzuloparib capsules of different specifications in healthy Chinese volunteers.

AIMS: Fuzuloparib, also known as fluzoparib or SHR3162, is a poly ADP-ribose polymerase (PARP) inhibitor developed for the treatment of malignant tumours. Three specifications of fuzuloparib capsules (10 mg, 40 mg and 100 mg) were originally developed for clinical trials. After the recommended dose was determined, a new specification of fuzuloparib capsule (50 mg) was produced for clinical use. This bridging study was conducted to determine the bioequivalence of the new specification to the three other specifications at the recommended dose. METHODS: A single-centre, randomized, open-label, two-period, crossover bridging study was conducted in 40 healthy Chinese subjects under fed conditions. Enrolled subjects received a single oral dose of test or reference preparations according to a randomization list in the first period and crossed over to receive the other preparations in the second period after a 6-day washout interval. Blood samples were collected pre-dose and post-dose at specified time intervals. Plasma fuzuloparib concentrations were analysed by liquid chromatography-mass spectroscopy (LC-MS). A non-compartment model was adopted to calculate pharmacokinetic parameters of investigational preparations. Primary PK parameters including area under the concentration-time curve (AUC) from administration to the last sampling time (AUC0-t ), AUC extrapolated to infinity (AUC0-∞ ) and Cmax of test and reference preparations were compared to evaluate their bioequivalence. RESULTS: The 90% confidence intervals (CIs) of geometric mean ratios of AUC0-t , AUC0-∞ and Cmax were 96.99-104.95%, 97.03-104.93% and 96.53-108.98%, respectively, all of which were within the bioequivalence range of 80-125%. No serious adverse events were observed in this study and no subjects withdrew from the study due to adverse events. CONCLUSIONS: The test preparations were bioequivalent to the reference preparations. All investigational products were well tolerated.

The mediating effect of psychological capital on the relationship between psychological stress and distress among chinese nursing students: a cross-sectional study.

BACKGROUND: With the COVID-19 outbreak in China, the Chinese government took measures to prevent and control the spread of the virus. In-person teaching was replaced by distance learning, which was an unknown challenge for students. In this context, little is known about the perceived distress of nursing students and the relationship between psychological capital, perceived distress, and psychological stress. This study examined the relationship between psychological capital, psychological distress, and perceived stress, and the mediating role of psychological capital in the relationship between perceived stress and psychological distress among nursing students. METHODS: This cross-sectional survey was conducted between January and December 2020 using a convenience sampling method involving 359 undergraduate and specialist nursing students at a tertiary hospital in Shandong Province. Standardised instruments were used to measure psychological capital, psychological stress, and perceived stress. We used SPSS 24.0 and PROCESS macro to analyse the data. RESULTS: There was a statistically significant difference in perceived stress among students based on whether they liked the nursing profession (P < 0.01). Relative to nursing college students, undergraduates experienced significantly higher levels of perceived stress (P < 0.01). Nevertheless, there were no significant differences in perceived stress according to gender, place of residence, and being an only child. Psychological distress was positively correlated (r = 0.632, p < 0.001) with perceived stress (r =-0.662, p < 0.001), whereas it was negatively correlated with psychological capital. Psychological capital played a potential mediating role in the relationship between psychological distress and perceived stress. CONCLUSIONS: Psychological distress was negatively correlated with psychological capital, and positively correlated with perceived stress. Mediation analyses indicated that psychological capital partially mediated the relationship between perceived stress and psychological distress. Educators should therefore heed students' perceived stress and develop appropriate mental health counselling programmes for students in the curriculum that could help them reduce their psychological distress. In clinical practice, nursing managers must take effective measures, such as skills training, to improve the psychological capital of nursing students and reduce the negative impact of their psychological distress.

Effect of Cu2+ on the Laccase-Inducted Formation of Non-Extractable Residues of Tetrabromobisphenol A in Humic Acids.

We used 14 C-radiolabelling to study the non-extractable residues (NERs) formation of tetrabromobisphenol A (TBBPA) in a humic acid (HA) suspension under catalysis of laccase in the presence of copper. When entering the suspension after TBBPA adsorbing to HA supramolecular associates, Cu2+ at low concentrations (even without toxicity to laccase) significantly reduced the amount and first-order kinetic constant of the NER formation, while Cu2+ had no significant effect on the formation after it was complexed with HA. The inhibition effect of Cu2+ on the NER formation is explained to be attributed to the prevention of laccase-induced oxidation of TBBPA in the voids of HA associates by complexation of Cu2+ with periphery molecules of the associates. The results provide insights into varying effects of heavy metals on the environmental fate of organic contaminants and suggest that co-existing heavy metals could increase their environmental risk by reducing their NER formation.

Novel fully human anti-CD47 antibodies stimulate phagocytosis and promote elimination of AML cells.

Although most patients with acute myeloid leukemia (AML) enter remission after induction chemotherapy, the risk of relapse remains considerable. Therefore, some novel therapeutic strategies are still required. This study found that the overexpression of CD47 on AML cells was at least twofold more than that on normal bone marrow (NBM) cells in 81% (17/21) of the investigated patients; no patients had lower expression level of CD47 compared with healthy donors. The study also demonstrated that blocking the CD47/SIRPα (signal regulatory protein α) signal with the established novel fully human anti-CD47 monoclonal antibodies increased the phagocytosis of AML cells by macrophages in vitro. Furthermore, in vivo experiments showed that the novel fully human anti-CD47 monoclonal antibodies could significantly prolong the survival time of mice. Overall, the novel fully human anti-CD47 antibodies could block CD47/SIRPα interaction, increase macrophage-mediated phagocytosis, and enhance the elimination of AML cells.

Phenotypically concordant but epigenetically discordant monozygotic dichorionic diamniotic twins with Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder caused by (epi)genetic alterations. The incidence of monozygotic (MZ) twins in BWS is higher than in the general population. Most MZ twins with BWS are female and have phenotypical discordance: one twin is clinically diagnosed with BWS, while the other shows a mild or normal phenotype. The most frequent (epi)genetic alteration in MZ twins is loss of methylation of imprinting control region 2 (ICR2-LOM) at 11p15.5. Intriguingly, ICR2-LOM is usually found in the peripheral blood leukocytes (PBL) of both twins, even if they are clinically discordant. Here, we present a rare pair of MZ dichorionic diamniotic female twins with BWS and concordant phenotypes (a Beckwith-Wiedemann spectrum score of 5 in each twin). Molecular analysis of genomic DNA from PBL revealed ICR2-LOM in one twin but not the other. Our analyses suggest that ICR2-LOM occurred between days 1 and 3 after fertilization, followed by twinning. We speculate that during embryogenesis, ICR2-LOM cells were distributed to the hematopoietic stem cells in different ratios in the two fetuses, and also to commonly affected tissues, such as the tongue, in similar ratios, although we were unable to analyze any tissues other than PBL.

Comparison of chemotherapy with or without asparaginase for extranodal nasal NK/T-cell lymphoma in children and adolescents.

PURPOSE: As extranodal natural killer/T-cell lymphoma (ENKTL) occurs rarely in children and adolescents, standardized therapy is yet to be determined. This study aimed to describe the clinical features and determine the optimal chemotherapy regimen for childhood ENKTL. METHODS: The treatment outcomes of radiotherapy combined with asparaginase-based (P-GEMOX or P-GMED) or asparaginase-absent chemotherapy regimens (CHOP, EPOCH, or NHL-BFM-90/95) in patients aged ≤18 years with newly diagnosed ENKTL from December 2006 to December 2018 were compared. RESULTS: Among the 34 patients included in the study, 21 had stage I/II disease. The overall response rates of chemotherapy with or without asparaginase were 85.0% and 78.6%, respectively. With a median follow-up of 54 months, the 5-year event-free survival (EFS) rates of patients with stage I/II and III/IV disease were 66.2 ± 11.3% and 26.0 ± 12.8%, respectively (P = .027). In stage III/IV patients treated with asparaginase-based or asparaginase-absent regimens, the 5-year EFS rates were 40.0 ± 17.4% and 0%, respectively (P = .236). The 5-year EFS rates of stage III/IV patients who received or did not receive hematopoietic stem cell transplant were 66.7 ± 27.2% and 11.1 ± 10.5%, respectively (P = .054). In addition, chemotherapy-associated side effects were significantly less in patients treated with asparaginase-based regimens as compared to asparaginase-absent regimens in this cohort. CONCLUSION: P-GEMOX and P-GMED regimens are effective and safe for treating childhood ENKTL.