FSP1-mediated ferroptosis in cancer: from mechanisms to therapeutic applications.

Ferroptosis is a new discovered regulated cell death triggered by the ferrous ion (Fe2+)-dependent accumulation of lipid peroxides associated with cancer and many other diseases. The mechanism of ferroptosis includes oxidation systems (such as enzymatic oxidation and free radical oxidation) and antioxidant systems (such as GSH/GPX4, CoQ10/FSP1, BH4/GCH1 and VKORC1L1/VK). Among them, ferroptosis suppressor protein 1 (FSP1), as a crucial regulatory factor in the antioxidant system, has shown a crucial role in ferroptosis. FSP1 has been well validated to ferroptosis in three ways, and a variety of intracellular factors and drug molecules can alleviate ferroptosis via FSP1, which has been demonstrated to alter the sensitivity and effectiveness of cancer therapies, including chemotherapy, radiotherapy, targeted therapy and immunotherapy. This review aims to provide important frameworks that, bring the regulation of FSP1 mediated ferroptosis into cancer therapies on the basis of existing studies.

Physiologically Based Pharmacokinetic Modeling of Lacosamide in Patients With Hepatic and Renal Impairment and Pediatric Populations to Support Pediatric Dosing Optimization.

PURPOSE: Lacosamide (LCM) is a new-generation anti-seizure medication that is efficacious in patients with focal seizures with or without secondary generalization. Until now, the efficacy, safety, and tolerability of LCM are still lacking in Chinese epilepsy patients, particularly for pediatric populations and patients with renal or hepatic impairment. METHODS: This study was conducted to develop a physiologically based pharmacokinetic (PBPK) model to characterize the pharmacokinetics of LCM in Chinese populations and predict the pharmacokinetics of LCM in Chinese pediatric populations and patients with renal or hepatic impairment. Using data from clinical investigations, the developed PBPK model was validated by comparing predicted and observed blood concentration data. FINDINGS: Doses should be reduced to approximately 82%, 75%, 63%, and 76% of the Chinese healthy adult dose in patients with mild, moderate, and severe renal impairment and end-stage renal disease; and approximately 89%, 72%, and 36% of the Chinese healthy adult dose in patients with Child Pugh-A, B, and C hepatic impairment. For pediatric populations, intravenous doses should be adjusted to 1.75 mg/kg for newborns, 2.5 mg/kg for toddlers, 2.2 mg/kg mg for preschool and school age, and 2 mg/kg mg for adolescents to achieve an equivalent plasma exposure of 2 mg/kg LCM in adults. The oral doses should be adjusted to 20 mg for toddlers, 32 mg for preschool, 45 mg for school age, and 95 mg for adolescents to achieve an approximately equivalent plasma exposure of 100 mg LCM in adults. IMPLICATIONS: The PBPK model of LCM can be utilized to optimize dosage regimens for special populations.

Effectiveness of comprehensive sexuality education curriculum on improving hostile and benevolent sexism among university students / 中国学校卫生

Objective@#To explore the effectiveness of a comprehensive sexuality education (CSE) curriculum on university students hostile and benevolent sexism, so as to provide a reference for evaluating the effects of CSE on reducing ambivalent sexism.@*Methods@#From September 2018 to January 2019, 165 university students from a university in Beijing were recruited using convenience sampling for a 5 month of CSE curriculum (36 sessions, 2 sessions per week, 45 min per session), including CSE and gender studies, sexual physiology and health, gender and gender roles, gender bias, intimate relationships and gender bias, gender based violence and gender bias, culture and gender bias, and gender and power. Students who took CSE curriculum were included in the intervention group ( n =97) and students from the same university who had not taken CSE curriculum were included in the control group ( n =68). Using the Ambivalent Sexism Inventory, both groups of university students were surveyed before and after the curriculum to analyze the effectiveness of the CSE curriculum. Chi -square test, ANOVA，cluster analysis and Kruskal Wallis test were used for statistical analysis.@*Results@#After the CSE curriculum, both hostile and benevolent sexism scores were lower in the intervention group (2.21±0.76, 2.36±0.68) than in the control group (2.81±0.61, 3.03±0.60) ( F =17.24, 33.26), and pre test scores were higher in the intervention group (2.64±0.67, 2.88±0.68) ( F =45.62, 66.93) ( P <0.01). On both hostile and benevolent sexism, female students scores (2.46±0.72, 2.65±0.70) were lower than male students scores (2.86±0.59, 3.09± 0.69 ) ( F=11.02, 14.20, P <0.01). Comparison of the curriculum effectiveness of hostile and benevolent sexism among clustered groups showed that the difference in hostile sexism scores was higher in the inconsistent type [0.63(0.25, 1.25)]than in the more consistent type [0.38(-0.16, 0.88)] and the lower consistent type [0.38(0.06, 0.63)] ( H=8.71, P <0.05); and the difference in benevolent sexism scores was higher in the more consistent type [0.75(0.53, 1.22)] than in the less consistent type [0.38(0.09, 0.88 )] and inconsistent type [0.38(-0.13,0.63)] ( H=10.82, P <0.05).@*Conclusions@#CSE can improve hostile and benevolent sexism in university students with sex and type differences. Attention should be paid to CSE curriculum to improve ambivalent sexism among university students with a view to fostering their awareness of gender equality.

Physiologically based pharmacokinetic modeling of candesartan to predict the exposure in hepatic and renal impairment and elderly populations.

Background: Candesartan cilexetil is a widely used angiotensin II receptor blocker with minimal adverse effects and high tolerability for the treatment of hypertension. Candesartan is administered orally as the prodrug candesartan cilexetil, which is wholly and swiftly converted to the active metabolite candesartan by carboxylesterase during absorption in the intestinal tract. In populations with renal or hepatic impairment, candesartan's pharmacokinetic (PK) behavior may be altered, necessitating dosage adjustments. Objectives: This study was conducted to examine how the physiologically based PK (PBPK) model characterizes the PKs of candesartan in adult and geriatric populations and to predict the PKs of candesartan in elderly populations with renal and hepatic impairment. Design: After developing PBPK models using the reported physicochemical properties of candesartan and clinical data, these models were validated using data from clinical investigations involving various dose ranges. Methods: Comparing predicted and observed blood concentration data and PK parameters was used to assess the fit performance of the models. Results: Doses should be reduced to approximately 94% of Chinese healthy adults for the Chinese healthy elderly population; approximately 92%, 68%, and 64% of that of the Chinese healthy adult dose in elderly populations with mild, moderate, and severe renal impairment, respectively; and approximately 72%, 71%, and 52% of that of the Chinese healthy adult dose in elderly populations with Child-Pugh-A, Child-Pugh-B, and Child-Pugh-C hepatic impairment, respectively. Conclusion: The results suggest that the PBPK model of candesartan can be utilized to optimize dosage regimens for special populations.

Background: Candesartan cilexetil is a widely used angiotensin II receptor blocker with minimal adverse effects and high tolerability for the treatment of hypertension. Candesartan cilexetil is wholly and swiftly converted to the active metabolite candesartan by carboxylesterase during absorption in the intestinal tract. Candesartan's pharmacokinetic behavior may be altered in patients with renal or hepatic impairment. Methods: We developed PBPK models using the reported physicochemical properties of candesartan and clinical data. We validated the PBPK models. Results: We found that the elderly population needs dosage adjustments.1. Doses should be reduced to approximately 94% of Chinese healthy adults for the Chinese healthy elderly population2. Doses should be reduced to approximately 92%, 68%, and 64% of that of the Chinese healthy adult dose in elderly populations with mild, moderate, and severe renal impairment3. Doses should be reduced to approximately 72%, 71%, and 52% of that of the Chinese healthy adult dose in elderly populations with Child Pugh-A, Child Pugh-B, and Child Pugh-C hepatic impairment. Conclusion: The PBPK model of candesartan can be utilized to optimize dosage regimens for special populations.

Develop a physiologically based pharmacokinetic model of candesartan to predict the exposure in Chinese elderly populations.

Purely positive or discriminatorily positive? The development of two-factor attitudes toward lesbians and gay men scales.

Unidimensional bipolar scales based on prejudice against homosexuality neglect the effect of preference for heterosexuality on attitudes toward homosexuality. Additionally, the term "homosexuality" used in these scales may compromise their validity. The current study uses person-centered and variable-centered approaches to examine the structure and classes of attitudes toward lesbians and gay men. In Study 1, we developed the Two-factor Attitudes toward Lesbians and Gay Men Scales, which have acceptable reliability and validity. The results obtained through variable-centered approaches suggested that a model comprising two factors (prejudice against homosexuality and preference for heterosexuality) was ideal. In Study 2, we explored the classes of attitudes toward lesbians and gay men through latent class analysis. The results supported a model containing three classes (purely positive, discriminatorily positive, and negative). This study validates a two-factor structure of attitudes toward lesbians and gay men and distinguishes between purely positive and discriminatorily positive attitudes, providing an important reference for future research and interventions to promote public attitudes toward lesbians and gay men.

Regulators of epigenetic change in ferroptosis­associated cancer (Review).

The occurrence of tumors is associated with the upregulation or downregulation of certain genes. The identification of novel tumor therapies has revealed that regulation of tumor cell death can either promote or suppress the occurrence and development of tumors. Iron­dependent lipid free oxygen radical accumulation causes tumor cells to die by ferroptosis, a form of regulated cell death. Multiple mechanisms mediate this mode of cell death, including redox homeostasis, iron metabolism, mitochondrial activity, breakdown of amino acids, lipids and sugars and epigenetic regulatory and disease­associated signaling pathways. The present review discussed epigenetic mechanism of ferroptosis with the aim of providing novel insight for optimization of the effects of antitumor therapy.

Strongylocentrotus nudus Eggs Polysaccharide Enhances Macrophage Phagocytosis Against E.coli Infection by TLR4/STAT3 Axis.

Antibiotics resistance is one of the most significant public health threats globally. Strategies that strengthen host defenses to control pathogen infection has become a hot research field. Macrophages are part of early host defense mechanisms, and are activated via host pattern recognition receptors (PRRs), such as Toll-like receptor 4 (TLR4), which then facilitates phagocytosis and elimination of invading pathogens. However, few activators of PRRs have been approved for clinical use because of their toxic effects. This study aimed to investigate whether Strongylocentrotus nudus eggs polysaccharide (SEP), a non-toxic extract from seafood, contributes to host defense against bacterial infection. Results showed that SEP promoted bacterial clearance by enhancing phagocytosis by macrophages during E. coli infection in vitro, but was inhibited by TLR4 specific inhibitor TAK-242, STAT3 inhibitor Stattic or blockade of CD64. In addition, SEP protected mice from E. coli induced mortality, reduced pulmonary inflammation and inhibited dissemination of bacteria to organs, while TAK-242 retarded the protection of SEP. Overall, SEP strengthened innate host defense and improved the outcome in bacterial infection, suggesting that SEP could be used as a potential immunomodulator in host-directed therapies.

Comprehensive Sexuality Education Improves Primary Students' Explicit and Implicit Attitudes Toward Homosexuality.

Comprehensive sexuality education (CSE) is a curriculum-based process that is inclusive to gender and sexual orientation. We used the attitude toward homosexuality scale and the single category implicit association test (SC-IAT) to measure differences between explicit and implicit attitudes toward homosexuality between migrant children with 6 years CSE learning experience (experimental group, N = 70) and those without (control group, N = 80). We found that the experimental group had more positive explicit and implicit attitudes toward homosexuality than the control group. In conclusion, CSE is a useful process for improving the explicit and implicit attitudes of migrant children toward homosexuality.

Esculetin protects against early sepsis via attenuating inflammation by inhibiting NF-κB and STAT1/STAT3 signaling.

Esculetin, a natural derivative from the traditional and widely-used Chinese medicinal herb Cortex Fraxini, has a variety of pharmacological effects, especially in anti-inflammation. However, it is not clear whether esculetin has a therapeutic effect on sepsis. This study aimed to investigate the anti-inflammatory and protective effects of esculetin on early sepsis. The results showed that the lung injury was significantly relieved with the treatment of esculetin, accompanied with the restrained production of inflammatory factors including IL-1ß, IL-6, TNF-α, CCL2 and iNOS during the early phase of E.coli-induced sepsis. Of note, activation of NF-κB and STAT1/STAT3 signals, the main upstream signals of many inflammatory factors, were attenuated by esculetin in both lung tissues from septic mice and LPS-stimulated macrophage. These findings suggested that the protection of esculetin against early sepsis should be related to its anti-inflammatory effect, which was at least partly due to its inhibition on NF-κB and STAT1/STAT3 signaling pathway in macrophage. Thus, esculetin could serve as a potential therapeutic agent by rebalancing innate immune response in macrophage for the treatment of early sepsis.

Curriculum standards and teaching materials in compulsory education in China from the perspective of comprehensive sexuality education / 中国学校卫生

Abstract@#Comprehensive sexuality education (CSE) is a instruction method based on curriculum, which explores the cognitive, emotional, physical and social significance of sexuality. Based on the analysis model of teaching materials and Interpretative Structural Model (ISM), this paper analyzes and evaluates the curriculum standards and teaching materials of compulsory education in China from the perspective of CSE. It reveals that the contents of CSE mainly appear in the 19 curriculum standards as well as in the teaching objectives, contents, practice activities and compiling elements of teaching materials. Based on CSE, the reliability of teaching objectives and content, the comprehensiveness of teaching content, the feasibility and effectiveness of teaching practice of curriculum standards and textbooks need to be further strengthened and improved.

Survey of sexual knowledge，attitudes and behaviors on 3-6 years old children in kindergartens in Changping District, Beijing / 中国学校卫生

Objective@#To understand the current situation of sexual knowledge, attitudes and behaviors of young children in kindergarten, based on the framework of comprehensive sexuality education.@*Methods@#Totally 354 children between the ages of 3-6 from two kindergartens in Changping District, Beijing, participated in one-to-one interviews. There were 164 girls and 190 boys.@*Results@#In the dimension of physical development, no child knew the scientific name of reproductive organs. In the dimension of social emotion, 44.07% of children could express love to their friends, and 40.68% of children could express their refusal when they were unwilling. In the dimension of sexual health, well-being and sexual rights，81.92% of children knew that they couldn t touch other people s genitals, and 54.80% of children could at least name one way to protect themselves when facing sexual abuse. In the dimension of gender equality, 33.62% and 28.53%of children had gender stereotypes in toy selection and career choice, 66.38% of children thought that boys are as smart as girls. In the dimension of pregnancy and birth，78.53% of children knew where babies come from and 26.27% of children think parenthood doesn t directly lead to happiness. Sexual knowledge, attitudes and behaviors of children had statistically significant difference in different grades（P<0.05).@*Conclusion@#Children already have good understanding about pregnancy, childbirth and prevention of sexual abuse. In the future, sexuality education in school and family need to promote physical cognition and gender equality education.

Survey of sexual knowledge, attitudes and behaviors of junior high school students: based on comprehensive sexuality education / 中国学校卫生

Objective@#To understand junior high school students’ sexual knowledge, sexual attitudes, sexual behaviors,as well as acess to sexual knowledge and related influencing factors, so as to provide reference for the practice of sexuality education.@*Methods@#Using stratified cluster sampling method, 7 341 junior high school students were selected from Anhui, Fujian, Gansu, Guangxi, Henan, Xinjiang, Yunnan, Zhejiang and Beijing, and self-compiled questionnaires were used.@*Results@#Junior high school students scored (61.71±18.79) in sexual knowledge, with pass rate and excellent rate being 59.02% and 18.53%. The attitudes towards LGBT was (65.44±20.01), the attitudes towards sexual and healthy behaviors was (67.04±49.23), and the attitudes towards sexual relations and behaviors was (70.75±10.46). Students had intimacy needs and sexual behaviors (18.70%), and some had such behaviors as kissing (13.80%), touching sensitive parts (6.70%) and sexual intercourse (2.20%). The results of multivariate Logistic regression analysis showed that students’ sexual knowledge was related to region, grade and school-based sexuality education (OR=2.11,P<0.05).@*Conclusion@#Junior high school students have sexual needs and behaviors, but their sexual knowledge is not sufficient; there are differences in sexual knowledge and attitudes of junior high school students across region,grade and gender; schools should promote school-based sexuality education for junior high school students’ sexual health.

Effectiveness of sexuality education curriculum to improve the attitude towards homosexuality in primary school / 中国学校卫生

Objective@#To analyze the influence of sexuality education on primary school students’ attitude towards homosexuality, and provide practical teaching evidence of intervening campus bullying based on sexual orientation.@*Methods@#A primary school offering school-based sexuality education curriculums in Beijing was selected as an experimental school, another school with similar location, nature and scale, quality of teachers and teaching environment was selected as a control school. The graduates in experimental school received 6 years of sexuality education in grade 1 to grade 6 of primary school. A survey was conducted in Jun. 2018 among all the graduates in grade 6 of the two schools through an attitude scale on homosexuality adopting cluster sampling.@*Results@#The scores of attitude towards homosexuality in experimental school and control school were (42.85±15.46) and (60.17±12.54) respectively, with significantly statistical difference(t=-9.47, P<0.01). There were interaction effects on attitudes of primary school students towards homosexuality between gender and experience of sexuality education (P<0.05). There was no significant difference in attitude towards homosexuality between male and female students in control school(t=0.58, P>0.05), but in experimental school, the attitude scores of male and female students respectively were (47.64±14.31) and (38.13±15.19), with significantly statistical difference(t=3.47, P<0.01). There was no significant difference in attitude towards different sexual orientation between experimental school students and control school students(t=0.10，1.53，P>0.05).@*Conclusion@#Sexuality education curriculum can help improve attitude towards homosexuality of primary school students, which has better intervention effects on female students than male students, attitudinal difference in gay and lesbian has not formed in primary school students.

Status quo and curriculum intervention of sexual psychological health during puberty in middle school / 中国学校卫生

Objective@#To explore the influence of comprehensive sexuality education (CSE) course based on International Technical Guidance onthe sexual psychological health of middle school students during puberty, and to provide a reference for mental health promotion.@*Methods@#This study used Adolescent Sexual Psychological Health Questionnaire as measuring tool and self-made textbook on sexuality education entitled Love and Life: Junior High School Students’ Sexual Health Education Textbook as intervention. Measurements were set before and after the first semester together with the end of the second semester, respectively were pretest, intermediate test and posttest.@*Results@#The sexual psychological health of middle school students was in the medium level, and girls(3.51±0.40) were generally better than boys(3.44±0.37)(t=3.62, P<0.05). According to one-way analysis of variance, the main effect of three dimensions of sexual health-sexual cognition(3.31±0.81, 3.68±0.80, 4.37±0.61), sexual values(3.43±0.51, 3.55±0.54, 3.85±0.58) and sexual adaptation(3.63±0.41, 3.85±0.49, 4.09±0.58) and the total score(3.51±0.39, 3.74±0.46, 4.10±0.47) before, during and after the acceptance of comprehensive sexuality education was significant(F=252.18, 281.68, 113.54, 114.60, P<0.05).@*Conclusion@#Comprehensive sexuality education course has a significant effect on improving sexual psychological health among junior high school students.

Evaluation of comprehensive sexuality education course on sexual knowledge and attitude of college students / 中国学校卫生

Objective@#To provide empirical evidence on the effectiveness of comprehensive sexuality education (CSE) on sexual knowledge and sexual attitudes improvement among college students.@*Methods@#Sexual knowledge and attitudes questionnaire survey was implemented among college students in Beijing, who later received the CSE for a full semester. Sexual knowledge and attitude were evaluated after intervention and were compared with control students.@*Results@#The average score of sexual knowledge was low among college students in Beijing. Most students held neutral attitudes towards "AIDS community" and "masturbation behavior" and positive attitudes towards "LGBT"(58.85%, 68.75%, 61.98%). Compared with the control group, after one semester of CSE curriculum intervention, the average scores of the five dimensions on sexual knowledge in the intervention group was significantly improved(11.79±1.16, 9.36±1.23, 4.84±0.88, 4.91±1.00, 5.35±1.03)(t=11.25, 15.74, 10.37, 5.59, 8.17, P<0.01), and the attitudes towards "sexual minorities", "AIDS communities" and "masturbation behavior" were also significantly improved(30.59±3.91, 17.70±3.41, 10.12±2.17)(t=5.16, 5.83, 2.97, P<0.01).@*Conclusion@#College students’ knowledge of sexuality is not optimistic. The attention to proper sexual attitudes is in great need. Systematic and comprehensive sexuality education curriculum could improve college students’ sexual knowledge and attitudes.

Ferroelectric behavior of orthogonal smectic phase made of bent-core molecules.

Ferroelectric behavior in the recently reported orthogonal ferroelectric Sm-A(d)P(F) phase in an unsymmetric bent-core molecule with a carbosilane terminal group was studied. The ferroelectricity of the Sm-A(d)P(F) phase was unambiguously confirmed by optical second-harmonic generation activity in the absence of an electric field, ferroelectric response, and high dielectric strength. The long-range polar order is a consequence of weakened interlayer coupling due to the formation of carbosilane sublayers, which allows for the parallel order of dipole moments of bent-core molecules in the neighboring layers. It develops in the system gradually through the second-order phase transition from the orthogonal Sm-A(d) phase. In the Sm-A(d)P(F) phase the strong surface anchoring results in the splay of polarization across the sample thickness. The polar surface anchoring also brings about strongly thickness-dependent polar fluctuations, as proved by the dielectric measurements (Goldstone-like mode). The relaxation frequency and dielectric strength vary more than one order of magnitude with cell thickness; in particular the dielectric strength attains more than 2000 in a 25 µm-thick cell and continues to increase for thicker cells. Simple theory developed qualitatively explains the experimental results, supporting the polarization splay model proposed.

Polar switching in the smectic- A(d)P(A) phase composed of asymmetric bent-core molecules.

We have studied mesogenic properties in the smectic- A(d)P(A) phase of an asymmetric bent-core liquid crystal by means of polarizing optical microscopy, second-harmonic generation (SHG), electro-optical (EO), and dielectric measurements. In homeotropically aligned cells, EO switching is clearly observed from a schlieren texture with both four- and two-brush defects to a uniform bright domain under the application of very low in-plane electric field below 1 V/microm. The phase is SHG active under an electric field, i.e., SHG gradually increases without a threshold and saturates with the increasing field. In homogeneous cells, by applying triangular wave field at saturated voltage, the splitting of the polarization switching current peak is observed, indicating that the mesophase is antiferroelectric. The dielectric studies indicate a Debye-type relaxation of the transverse dipoles associated with the rotation of the molecules about their long axis. The dc bias-dependent dielectric relaxation time and the dielectric strength suggest that a field-induced antiferroelectric-ferroelectric phase transition occurs continuously beyond 1.2 V/microm and is reversible. The field-dependent texture observation is consistent with the dielectric measurements. Two possible models are proposed to interpret the continuous phase transition.

First symmetrical banana compounds exhibiting SmAP(R) mesophase and unique transition between two orthogonal polar phases.

Novel banana-shaped liquid crystals with stilbene bridges were synthesized. All presented materials exhibit the polarization-randomized non-tilted smectic phase (SmAP(R)) in a broad temperature range and the antiferroelectric non-tilted smectic phase (SmAP(A)) at room temperature.