Metabolic enzymes aldo-2 and pdhb-1 as potential epigenetic regulators during C. elegans embryogenesis.

The intersection of metabolic processes and epigenetic regulation during embryogenesis is crucial yet not fully understood. Through a candidate RNAi screen in Caenorhabditis elegans , we identified metabolic enzymes ALDO-2 and PDHB-1 as potential epigenetic regulators. Mild alteration of the chromatin remodeler LET-418 /Mi2 activity rescues embryonic lethality induced by suppressing aldo-2 or pdhb-1 , suggesting a critical role for glucose and pyruvate metabolism in chromatin remodeling during embryogenesis. Given the conservation of central metabolic pathways and chromatin modifiers across species, our findings lay the foundation for future mechanistic investigations into the interplay between epigenetics and metabolism during development and upon disease.

Tumor Regression Following Engineered Polyomavirus-Specific T Cell Therapy in Immune Checkpoint Inhibitor-Refractory Merkel Cell Carcinoma.

Although immune check-point inhibitors (CPIs) revolutionized treatment of Merkel cell carcinoma (MCC), patients with CPI-refractory MCC lack effective therapy. More than 80% of MCC express T-antigens encoded by Merkel cell polyomavirus, which is an ideal target for T-cell receptor (TCR)-based immunotherapy. However, MCC often repress HLA expression, requiring additional strategies to reverse the downregulation for allowing T cells to recognize their targets. We identified TCRMCC1 that recognizes a T-antigen epitope restricted to human leukocyte antigen (HLA)-A*02:01. Seven CPI-refractory metastatic MCC patients received CD4 and CD8 T cells transduced with TCRMCC1 (TTCR-MCC1) preceded either by lymphodepleting chemotherapy or an HLA-upregulating regimen (single-fraction radiation therapy (SFRT) or systemic interferon gamma (IFNγ)) with concurrent avelumab. Two patients who received preceding SFRT and IFNγ respectively experienced tumor regression. One experienced regression of 13/14 subcutaneous lesions with 1 'escape' lesion and the other had delayed tumor regression in all lesions after initial progression. Although TTCR-MCC1 cells with an activated phenotype infiltrated tumors including the 'escape' lesion, all progressing lesions transcriptionally lacked HLA expression. While SFRT/IFNγ did not immediately upregulate tumor HLA expression, a secondary endogenous antigen-specific T cell infiltrate was detected in one of the regressing tumors and associated with HLA upregulation, indicating in situ immune responses have the potential to reverse HLA downregulation. Indeed, supplying a strong co-stimulatory signal via a CD200R-CD28 switch receptor allows TTCR-MCC1 cells to control HLA-downregulated MCC cells in a xenograft mouse model, upregulating HLA expression. Our results demonstrate the potential of TCR gene therapy for metastatic MCC and propose a next strategy for overcoming epigenetic downregulation of HLA in MCC.

Improved resilience and proteostasis mediate longevity upon DAF-2 degradation in old age.

Little is known about the possibility of reversing age-related biological changes when they have already occurred. To explore this, we have characterized the effects of reducing insulin/IGF-1 signaling (IIS) during old age. Reduction of IIS throughout life slows age-related decline in diverse species, most strikingly in the nematode Caenorhabditis elegans. Here we show that even at advanced ages, auxin-induced degradation of DAF-2 in single tissues, including neurons and the intestine, is still able to markedly increase C. elegans lifespan. We describe how reversibility varies among senescent changes. While senescent pathologies that develop in mid-life were not reversed, there was a rejuvenation of the proteostasis network, manifesting as a restoration of the capacity to eliminate otherwise intractable protein aggregates that accumulate with age. Moreover, resistance to several stressors was restored. These results support several new conclusions. (1) Loss of resilience is not solely a consequence of pathologies that develop in earlier life. (2) Restoration of proteostasis and resilience by inhibiting IIS is a plausible cause of the increase in lifespan. And (3), most interestingly, some aspects of the age-related transition from resilience to frailty can be reversed to a certain extent. This raises the possibility that the effect of IIS and related pathways on resilience and frailty during aging in higher animals might possess some degree of reversibility.

Extracellular Matrix Dynamics as an Emerging yet Understudied Hallmark of Aging and Longevity.

The biomechanical properties of extracellular matrices (ECM) and their consequences for cellular homeostasis have recently emerged as a driver of aging. Here we review the age-dependent deterioration of ECM in the context of our current understanding of the aging processes. We discuss the reciprocal interactions of longevity interventions with ECM remodeling. And the relevance of ECM dynamics captured by the matrisome and the matreotypes associated with health, disease, and longevity. Furthermore, we highlight that many established longevity compounds promote ECM homeostasis. A large body of evidence for the ECM to qualify as a hallmark of aging is emerging, and the data in invertebrates is promising. However, direct experimental proof that activating ECM homeostasis is sufficient to slow aging in mammals is lacking. We conclude that further research is required and anticipate that a conceptual framework for ECM biomechanics and homeostasis will provide new strategies to promote health during aging.

Strategic outline of interventions targeting extracellular matrix for promoting healthy longevity.

The extracellular matrix (ECM), composed of interlinked proteins outside of cells, is an important component of the human body that helps maintain tissue architecture and cellular homeostasis. As people age, the ECM undergoes changes that can lead to age-related morbidity and mortality. Despite its importance, ECM aging remains understudied in the field of geroscience. In this review, we discuss the core concepts of ECM integrity, outline the age-related challenges and subsequent pathologies and diseases, summarize diagnostic methods detecting a faulty ECM, and provide strategies targeting ECM homeostasis. To conceptualize this, we built a technology research tree to hierarchically visualize possible research sequences for studying ECM aging. This strategic framework will hopefully facilitate the development of future research on interventions to restore ECM integrity, which could potentially lead to the development of new drugs or therapeutic interventions promoting health during aging.

Effectiveness of educational poster on knowledge of emergency management of dental trauma--part 2: cluster randomised controlled trial for secondary school students.

OBJECTIVE: To investigate the effectiveness of educational poster on improving secondary school students' knowledge of emergency management of dental trauma. METHODS: A cluster randomised controlled trial was conducted. 16 schools with total 671 secondary students who can read Chinese or English were randomised into intervention (poster, 8 schools, 364 students) and control groups (8 schools, 305 students) at the school level. Baseline knowledge of dental trauma was obtained by a questionnaire. Poster containing information of dental trauma management was displayed in a classroom for 2 weeks in each school in the intervention group whereas in the control group there was no display of such posters. Students of both groups completed the same questionnaire after 2 weeks. RESULTS: Two-week display of posters improved the knowledge score by 1.25 (p-value = 0.0407) on average. CONCLUSION: Educational poster on dental trauma management significantly improved the level of knowledge of secondary school students in Hong Kong. TRIAL REGISTRATION: HKClinicalTrial.com HKCTR-1343 ClinicalTrials.gov NCT01809457.

A survey on Hong Kong secondary school students' knowledge of emergency management of dental trauma.

OBJECTIVES: To investigate Hong Kong secondary school students' knowledge of emergency management of dental trauma. METHOD: A questionnaire survey on randomly selected secondary school students using cluster sampling. RESULTS: Only 36.6% (209/571) of the respondents were able to correctly identify the appropriate place for treatment of dental injury. 55.2% of the respondents knew the suitable time for treatment. Only 24.7% of the respondents possessed the knowledge of how to correctly manage fractured teeth. Only 23.6% of them knew how to manage displaced teeth. 62.5% of them correctly answered that knocked-out deciduous teeth should not be replanted to the original position, but few of them (23.6%) knew that permanent teeth should be replanted. Moreover, 37.1% of the respondents correctly identified at least one of the appropriate media for storing a knocked-out tooth. First-aid training and acquisition of dental injury information from other sources were significant factors that positive responses from these questions would lead to higher scores. CONCLUSION: Hong Kong secondary school students' knowledge of emergency management of dental trauma is considered insufficient. An educational campaign in secondary schools dedicated to students is recommended. Prior first-aid training and acquisition of dental injury information from other sources positively relate to the level of knowledge. Dental trauma emergency management is recommended to be added to first-aid publications and be taught to students and health professionals. TRIAL REGISTRATION: Hong Kong Clinical Trial Centre HKCTR-1344.

Effectiveness of educational poster on knowledge of emergency management of dental trauma-part 1. Cluster randomised controlled trial for primary and secondary school teachers.

OBJECTIVE: To investigate the effectiveness of educational posters in improving the knowledge level of primary and secondary school teachers regarding emergency management of dental trauma. METHODS: A cluster randomised controlled trial was conducted. 32 schools with a total of 515 teachers were randomised into intervention (poster) and control groups at the school level. Teachers' baseline levels of knowledge about dental trauma were obtained by using a questionnaire. Posters containing information on dental trauma management were displayed in the school medical room, the common room used by staff, and on a notice board for 2 weeks in each school of the intervention group; in the control group, no posters were displayed. Teachers in both groups completed the questionnaire after 2 weeks. RESULTS: The teachers in the intervention schools (where posters were displayed for 2 weeks) showed statistically significant improvement in scores in cases where they had not previously learned about dental emergencies from sources other than first aid training, with an average score increase of 2.6656 (score range of questionnaire, -13 to 9; p-value <0.0001). CONCLUSION: Educational posters on the management of dental trauma can significantly improve the level of knowledge of primary and secondary school teachers in Hong Kong. KClinicalTrials.com HKCTR-1307 ClinicalTrials.gov: NCT01707355.

Quadrivalent human papillomavirus vaccine effectiveness: a Swedish national cohort study.

BACKGROUND: Incidence of condyloma, or genital warts (GW), is the earliest possible disease outcome to measure when assessing the effectiveness of human papillomavirus (HPV) vaccination strategies. Efficacy trials that follow prespecified inclusion and exclusion criteria may not be fully generalizable to real-life HPV vaccination programs, which target a broader segment of the population. We assessed GW incidence after on-demand vaccination with quadrivalent HPV vaccine using individual-level data from the entire Swedish population. METHODS: An open cohort of girls and women aged 10 to 44 years living in Sweden between 2006 and 2010 (N > 2.2 million) was linked to multiple population registers to identify incident GW in relation to HPV vaccination. For vaccine effectiveness, incidence rate ratios of GW were estimated using time-to-event analyses with adjustment for attained age and parental education level, stratifying on age at first vaccination. RESULTS: A total of 124 000 girls and women were vaccinated between 2006 and 2010. Girls and women with at least one university-educated parent were 15 times more likely to be vaccinated before age 20 years than girls and women whose parents did not complete high school (relative risk ratio = 15.45, 95% confidence interval [CI] = 14.65 to 16.30). Among those aged older than 20 years, GW rates declined among the unvaccinated, suggesting that HPV vaccines were preferentially used by women at high risk of GW. Vaccination effectiveness was 76% (95% CI = 73% to 79%) among those who received three doses of the vaccine with their first dose before age 20 years. Vaccine effectiveness was highest in girls vaccinated before age 14 years (effectiveness = 93%, 95% CI = 73% to 98%). CONCLUSIONS: Young age at first vaccination is imperative for maximizing quadrivalent HPV vaccine effectiveness.

Emergency management of dental trauma: knowledge of Hong Kong primary and secondary school teachers.

OBJECTIVES. To investigate the level of knowledge about emergency management of dental trauma among Hong Kong primary and secondary school teachers. DESIGN. Questionnaire survey. SETTING. A teachers' union that unites 90% of teachers in Hong Kong. PARTICIPANTS. Randomly selected primary and secondary school teachers. RESULTS. Only 32.8% of respondents correctly stated that a person sustaining dental trauma should go to dentists directly. In all, 73.1% of teachers correctly stated that a dental trauma patient should go for treatment immediately. Only 32.5% knew that a fractured tooth should be put in liquid. Even fewer (23.2%) realised that the displaced tooth should be repositioned back to the original position. Relatively more respondents (74.7%) understood that an avulsed baby tooth should not be put back. Disappointingly, only 16.3% of teachers knew that an avulsed permanent tooth should be replanted. Furthermore, only 29.6% of teachers thought that they were able to distinguish between deciduous teeth and permanent teeth, whilst 20.4% correctly identified at least one of the appropriate mediums: milk, physiological saline or saliva, for storing an avulsed tooth. Teachers who previously received first-aid training with dental content or acquired dental injury information from other sources, scored significantly higher than teachers without such training or acquired information. CONCLUSION. The knowledge on emergency management of dental trauma among primary and secondary school teachers in Hong Kong is insufficient, particularly on the handling of permanent tooth avulsion and the appropriate storage medium for avulsed teeth. Receipt of first-aid training with dental contents and acquisition of dental injury information from other sources were positively correlated with knowledge in managing dental trauma.

Pre-vaccination incidence of genital warts in 15-23-year-old women and men attending youth clinics in Stockholm, Sweden.

BACKGROUND: Human papillomavirus (HPV) vaccines were introduced to the market in 2006 and 2007. The present pilot study was designed to examine the incidence of genital warts in the population up to 23 y of age in the county of Stockholm before the start of mass HPV vaccination. METHODS: Data from the electronic health records of 9 youth clinics in the county of Stockholm were collected retrospectively for the y 2006-2008. RESULTS: In total, 49,985 patients visited the study youth clinics during 2006-2008. Of these, 1817 were denoted genital warts patients. An extrapolation of the study data was done in an attempt to estimate the annual number of genital warts cases in the full Stockholm County population aged 15-23 y. Results showed that there were approximately 1792 genital warts patients in the age group 15-23 y each year in Stockholm County. Female cases represented approximately 62% of all cases in the age group 15-23 y. The peak incidence was at around 20 y of age for females, while males had a more flattened peak incidence around 19-23 y of age. CONCLUSION: This pilot study demonstrates that, compared to other reported data, genital warts are at least as common in Sweden as in other countries among 15-23 y old females and males.

Awareness and knowledge of human papillomavirus in the Swedish adult population.

PURPOSE: To assess awareness and knowledge of human papillomavirus (HPV) in the adult Swedish population. METHODS: A cross-sectional study among young adults aged 18-30 years and the parents of children aged 12-15 years was conducted in 2007 to collect information on awareness and knowledge of HPV. Correlates of HPV knowledge were investigated. RESULTS: Awareness of cervical cancer and condyloma were high but awareness of HPV was low. Many participants were uncertain or did not know about the causal relation between HPV and condyloma, and cancers other than cervical cancer. Among parents, gender, age, country of origin, and education were the most important correlates of HPV knowledge. Among young adults, these factors were gender, income, and education. CONCLUSIONS: HPV education campaigns should particularly target young men and those with low education. Educational messages should clarify the risk of HPV, and the causal relationship between HPV and condyloma, and other cancers.

Acceptability of HPV vaccination among young adults aged 18-30 years--a population based survey in Sweden.

Acceptability of human papillomavirus (HPV) vaccination seems to be high in the Western world but fewer data are available for men than for women. There are also concerns that HPV vaccination might lead young people to change their healthcare-related behaviours. We investigated these issues in a population-based survey performed in Sweden during January-May, 2007, just after HPV vaccination had been licensed. A total of 10567 men and women aged 18 to 30 years participated. The intention to accept HPV vaccination among these young adults was relatively high but could likely be improved with higher awareness of HPV-related diseases as well as of the safety and efficacy of vaccines in general. Also, the cost of the vaccine needs to be affordable. Even though few young adults stated their healthcare-related behaviours would change after HPV vaccination, a significant number were uncertain, suggesting a need for continued educational efforts when HPV-vaccinating this group.

Attitudes to HPV vaccination among parents of children aged 12-15 years-a population-based survey in Sweden.

In this population-based survey undertaken in Sweden in 2007, we investigated correlates of attitudes to human papillomavirus (HPV) vaccination among parents of children aged 12-15 years. We invited 16,000 parents of girls and 4,000 parents of boys, randomly selected from the Swedish population. Response rates were 70 and 69%, respectively. Multinomial logistic regression models were applied to investigate correlates of acceptability to HPV vaccination. Among studied parents, 76% were willing to vaccinate their child if the vaccine is for free and 63% were willing to vaccinate even if the vaccine comes with a cost. Having heard of HPV was associated with both willingness to vaccinate if the vaccine is free (odds ratio [OR]: 1.42; 95% confidence interval [CI]: 1.21-1.66) and willingness to vaccinate even if the vaccine is not free (OR: 1.96; 95% CI: 1.75-2.20) compared with those who never heard of HPV. Beliefs about vaccine safety and efficacy were also strong correlates of willingness to vaccinate. Parents born outside Europe and those with higher education were less willing to vaccinate if the vaccine is not free. In conclusion, the willingness to vaccinate was reasonably high and cost did not appear to be a major barrier. Information about vaccine safety and efficacy is important and parents need information about HPV and the HPV vaccine.

A survey on misunderstanding of dental scaling in Hong Kong.

UNLABELLED: There is no information on the misunderstanding of dental scaling; on whether the misunderstanding affects the general public to go for scaling or not; on complaints about dental scaling and suggestion of who should educate the public in the existing literature. This study gives the information from the general public in Hong Kong. METHODS: A cross-sectional survey by telephone interview on a random sample of 1412 subjects aged 13 years and above in Hong Kong was conducted from 3rd January to 15th February 2006. RESULTS: More females had received scaling (adjusted OR = 1.73, 95%CI 1.31-2.29 P < 0.001), 51-60 years age group had the highest scaling experience (adjusted OR = 2.69, 95% CI 1.55-4.68, P < 0.001). Higher education was related to scaling experience (P < 0.001). Of the subjects with complete data, 22.5% (307/1364) had never received dental scaling, 17.9% (55/307) did not understand the purpose, 12.1% (37/307) replied that it would make the teeth thinner, 11.4% (35/307) replied that the gum space would become wider, and 11.4% (35/307) stated that scaling would damage the gum. In all, 45.9% (298/649) of the subject reported bleeding, 33.7% (139/413) sensitivity, 40.5% (62/153) smaller teeth and 23.9% (84/351) widened gum space because of mistakes made during the procedure; 8.6% (56/649) of those who experienced bleeding, 17.8% (27/152) of those who reported the teeth became smaller and 12% (42/350) of those who stated that the gum space became wider intended to reduce the frequency, delay or not go for scaling. A total of 79.6% (841/1057) experienced one of the perceived problems; 27.8% (234/841) had complained about scaling. CONCLUSION: This study shows a common lack of knowledge of dental scaling in the Hong Kong population. Patients should be better informed about the aim before the procedure.

Making space for racial dialogue: our experience in a marriage and family therapy training program.

Marriage and family therapy (MFT) training programs need to create opportunities for all students to develop cultural competency by raising their racial awareness and sensitivity. Likewise, therapists of color need to be offered space in MFT programs to voice their experiences and venues for their voices to be heard. This article reports on the efforts within a master's level, accredited MFT training program to create space, through participatory action research, for the unique experiences of therapists of color and White therapists who are deeply committed to racial sensitivity.

Transforming an MFT program: a model for enhancing diversity.

Marriage and family therapy programs need to go beyond the typical practices of recruiting and retaining students of color. Marriage and family therapy educators must assume positions of leadership by transforming graduate programs to reflect a deep, active, systemic commitment to both diversity and social justice. In this article, we argue that it is through this type of transformation that programs become truly ready to support students of color and to prepare all therapists to advocate for equity in a diverse, often unfair society. This article offers a model that addresses readiness, recruitment, retention, assessment, and professional development from this perspective.