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Background: The COVID-19 pandemic has caused distress in students globally. The mental health of international students studying abroad has been neglected during the COVID-19 pandemic, especially Chinese students who have been unfairly targeted. Objective: To explore and document the positive and negative experiences of a group of Hong Kong Chinese international students studying in the U.K. and U.S. from an insider perspective in the early stage of the COVID-19 pandemic. Methods: The qualitative study used four 1.5-h online focus group interviews of 20 Chinese international students from Hong Kong aged 18 or older studying in universities in the United Kingdom or the United States, from 3 May to 12 May 2020. A framework approach with a semi-structured interview guide was used to reflect students' stressors, cognitive appraisals, coping, and outcomes (negative impacts and positive gains), in the early stages of COVID-19. Different strategies were used to ensure the credibility, dependability, confirmability, and transferability of the study. Transcripts were analyzed using qualitative thematic content analysis. Results: Twenty full-time international University students (60% female, 90% aged 18-25 years and 65% undergraduates) were recruited. Students reported (i) stress from personal (e.g., worries about health and academic attainment), interpersonal (e.g., perceived prejudice and lack of social support), and environmental factors (e.g., uncertainties about academic programme and unclear COVID-19-related information); (ii) significant differences in culture and cognitive appraisal in the levels of perceived susceptibility and severity; (iii) positive thinking and using alternative measures in meeting challenges, which included effective emotion and problem coping strategies, and the importance of support from family, friends and schools; and (iv) negative psychological impact (e.g., worries and stress) and positive personal growth in crisis management and gains in family relationships. Conclusions: With the rise in sinophobia and uncertain developments of the pandemic, proactive support from government and academic institutions are urgently needed to reduce stress and promote the well-being of international students, especially Chinese students in the U.K. and U.S. Clear information, public education and policies related to the pandemic, appropriate academic arrangements from universities and strong support systems play important roles in maintaining students' psychological health. Clinical Trial Registration: The study was registered with the National Institutes of Health (https://clinicaltrials.gov/, identifier: NCT04365361)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lai, Sit, Lam, Choi, Yiu, Lai, Ip and Lam.)

Importance: A total of 1% to 3% of patients treated with a poly(adenosine diphosphate-ribose) polymerase inhibitor for high-grade ovarian cancer (HGOC) develop therapy-related myeloid neoplasms (t-MNs), which are rare but often fatal conditions. Although the cause of these t-MNs is unknown, clonal hematopoiesis of indeterminate potential (CHIP) variants can increase the risk of primary myeloid malignant neoplasms and are more frequent among patients with solid tumors., Objectives: To examine whether preexisting CHIP variants are associated with the development of t-MNs after rucaparib treatment and how these CHIP variants are affected by treatment., Design, Setting, and Participants: This retrospective genetic association study used peripheral blood cell (PBC) samples collected before rucaparib treatment from patients in the multicenter, single-arm ARIEL2 (Study of Rucaparib in Patients With Platinum-Sensitive, Relapsed, High-Grade Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer) (n = 491; between October 30, 2013, and August 9, 2016) and the multicenter, placebo-controlled, double-blind ARIEL3 (Study of Rucaparib as Switch Maintenance Following Platinum-Based Chemotherapy in Patients With Platinum-Sensitive, High-Grade Serous or Endometrioid Epithelial Ovarian, Primary Peritoneal or Fallopian Tube Cancer) (n = 561; between April 7, 2014, and July 19, 2016), which tested rucaparib as HGOC therapy in the treatment and maintenance settings, respectively. The follow-up data cutoff date was September 1, 2019. Of 1052 patients in ARIEL2 and ARIEL3, PBC samples from 20 patients who developed t-MNs (cases) and 44 randomly selected patients who did not (controls) were analyzed for the presence of CHIP variants using targeted next-generation sequencing. Additional longitudinal analysis was performed on available ARIEL2 samples collected during treatment and at the end of treatment., Main Outcomes and Measures: Enrichment analysis of preexisting variants in 10 predefined CHIP-associated genes in cases relative to controls; association with clinical correlates., Results: Among 1052 patients (mean [SE] age, 61.7 [0.3] years) enrolled and dosed in ARIEL2 and ARIEL3, 22 (2.1%) developed t-MNs. The t-MNs were associated with longer overall exposure to prior platinum therapies (13.2 vs 9.0 months in ARIEL2, P = .04; 12.4 vs 9.6 months in ARIEL3, P = .003). The presence of homologous recombination repair gene variants in the tumor, either germline or somatic, was associated with increased prevalence of t-MNs (15 [4.1%] of 369 patients with HGOC associated with an HRR gene variant vs 7 [1.0%] of 683 patients with wild-type HGOC, P = .002). The prevalence of preexisting CHIP variants in TP53 but not other CHIP-associated genes at a variant allele frequency of 1% or greater was significantly higher in PBCs from cases vs controls (9 [45.0%] of 20 cases vs 6 [13.6%] of 44 controls, P = .009). TP53 CHIP was associated with longer prior exposure to platinum (mean 14.0 months of 15 TP53 CHIP cases vs 11.1 months of 49 non-TP53 CHIP cases; P = .02). Longitudinal analysis showed that preexisting TP53 CHIP variants expanded in patients who developed t-MNs., Conclusions and Relevance: The findings of this genetic association study suggest that preexisting TP53 CHIP variants may be associated with t-MNs after rucaparib treatment.

Background: The mental health of international students studying abroad has been neglected during the COVID-19 pandemic. Objective: This mixed-method study examined perceived public attitudes, personal beliefs, practice and stress toward facemask wearing as a preventive measure against COVID-19 among international University students from Hong Kong studying in the United Kingdom (UK) in the early stage (January-March 2020) of the pandemic. Methods: Our study included 2 parts: (i) an exponential, non-discriminative snowball sampling strategy was used to recruit 91 Chinese students studying in the UK to complete an online questionnaire survey, and (ii) online Zoom focus group interviews were conducted with 16 students who completed the online survey to gain an in-depth understanding of their experiences and coping methods during the pandemic. Results: Of the 91 students, 92.3% reported the UK public did not view facemask wearing as a preventive measure. 98.9% believed facemask wearing was an effective preventive measure, but 56% wore facemasks more than half of the time when out in public. 50.5% had internal conflicts of stress both when wearing and not wearing facemasks, which was more common in females than males [(62.5 vs. 31.5%), P = 0.004, Relative Risk (RR): 1.99 (1.17, 3.38)]. 61.5% reported public prejudiced attitudes against facemask wearing, also more common in females than males (71.4 vs. 45.7%), P = 0.02, RR: 1.56 (1.05, 2.32). The qualitative findings corroborated with the quantitative findings and reported that peer and family support were important for them to face such difficulties, and positive thinking and adaptability were effective methods on stress management. Conclusions: Since the outbreak of COVID-19, Chinese international students have been faced with a difficult, confusing, and sensitive situation. Owing to the ongoing pandemic, rising xenophobia and racist behaviors and the resumption of students' studies studies in the U.K., support from global communities are needed in their pursuit of quality education overseas. Our findings have significant implications on the proactive roles that governments should have, and the need for clear and accurate public health messaging to change public attitudes and mitigate prejudice. Academic institutions and mental health professionals need to proactively provide additional support to Chinese international students., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lai, Sit, Lai, Wang, Kong, Cheuk, Feng, Ip and Lam.)

ARIEL2 (NCT01891344) is a single-arm, open-label phase 2 study of the PARP inhibitor (PARPi) rucaparib in relapsed high-grade ovarian carcinoma. In this post hoc exploratory biomarker analysis of pre- and post-platinum ARIEL2 samples, RAD51C and RAD51D mutations and high-level BRCA1 promoter methylation predict response to rucaparib, similar to BRCA1/BRCA2 mutations. BRCA1 methylation loss may be a major cross-resistance mechanism to platinum and PARPi. Genomic scars associated with homologous recombination deficiency are irreversible, persisting even as platinum resistance develops, and therefore are predictive of rucaparib response only in platinum-sensitive disease. The RAS, AKT, and cell cycle pathways may be additional modulators of PARPi sensitivity.

Background: The coronavirus disease 2019 (COVID-19) pandemic has disrupted university teaching globally. The mental health impacts on international university students have been overlooked. Aims: This study examined the differences in COVID-19-related stressors and mental health impacts between international university students studying in the UK or USA who returned to their home country or region (returnees) and those who stayed in their institution country (stayers), and identified COVID-19-related stressors and coping strategies that were predictors of mental health. Method: An online questionnaire survey was conducted from April 28 through May 12, 2020 using an exponential, non-discriminative snowball sampling strategy (registered at the National Institutes of Health: NCT04365361). Results: A total of 124 full-time international university students (36.3% male) were included: 75.8% had returned to their home country or region for reasons related to COVID-19; 77.4% were pursuing a bachelor's program, and 53.2% were in programs with practicum component. 84.7% of all students had moderate-to-high perceived stress, 12.1% had moderate-to-severe symptoms of anxiety and depression, and 17.7% had moderate-to-severe symptoms of insomnia. Compared with returnees, stayers had significantly higher stress from COVID-19-related stressors such as personal health and lack of social support (Cohen's d: 0.57-1.11), higher perceived stress [10-item Perceived Stress Scale (PSS-10)] {22.6 ± 6.2 vs. 19.1 ± 6.1, β [95% confidence interval (CI)]: 4.039 (0.816, 7.261), Cohen's d: 0.52}, and more severe insomnia symptoms [Insomnia Severity Index (ISI)] [11.8 ± 6.1 vs. 7.6 ± 5.2, β (95% CI): 3.087 (0.262, 5.912), Cohen's d: 0.45], with moderate-to-large effect sizes. Compared with males, females reported significantly higher stress from uncertainties about academic program (Cohen's d: 0.45) with a small effect size. In the total sample, stress related to academics (e.g., personal attainment, uncertainties about academic program, and changes in teaching/learning format), health (including personal health and health of family and friends), availability of reliable COVID-19-related information, and lack of social support predicted more negative mental health impacts. Resilience, positive thinking, and exercise were predictors of less severe mental health impacts. Conclusions: Stayers experienced more adverse mental health impacts than returnees. We call on educators and mental health professionals to provide appropriate support for international students, particularly the stayers, during the pandemic., (Copyright © 2020 Lai, Lee, Wang, Feng, Lai, Ho, Lam, Ip and Lam.)

Circulating tumor cells (CTCs) provide valuable information about the molecular evolution of cancers, as they may initially respond and ultimately progress on therapy. As intact tumor cells isolated from the bloodstream, CTCs also enable assessment of heterogeneous subpopulations, and their analysis may include DNA, RNA, and protein biomarkers. New microfluidic cell isolation strategies greatly facilitate the challenge of enriching viable tumor cells from the billions of hematopoietic cells within a standard blood specimen. While counting and characterization of enriched CTCs have primarily relied on immunostaining for tumor cell-specific antigens, new RNA-based analytic platforms are providing new insight into the identity of CTCs and providing new tools for clinical applications. Single-cell RNA sequencing of CTCs reveals a high degree of heterogeneity among cancer cells from a single individual, while new digital RNA-based amplification platforms may now allow high-sensitivity and high-throughput quantitative scoring of CTCs for clinical applications. Here, we focus on transcriptomic analysis of CTCs and its relevance in understanding metastatic cancer progression and in developing diagnostic assays to monitor cancer.

Stapled peptides have great potential as modulators of protein-protein interactions (PPIs). However, there is a vast landscape of chemical features that can be varied for any given peptide, and identifying a set of features that maximizes cellular uptake and subsequent target engagement remains a key challenge. Herein, we present a systematic analysis of staple functionality on the peptide bioactivity landscape in cellular assays. Through application of a "toolbox" of diversified dialkynyl linkers to the stapling of MDM2-binding peptides via a double-click approach, we conducted a study of cellular uptake and p53 activation as a function of the linker. Minor changes in the linker motif and the specific pairing of linker with peptide sequence can lead to substantial differences in bioactivity, a finding which may have important design implications for peptide-based inhibitors of other PPIs. Given the complexity of the structure-activity relationships involved, the toolbox approach represents a generalizable strategy for optimization when progressing from in vitro binding assays to cellular efficacy studies.

Background: Pressure injury is a common clinical parameter of patient care outcome. Various risk factors increase the risk of palliative care patients to pressure injuries and difficult wound healing. Healthcare professionals are aware that wound healing is difficult, but they still focus on this process instead of providing the needs of patients with unhealed wounds., Methods: This study aims to identify the clinical parameters of pressure injuries in relation to patients with advanced illness. A retrospective analysis of the records of patients with pressure injuries admitted over 18 months was performed. Descriptive analysis and Spearman's correlation coefficient were used., Results: A total of 127 clinical records were reviewed. The study revealed that patients of old age, high creatinine level, advanced wound age, reduced palliative performance scale (PPS) and low Norton scores are prone to suffer from unhealed wounds., Conclusions: Pressure injuries are prone to non-healing in patients with old age, high creatinine level, advanced wound stage, low PPS and low Norton scores. Further studies involving patients in earlier stage can be considered.

[This corrects the article DOI: 10.1039/C8SC04645J.].

Antibody-drug conjugates (ADCs) are a class of targeted therapeutics that utilize the specificity of antibodies to selectively deliver highly potent cytotoxins to target cells. Although recent years have witnessed significant interest in ADCs, problems remain with the standard linkage chemistries used for cytotoxin-antibody bioconjugation. These typically (1) generate unstable constructs, which may lead to premature cytotoxin release, (2) often give a wide variance in drug-antibody ratios (DAR) and (3) have poor control of attachment location on the antibody, resulting in a variable pharmacokinetic profile. Herein, we report a novel divinylpyrimidine (DVP) linker platform for selective bioconjugation via covalent re-bridging of reduced disulfide bonds on native antibodies. Model studies using the non-engineered trastuzumab antibody validate the utility of this linker platform for the generic generation of highly plasma-stable and functional antibody constructs that incorporate variable biologically relevant payloads (including cytotoxins) in an efficient and site-selective manner with precise control over DAR. DVP linkers were also used to efficiently re-bridge both monomeric and dimeric protein systems, demonstrating their potential utility for general protein modification, protein stabilisation or the development of other protein-conjugate therapeutics.

The multiplicity of new therapies for breast cancer presents a challenge for treatment selection. We describe a 17-gene digital signature of breast circulating tumor cell (CTC)-derived transcripts enriched from blood, enabling high-sensitivity early monitoring of response. In a prospective cohort of localized breast cancer, an elevated CTC score after three cycles of neoadjuvant therapy is associated with residual disease at surgery ( P = 0.047). In a second prospective cohort with metastatic breast cancer, baseline CTC score correlates with overall survival ( P = 0.02), as does persistent CTC signal after 4 weeks of treatment ( P = 0.01). In the subset with estrogen receptor (ER)-positive disease, failure to suppress ER signaling within CTCs after 3 weeks of endocrine therapy predicts early progression ( P = 0.008). Drug-refractory ER signaling within CTCs overlaps partially with presence of ESR1 mutations, pointing to diverse mechanisms of acquired endocrine drug resistance. Thus, CTC-derived digital RNA signatures enable noninvasive pharmacodynamic measurements to inform therapy in breast cancer. Significance: Digital analysis of RNA from CTCs interrogates treatment responses of both localized and metastatic breast cancer. Quantifying CTC-derived ER signaling during treatment identifies patients failing to respond to ER suppression despite having functional ESR1. Thus, noninvasive scoring of CTC-RNA signatures may help guide therapeutic choices in localized and advanced breast cancer. Cancer Discov; 8(10); 1286-99. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 1195 ., (©2018 American Association for Cancer Research.)

A subset of patients with metastatic melanoma have sustained remissions following treatment with immune checkpoint inhibitors. However, analyses of pretreatment tumor biopsies for markers predictive of response, including PD-1 ligand (PD-L1) expression and mutational burden, are insufficiently precise to guide treatment selection, and clinical radiographic evidence of response on therapy may be delayed, leading to some patients receiving potentially ineffective but toxic therapy. Here, we developed a molecular signature of melanoma circulating tumor cells (CTCs) to quantify early tumor response using blood-based monitoring. A quantitative 19-gene digital RNA signature (CTC score) applied to microfluidically enriched CTCs robustly distinguishes melanoma cells, within a background of blood cells in reconstituted and in patient-derived ( n = 42) blood specimens. In a prospective cohort of 49 patients treated with immune checkpoint inhibitors, a decrease in CTC score within 7 weeks of therapy correlates with marked improvement in progression-free survival [hazard ratio (HR), 0.17; P = 0.008] and overall survival (HR, 0.12; P = 0.04). Thus, digital quantitation of melanoma CTC-derived transcripts enables serial noninvasive monitoring of tumor burden, supporting the rational application of immune checkpoint inhibition therapies., Competing Interests: Conflict of interest statement: Massachusetts General Hospital and the authors have applied for patent protection for the CTC-iChip technology and the molecular signatures of melanoma cells., (Copyright © 2018 the Author(s). Published by PNAS.)

Blood-based biomarkers are critical in metastatic prostate cancer, where characteristic bone metastases are not readily sampled, and they may enable risk stratification in localized disease. We established a sensitive and high-throughput strategy for analyzing prostate circulating tumor cells (CTC) using microfluidic cell enrichment followed by digital quantitation of prostate-derived transcripts. In a prospective study of 27 patients with metastatic castration-resistant prostate cancer treated with first-line abiraterone, pretreatment elevation of the digital CTC M score identifies a high-risk population with poor overall survival (HR = 6.0; P = 0.01) and short radiographic progression-free survival (HR = 3.2; P = 0.046). Expression of HOXB13 in CTCs identifies 6 of 6 patients with ≤12-month survival, with a subset also expressing the ARV7 splice variant. In a second cohort of 34 men with localized prostate cancer, an elevated preoperative CTC L score predicts microscopic dissemination to seminal vesicles and/or lymph nodes ( P < 0.001). Thus, digital quantitation of CTC-specific transcripts enables noninvasive monitoring that may guide treatment selection in both metastatic and localized prostate cancer. Significance: There is an unmet need for biomarkers to guide prostate cancer therapies, for curative treatment of localized cancer and for application of molecularly targeted agents in metastatic disease. Digital quantitation of prostate CTC-derived transcripts in blood specimens is predictive of abiraterone response in metastatic cancer and of early dissemination in localized cancer. Cancer Discov; 8(3); 288-303. ©2018 AACR. See related commentary by Heitzer and Speicher, p. 269 This article is highlighted in the In This Issue feature, p. 253 ., (©2018 American Association for Cancer Research.)

Transition metal catalysis has emerged as a powerful strategy to expand synthetic flexibility of protein modification. Herein, we report a cationic Ru(ii) system that enables the first example of alkyne hydrosilylation between dimethylarylsilanes and O -propargyl-functionalized proteins using a substoichiometric amount or low-loading of Ru(ii) catalyst to achieve the first C-Si bond formation on full-length substrates. The reaction proceeds under physiological conditions at a rate comparable to other widely used bioorthogonal reactions. Moreover, the resultant gem -disubstituted vinylsilane linkage can be further elaborated through thiol-ene coupling or fluoride-induced protodesilylation, demonstrating its utility in further rounds of targeted modifications.

Circulating tumor cells (CTCs) are shed into the bloodstream by invasive cancers, but the difficulty inherent in identifying these rare cells by microscopy has precluded their routine use in monitoring or screening for cancer. We recently described a high-throughput microfluidic CTC-iChip, which efficiently depletes hematopoietic cells from blood specimens and enriches for CTCs with well-preserved RNA. Application of RNA-based digital PCR to detect CTC-derived signatures may thus enable highly accurate tissue lineage-based cancer detection in blood specimens. As proof of principle, we examined hepatocellular carcinoma (HCC), a cancer that is derived from liver cells bearing a unique gene expression profile. After identifying a digital signature of 10 liver-specific transcripts, we used a cross-validated logistic regression model to identify the presence of HCC-derived CTCs in nine of 16 (56%) untreated patients with HCC versus one of 31 (3%) patients with nonmalignant liver disease at risk for developing HCC (P < 0.0001). Positive CTC scores declined in treated patients: Nine of 32 (28%) patients receiving therapy and only one of 15 (7%) patients who had undergone curative-intent ablation, surgery, or liver transplantation were positive. RNA-based digital CTC scoring was not correlated with the standard HCC serum protein marker alpha fetoprotein (P = 0.57). Modeling the sequential use of these two orthogonal markers for liver cancer screening in patients with high-risk cirrhosis generates positive and negative predictive values of 80% and 86%, respectively. Thus, digital RNA quantitation constitutes a sensitive and specific CTC readout, enabling high-throughput clinical applications, such as noninvasive screening for HCC in populations where viral hepatitis and cirrhosis are prevalent., Competing Interests: The authors declare no conflict of interest.

Background: The RNA guided CRISPR/Cas9 nucleases have been proven to be effective for gene disruption in various animal models including Xenopus tropicalis. The neural crest (NC) is a transient cell population during embryonic development and contributes to a large variety of tissues. Currently, loss-of-function studies on NC development in X. tropicalis are largely based on morpholino antisense oligonucleotide. It is worthwhile establishing targeted gene knockout X. tropicails line using CRISPR/Cas9 system to study NC development., Methods: We utilized CRISPR/Cas9 to disrupt genes that are involved in NC formation in X. tropicalis embryos. A single sgRNA and Cas9 mRNA synthesized in vitro, were co-injected into X. tropicalis embryos at one-cell stage to induce single gene disruption. We also induced duplex mutations, large segmental deletions and inversions in X. tropicalis by injecting Cas9 and a pair of sgRNAs. The specificity of CRISPR/Cas9 was assessed in X. tropicalis embryos and the Cas9 nickase was used to reduce the off-target cleavages. Finally, we crossed the G0 mosaic frogs with targeted mutations to wild type frogs and obtained the germline transmission., Results: Total 16 target sites in 15 genes were targeted by CRISPR/Cas9 and resulted in successful indel mutations at 14 loci with disruption efficiencies in a range from 9.3 to 57.8 %. Furthermore, we demonstrated the feasibility of generation of duplex mutations, large segmental deletions and inversions by using Cas9 and a pair of sgRNAs. We observed that CRISPR/Cas9 displays obvious off-target effects at some loci in X. tropicalis embryos. Such off-target cleavages was reduced by using the D10A Cas9 nickase. Finally, the Cas9 induced indel mutations were efficiently passed to G1 offspring., Conclusion: Our study proved that CRISPR/Cas9 could mediate targeted gene mutation in X. tropicalis with high efficiency. This study expands the application of CRISPR/Cas9 platform in X. tropicalis and set a basis for studying NC development using genetic approach.

Cancer-related fatigue (CRF) is common in women with breast cancer, but little is known of its relationship with perceived stress. We conducted a cross-sectional study to explore the associations of CRF with perceived stress, anxiety, depression, pain and sleep quality in 133 Chinese women (aged 25-68 years) with early stage breast cancer. The majority of women had completed surgery and chemotherapy and were awaiting radiotherapy. Self-administered questionnaires consisting of the Brief Fatigue Inventory, Perceived Stress Scale-10, Hospital Anxiety and Depression Scale, Brief Pain Inventory, and Pittsburgh Sleep Quality Index were used to collect data. Forty-five per cent of the women were severely fatigued. Compared with local healthy women and US breast cancer patients, the group's mean perceived stress score was significantly higher (both p < 0.01). Higher perceived stress (β = 0.18, p = 0.032), higher anxiety (β = 0.30, p < 0.001) and higher pain severity (β = 0.38, p < 0.001) were associated with increased severity of CRF. The association of CRF with perceived stress was partially mediated by anxiety, suggesting a possible pathway from cancer and cancer treatment to CRF via stress appraisals and emotional distress. The findings indicate the importance of monitoring the psychological status of patients during treatment., (Copyright © 2013 John Wiley & Sons, Ltd.)

Small molecules are useful tools for probing the biological function and therapeutic potential of individual proteins, but achieving selectivity is challenging when the target protein shares structural domains with other proteins. The Bromo and Extra-Terminal (BET) proteins have attracted interest because of their roles in transcriptional regulation, epigenetics, and cancer. The BET bromodomains (protein interaction modules that bind acetyl-lysine) have been targeted by potent small-molecule inhibitors, but these inhibitors lack selectivity for individual family members. We developed an ethyl derivative of an existing small-molecule inhibitor, I-BET/JQ1, and showed that it binds leucine/alanine mutant bromodomains with nanomolar affinity and achieves up to 540-fold selectivity relative to wild-type bromodomains. Cell culture studies showed that blockade of the first bromodomain alone is sufficient to displace a specific BET protein, Brd4, from chromatin. Expansion of this approach could help identify the individual roles of single BET proteins in human physiology and disease., (Copyright © 2014, American Association for the Advancement of Science.)

Aim: This study aims to investigate the areas of concerns that women have regarding human papillomavirus (HPV) vaccination., Material and Methods: A cross-sectional questionnaire survey was conducted in a convenience sample of 1450 women attending outpatient family planning clinics in Hong Kong to assess women's concerns regarding HPV vaccination. The associations between each demographic characteristics and the importance of various issues concerning the vaccine, such as short and long-term side-effects, side-effect affecting appearance, number of women who have had it, effectiveness, effect duration and cost were explored using χ(2) tests for comparison of proportions. Multiple binary logistic regression analysis was applied to further identify independent demographic characteristics which were significantly associated with each of these issues., Results: The top three factors that most women felt very important were vaccine effectiveness (45.4%), effect duration (44.0%) and long-term side-effects (43.7%). Education level significantly affected the degree of concerns in these areas (OR=1.15, P<0.001, 1.14, P<0.001 and 1.09, P=0.006, respectively) while income was significantly inversely associated with the importance of cost (OR=0.92, P<0.001) and effectiveness (OR=0.95, P=0.047)., Conclusion: The above issues should be specifically addressed when vaccine information is given, bearing in mind the particular concerns in women with different socio-economic backgrounds., (© 2011 The Authors. Journal of Obstetrics and Gynaecology Research © 2011 Japan Society of Obstetrics and Gynecology.)

Objective: To assess knowledge and stigmatizing attitudes related to human papillomavirus (HPV) and HPV testing among Chinese healthcare providers in Hong Kong., Methods: Between May and September 2010, an anonymous self-administered questionnaire was sent to 247 doctors, nurses, and smear-taking trainees providing cervical screening in Hong Kong., Results: In total, 137 questionnaires were returned. Most participants had basic knowledge about HPV infection and HPV vaccination. Only about 33% knew that high-risk HPV does not cause genital warts, infection is most common among young women, or infected individuals might not have any identifiable sexual risk factors. Regarding HPV testing, 6 of 7 knowledge items were answered incorrectly by many participants (≥ 50%), highlighting a lack of understanding of the indications for HPV testing and the implications of a positive result. About 30% of participants agreed that individuals with HPV infection were sexually easy, responsible for their infection, or had more than 1 sexual partner. More knowledge about HPV infection predicted less stigmatizing attitudes., Conclusion: Continued education on HPV and HPV testing is needed for frontline healthcare providers of screening in Hong Kong. The stigmatizing attitudes toward HPV-infected individuals warrant further exploration of the impact of HPV infection on patient care and interventions., (Copyright © 2011 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.)

Objective: To evaluate the effects of school-based cervical cancer education on Hong Kong Chinese adolescent girls., Methods: Adolescent girls (n=953) in local secondary schools attended a tailored educational program on cervical cancer prevention. Self-administered questionnaires were used before and after the program to measure its effects on participants' knowledge, attitude and perceived social norms towards human papillomavirus (HPV) vaccination and their intention to be HPV vaccinated., Results: Before the program, HPV vaccine acceptance was favorable but relevant knowledge was low. After the program, participants had greater knowledge and a more positive attitude (both p<0.001), with more girls anticipating family (41.6% before vs. 58.9% after) and peer support (32.8% before vs. 56.9% after). There were 11.3% more girls who indicated an intention to accept the vaccine afterward. More knowledge, a more positive attitude and perceived support from significant others predicted a stronger intention to be HPV vaccinated., Conclusion: The educational program had a positive impact on participants' perceptions towards HPV vaccination and their intention to be vaccinated., Practice Implications: School-based cervical cancer education is a viable means to meet the substantial educational needs of adolescents. Promotion of HPV vaccination should also include educating and influencing perceptions of families and peers., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Objective: To assess the psychological burden of testing positive for high-risk human papillomavirus (HPV) on Chinese women with atypical squamous cells of undetermined significance (ASCUS)., Design: Prospective observational study., Setting: Five community women's health clinics in Hong Kong., Population: Ethnic Chinese women (n=299) with ASCUS who underwent reflex HPV testing (of whom 142 tested HPV negative and 157 tested HPV positive)., Methods: Women's psychological condition was assessed by self-administered questionnaires at smear result notification and by structured telephone interviews six months after notification. All women who tested positive for HPV were referred for colposcopy., Main Outcome Measures: State anxiety, cervical cancer worry and psychosocial burden., Results: At result notification, the HPV-positive group had significantly higher state anxiety, cervical cancer worry and psychosocial burden than the HPV-negative group (all p<0.001). Irrespective of the HPV results, all outcome scores decreased over time. About 80% of the women who were HPV positive attended colposcopy as recommended. At six months, the two groups did not differ in state anxiety, cervical cancer worry, perceived risk of cervical cancer and satisfaction with intimate relationship, but psychosocial burden remained higher in the HPV-positive group (p=0.001)., Conclusions: A concurrent positive HPV result intensified the distress of women with ASCUS at result notification. With time and after colposcopy, their initial heightened anxiety and cervical cancer worry were significantly lowered. However, HPV positivity may pose a prolonged psychosocial burden on women even after having had the necessary follow-up for their cervical abnormalities., (© 2011 The Authors Acta Obstetricia et Gynecologica Scandinavica © 2011 Nordic Federation of Societies of Obstetrics and Gynecology.)

Objective: To identify the components of a human papillomavirus (HPV) message contributing to reducing the stigma of HPV in cervical cancer., Methods: 294 ethnic Chinese women attending a community-based clinic in Hong Kong were randomly allocated to read one of three written HPV messages: Group 'lr+hrHPV': low-risk and high-risk HPVs facts, Group 'hrHPV': high-risk HPV facts only and Group 'ds+hrHPV': high-risk HPV facts and de-stigmatising components, namely being anti-stereotypical, motivational and low in complexity. Main outcome measures were high-risk HPV-related sexual stigma, knowledge, attitude towards message, and intention to be HPV-tested measured by self-administered questionnaires immediately before and after reading., Results: Message allocation had a significant effect on sexual stigma (F = 5.219, p = 0.006). Participants who read message ds+hrHPV showed the least stigma, and were significantly less likely to believe that high-risk HPV infection implicated promiscuity, non-monogamy or that monogamy offered complete protection against high-risk HPV. The genital HPV-focused message was more stigmatising than cervical cancer-focused messages. Of all participants, 93% (237/254) and 97% (260/269) indicated a positive intention to be HPV-tested before and after reading, respectively. There were no between-group differences noted in terms of knowledge and intention to be HPV-tested before or after reading., Conclusions: Our findings show that an HPV message containing specific de-stigmatising components may reduce public stigma towards high-risk HPV. Also, focusing solely on high-risk HPV in the context of cervical cancer helps to avoid the stigmatising effect of genital warts from tainting perceptions about high-risk HPV infection., (Copyright © 2010 John Wiley & Sons, Ltd.)

Objective: To explore Chinese women's perceptions of human papillomavirus (HPV) vaccination and their intention to be vaccinated., Design: A cross-sectional community-based survey study., Setting: Thirteen community women's health centres of The Family Planning Association of Hong Kong., Sample: A total of 1450 ethnic Chinese women aged 18 or above who attended the health centres., Methods: Participants completed a written consent and an anonymous questionnaire onsite., Main Outcome Measures: Knowledge and beliefs about HPV and HPV vaccination against cervical cancer and participants' own intention to be vaccinated., Results: About 38% of the participants (n = 527) had heard of HPV and 50% (n = 697) had heard of vaccination against cervical cancer. HPV infection was perceived to be stigmatising and detrimental to intimate, family and social relationships. Despite misconceptions and a grossly inadequate knowledge about HPV and HPV vaccination, 88% of the participants (n = 1219) indicated that they would likely be vaccinated. Majority of the participants believed that sexually experienced women should be vaccinated, while 27% opposed vaccinating sexually naive women. Younger age women who perceived a disruptive impact of HPV infection on intimate relationship and their partners' approval were significantly associated with a positive intention to be HPV vaccinated., Conclusions: The easy acceptability of HPV vaccination among the mostly sexually experienced Chinese participants and their knowledge deficit on the subject may implicate potential misuse of the vaccines and a false sense of security against cervical cancer. There is a dire need for culturally sensitive and tailored education for the public, women of different ages and their partners about HPV and HPV vaccination. Emphasis must be placed on the prophylactic nature of the current vaccines, the uncertain effects when given to sexually experienced women, the importance of adolescent vaccination and the need for continued cervical screening whether vaccinated or not.

Objectives: To explore perceptions towards cervical cancer, human papillomavirus (HPV) infection and HPV vaccination and to identify factors affecting the acceptability of HPV vaccination among Chinese adolescent girls in Hong Kong., Methods: Six focus groups were conducted with Chinese adolescent girls (median age 16 years, age range 13-20, n = 64) in Hong Kong in April 2007. Thematic analysis was employed to identify major themes related to cervical cancer and HPV vaccination. A supplementary questionnaire was administered to all participants before and after group discussion to assess their knowledge, attitudes and intention to be vaccinated and to collect demographic information., Results: Participants' knowledge on cervical cancer was limited and HPV was largely unheard of. They had difficulty understanding the mechanism linking cervical cancer with HPV infection. Participants held a favourable attitude towards HPV vaccination but the perceived timing of vaccination varied. Barriers to vaccination include high monetary cost, uncertain length of vaccine effectiveness, low perceived risk of HPV infection, no immediate perceived need of vaccination, anticipated family disapproval and fear of the pain of injection. Factors conducive to vaccination include perceived family and peer support and medical reassurance on safety and efficacy of vaccine. The differences on knowledge, attitudes, intention to be vaccinated now and willingness to conform to significant others before and after the discussion were statistically significant, with an increased tendency towards favouring vaccination after the focus group., Conclusions: Participants favoured HPV vaccination despite not feeling an immediate need to be vaccinated. Interventions could focus on providing professional information on HPV vaccination and raising adolescents' perceived need to take preventive measures against HPV infection.

Objective: To assess the knowledge and beliefs on cervical cancer and HPV infection and to evaluate the acceptability of HPV vaccination among Chinese women., Methods: Seven focus groups were conducted with ethnic Chinese women aged 18-25 (n=20), 26-35 (n=13), and 36 and above (n=16) in a community women's health clinic in Hong Kong in 2006. The discussions were audio taped, transcribed and analyzed. Recurrent themes related to cervical cancer, HPV infection and vaccination were highlighted., Results: Diverse conceptions on likely causes of cervical cancer were noted, covering biological, psychological, environmental, lifestyle and sexual factors. Most women had not heard of HPV and its mode of transmission. The participants had difficulties understanding and accepting the linkage between cervical cancer and the sexually transmitted HPV infection. HPV infection was seen as personally stigmatizing with significant adverse impact on self-esteem and significant relationships. Participants favored HPV vaccination both for themselves and their teenage daughters if authoritative endorsement was provided., Conclusion: Inadequate knowledge and misconceptions on cervical cancer and HPV were common. Most participants welcomed and favored having HPV vaccination. Apart from promoting HPV vaccination, cervical cancer prevention should also include strategies to promote knowledge and minimize the stigmatizing effect of a sexually transmitted HPV infection.

Background: Radiotherapy (RT) promises optimistic results in the treatment of nasopharyngeal cancer (NPC). The objective of the current study was to map out prospectively the impact of NPC and RT on patients from diagnosis to 1 year posttreatment., Methods: For this study, 67 Chinese patients (46 men and 21 women) with newly diagnosed stage I or II NPC who received primary RT were recruited. Physical and psychosocial adjustments were measured by using the Rotterdam Symptom Checklist, Beck Anxiety Inventory, Beck Depression Inventory, Perceived Stress Scale, and the 36-item Short-Form Health Survey (SF-36). Semistructured clinical interviews were conducted at bimonthly intervals from pre-RT to 1 year post-RT., Results: Physical and psychosocial adjustments were poorest from pre-RT to the end of RT. Rapid improvements in all areas were noted in the first 2 months post-RT and reached a plateau at around the 6th month. At 1 year, except for physical symptoms and perceived stress, patient measures recovered to their pre-RT levels. At 1 year, patients had more physical complaints (P < .001) but less perceived stress (P = .002). The percentage of patients who expressed fear of dying dropped from 28% pre-RT to 2% at 1 year. However, patients who expressed "fear of the worst happening" increased from 51% pre-RT to 57% at 1 year., Conclusions: Different periods in treatment of NPC imposed different psychosocial demands on patients. The current results indicated that the period from diagnosis to 2-month post-RT was a high-risk period both physically and emotionally. After treatment, most patients showed resilience despite persistent side effects of RT and successfully resumed their pretreatment level of functioning by the end of the year. Despite resuming a normal or near-normal living, patients still noted a subdued fear of recurrence., ((c) 2007 American Cancer Society.)

Objective: We investigated the regulatory mechanism of primitive hematopoiesis in zebrafish (Danio rerio) embryos with particular reference to the role of a death receptor (zDR) gene, based on a morpholino (MO) knockdown approach., Methods: MOs targeting the zDR and chordin (Chd) were injected into naturally spawned embryos at one- to four-cell stage. A random sequence (RS) MO was used as a control. Effects on hemoglobin formation (Hb), apoptosis, and lineage-specific gene expression were examined. Embryos injected with zDR, Chd, and RS-MOs were denoted zDR(mo), zChd(mo), and zRS(mo), respectively. Those co-injected with Chd+zDR-MOs and Chd+RS-MOs were abbreviated zChd+DR(mo) and zChd+RS(mo)., Results: zDR mRNA expression was restricted to the intermediate cell mass of wild-type (WT) and zChd(mo) embryos. At 48 hours postfertilization, zDR(mo) embryos showed increased Hb compared with WT or zRS(mo) embryos (2.36 x 10(-2) +/- 1.13 x 10(-3) vs 1.85 x 10(-2) +/- 5.60 x 10(-4) vs 1.79 x 10(-2) +/- 1.31 x 10(-3) U, p < 0.05). zChd+DR(mo) embryos also showed increased Hb compared with zChd(mo) or zChd+RS(mo) embryos (4.60 x 10(-2) +/- 2.79 x 10(-3) vs 3.17 x 10(-2) +/- 1.07 x 10(-3) vs 3.05 x 10(-2) +/- 1.25 x 10(-3) U, p < 0.05). zDR-MO reduced apoptosis, as shown by reduced terminal transferase-mediated dUTP nick end-labeling staining in zChd+DR(mo) compared with zChd+RS(mo) embryos and caspase-3 activity in zDR(mo) vs zRS(mo) (0.525 +/- 0.094 vs 0.953 +/- 0.113 U, p < 0.05), and zChd+DR(mo) vs zChd+RS(mo) embryos (0.247 +/- 0.121 vs 1.180 +/- 0.082, p < 0.05). zChd+DR(mo) embryos showed upregulation of erythroid-specific embryonic hemoglobin gene expression but not that of a myeloid-specific myeloperoxidase gene., Conclusion: Knockdown of zDR in zebrafish embryos decreased apoptosis and increased Hb, suggesting that zDR may regulate primitive hematopoiesis during development.

We investigated the expression of proliferative cell nuclear antigen (PCNA) in zebrafish to delineate the proliferative hematopoietic component during adult and embryonic hematopoiesis. Immunostaining for PCNA and enhanced green fluorescence protein (eGFP) was performed in wild-type and fli1-eGFP (endothelial marker) and gata1-eGFP (erythroid cell marker) transgenic fish. Expression of PCNA mRNA was examined in wild-type and chordin morphant embryos. In adult zebrafish kidney, the renal tubules are surrounded by endothelial cells and it is separated into hematopoietic and excretory compartments. PCNA was expressed in hematopoietic progenitor cells but not in mature neutrophils, eosinophils or erythroid cells. Some PCNA+ cells are scattered in the hematopoietic compartment of the kidney while others are closely associated with renal tubular cells. PCNA was also expressed in spermatogonial stem cells and intestine crypts, consistent with its role in cell proliferation and DNA synthesis. In embryos, PCNA is expressed in the brain, spinal cord and intermediate cell mass (ICM) at 24 h-post fertilization. In chordin morphants, PCNA is significantly upregulated in the expanded ICM. Therefore, PCNA can be used to mark cell proliferation in zebrafish hematopoietic tissues and to identify a population of progenitor cells whose significance would have to be further investigated.

We investigated the mechanisms of intermediate cell mass (ICM) expansion in zebrafish chordin (Chd) morphant embryos and examined the role of BMPs in relation to this phenotype. At 24 h post-fertilization (hpf), the expanded ICM of embryos injected with chd morpholino (MO) (ChdMO embryos) contained a monotonous population of hematopoietic progenitors. In situ hybridization showed that hematopoietic transcription factors were ubiquitously expressed in the ICM whereas vascular gene expression was confined to the periphery. BMP4 (but not BMP2b or 7) and smad5 mRNA were ectopically expressed in the ChdMO ICM. At 48 hpf, monocytic cells were evident in both the ICM and circulation of ChdMO but not WT embryos. While injection of BMP4 MO had no effect on WT hematopoiesis, co-injecting BMP4 with chd MOs significantly reduced ICM expansion. Microarray studies revealed a number of genes that were differentially expressed in ChdMO and WT embryos and their roles in hematopoiesis has yet to be determined. In conclusion, the expanded ICM in ChdMO embryos represented an expansion of embryonic hematopoiesis that was skewed towards a monocytic lineage. BMP4, but not BMP2b or 7, was involved in this process. The results provide ground for further research into the mechanisms of embryonic hematopoietic cell expansion.