Acceptability of self-collected vaginal samples for human papillomavirus testing for primary cervical cancer screening: comparison of face-to-face and online recruitment modes.

BACKGROUND: This study aimed to assess the acceptability and attitudes of women towards human papillomavirus (HPV) self-sampling and compare the effectiveness of two delivery modes utilising face-to-face and online website for cervical cancer screening in Hong Kong. METHODS: Women aged 30-65 years were invited to participate by distributing the study information pamphlets at the specialist clinics of a regional acute hospital. Those who were interested in participating were given the option to join directly face-to-face or through an online website. All participants provided informed consent and received self-sampling kits and acceptability questionnaires either immediately (face-to-face) or through the post after registering at the website (online). All participants were requested to collect their own vaginal samples using a swab which was then brushed on a DNA sample storage card and returned to the hospital either in person or by post. The self-collected samples were tested for high-risk HPV using the Sentis™ HPV assay, a validated isothermal nucleic acid amplification real-time fluorescent detection assay. The primary outcome was the uptake rate of HPV self-sampling. RESULTS: Of the 1998 women recruited (1200 face-to-face, 798 online), 1377 returned their samples, giving an overall uptake rate of 68.9%. The uptake rate was significantly greater in the face-to-face mode than in the online mode (74.6% vs. 60.4%, p < 0.001). The median age of the participants was 49 years, 43.7% were never or under-screened, and 7.1% had high-risk HPV detected. Overall, 82.1% of the participants reported self-sampling convenient, and 79.3% were not embarrassed when collecting self-samples. However, only 49.8% were confident that they had collected the self-samples correctly. Most (91.1%) of the participants expressed willingness to perform self-sampling again, mostly because it was simple (79.2%) and quick (56.3%). CONCLUSIONS: HPV self-sampling can serve as an alternative primary screening method for cervical cancer in Hong Kong, especially for individuals who have not been adequately screened in the past. Both face-to-face and online website recruitment were associated with high acceptability, emphasising the potential benefits of utilising different platforms and strategies for reaching diverse populations.

Predictive and prognostic biomarkers in female genital tract tumours: an update highlighting their clinical relevance and practical issues.

The evaluation of biomarkers by molecular techniques and immunohistochemistry has become increasingly relevant to the treatment of female genital tract tumours as a consequence of the greater availability of therapeutic options and updated disease classifications. For ovarian cancer, mutation testing for BRCA1/2 is the standard predictive biomarker for poly(ADP-ribose) polymerase inhibitor therapy, while homologous recombination deficiency testing may allow the identification of eligible patients among cases without demonstrable BRCA1/2 mutations. Clinical recommendations are available which specify how these predictive biomarkers should be applied. Mismatch repair (MMR) protein and folate receptor alpha immunohistochemistry may also be used to guide treatment in ovarian cancer. In endometrial cancer, MMR immunohistochemistry is the preferred test for predicting benefit from immune checkpoint inhibitor (ICI) therapy, but molecular testing for microsatellite instability may have a supplementary role. HER2 testing by immunohistochemistry and in situ hybridisation is applicable to endometrial serous carcinomas to assess trastuzumab eligibility. Immunohistochemistry for oestrogen receptor and progesterone receptor expression may be used for prognostication in endometrial cancer, but its predictive value for hormonal therapy is not yet proven. POLE mutation testing and p53 immunohistochemistry (as a surrogate for TP53 mutation status) serve as prognostic markers for favourable and adverse outcomes, respectively, in endometrial cancer, especially when combined with MMR testing for molecular subtype designation. For cervical cancer, programmed death ligand 1 immunohistochemistry may be used to predict benefit from ICI therapy although its predictive value is under debate. In vulvar cancer, p16 and p53 immunohistochemistry has established prognostic value, stratifying patients into three groups based on the human papillomavirus and TP53 mutation status of the tumour. Awareness of the variety and pitfalls of expression patterns for p16 and p53 in vulvar carcinomas is crucial for accurate designation. It is hoped that collaborative efforts in standardising and optimising biomarker testing for gynaecological tumours will contribute to evidence-based therapeutic decisions.

Evaluation of an Isothermal Amplification HPV Assay on Self-Collected Vaginal Samples as Compared to Clinician-Collected Cervical Samples.

This study aimed to evaluate the concordance of HPV results between the SentisTM HPV assay (Sentis) (BGI Group, Shenzhen, China), an isothermal amplification-based HPV assay, on self-collected and clinician-collected samples and the agreement of Sentis on self-collected samples with the BD OnclarityTM HPV assay (Onclarity) (Becton, Dickinson, and Company, Franklin Lakes, New Jersey, USA), a PCR-based HPV assay, on clinician-collected samples. This was a prospective study of 104 women attending the colposcopy clinic for abnormal smears. After informed consent, participants self-collected vaginal samples before having clinician-collected cervical samples. Self-collected samples underwent HPV testing with Sentis (Self-Sentis HPV) and clinician-collected samples were tested with Sentis (Clinician-Sentis HPV) and Onclarity (Clinician-Onclarity), which was used as a reference standard. The concordance was assessed using Cohen's kappa. The prevalence of HPV and the acceptability of self-sampling were also evaluated. The concordance rate between Self-Sentis HPV and Clinician-Sentis HPV was 89.8% with a kappa of 0.769. The concordance rate between Self-Sentis HPV and Clinician-Onclarity was 84.4% with a kappa of 0.643. The prevalence of HPV was 26.0% on Clinician-Onclarity, 29.3% on Clinician-Sentis HPV, and 35.6% on Self-Sentis HPV. Overall, 65% of participants would undergo self-sampling again. This was attributed to mainly not feeling embarrassed (68%) and being convenient (58%). Our study showed a substantial agreement between Self-Sentis HPV with Clinician-Sentis HPV and Clinician-Onclarity. Self-sampling was also shown to be a generally well-accepted method of screening.

The Value of Four-Quadrant Cervical Biopsy in Women with Different Colposcopic Impressions.

The aim of this study was to compare the diagnostic efficacy of colposcopic-directed biopsy and four-quadrant biopsy in detecting high-grade cervical intra-epithelial neoplasia (CIN). Women attending three women's clinics for routine cervical screening were recruited. Colposcopy was arranged for women with any cytologic abnormalities greater than atypical squamous cells of undetermined significance (ASCUS), two consecutive ASCUS results or positive HPV testing. During colposcopy, a cervical biopsy was taken from the most suspicious area, but more than one biopsy was allowed. Four-quadrant biopsies at 3, 6, 9 and 12 o'clock and an endocervical curettage were also taken in all cases. A total of 1522 colposcopies were performed in 1311 subjects from June 2010 to August 2017, with 118 cases of high-grade CIN diagnosed. Colposcopic-directed biopsy detected 50.8% of the 118 high-grade CIN, while four-quadrant biopsy detected 86.4% (p < 0.0001). Twenty-seven cases (22.9%) of high-grade CIN were diagnosed in women with normal or unsatisfactory colposcopy. Among the 64 cases with low-grade colposcopic impression, four-quadrant biopsy detected significantly more high-grade CIN (53 cases, 82.8%) than colposcopic-directed biopsy (35 cases, 56.3%) (p = 0.0011). Four-quadrant cervical biopsies should be considered for all women with an abnormal smear or positive HPV testing, especially in patients with low-grade/normal/unsatisfactory colposcopy.

Association of social isolation with health status among community-dwelling Chinese older adults living with homecare services: a cross-sectional survey in Hong Kong.

Background: Defined as having few social relationships or infrequent social contact with family, friends, and the community, social isolation is a public health crisis. We aimed to evaluate the prevalence of social isolation and explore the association between social isolation and health status among community-dwelling Chinese Older Adults living with homecare services. Methods: This is a cross-sectional survey with a structured questionnaire conducted among older adults aged ≥60 in the Central Kowloon District of Hong Kong during 2017-2018. Social isolation was assessed by the Lubben Social Network Scale-6 and a score less than 12 was defined as socially isolated. Six aspects of health status including fall risk, cognitive function, depression, activities of daily living (ADL), instrumental activities of daily living (IADL), and functional mobility were measured by standardized instruments. Multi-criteria decision analysis (MCDA) was applied to estimate an index to represent the overall health status of the respondents. Multivariate logistic/linear regression models were applied to examine the associations between social isolation and health status after adjusting the sociodemographic characteristics. Results: Among the 1,616 participants included in this analysis, the mean age was 80.9 years, 66.3% were female and 41.4% were identified as socially isolated. Compared with the non-isolated group, the socially isolated group had higher proportions of males, divorced or unmarried, ever smoking and drinking, living alone, and living in public housing without religion. After adjusting for confounders, the odds ratios (OR) comparing the socially isolated vs. non-isolated groups were 2.52 (95%CI: 1.79, 3.56) for high fall risk, 1.51 (1.17, 1.94) for cognitive impairment, and 1.78 (1.31, 2.43) for depression. The socially isolated group increased the odds of abnormal ADL, IADL, and functional mobility by 105-150%, and decreased the overall health score by 5.30 (3.42, 7.18). Conclusion: We demonstrated the association of social isolation with poorer physical function and mental health and overall health status among the community-dwelling Chinese older adults living with homecare services. These findings provided new knowledge about the association of social isolation with both physical and mental function for daily living even for those receiving an integrated homecare service in the community. It implies that an unmet healthcare need existed when comparing the service scope of the current homecare services in the community. It also highlighted the need for targeted prevention and intervention initiatives among community-dwelling old adults to alleviate social isolation for better health and good functioning in the community.

M6PR- and EphB4-Rich Exosomes Secreted by Serglycin-Overexpressing Esophageal Cancer Cells Promote Cancer Progression.

Accumulating evidence shows that exosomes participate in cancer progression. However, the functions of cancer cell exosome-transmitted proteins are rarely studied. Previously, we reported that serglycin (SRGN) overexpression promotes invasion and metastasis of esophageal squamous cell carcinoma (ESCC) cells. Here, we investigated the paracrine effects of exosomes from SRGN-overexpressing ESCC cells (SRGN Exo) on ESCC cell invasion and tumor angiogenesis, and used mass spectrometry to identify exosomal proteins involved. Cation-dependent mannose-6-phosphate receptor (M6PR) and ephrin type-B receptor 4 (EphB4) were pronouncedly upregulated in SRGN Exo. Upregulated exosomal M6PR mediated the pro-angiogenic effects of SRGN Exo both in vitro and in vivo, while augmented exosomal EphB4 mediated the pro-invasive effect of SRGN Exo on ESCC cells in vitro. In addition, in vitro studies showed that manipulation of M6PR expression affected the viability and migration of ESCC cells. Both M6PR and EphB4 expression levels were positively correlated with that of SRGN in the serum of patients with ESCC. High level of serum M6PR was associated with poor overall survival rates. Taken together, this study presents the first proof that exosomal M6PR and EphB4 play essential roles in tumor angiogenesis and malignancy, and that serum M6PR is a novel prognostic marker for ESCC patients.

Dataset for the Reporting of Gestational Trophoblastic Neoplasia: Recommendations From the International Collaboration on Cancer Reporting (ICCR).

Comprehensive pathology reporting of cancers is important for patient management, tumor staging, and prognostication. Standardized cancer datasets are essential in guiding pathology reporting in a consistent and concise manner and this facilitates effective global cancer information exchange and comparison. The International Collaboration on Cancer Reporting (ICCR) is an alliance of several national and international pathology societies in many countries as well as bodies which are involved in tumor classification and staging. One function of the ICCR is to develop evidence-based, standardized reporting datasets for each cancer site. Herein, we report the development of an evidence-based cancer dataset by an ICCR panel of international experts for the reporting of primary uterine gestational trophoblastic neoplasia. We present the core elements that should be included and noncore elements that are recommended for inclusion in pathology reports. Lists of the response values are provided for each element, along with explanatory commentaries. The dataset also discusses controversial issues in the reporting of gestational trophoblastic neoplasia. Such evidence-based and structured pathology datasets developed through an international effort will facilitate consistent and accurate exchange and comparison of epidemiological and pathologic parameters among different populations and countries. This will ultimately improve gestational trophoblastic neoplasia patient care and facilitate future research.

Clinical performance of the Roche Cobas 4800 HPV test for primary cervical cancer screening in a Chinese population.

High-risk human papillomavirus (HR-HPV) testing has become an increasing important strategy in primary cervical cancer screening in recent years. It warrants the evaluation of molecular-based HPV tests for accuracy and efficacy of screening. The performance of Roche Cobas 4800 HPV test was validated and compared with Digene Hybrid Capture 2 (HC2) high-risk HPV DNA test for primary screening in a large Chinese screening cohort. Of 6345 women screened, overall agreement between Cobas and HC2 was 92.23% (95% CI: 91.57-92.89). The inter-assay agreement was correlated with the severity of underlying biology, with an increasing concordance found in samples with more severe abnormalities. Most of the discordant samples had the test signal strength closer to the test limits of the detection than concordant samples, reflecting a low viral load and infection of a cluster of low-risk HPV in these samples. The Cobas test demonstrated significantly higher specificity in identifying CIN2+/CIN3+ cases than HC2 test (66.46% vs 43.67% and 65.42% vs 42.86%, p<0.001), with comparable sensitivity in clinical evaluation. Increased specificity of Cobas test would accent women having the highest risk of developing CIN2+, with the potential to reduce unnecessary colposcopy referral in a screening population.

Molecular Epidemiology of Human Papillomavirus Infection Among Chinese Women With Cervical Cytological Abnormalities.

Background: Virtually all invasive cervical cancers are caused by persistent genital human papillomavirus (HPV) infection. Therefore, HPV-based screening becomes an essential tool as one of the cervical prevention strategies to reduce the disease burden. Population-specific epidemiologic information on HPV infection among women with cytological abnormalities is essential to inform the strategy of HPV-based screening programme. The study also explored the presence of cutaneous HPV types (Beta-ß and Gamma-γ) in cervical infections. Methods: A cross-sectional study on Chinese women aged ≥25 years who were referred to public specialist out-patient clinics for colposcopy or further management of cervical cytological abnormalities were recruited between 2015 and 2016 in Hong Kong. HPV was detected and typified by the novel PCR-based Next-Generation Sequencing (NGS) strategies. Results: The overall HPV infection rate was 74% and detected in 222 of the 300 respondents, with the prevalence of cutaneous HPV infection being 2.3%. The overall prevalence of HPV infection among women with current cytological abnormalities was 79.1% (197/249). The age-specific prevalence of HPV (any-type HPV infection) among women with cytological abnormalities reached the first peak with 87.9% in the age group of 35-39 years and gradually declined to 56.0% at 55-59 years. While a second peak occurred at 65 years or above (92.9%). HPV58 (13.7%), HPV52 (11.7%), HPV53 (11.2%), HPV16 (10.0%), HPV18 (5.2%), and HPV51 (5.2%) were the top five high-risk HPV genotypes among women with cytological abnormalities. Any-HPV type infection was significantly associated with an abnormal cervical smear (OR = 3.7; 95% CI 2.0-7.1), and high-risk HPV infection was also significantly associated with an abnormal cervical smear (OR = 6.3; 95% CI 3.0-13.5). Conclusion: New evidence on the second peak of HPV infection at ≥65 years old suggests the necessity to review the current guideline for the cervical screening program extending to age 65 and above. Moreover, the high prevalence of two HPV genotypes-high-risk HPV51 and potential high-risk HPV53, among women with cytological abnormalities-suggests further research work is needed to confirm the contributory role of HPV51 and HPV53 in cervical cancer and the need for inclusion in the next generation of the HPV vaccine.

Prohibitin 1 interacts with p53 in the regulation of mitochondrial dynamics and chemoresistance in gynecologic cancers.

BACKGROUND: Mitochondrial dynamics (e.g. fission/fusion) play an important role in controlling chemoresistance in representative gynecologic malignancies, ovarian and cervical cancer. Processing the long form of Optic atrophy (L-Opa)1 is a distinctive character of mitochondrial fragmentation, associated with chemosensitivity. Here, we examined the role of prohibitin (Phb)1 in increasing L-Opa1 processing via the regulating mitochondrial protease, Oma1 and its direct interaction with p-p53 (ser15) and pro-apoptotic Bcl-2 antagonist/killer (Bak) 1 in the signaling axis and if this phenomenon is associated with prognosis of patients. METHODS: We compared Cisplatin (CDDP)-induced response of mitochondrial dynamics, molecular interaction among p-p53 (ser15)-Phb1-Bak, and chemoresponsiveness in paired chemosensitive and chemoresistant gynecologic cancer cells (ovarian and cervical cancer cell lines) using western blot, immunoprecipitation, sea horse, and immunofluorescence. Translational strategy with proximity ligation assessment in phb1-p-p53 (ser15) in human ovarian tumor sections further confirmed in vitro finding, associated with clinical outcome. RESULTS: We report that: (1) Knock-down of Phb1 prevents Cisplatin (cis-diamine-dichloroplatinum; CDDP) -induced changes in mitochondrial fragmentation and Oma1 mediated cleavage, and Opa1 processing; (2) In response to CDDP, Phb1 facilitates the p-p53 (ser15)-Phb1-Bak interaction in mitochondria in chemosensitive gynecologic cancer cells but not in chemoresistant cells; (3) Akt overexpression results in suppressed p-p53(Ser15)-Phb1 interaction and dysregulated mitochondrial dynamics, and (4) Consistent with in vitro findings, proximity ligation assessment (PLA) in human ovarian tumor sections demonstrated that p-p53(ser15)-Phb1-Bak interaction in mitochondria is associated with better chemoresponsiveness and clinical outcome of patients. Determining the molecular mechanisms by which Phb1 facilitates mitochondrial fragmentation and interacts with p53 may advance the current understanding of chemoresistance and pathogenesis of gynecologic cancer. CONCLUSION: Determining the key molecular mechanisms by which Phb1 facilitates the formation of p-p53 (ser15)-Bak-Phb1 and its involvement in the regulation of mitochondrial dynamics and apoptosis may ultimately contribute to the current understanding of molecular and cellular basis of chemoresistance in this gynecologic cancer.

The Efficacy of Herbal Supplement Danggui Buxue Tang for Relieving Menopausal Symptoms.

OBJECTIVES: This study aimed to further explore the efficacy and safety of Danggui Buxue Tang (DBT), a simple herbal formula, for improving the quality of life of women suffering from menopausal symptoms. METHODS: A third clinical trial to determine the clinical efficacy of high-dose DBT for a period of 12 weeks was carried out. The standard Menopause-Specific Quality of Life (MENQOL) assessment chart was used for the evaluation. Safety was defined as an absence of direct estrogenic effects, serum inflammatory cytokines. Notably, interleukin IL-6, IL-8 and tumor necrosis factor TNF-α, known to be directly related to estrogenic reactions in menopause studies, were monitored. RESULTS: The third clinical trial indicated an overall improvement in the four domains of MENQOL, offering further proof of the efficacy of DBT demonstrated in the two previous trials. The serial checks of the three cytokines related to estrogen activities did not show either upward or downward trends. The haphazard behavior reactions of the three cytokines offered indirect indications that DBT improved the MENQOL independently from estrogen activities. CONCLUSIONS: The three clinical trials using DBT to relieve menopausal syndrome have offered solid evidence for its efficacy. The uncertainty regarding whether the "phytoestrogen" contained in DBT had bioactivities similar to estrogen was alleviated through the confirmation that no strict estrogenic bioactivities were observed. The issue of safety was further clarified via laboratory platform studies on DBT, which not only showed the lack of similarity with estrogen actions but also confirmed the value of combining the two herbs in the classic formula.

Human Papillomavirus Self-Sampling for Primary Cervical Cancer Screening in Under-Screened Women in Hong Kong during the COVID-19 Pandemic.

The aim of this study was to assess the effectiveness of HPV self-sampling for cervical cancer screening and the best means of service delivery, with a specific focus on under-screened women, particularly during the COVID-19 pandemic. Using three arms of service delivery (social media, school outreach and underserved outreach), we recruited under-screened women aged 30-65 years from two population groups: the general public and specific underserved communities, from whom self-sampled specimens and optional clinician-sampled cervical specimens were obtained for HPV testing. A total of 521 self-sampling kits were distributed, of which 321 were returned, giving an overall uptake rate of 61.6%. The response rate was higher in the face-to-face underserved outreach (65.5%) compared to social media (22.8%) and school outreach (18.2%). The concordance for HPV detection between self-sampled and clinician-sampled specimens was 90.2% [95% confidence interval (CI) 85.1-93.8%; Cohen's kappa 0.59 (95% CI 0.42-0.75)]. Overall, 89.2% of women were willing to have self-sampling again. In conclusion, HPV self-sampling is an effective method for cervical cancer screening and can be considered as an option, particularly in women who are reluctant or unable to attend regular screening. Various service deliveries could be considered to increase participation in cervical cancer screening.

Finding the positives from the COVID-19 pandemic: factors associated with posttraumatic growth among nurses in Hong Kong.

Background: Due to active involvement with patients for COVID-19 treatments, nurses are susceptible to adverse psychological outcomes amid the COVID-19 pandemic. Despite the distress, studies have suggested that nurses are able to experience positive changes (i.e. posttraumatic growth; PTG) during the pandemic. Research on other populations has also indicated that COVID-19-specific worries and work-related coping resources are associated with people's positive changes during the pandemic. Objective: This study examined how socio-demographic characteristics, COVID-19-related worries, and work-related variables (satisfaction with work and workplace pandemic guidelines) were associated with PTG among nurses in Hong Kong. Methods: Nurses (N = 1510) working in hospitals and community settings were recruited through nursing associations in Hong Kong between 8 August 2020 and 22 September 2020. They were invited to complete a cross-sectional survey measuring their sociodemographic characteristics, COVID-19 worries, and satisfaction with work and workplace pandemic-control measures. Results: Results from hierarchical regressions found that those working non-full-time (ß = -0.06), affiliating with a religion (ß = 0.24), having higher COVID-19-related worries and psychological distress (ßs ranging from 0.12-0.15), and having higher work satisfaction (ß = 0.14) were associated with higher PTG (ps < .05). Moreover, a significant interaction between psychological distress and satisfaction with workplace pandemic control guidelines emerged in explaining PTG (ß = 0.08, p < .05), such that guideline satisfaction was only associated with higher PTG among those with higher distress (ß = 0.09, p = .03), but not those with lower distress (ß = -0.05, p > .05). Conclusions: Nurses in Hong Kong did report positive changes amid the COVID-19 pandemic. Future studies could focus on the contributing factors of PTG to design for effective strategies to enhance resources for nurses to promote positive psychosocial outcomes.

Antecedentes: Debido a la participación activa de pacientes en los tratamientos de COVID-19, las/os enfermeras son susceptibles a resultados psicológicos adversos en medio de la pandemia de COVID-19. A pesar de la angustia, los estudios han sugerido que las(os) enfermeras(os) pueden experimentar cambios positivos (es decir, crecimiento postraumático; CPT) durante la pandemia. Investigación en otras poblaciones también ha indicado que las preocupaciones específicas por COVID-19 y los recursos de afrontamiento relacionados con el trabajo están asociados a cambios positivos de las personas durante la pandemia.Objetivo: Este estudio examinó cómo las características sociodemográficas, las preocupaciones relacionadas a COVID-19 y las variables relacionadas con el trabajo (satisfacción con el trabajo y pautas pandémicas en el lugar de trabajo) se asociaron con el CPT entre las(os) enfermeras(os) de Hong Kong.Métodos: Las(os) enfermeras(os) (N = 1510) que trabajan en hospitales y entornos comunitarios fueron reclutadas(os) a través de asociaciones de enfermería en Hong Kong entre el 8 de agosto del 2020 y el 22 de septiembre del 2020. Los participantes fueron invitados a completar una encuesta transversal que midió sus características sociodemográficas, preocupaciones sobre COVID-19 y satisfacción con el trabajo y las medidas de control de pandemias en el lugar de trabajo.Resultados: Los resultados de regresiones jerárquicas encontraron que aquellos que: no trabajaban a tiempo completo (ß = −0.06), se afiliaban a una religión (ß = 0.24), tenían mayores preocupaciones y angustia psicológica relacionadas por COVID-19 (ßs que oscilan entre 0.12­0.15) y tenían una mayor satisfacción laboral (ß = 0.14), se asociaron con CPT más alto (ps < .05). Además, una interacción significativa entre la angustia psicológica y la satisfacción con las pautas de control de la pandemia en el lugar de trabajo, surgió al explicar el CPT (ß = 0.08, p < .05), de modo que la satisfacción de la guía sólo se asoció con un CPT más alto entre aquéllos con mayor angustia (ß = 0.09, p = .03), pero no en aquéllos con menor angustia (ß = −0.05, p > .05).Conclusiones: Las(os) enfermeras(os) en Hong Kong informaron cambios positivos en medio de la pandemia por COVID-19. Los estudios futuros podrían centrarse en los factores que contribuyen a la CPT para diseñar estrategias eficaces con el fin de mejorar los recursos de las(os) enfermeras(os) para promover resultados psicosociales positivos.

PFKFB3 Regulates Chemoresistance, Metastasis and Stemness via IAP Proteins and the NF-κB Signaling Pathway in Ovarian Cancer.

Glycolysis has been reported to be critical for cancer stem cells (CSCs), which are associated with tumor chemoresistance, metastasis and recurrence. Thus, selectively targeting glycolytic enzymes may be a potential therapy for ovarian cancer. 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), the main source of fructose-2,6-bisphosphate, controls the first committed step in glycolysis. We investigate the clinical significance and roles of PFKFB3 in ovarian cancer using in vitro and in vivo experiments. We demonstrate that PFKFB3 is widely overexpressed in ovarian cancer and correlates with advanced stage/grade and poor outcomes. Significant up-regulation of PFKFB3 was found in ascites and metastatic foci, as well as CSC-enriched tumorspheres and ALDH+CD44+ cells. 3PO, a PFKFB3 inhibitor, reduced lactate level and sensitized A2780CP cells to cisplatin treatment, along with the modulation of inhibitors of apoptosis proteins (c-IAP1, c-IAP2 and survivin) and an immune modulator CD70. Blockade of PFKFB3 by siRNA approach in the CSC-enriched subset led to decreases in glycolysis and CSC properties, and activation of the NF-κB cascade. PFK158, another potent inhibitor of PFKFB3, impaired the stemness of ALDH+CD44+ cells in vitro and in vivo, whereas ectopic expression of PFKFB3 had the opposite results. Overall, PFKFB3 was found to mediate metabolic reprogramming, chemoresistance, metastasis and stemness in ovarian cancer, possibly via the modulation of inhibitors of apoptosis proteins and the NF-κB signaling pathway; thus, suggesting that PFKFB3 may be a potential therapeutic target for ovarian cancer.

Targeting DNA Damage Response Pathway in Ovarian Clear Cell Carcinoma.

Ovarian clear cell carcinoma (OCCC) is one of the major types of ovarian cancer and is of higher relative prevalence in Asians. It also shows higher possibility of resistance to cisplatin-based chemotherapy leading to poor prognosis. This may be attributed to the relative lack of mutations and aberrations in homologous recombination-associated genes, which are crucial in DNA damage response (DDR), such as BRCA1, BRCA2, p53, RAD51, and genes in the Fanconi anemia pathway. On the other hand, OCCC is characterized by a number of genetic defects rendering it vulnerable to DDR-targeting therapy, which is emerging as a potent treatment strategy for various cancer types. Mutations of ARID1A, PIK3CA, PTEN, and catenin beta 1 (CTNNB1), as well as overexpression of transcription factor hepatocyte nuclear factor-1ß (HNF-1ß), and microsatellite instability are common in OCCC. Of particular note is the loss-of-function mutations in ARID1A, which is found in approximately 50% of OCCC. ARID1A is crucial for processing of DNA double-strand break (DSB) and for sustaining DNA damage signaling, rendering ARID1A-deficient cells prone to impaired DNA damage checkpoint regulation and hence sensitive to poly ADP ribose polymerase (PARP) inhibitors. However, while preclinical studies have demonstrated the possibility to exploit DDR deficiency in OCCC for therapeutic purpose, progress in clinical application is lagging. In this review, we will recapitulate the preclinical studies supporting the potential of DDR targeting in OCCC treatment, with emphasis on the role of ARID1A in DDR. Companion diagnostic tests (CDx) for predicting susceptibility to PARP inhibitors are rapidly being developed for solid tumors including ovarian cancers and may readily be applicable on OCCC. The potential of various available DDR-targeting drugs for treating OCCC by drawing analogies with other solid tumors sharing similar genetic characteristics with OCCC will also be discussed.

Roles of microRNAs in tumorigenesis and metastasis of esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is the major subtype of esophageal cancer that is prevalent in Eastern Asia. Despite recent advances in therapy, the outcome of ESCC patients is still dismal. MicroRNAs (miRNAs) are non-coding RNAs which can negatively modulate gene expression at the post-transcriptional level. The involvement and roles of miRNAs have become one of the hot topics of cancer research in recent years. In ESCC, genetic variations within miRNA coding genes were found to have distinct epidemiological significance in different populations. Dysregulated expression of several miRNAs was reported to be associated with therapeutic response. Functionally, miRNAs can act either in an oncogenic or a tumor-suppressive manner during tumorigenesis of ESCC by interrupting signaling pathways associated with cell proliferation, metabolism, cancer stemness, and resistance to chemo- or radiotherapy. Moreover, miRNAs modulate metastasis of ESCC by targeting genes that regulate cytoskeleton dynamics, extracellular matrix remodeling, epithelial-mesenchymal transition, and tumor microenvironment. Most importantly, mounting evidence suggests that inhibiting oncogenic miRNAs or restoring the loss of tumor-suppressive miRNAs has therapeutic potential in the treatment of ESCC. Here, we review and discuss recent studies on the significance, biological functions, and therapeutic potential of miRNAs in tumorigenesis and metastasis of ESCC.

Proteoglycans and their functions in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a highly malignant disease that has a poor prognosis. Its high lethality is mainly due to the lack of symptoms at early stages, which culminates in diagnosis at a late stage when the tumor has already metastasized. Unfortunately, the common cancer biomarkers have low sensitivity and specificity in esophageal cancer. Therefore, a better understanding of the molecular mechanisms underlying ESCC progression is needed to identify novel diagnostic markers and therapeutic targets for intervention. The invasion of cancer cells into the surrounding tissue is a crucial step for metastasis. During metastasis, tumor cells can interact with extracellular components and secrete proteolytic enzymes to remodel the surrounding tumor microenvironment. Proteoglycans are one of the major components of extracellular matrix. They are involved in multiple processes of cancer cell invasion and metastasis by interacting with soluble bioactive molecules, surrounding matrix, cell surface receptors, and enzymes. Apart from having diverse functions in tumor cells and their surrounding microenvironment, proteoglycans also have diagnostic and prognostic significance in cancer patients. However, the functional significance and underlying mechanisms of proteoglycans in ESCC are not well understood. This review summarizes the proteoglycans that have been studied in ESCC in order to provide a comprehensive view of the role of proteoglycans in the progression of this cancer type. A long term goal would be to exploit these molecules to provide new strategies for therapeutic intervention.

Nuclear HKII-P-p53 (Ser15) Interaction is a Prognostic Biomarker for Chemoresponsiveness and Glycolytic Regulation in Epithelial Ovarian Cancer.

In epithelial ovarian cancer (EOC), carboplatin/cisplatin-induced chemoresistance is a major hurdle to successful treatment. Aerobic glycolysis is a common characteristic of cancer. However, the role of glycolytic metabolism in chemoresistance and its impact on clinical outcomes in EOC are not clear. Here, we show a functional interaction between the key glycolytic enzyme hexokinase II (HKII) and activated P-p53 (Ser15) in the regulation of bioenergetics and chemosensitivity. Using translational approaches with proximity ligation assessment in cancer cells and human EOC tumor sections, we showed that nuclear HKII-P-p53 (Ser15) interaction is increased after chemotherapy, and functions as a determinant of chemoresponsiveness as a prognostic biomarker. We also demonstrated that p53 is required for the intracellular nuclear HKII trafficking in the control of glycolysis in EOC, associated with chemosensitivity. Mechanistically, cisplatin-induced P-p53 (Ser15) recruits HKII and apoptosis-inducing factor (AIF) in chemosensitive EOC cells, enabling their translocation from the mitochondria to the nucleus, eliciting AIF-induced apoptosis. Conversely, in p53-defective chemoresistant EOC cells, HKII and AIF are strongly bound in the mitochondria and, therefore, apoptosis is suppressed. Collectively, our findings implicate nuclear HKII-P-p53(Ser15) interaction in chemosensitivity and could provide an effective clinical strategy as a promising biomarker during platinum-based therapy.

Dual inhibition of cMET and EGFR by microRNA-338-5p suppresses metastasis of esophageal squamous cell carcinoma.

MicroRNAs, as a group of post-transcriptional regulators, regulate multiple pathological processes including metastasis during tumor development. Here, we demonstrated the metastasis-suppressive function of microRNA (miR)-338-5p in esophageal squamous cell carcinoma (ESCC). Overexpression of miR-338-5p had inhibitory effect on invasive ability of ESCC cells and extracellular matrix degradation, whereas silencing miR-338-5p had opposite effects. Mechanistically, miR-338-5p directly targeted the 3' untranslated regions of hepatocellular growth factor receptor cMet (cMET) and epidermal growth factor receptor (EGFR). As a result, miR-338-5p inhibited the downstream signaling cascades of cMET and EGFR and repressed cMET- and EGFR-mediated ESCC cell invasion. Re-expression of cMET or EGFR in miR-338-5p overexpressing ESCC cells was sufficient to derepress ESCC cell invasion both in vitro and in vivo. We further showed that such manipulation downregulated the expression and secretion of matrix metalloproteinases 2 and 9, which resulted in impaired extracellular matrix degradation and cell invasion. Most importantly, systemic delivery of miR-338-5p mimic significantly inhibited metastasis of ESCC cells in nude mice. Taken together, our results uncovered a previously unknown mechanism through which miR-338-5p suppresses ESCC invasion and metastasis by regulating cMET/EGFR-matrix metalloproteinase 2/9 axis and highlighted the potential significance of miR-338-5p-based therapy in treating patients with metastatic ESCC.