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1.
J Med Internet Res ; 26: e50976, 2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38815258

RESUMO

BACKGROUND: Due to their accessibility and anonymity, web-based counseling services are expanding at an unprecedented rate. One of the most prominent challenges such services face is repeated users, who represent a small fraction of total users but consume significant resources by continually returning to the system and reiterating the same narrative and issues. A deeper understanding of repeated users and tailoring interventions may help improve service efficiency and effectiveness. Previous studies on repeated users were mainly on telephone counseling, and the classification of repeated users tended to be arbitrary and failed to capture the heterogeneity in this group of users. OBJECTIVE: In this study, we aimed to develop a systematic method to profile repeated users and to understand what drives their use of the service. By doing so, we aimed to provide insight and practical implications that can inform the provision of service catering to different types of users and improve service effectiveness. METHODS: We extracted session data from 29,400 users from a free 24/7 web-based counseling service from 2018 to 2021. To systematically investigate the heterogeneity of repeated users, hierarchical clustering was used to classify the users based on 3 indicators of service use behaviors, including the duration of their user journey, use frequency, and intensity. We then compared the psychological profile of the identified subgroups including their suicide risks and primary concerns to gain insights into the factors driving their patterns of service use. RESULTS: Three clusters of repeated users with clear psychological profiles were detected: episodic, intermittent, and persistent-intensive users. Generally, compared with one-time users, repeated users showed higher suicide risks and more complicated backgrounds, including more severe presenting issues such as suicide or self-harm, bullying, and addictive behaviors. Higher frequency and intensity of service use were also associated with elevated suicide risk levels and a higher proportion of users citing mental disorders as their primary concerns. CONCLUSIONS: This study presents a systematic method of identifying and classifying repeated users in web-based counseling services. The proposed bottom-up clustering method identified 3 subgroups of repeated users with distinct service behaviors and psychological profiles. The findings can facilitate frontline personnel in delivering more efficient interventions and the proposed method can also be meaningful to a wider range of services in improving service provision, resource allocation, and service effectiveness.


Assuntos
Aconselhamento , Humanos , Estudos Longitudinais , Análise por Conglomerados , Feminino , Adulto , Masculino , Aconselhamento/métodos , Aconselhamento/estatística & dados numéricos , Pessoa de Meia-Idade , Envio de Mensagens de Texto/estatística & dados numéricos , Adulto Jovem
2.
J Consult Clin Psychol ; 91(11): 640-651, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37616124

RESUMO

OBJECTIVE: With its anonymity and accessibility, text-based online counseling has shown great potential in reaching people with mental health needs. One strategy adopted to meet the service gap is concurrent counseling, that is, each counselor attending to more than one client at a time. To date, there is no reported evidence supporting its rationality and effectiveness. This study investigated the potential opportunities, effectiveness, and caveats in concurrent service delivery and identified the optimal cutoff number of concurrent sessions while maintaining the quality of service at or above a set threshold. METHOD: We analyzed the transcript of 54,716 online counseling sessions from Open Up, a free, 24/7 text-based counseling service, to develop an attention score that measures the attention allocation of counselors and examined the impact of the counselor's attention allocation on client satisfaction and service outcomes. RESULTS: On average, compared to nonconcurrent sessions, concurrent sessions were longer, more likely to end prematurely, and had lower client satisfaction. We also identified an optimal attention score of approximately 0.4 (out of 1.0, which denotes full attention), which translates to two to three concurrent sessions. CONCLUSIONS: This study provides empirical evidence for the feasibility of conducting multiple text-based sessions concurrently without compromising service quality and client experience. Our method of measuring the counselor attention allocation offers a way to systematically assess and evaluate concurrent sessions. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Assuntos
Conselheiros , Humanos , Aconselhamento/métodos , Satisfação do Paciente , Saúde Mental , Relações Profissional-Paciente
3.
Lancet Reg Health West Pac ; 36: 100752, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37547048

RESUMO

Background: Suicide is a complex and multifaceted issue, and suicidal behaviors are often driven by multiple, interacting factors. It has been challenging to identify reasons for suicide using existing scientific methodologies. This study aims to identify critical reasons for suicide and suicidal behaviors through the application of novel network science methods. Methods: Based on cases investigated by the Hong Kong Coroner's Court from 2002 to 2019, we modelled identified reasons for 13,001 suicide cases as a co-occurrence network, and calculated each reason's eigencentrality to determine their respective relative importance. We then analyzed the temporal and demographic changes in the structure and eigencentrality of the network. We further conducted simulation studies based on the United Nations population projection to assess potential burden of different reasons for suicide on the population in the coming years. Findings: School-related issues had the highest eigencentrality (eigencentrality = 0.49) for individuals younger than 20 years of age. Financial issues were crucial for adults aged 20-59 years, but their importance differed between males (eigencentrality = 0.51) and females (eigencentrality = 0.14). Physical illness (eigencentrality = 0.80) was the core concern for adults over 60 years. Across the Hong Kong population, the reasons for suicide appear to have shifted from financial issues in the early 2000s (eigencentrality = 0.46) to issues related to physical illnesses since 2011 (eigencentrality = 0.58). Simulation findings indicate that, by 2050, most suicides in Hong Kong will be due to physical illness-related issues (eigencentrality = 0.69) due to the rapidly aging population. Interpretation: There have been important sex and age differences over time, in reasons for suicide. Given the projected increasing age of the Hong Kong population over the next decades, older adults with physical illnesses appear to be the highest contributors to suicide cases in the overall population. This novel network analysis approach provides important data-driven information upon which to base effective proactive public health suicide prevention strategies and interventions. Funding: Hong Kong Jockey Club Charities Trust, Collaborative Research Fund (C7151-20G), and General Research Fund (17606521).

4.
Clin Case Rep ; 11(6): e7488, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37305870

RESUMO

Key Clinical Message: When faced with a slowly enlarging firm mass in the parotid gland accompanied by a histological picture of unusual sclerosis with abundant Langerhans cells and eosinophilic infiltrates, sclerosing mucoepidermoid carcinoma with eosinophilia should be considered as one of the differential diagnoses. Further studies are warranted for accurate diagnosis and appropriate treatment. Abstract: Sclerosing mucoepidermoid carcinoma of the salivary gland with eosinophilia is a rare tumor mostly negative for the MAML2 rearrangement commonly seen in salivary mucoepidermoid carcinoma. It was not listed as an entity in the 2022 WHO Classification of Head and Neck Tumors. We presented one case initially diagnosed as Langerhans cell histiocytosis and recurred as a frankly invasive carcinoma. Molecular studies showed CSF1 gene derangement and provided new understanding concerning the Langerhans cell and eosinophilic reaction. Further molecular studies on this entity would throw light on its oncogenesis and refine its nomenclature.

5.
J Affect Disord ; 335: 228-232, 2023 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-37150217

RESUMO

BACKGROUND: Advances in text-mining can potentially aid online text-based mental health services in detecting suicidality. However, false positive remains a challenge. METHODS: Data of a free 24/7 online text-based counseling service in Hong Kong were used to develop a novel parser-based algorithm (PBSD) to detect suicidal ideation while minimizing false alarms. Sessions containing keywords related to suicidality were extracted (N = 1267). PBSD first applies a sentence parser to work out the grammatical structure of each sentence, including subject, object, dependent and modifier. Then a set of syntax rules were applied to judge if a flagged sentence is a true or false positive. Half of the sessions were randomly selected to train PBSD, the remaining were used as the test set. A standard keywords matching model was adopted as the baseline comparison. Accuracy and recall were reported to demonstrate models' performance. RESULTS: Of the 1267 sessions, 585 (46.2 %) were false alarms. The false alarms were categorized into four types: negation-induced false alarms (NIFA; 14 %), subject-induced false alarms (SIFA; 19 %), tense-induced false alarms (TIFA; 30 %), and other types of false alarms (OTFA; 37 %). PBSD significantly outperforms the baseline keywords matching model on accuracy (0.68 vs 0.53, 28.3 %). It successfully amended 36.8 % (105/297) lexicon matching-caused false alarms. The reduction on recall was marginal (1 vs 0.96, 4 %). CONCLUSIONS: The proposed model significantly improves the use of lexicon-based method by reducing false alarms and improving the accuracy of suicidality detection. It can potentially reduce unnecessary panic and distraction caused by false alarms among frontline service-providers.


Assuntos
Serviços de Saúde Mental , Suicídio , Humanos , Ideação Suicida , Software , Algoritmos
6.
Commun Med (Lond) ; 2(1): 156, 2022 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-36474010

RESUMO

BACKGROUND: In psychological services, the transition to the disclosure of ideation about self-harm and suicide (ISS) is a critical point warranting attention. This study developed and tested a succinct descriptor to predict such transitions in an online synchronous text-based counseling service. METHOD: We analyzed two years' worth of counseling sessions (N = 49,770) from Open Up, a 24/7 service in Hong Kong. Sessions from Year 1 (N = 20,618) were used to construct a word affinity network (WAN), which depicts the semantic relationships between words. Sessions from Year 2 (N = 29,152), including 1168 with explicit ISS, were used to train and test the downstream ISS prediction model. We divided and classified these sessions into ISS blocks (ISSBs), blocks prior to ISSBs (PISSBs), and non-ISS blocks (NISSBs). To detect PISSB, we adopted complex network approaches to examine the distance among different types of blocks in WAN. RESULTS: Our analyses find that words within a block tend to form a module in WAN and that network-based distance between modules is a reliable indicator of PISSB. The proposed model yields a c-statistic of 0.79 in identifying PISSB. CONCLUSIONS: This simple yet robust network-based model could accurately predict the transition point of suicidal ideation prior to its explicit disclosure. It can potentially improve the preparedness and efficiency of help-providers in text-based counseling services for mitigating self-harm and suicide.


In online counseling, the help-provider can often be engaging with several service users simultaneously. Therefore, new tools that could help to alert and assist the help-provider and increase their preparedness for getting further help for service users could be useful. In this study, we developed and tested a new tool that is designed to alert help-providers to the disclosure of self-harm and suicidal thoughts, based on the words that the service user has been typing. The tool is developed on the basis that word usage may have a specific pattern when suicidal thoughts are more likely to occur. We tested our tool using two years' worth of online counseling conversations and we show that our approach can help to predict the confession of suicidal thoughts. As such, we are taking a step forward in helping to improve these counseling services.

7.
Case Rep Med ; 2022: 1992541, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36158567

RESUMO

We presented a case of diffuse-type tenosynovial giant cell tumour (DTSGCT) of foot masquerading as Langerhans cell histiocytosis. Preliminary diagnosis by needle biopsy was difficult due to the major involvement of bones and the overshadowing effect of the accompanying Langerhans cells. The complete curettage specimen with relevant immunohistochemistry and molecular tests made the final diagnosis of DTSGCT possible. The biomolecular mechanism for the masquerading phenomenon was explained by CSF1 overexpression in the neoplastic cells attracting migration and proliferation of CSF1R-positive Langerhans cells.

8.
Artigo em Inglês | MEDLINE | ID: mdl-36141964

RESUMO

Vessel is a landmark created by Heatherwick Studio where visitors can enjoy views of New York City from different heights and perspectives. However, between February 2020 and July 2021, four individuals jumped to their deaths from the landmark. Effective preventive solutions have yet to be identified, and the site is currently closed. In this study, we examined the trajectory of public sentiment on the suicide-related activity at Vessel on Twitter by investigating the engagement patterns and identifying themes about the four suicides from February 2020 to August 2021 (n = 3058 tweets). The results show increased levels of discussion about each successive suicide case in the first 14 days following each incident (from 6 daily tweets for the first case to 104 for the fourth case). It also took longer for relevant discussions to dissipate (4 days for the first and 14 days for the fourth case, KS statistic = 0.71, p < 0.001). Thematic analysis shows a shift from expressions of emotion to urging suicide prevention actions in the third and fourth cases; additionally, we detected growing support for restricting means. We suggest that, prior to the reopening of Vessel, collective efforts should be made to install safety protections and reduce further suicide risks.


Assuntos
Mídias Sociais , Suicídio , Atitude , Humanos , Cidade de Nova Iorque/epidemiologia
9.
Internet Interv ; 26: 100486, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34877263

RESUMO

BACKGROUND: More so than face-to-face counseling, users of online text-based services might drop out from a session before establishing a clear closure or expressing the intention to leave. Such premature departure may be indicative of heightened risk or dissatisfaction with the service or counselor. However, there is no systematic way to identify this understudied phenomenon. PURPOSE: This study has two objectives. First, we developed a set of rules and used logic-based pattern matching techniques to systematically identify premature departures in an online text-based counseling service. Second, we validated the importance of premature departure by examining its association with user satisfaction. We hypothesized that the users who rated the session as less helpful were more likely to have departed prematurely. METHOD: We developed and tested a classification model using a sample of 575 human-annotated sessions from an online text-based counseling platform. We used 80% of the dataset to train and develop the model and 20% of the dataset to evaluate the model performance. We further applied the model to the full dataset (34,821 sessions). We compared user satisfaction between premature departure and completed sessions based on data from a post-session survey. RESULTS: The resulting model achieved 97% and 92% F1 score in detecting premature departure cases in the training and test sets, respectively, suggesting it is highly consistent with the judgment of human coders. When applied to the full dataset, the model classified 15,150 (43.5%) sessions as premature departure and the remaining 19,671 (56.5%) as completed sessions. Completed cases (15.2%) were more likely to fill the post-chat survey than premature departure cases (4.0%). Premature departure was significantly associated with lower perceived helpfulness and effectiveness in distress reduction. CONCLUSIONS: The model is the first that systematically and accurately identifies premature departure in online text-based counseling. It can be readily modified and transferred to other contexts for the purpose of risk mitigation and service evaluation and improvement.

10.
Artigo em Inglês | MEDLINE | ID: mdl-34948802

RESUMO

We present the opportunities and challenges of Open Up, a free, 24/7 online text-based counselling service to support youth in Hong Kong. The number of youths served more than doubled within the first three years since its inception in 2018 in response to increasing youth suicidality and mental health needs. Good practice models are being developed in order to sustain and further scale up the service. We discuss the structure of the operation, usage pattern and its effectiveness, the use of AI to improve users experience, and the role of volunteer in the operation. We also present the challenges in further enhancing the operation, calling for more research, especially on the identification of the optimal number of users that can be concurrently served by a counsellor, the effective approach to respond to a small percentage of repeated users who has taken up a disproportional volume of service, and the way to optimize the use of big data analytics and AI technology to enhance the service. These advancements will benefit not only Open Up but also similar services across the globe.


Assuntos
Saúde Mental , Envio de Mensagens de Texto , Adolescente , Aconselhamento , Hong Kong , Humanos , Ideação Suicida , Adulto Jovem
11.
Soc Sci Med ; 283: 114176, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34214846

RESUMO

RATIONALE: Detecting users at risk of suicide in text-based counseling services is essential to ensure that at-risk individuals are flagged and prioritized. OBJECTIVE: The objective of this study is to develop a domain knowledge-aware risk assessment (KARA) model to improve our ability of suicide detection in online counseling systems. METHODS: We obtained the largest known de-identified dataset from an emotional support system established in Hong Kong, comprising 5682 Cantonese conversations between help-seekers and counselors. Of those, 682 conversations disclosed crisis intentions of suicide. We constructed a suicide-knowledge graph, representing suicide-related domain knowledge as a computer-processible graph. Such knowledge graph was embedded into a deep learning model to improve its ability to identify help-seekers in crisis. As the baseline, a standard NLP model was applied to the same task. 80% of the study samples were randomly sampled to train model parameters. The remaining 20% were used for model validation. Evaluation metrics including precision, recall, and c-statistic were reported. RESULTS: Both KARA and the baseline achieved high precision (0.984 and 0.951, shown in Table 2) and high recall (0.942 and 0.947) towards non-crisis cases. For crisis cases, however, KARA model achieved a much higher recall than the baseline (0.870 vs 0.791). The c-statistics of KARA and the baseline were 0.815 and 0.760, respectively. CONCLUSION: KARA significantly outperformed standard NLP models, demonstrating good translational value and clinical relevance.


Assuntos
Prevenção do Suicídio , Envio de Mensagens de Texto , Aconselhamento , Humanos , Conhecimento , Processamento de Linguagem Natural
12.
Sci Rep ; 7(1): 12012, 2017 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-28931826

RESUMO

MicroRNAs (miRNAs) are small non-coding RNAs that play a crucial role in pathogenesis of human cancers. Several miRNAs have been shown to involve in nasopharyngeal carcinoma (NPC) pathogenesis through alteration of gene networks. A global view of the miRNA expression profile of clinical specimens would be the best way to screen out the possible miRNA candidates that may be involved in disease pathogenesis. In this study, we investigated the expression profiles of miRNA in formalin-fixed paraffin-embedded tissues from patients with undifferentiated NPC versus non-NPC controls using a miRNA real-time PCR platform, which covered a total of 95 cancer-related miRNAs. Hierarchical cluster analysis revealed that NPC and non-NPC controls were clearly segregated. Promisingly, 10 miRNA candidates were differentially expressed. Among them, 9 miRNAs were significantly up-regulated of which miR-205 and miR-196a showed the most up-regulated in NPC with the highest incidence percentage of 94.1% and 88.2%, respectively, while the unique down-regulated miR-150 was further validated in patient sera. Finally, the in vitro gain-of-function and loss-of-function assays revealed that miR-150 can modulate the epithelial-mesenchymal-transition property in NPC/HK-1 cells and led to the cell motility and invasion. miR-150 may be a potential biomarker for NPC and plays a critical role in NPC tumourigenesis.


Assuntos
Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Adulto , Idoso , Linhagem Celular Tumoral , Movimento Celular/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/patologia , Metástase Neoplásica
13.
Surg J (N Y) ; 3(2): e58-e61, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28825022

RESUMO

Intra-articular fibroma of tendon sheath is a rare disease. To our knowledge, less than 20 cases have been reported in the literature, and none of them was a Chinese patient. In this case report, we present a Chinese patient with intra-articular fibroma of tendon sheath of the knee joint which was excised arthroscopically. We also summarized the clinical presentation, diagnosis, and subsequent management of intra-articular fibroma of tendon sheath.

14.
Endocr Relat Cancer ; 24(12): T283-T295, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28754821

RESUMO

Recent success in immunomodulating strategies in lung cancer and melanoma has prompted much enthusiasm in their potential to treat other advanced solid malignancies. However, their applications have shown variable success and are even ineffective against some tumours. The efficiency of immunotherapies relies on an immunogenic tumour microenvironment. The current field of cancer immunology has focused on understanding the interaction of cancer and host immune cells to break the state of immune tolerance and explain how molecular patterns of cytokines and chemokines affect tumour progression. Here, we review our current knowledge of how inherent properties of tumours and their different tumour microenvironments affect therapeutic outcome. We also discuss insights into recent multimodal therapeutic approaches that target tumour immune evasion and suppression to restore anti-tumour immunity.


Assuntos
Imunoterapia/métodos , Humanos , Microambiente Tumoral
15.
Mech Ageing Dev ; 165(Pt A): 33-46, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-27614000

RESUMO

The presence of damaged and microbial DNA can pose a threat to the survival of organisms. Cells express various sensors that recognize specific aspects of such potentially dangerous DNA. Recognition of damaged or microbial DNA by sensors induces cellular processes that are important for DNA repair and inflammation. Here, we review recent evidence that the cellular response to DNA damage and microbial DNA are tightly intertwined. We also discuss insights into the parameters that enable DNA sensors to distinguish damaged and microbial DNA from DNA present in healthy cells.


Assuntos
Bactérias/imunologia , Reparo do DNA/imunologia , DNA Bacteriano/imunologia , Animais , Bactérias/genética , Reparo do DNA/genética , DNA Bacteriano/genética , Humanos , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia
16.
Immunity ; 44(5): 1177-89, 2016 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-27178469

RESUMO

Self-DNA is present in the cytosol of many cancer cells and can promote effective immune rejection of tumor cells, but the mechanisms leading to the presence of cytosolic DNA are unknown. Here, we report that the cleavage of genomic DNA by DNA structure-specific endonuclease MUS81 and PARP-dependent DNA repair pathways leads to the accumulation of cytosolic DNA in prostate cancer cells. The number of nuclear MUS81 foci and the amount of cytosolic dsDNA increased in tandem from hyperplasia to clinical stage II prostate cancers and decreased at stage III. Cytosolic DNA generated by MUS81 stimulated DNA sensor STING-dependent type I interferon (IFN) expression and promoted phagocytic and T cell responses, resulting in type I and II IFN-mediated rejection of prostate tumor cells via mechanisms that partly depended on macrophages. Our results demonstrate that the tumor suppressor MUS81 alerts the immune system to the presence of transformed host cells.


Assuntos
Autoantígenos/metabolismo , Proteínas de Ligação a DNA/metabolismo , DNA/metabolismo , Endonucleases/metabolismo , Neoplasias da Próstata/imunologia , Linfócitos T/imunologia , Animais , Autoantígenos/imunologia , Linhagem Celular Tumoral , DNA/imunologia , Humanos , Interferon Tipo I/metabolismo , Ativação Linfocitária , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estadiamento de Neoplasias , Neoplasias Experimentais , Fagocitose , Neoplasias da Próstata/patologia
17.
Proc Natl Acad Sci U S A ; 113(12): 3317-22, 2016 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-26951679

RESUMO

Multiple factors, including host genetics, environmental factors, and Epstein-Barr virus (EBV) infection, contribute to nasopharyngeal carcinoma (NPC) development. To identify genetic susceptibility genes for NPC, a whole-exome sequencing (WES) study was performed in 161 NPC cases and 895 controls of Southern Chinese descent. The gene-based burden test discovered an association between macrophage-stimulating 1 receptor (MST1R) and NPC. We identified 13 independent cases carrying the MST1R pathogenic heterozygous germ-line variants, and 53.8% of these cases were diagnosed with NPC aged at or even younger than 20 y, indicating that MST1R germline variants are relevant to disease early-age onset (EAO) (age of ≤20 y). In total, five MST1R missense variants were found in EAO cases but were rare in controls (EAO vs. control, 17.9% vs. 1.2%, P = 7.94 × 10(-12)). The validation study, including 2,160 cases and 2,433 controls, showed that the MST1R variant c.G917A:p.R306H is highly associated with NPC (odds ratio of 9.0). MST1R is predominantly expressed in the tissue-resident macrophages and is critical for innate immunity that protects organs from tissue damage and inflammation. Importantly, MST1R expression is detected in the ciliated epithelial cells in normal nasopharyngeal mucosa and plays a role in the cilia motility important for host defense. Although no somatic mutation of MST1R was identified in the sporadic NPC tumors, copy number alterations and promoter hypermethylation at MST1R were often observed. Our findings provide new insights into the pathogenesis of NPC by highlighting the involvement of the MST1R-mediated signaling pathways.


Assuntos
Exoma , Predisposição Genética para Doença , Neoplasias Nasofaríngeas/genética , Receptores Proteína Tirosina Quinases/genética , Análise de Sequência , Adolescente , Adulto , Carcinoma , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo , Adulto Jovem
18.
Mol Pharm ; 13(1): 144-54, 2016 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-26580496

RESUMO

Human organic anion transporting polypeptides (OATPs) mediate the influx of many important drugs into cells. Casein kinase 2 (CK2) is a critical protein kinase that phosphorylates >300 protein substrates and is dysregulated in a number of disease states. Among the CK2 substrates are several transporters, although whether this includes human OATPs has not been evaluated. The current study was undertaken to evaluate the regulation of human OATP1A2 by CK2. HEK-239T cells in which OATP1A2 was overexpressed were treated with CK2 specific inhibitors or transfected with CK2 specific siRNA, and the activity, expression, and subcellular trafficking of OATP1A2 was evaluated. CK2 inhibition decreased the uptake of the prototypic OATP1A2 substrate estrone-3-sulfate (E3S). Kinetic studies revealed that this was due to a decrease in the maximum velocity (Vmax) of E3S uptake, while the Michaelis constant was unchanged. The cell surface expression, but not the total cellular expression of OATP1A2, was impaired by CK2 inhibition and knockdown of the catalytic α-subunits of CK2. CK2 inhibition decreased the internalization of OATP1A2 via a clathrin-dependent pathway, decreased OATP1A2 recycling, and likely impaired OATP1A2 targeting to the cell surface. Consistent with these findings, CK2 inhibition also disrupted the colocalization of OATP1A2 and Rab GTPase (Rab)4-, Rab8-, and Rab9-positive endosomal and secretory vesicles. Taken together, CK2 has emerged as a novel regulator of the subcellular trafficking and stability of OATP1A2. Because OATP1A2 transports many molecules of physiological and pharmacological importance, the present data may inform drug selection in patients with diseases in which CK2 and OATP1A2 are dysregulated.


Assuntos
Caseína Quinase II/metabolismo , Transportadores de Ânions Orgânicos/metabolismo , Caseína Quinase II/genética , Linhagem Celular , Inativação Gênica/fisiologia , Humanos , Immunoblotting , Estabilidade Proteica , Transporte Proteico/fisiologia
19.
Int J Cancer ; 138(1): 160-70, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-26227166

RESUMO

Tumor suppressor genes (TSGs) play a prominent role in cancer and are important in the development of nasopharyngeal carcinoma (NPC), which is endemic in Southern China as well as Southeast Asia. Apart from TSGs, aberrant signalling pathways are also commonly associated with tumor progression. Unsurprisingly, the NF-κB pathway is frequently associated with angiogenesis and promoting tumor growth and development. Functional complementation studies using microcell-mediated chromosome transfer helped to identify IKBB as a putative TSG in NPC. IKBB, an inhibitor of NF-κB, has recently been shown to be inversely associated with tumor growth and metastasis via inactivation of the NF-κB pathway, but its suppressive role is still only poorly understood. This study takes the lead in revealing the suppressive role of IKBB in NPC. IKBB is silenced in the majority of NPC tumor tissues in all stages. Its suppressive role is substantiated by perturbation in tumor formation, cell migration and angiogenesis. Interestingly, IKBB not only affects the 'seed', but also influences the 'soil' by downregulating the transcriptional level of proangiogenic factors Rantes, Upar, IL6, and IL8. For the first time, our data establish the importance of a novel tumor suppressive IKBB gene in abrogating angiogenesis in NPC via the NF-κB signalling pathway, which is likely mediated by crosstalk with the Akt/Gsk3ß signalling pathway.


Assuntos
Proteínas I-kappa B/metabolismo , NF-kappa B/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Transdução de Sinais , Proteínas Supressoras de Tumor/metabolismo , Adulto , Idoso , Carcinoma , Linhagem Celular Tumoral , Movimento Celular/genética , Citocinas/genética , Citocinas/metabolismo , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Proteínas I-kappa B/genética , Masculino , Pessoa de Meia-Idade , NF-kappa B/genética , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/mortalidade , Neoplasias Nasofaríngeas/patologia , Estadiamento de Neoplasias , Neovascularização Patológica/genética , Prognóstico , Ligação Proteica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Supressoras de Tumor/genética
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