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  • 1
    In: Gastroenterology, Elsevier BV, Vol. 149, No. 6 ( 2015-11), p. 1415-1424
    Type of Medium: Online Resource
    ISSN: 0016-5085
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    Language: English
    Publisher: Elsevier BV
    Publication Date: 2015
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  • 2
    Online Resource
    Online Resource
    The Company of Biologists ; 2013
    In:  Journal of Cell Science Vol. 126, No. 2 ( 2013-01-15), p. 688-695
    In: Journal of Cell Science, The Company of Biologists, Vol. 126, No. 2 ( 2013-01-15), p. 688-695
    Abstract: Plexin B1, the receptor for Semaphorin 4D (Sema4D), is expressed by melanocytes in the skin. We recently showed that Sema4D suppresses activation of the hepatocyte growth factor receptor, MET, in melanocytes, and that knockdown of Plexin B1 results in activation of MET. MET signaling mediates proliferation, survival and migration in melanocytes, and its activation is associated with transformation of melanocytes to melanoma. In this report we investigated the mechanism by which Plexin B1 inhibits MET activation. Our results show that Plexin B1 and MET exist as an oligomeric receptor-receptor complex in melanocytes, and that receptor association is increased by Sema4D. MET and Plexin B1 receptor complexes were identified along the cell body of melanocytes, and Sema4D increased receptor association on dendrites, suggesting that Sema4D regulates MET-dependent processes at precise locations on the melanocyte. Despite activation of MET, Plexin B1 knockdowns proliferated slowly and showed increased apoptosis compared with controls. Shp2, a non-receptor protein tyrosine phosphatase, translates growth and survival signals from MET and other receptor tyrosine kinases. Plexin B1 knockdowns had markedly lower levels of Shp2 compared with controls, and Sema4D upregulated Shp2 expression at the protein and message level in normal melanocytes. Functional studies showed that blockade of Shp2 activity abrogated MET-dependent activation of Erk1/Erk2 and Akt in melanocytes. These results suggest a complex role for Sema4D and Plexin B1 in orchestrating signaling from the MET receptor in melanocytes. Because Shp2 is a downstream adaptor protein for multiple receptors, Sema4D may control the effects of several growth factors on melanocytes through regulation of Shp2.
    Type of Medium: Online Resource
    ISSN: 1477-9137 , 0021-9533
    Language: English
    Publisher: The Company of Biologists
    Publication Date: 2013
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    SSG: 12
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  • 3
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. e22522-e22522
    Abstract: e22522 Background: Breast cancer is the most common cancer in women worldwide. Both intrinsic and environmental factors contribute to the disparities in breast cancer incidence across different regions. In Hong Kong, the incidence has been increasing in the past decades. With over 4700 women diagnosed in 2019, breast cancer is responsible for 27% of all female cancers in Hong Kong. Apart from intrinsic non-modifiable risk factors, some risk factors are modifiable and may reduce cancer risk. Methods: We conducted a case-control study that involved breast cancer patients from the Hong Kong Breast Cancer Registry with matched healthy controls from the community between 2014 and 2017. A standardized written questionnaire was used through face-to-face interviews of all study participants. The questionnaire collected information on participants’ demographics, general health, smoking history and other lifestyle factors including physical activity, self-assessed dietary habits (balanced, vegetarian, meat and dairy-rich diets), self-perceived stress levels (measured with a 4-point Likert scale, and high stress level was defined as having over 50% of the participant’s time with stress being scored 3 or above out of a Likert scale of 4), body mass index, family history, menstrual and reproductive history, and history on the use of oral contraceptives and hormone replacement therapy. Multiple logistic regression was fitted to compare all risk factors. Results: A total of 5,186 breast cancer patients and 5,571 controls were recruited. Modifiable risk factors that were shown to be associated with an increased risk of breast cancer included self-perceived high stress level (adjusted odd ratios [aOR] = 3.44; 95% CI = 3.13-3.78), meat-rich diet (aOR = 1.77; 95% CI = 1.54-2.04), dairy-rich diet (aOR = 3.33; 95% CI = 2.01-5.52), overweight/obese status (aOR = 1.21; 95% CI = 1.10-1.32), delayed child-bearing (aOR = 2.23; 95% CI = 1.79-2.79), nulliparity (aOR = 1.21; 95% CI = 1.08-1.35) and ever use of oral contraceptives (aOR = 1.34; 95% CI = 1.22-1.47), while exercise (OR = 0.62; 95% CI = 0.56-0.68) and breast-feeding (aOR = 0.76; 95% CI = 0.69-0.83) were associated with reduced risk. Conclusions: In Hong Kong, high stress level, meat- and dairy- rich diet, overweight/obese, reproductive history and use of oral contraceptives were identified to be modifiable risk factors for breast cancer. Adjusting these factors through lifestyle modification may curb the increasing trend of breast cancer incidences in the coming decades.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
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  • 4
    In: Family Practice, Oxford University Press (OUP), Vol. 37, No. 4 ( 2020-09-05), p. 547-553
    Abstract: Breast cancer is prevalent and has high cure rates. The resultant increase in numbers of breast cancer survivors (BCS) may overwhelm the current oncology workforce in years to come. We postulate that primary care physicians (PCPs) could play an expanded role in comanaging survivors, provided they are given the appropriate tools and training to do so. Objective To explore the perspectives of PCPs towards managing BCS in a community-based shared-care programme with oncologists. Methods Eleven focus groups and six in-depth interviews were conducted with seventy PCPs recruited by purposive sampling. All sessions were audio-recorded, transcribed verbatim and coded by three independent investigators. Thematic data analysis was performed and the coding process facilitated by NVivo 12. Results Majority of PCPs reported currently limited roles in managing acute and non-cancer issues, optimizing comorbidities and preventive care. PCPs aspired to expand their role to include cancer surveillance, risk assessment and addressing unmet psychosocial needs. PCPs preferred to harmonize cancer survivorship management of their primary care patients who are also BCS, with defined role distinct from oncologists. Training to understand the care protocol, enhancement of communication skills, confidence and trust were deemed necessary. PCPs proposed selection criteria of BCS and adequacy of their medical information; increased consultation time; contact details and timely access to oncologists (if needed) in the shared-care programme. Conclusions PCPs were willing to share the care of BCS with oncologists but recommended role definition, training, clinical protocol, resources and access to oncologist’s consultation to optimize the programme implementation.
    Type of Medium: Online Resource
    ISSN: 1460-2229
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
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  • 5
    In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 4032-4032
    Abstract: Background: Infusion of peripheral blood stem cell (PBSC) in patients undergoing autologous transplantation (ASCT) has been conventionally performed using central venous catheters (CVC) inserted through the subclavian or internal jugular vein. Peripheral inserted central catheters (PICC) are routinely used for infusion of blood products and medication, but its use for PBSC infusion has not been well established. Our study aimed to evaluate the feasibility and safety of using PICC to deliver PBSC for ASCT through an in-vitro lab-based validation process, followed by a clinical review. Methods:  Lab based validation In vitro infusion of 6 cryopreserved PBSCs was performed, 3 infused PICC whist 3 via CVC. Each product was thawed for the same amount of time and drained by gravity. Pre-infusion and post-infusion total nucleated cell counts (TNC), CD34 counts and CD34 viability of the PBSCs were analysed by flow-cytometry and compared using paired T test. In vitro infusion rates were also compared between PICC and CVC groups. Clinical Outcome Analysis The clinical study included 31 patients (Lymphoma N=21, myeloma N=5, Others, N=4) who underwent ASCT at National University Cancer Institute, Singapore (NCIS) from September 2019 to July 2021. All patients had a 19G BARDS dual lumen PICC inserted in either the brachial or basilic veins and used for PBSC infusion. The PBSC infusion rate, infusion associated complications, time to absolute neutrophil count (ANC) & gt;1, and platelet count engraftment & gt;100K were analysed. Clinical outcomes in the lymphoma cohort, who received BEAM conditioning (N=17) were also compared with a control group, matched for conditioning, cell dose and age, who had PBSC infused via CVC. Results:  In vitro findings: Overall flow rates for infusion through PICC was slower (mean 0.1mls/s vs 0.3mls/s, p & lt; 0.05). However, there were no significant % differences in TNC counts (5% vs 9%, p=0.4), CD34 counts (17% vs 15%, p=0.9) and viability (4% vs 7%, p=0.2) between pre and post infusion samples for PICC and CVC.. Clinical findings: 30 patients (Lymphoma N=21, myeloma N=5, N=4) were included. 15 (50% of patients) had a for ASCT while 15 (50%) had an existing PICC. For patients with an existing PICC, the median duration of catheter in situ was 86 days. New lines were inserted 2-7 days prior to the PBSC infusion. The median age of the patients was 54 (20-71) with 19 males (63%). . There were 5 infusion related complications, 2 in an existing PICC and 3 in new PICCs. 4 were related to slow flow rate and 1 was related to sediments seen in the line. None led to a need for alternative line for infusion. The median time to ANC recovery was 10 (range 9-14), 10 (range 9-11) and 11 days (range 10-12), while the median time to platelet engraftment was 18 (range 10-195), 20 (range 15-55) and 22 (16-85 days) for the lymphoma BEAM conditioning (N=17), lymphoma Carmustine/ Thiotepa conditioning (N=4), and the myeloma (N=5) cohorts respectively. Clinical outcomes in the lymphoma cohort, who also compared with a control group matched for conditioning, cell dose and conditioning. The in-vivo infusion rate was slower in the PICC group, compared to the CVC group (3.1 mls/min vs 4.5mls/min, p & lt;0.05).There was however no differences in engraftment with median time to ANC recovery 10 days (range 9-14) vs 11 days (range 9-13) (p & gt;0.05) and median time to platelet engraftment 18 (range 14-195) vs 19 days (range 14 -57) (p & gt;0.05) in the PICC vs CVC groups respectively. Conclusion: Our in-vitro and clinical findings confirmed that the use of PICC for PBSC infusion is safe and efficacious and reduces the need for CVC insertion. Our findings have led to change in clinical practice with utilization of PICCs for PBSC infusions for ASCT. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
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    detail.hit.zdb_id: 80069-7
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  • 6
    Online Resource
    Online Resource
    American Meteorological Society ; 1987
    In:  Journal of the Atmospheric Sciences Vol. 44, No. 21 ( 1987-11), p. 3175-3187
    In: Journal of the Atmospheric Sciences, American Meteorological Society, Vol. 44, No. 21 ( 1987-11), p. 3175-3187
    Type of Medium: Online Resource
    ISSN: 0022-4928 , 1520-0469
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    Language: English
    Publisher: American Meteorological Society
    Publication Date: 1987
    detail.hit.zdb_id: 218351-1
    detail.hit.zdb_id: 2025890-2
    SSG: 16,13
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  • 7
    In: BMC Primary Care, Springer Science and Business Media LLC, Vol. 23, No. 1 ( 2022-12)
    Abstract: The adaptability of existing recommendations on shared care implementation to Asian settings is unknown. This qualitative study aims to elicit public- and private-sectors primary care practitioners’ (PCPs) perspectives on the sustainable implementation of a shared care model among breast cancer survivors in Singapore. Methods Purposive sampling was employed to engage 70 PCPs from SingHealth Polyclinics, National University Polyclinics, National Healthcare Group Polyclinics, and private practice. Eleven focus groups and six in-depth interviews were conducted between June to November 2018. All sessions were audio-recorded and transcribed verbatim. Guided by the RE-AIM framework, we performed deductive thematic analysis in QSR NVivo 12. Results PCPs identified low-risk breast cancer survivors who demonstrated clear acceptability of PCPs’ involvement in follow-up as suitable candidates for shared care. Engagement with institution stakeholders as early adopters is crucial with adequate support through PCP training, return pathways to oncologists, and survivorship care plans as communication tools. Implementation considerations differed across practices. Selection of participating PCPs could consider seniority and interest for public and private practice, respectively. Proposed adoption incentives included increased renumeration for private PCPs and work recognition for public PCPs. Public PCPs further proposed integrating shared care elements to their existing family medicine clinics. Conclusions PCPs perceived shared care favorably as it echoed principles of primary care to provide holistic and well-coordinated care. Contextual factors should be considered when adapting implementation recommendations to Asian settings like Singapore. With limited competitive pressure, the government is then pivotal in empowering primary care participation in survivorship shared care delivery.
    Type of Medium: Online Resource
    ISSN: 2731-4553
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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  • 8
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. 2868-2868
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 2868-2868
    Abstract: The PI3K/AKT/mTOR pathway is frequently deregulated in breast cancer. Specific inhibition of its key signaling nodes results in cell death and tumor growth arrest, but also in activation of feedback loops that ultimately limit therapeutic activity. The subcellular localization and activity of Forkhead box O3 (FOXO3) transcription factor is heavily regulated by the PI3K pathway. Phosphorylation of FOXO3 by AKT inhibits its transcriptional functions leading to cell survival and growth. Although our understanding of the transcription function of FOXO3 downstream of the PI3K pathway has increased significantly in recent years, it is still unclear how FOXO3 acts in concert with other cofactors of the transcription machinery. We conjectured that inhibition of the PI3K/AKT/mTOR signaling by specific agents targeting the pathway at different nodes leads to unique FOXO3-mediated transcriptional programs unveiling a complex network of regulation. We therefore sought to identify proteins that differentially co-immunoprecipitate with FOXO3 upon PI3K, AKT or mTOR blockade. To target the pathway at different levels, we used BYL719, a PI3Kα inhibitor; MK2206, an allosteric AKT inhibitor; and RAD001, an allosteric mTORC1 inhibitor. Upon treatment, we immunopreciptated endogenous FOXO3 and searched for FOXO3 interactors by mass spectrometry analysis. In parallel RNA samples from each treatment were analyzed using gene expression microarrays. Gene expression analyses revealed that each specific compound originated distinct transcriptional signatures. Accordingly, mass spectrometry analysis revealed novel FOXO3 co-interactors engaging in different transcriptional complexes at each treatment conditions. We identified some of these proteins as CUL1, the core component of the SCF (SKP1-CUL1-F-BOX protein) E3 ubiquitin-protein ligase complex, the cyclin-dependent kinase 5 (CDK5), the upstream binding transcription factor (UBTF), and the core component of RNA polymerase I POLR1C (polymerase RNA I polypeptide C). We performed coimmunoprecipitation analyses to confirm that these cofactors are bona fide FOXO3-interacting proteins. We then analyzed the effects of overexpressing these proteins on FOXO3 transcriptional activity. Luciferase assays demonstrated an increase in FOXO3 transcriptional activity when CUL1, UBTF, CDK5 or POLR1C were overexpressed. The overexpression of cofactors also induced the expression of FOXO3 target genes such as TRAIL or IRS2. Furthermore, overexpression of these co-interactors enhanced the binding of FOXO3 to its target gene promoters. We are now engaged in both elucidating how these cofactors can modulate the transcriptional activity of FOXO3 upon PI3K/AKT/mTOR inhibition and understanding the therapeutic implications of these FOXO3-containing complexes. Citation Format: Vasilis Hristidis, James Cownie, Ana Bosch, Joanne Soong, Pau Castel, Maurizio Scaltriti, Baselga José. Mechanisms of transcriptional regulation of FOXO3 by cofactors upon PI3K/AKT/mTOR inhibition. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2868.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 9
    Online Resource
    Online Resource
    Proceedings of the National Academy of Sciences ; 2022
    In:  Proceedings of the National Academy of Sciences Vol. 119, No. 32 ( 2022-08-09)
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 119, No. 32 ( 2022-08-09)
    Abstract: L-type Ca V 1.3 calcium channels are expressed on the dendrites and soma of neurons, and there is a paucity of information about its role in hippocampal plasticity. Here, by genetic targeting to ablate Ca V 1.3 RNA editing, we demonstrate that unedited Ca V 1.3 ΔECS mice exhibited improved learning and enhanced long-term memory, supporting a functional role of RNA editing in behavior. Significantly, the editing paradox that functional recoding of Ca V 1.3 RNA editing sites slows Ca 2+ -dependent inactivation to increase Ca 2+ influx but reduces channel open probability to decrease Ca 2+ influx was resolved. Mechanistically, using hippocampal slice recordings, we provide evidence that unedited Ca V 1.3 channels permitted larger Ca 2+ influx into the hippocampal pyramidal neurons to bolster neuronal excitability, synaptic transmission, late long-term potentiation, and increased dendritic arborization. Of note, RNA editing of the Ca V 1.3 IQ-domain was found to be evolutionarily conserved in mammals, which lends support to the importance of the functional recoding of the Ca V 1.3 channel in brain function.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2022
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    SSG: 11
    SSG: 12
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  • 10
    Online Resource
    Online Resource
    Oxford University Press (OUP) ; 2022
    In:  Oxford Open Neuroscience Vol. 1 ( 2022-05-01)
    In: Oxford Open Neuroscience, Oxford University Press (OUP), Vol. 1 ( 2022-05-01)
    Abstract: Adenosine-to-inosine (A-to-I) RNA editing is a post-transcriptional modification that diversifies protein functions by recoding RNA or alters protein quantity by regulating mRNA level. A-to-I editing is catalyzed by adenosine deaminases that act on RNA. Millions of editing sites have been reported, but they are mostly found in non-coding sequences. However, there are also several recoding editing sites in transcripts coding for ion channels or transporters that have been shown to play important roles in physiology and changes in editing level are associated with neurological diseases. These editing sites are not only found to be evolutionary conserved across species, but they are also dynamically regulated spatially, developmentally and by environmental factors. In this review, we discuss the current knowledge of A-to-I RNA editing of ion channels and receptors in the context of their roles in physiology and pathological disease. We also discuss the regulation of editing events and site-directed RNA editing approaches for functional study that offer a therapeutic pathway for clinical applications.
    Type of Medium: Online Resource
    ISSN: 2753-149X
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 3123698-4
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