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  1. Article: The burden of type 2 diabetes pre-and during the COVID-19 pandemic - a review.

    Sciberras, Justine / Camilleri, Lara Maria / Cuschieri, Sarah

    Journal of diabetes and metabolic disorders

    2020  Volume 19, Issue 2, Page(s) 1357–1365

    Abstract: Introduction: Diabetes Mellitus is a chronic disease and a global epidemic. It is a known fact that co-morbidities, including Diabetes Mellitus, pose a higher risk of infection by COVID-19. Additionally, the outcomes following infection are far worse ... ...

    Abstract Introduction: Diabetes Mellitus is a chronic disease and a global epidemic. It is a known fact that co-morbidities, including Diabetes Mellitus, pose a higher risk of infection by COVID-19. Additionally, the outcomes following infection are far worse than in people without such co-morbities.Factors contributing to the development of type 2 diabetes mellitus (T2DM) have long been established, yet this disease still bestows a substantial global burden. The aim was to provide a comprehensive review of the burden of diabetes pre-COVID-19 and the additional impact sustained by the diabetes population and healthcare systems during the COVID-19 pandemic, while providing recommendations of how this burden can be subsided.
    Methodology: Literature searches were carried out on 'Google Scholar' and 'PubMed' to identify relevant articles for the scope of this review. Information was also collected from reliable sources such as the World Health Organisation and the International Diabetes Federation.
    Results: T2DM presented with economic, social and health burdens prior to COVID-19 with an significant 'Disability Adjusted Life Years' impact. Whilst people with diabetes are more susceptible to COVID-19, enforcing lockdown regulations set by the Public Health department to reduce risk of infection brought about its own challenges to T2DM management. Through recommendations and adapting to new methods of management such as telehealth, these challenges and potential consequences of mismanagement are kept to a minimum whilst safeguarding the healthcare system.
    Conclusion: By understanding the challenges and burdens faced by this population both evident pre-covid and during, targeted healthcare can be provided during the COVID-19 pandemic. Furthermore, implementation of targeted action plans and recommendations ensures the care provided is done in a safe and effective environment.
    Keywords covid19
    Language English
    Publishing date 2020-10-19
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2680289-2
    ISSN 2251-6581
    ISSN 2251-6581
    DOI 10.1007/s40200-020-00656-4
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  2. Article ; Online: Splenic artery angioembolization for high-grade splenic injury: Are we wasting money?

    Senekjian, Lara / Cuschieri, Joseph / Robinson, Bryce R H

    American journal of surgery

    2020  Volume 221, Issue 1, Page(s) 204–210

    Abstract: Background: Non-operative management (NOM) is accepted treatment of splenic injury, but this may fail leading to splenectomy. Splenic artery embolization (SAE) may improve rate of salvage. The purpose is to determine the cost-utility of the addition of ... ...

    Abstract Background: Non-operative management (NOM) is accepted treatment of splenic injury, but this may fail leading to splenectomy. Splenic artery embolization (SAE) may improve rate of salvage. The purpose is to determine the cost-utility of the addition of SAE for high-grade splenic injuries.
    Methods: A cost-utility analysis was developed to compared NOM to SAE in patients with blunt splenic injury. Sensitivity analysis was completed to account for uncertainty. Utility outcome was quality-adjusted life years (QALY).
    Results: For patients with grade III, IV and V injury NOM is the dominant strategy. The probability of NOM being the more cost-effective strategy is 87.5% in patients with grade V splenic injury. SAE is not the favored strategy unless the probability of failure of NOM is greater than 70.0%.
    Conclusion: For grade III-V injuries, NOM without SAE yields more quality-adjusted life years. NOM without SAE is the most cost-effective strategy for high-grade splenic injuries.
    MeSH term(s) Cost-Benefit Analysis ; Embolization, Therapeutic/economics ; Humans ; Injury Severity Score ; Spleen/blood supply ; Spleen/injuries ; Splenic Artery ; Wounds, Nonpenetrating/therapy
    Language English
    Publishing date 2020-07-07
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2953-1
    ISSN 1879-1883 ; 0002-9610
    ISSN (online) 1879-1883
    ISSN 0002-9610
    DOI 10.1016/j.amjsurg.2020.06.011
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  3. Article ; Online: Nonoperative Management in Blunt Splenic Trauma: Can Shock Index Predict Failure?

    Senekjian, Lara / Robinson, Bryce R H / Meagher, Ashley D / Gross, Joel A / Maier, Ronald V / Bulger, Eileen M / Arbabi, Saman / Cuschieri, Joseph

    The Journal of surgical research

    2022  Volume 276, Page(s) 340–346

    Abstract: Introduction: Predicting failure of nonoperative management (NOM) in splenic trauma remains elusive. Shock index (SI) is an indicator of physiologic burden in an injury but is not used as a prediction tool. The purpose of this study was to determine if ... ...

    Abstract Introduction: Predicting failure of nonoperative management (NOM) in splenic trauma remains elusive. Shock index (SI) is an indicator of physiologic burden in an injury but is not used as a prediction tool. The purpose of this study was to determine if elevated SI would be predictive of failure of NOM in patients with a blunt splenic injury.
    Methods: Adult patients admitted to a level-1 trauma center from January 2011 to April 2017 for NOM of splenic injury were reviewed. Patients were excluded if they underwent a procedure (angiography or surgery) prior to admission. The primary outcome was requiring intervention after an initial trial of noninterventional management (NIM). An SI > 0.9 at admission was considered a high risk. Univariate and multivariate analyses were used to identify predicators of the failure of NOM. Findings were subsequently verified on a validation cohort of patients.
    Results: Five hundred and eighty-five patients met inclusion criteria; 7.4% failed NIM. On an univariate analysis, findings of pseudoaneurysm or extra-arterial contrast on computed tomography did not differentiate successful NIM versus failure (8.1% versus 14.0%, P = 0.18). Age, the American Association for the Surgery of Trauma injury grade, and elevated SI were included in multivariate modeling. Grade of injury (OR 3.49, P = 0.001), age (OR 1.02, P = 0.009), and high SI (OR 3.49, P = 0.001) were each independently significant for NIM failure. The risk-adjusted odds of failure were significantly higher in patients with a high risk SI (OR 2.35, P < 0.001). Validation of these findings was confirmed for high SI on a subsequent 406 patients with a c-statistic of 0.71 (95% CI 0.62-0.80).
    Conclusions: Elevated SI is an independent risk factor for failure of NIM in those with splenic injury. SI along with age and computed tomography findings may aid in predicting the failure of NIM. Trauma providers should incorporate SI into decision-making tools for splenic injury management.
    MeSH term(s) Abdominal Injuries/complications ; Abdominal Injuries/diagnosis ; Abdominal Injuries/diagnostic imaging ; Abdominal Injuries/therapy ; Adult ; Humans ; Injury Severity Score ; Retrospective Studies ; Shock/diagnosis ; Shock/etiology ; Shock/therapy ; Spleen/diagnostic imaging ; Spleen/injuries ; Splenectomy ; Trauma Centers ; Treatment Failure ; Treatment Outcome ; Wounds, Nonpenetrating/complications ; Wounds, Nonpenetrating/diagnosis ; Wounds, Nonpenetrating/diagnostic imaging ; Wounds, Nonpenetrating/therapy
    Language English
    Publishing date 2022-04-12
    Publishing country United States
    Document type Journal Article
    ZDB-ID 80170-7
    ISSN 1095-8673 ; 0022-4804
    ISSN (online) 1095-8673
    ISSN 0022-4804
    DOI 10.1016/j.jss.2022.02.035
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    Zs.A 178: Show issues Location:
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  4. Article: The burden of type 2 diabetes pre-and during the COVID-19 pandemic - a review

    Sciberras, Justine / Camilleri, Lara Maria / Cuschieri, Sarah

    J Diabetes Metab Disord

    Abstract: Introduction: Diabetes Mellitus is a chronic disease and a global epidemic. It is a known fact that co-morbidities, including Diabetes Mellitus, pose a higher risk of infection by COVID-19. Additionally, the outcomes following infection are far worse ... ...

    Abstract Introduction: Diabetes Mellitus is a chronic disease and a global epidemic. It is a known fact that co-morbidities, including Diabetes Mellitus, pose a higher risk of infection by COVID-19. Additionally, the outcomes following infection are far worse than in people without such co-morbities.Factors contributing to the development of type 2 diabetes mellitus (T2DM) have long been established, yet this disease still bestows a substantial global burden. The aim was to provide a comprehensive review of the burden of diabetes pre-COVID-19 and the additional impact sustained by the diabetes population and healthcare systems during the COVID-19 pandemic, while providing recommendations of how this burden can be subsided. Methodology: Literature searches were carried out on 'Google Scholar' and 'PubMed' to identify relevant articles for the scope of this review. Information was also collected from reliable sources such as the World Health Organisation and the International Diabetes Federation. Results: T2DM presented with economic, social and health burdens prior to COVID-19 with an significant 'Disability Adjusted Life Years' impact. Whilst people with diabetes are more susceptible to COVID-19, enforcing lockdown regulations set by the Public Health department to reduce risk of infection brought about its own challenges to T2DM management. Through recommendations and adapting to new methods of management such as telehealth, these challenges and potential consequences of mismanagement are kept to a minimum whilst safeguarding the healthcare system. Conclusion: By understanding the challenges and burdens faced by this population both evident pre-covid and during, targeted healthcare can be provided during the COVID-19 pandemic. Furthermore, implementation of targeted action plans and recommendations ensures the care provided is done in a safe and effective environment.
    Keywords covid19
    Publisher WHO
    Document type Article
    Note WHO #Covidence: #885143
    Database COVID19

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  5. Article ; Online: The role of liquid biopsy in management of the neck with indeterminate response on post-treatment imaging following non-surgical management of oropharyngeal cancer.

    Li, Lucy Q / Adamowicz, Martyna / Wescott, Robert A / Warlow, Sophie J / Thomson, John P / Robert, Christelle / Carey, Lara M / Thain, Helen / Cuschieri, Kate / Conn, Brendan / Hay, Ashley / Aitman, Timothy J / Nixon, Iain J

    European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology

    2022  Volume 49, Issue 1, Page(s) 55–59

    Abstract: Introduction: This study aimed to determine if post-treatment HPV cell-free DNA (cfDNA) can assist in the decision-making process for salvage neck dissection in patients following non-surgical treatment of oropharyngeal squamous cell carcinoma (OPSCC) ... ...

    Abstract Introduction: This study aimed to determine if post-treatment HPV cell-free DNA (cfDNA) can assist in the decision-making process for salvage neck dissection in patients following non-surgical treatment of oropharyngeal squamous cell carcinoma (OPSCC) with a partial response in the neck on imaging at 12 weeks post-treatment.
    Methods: 86 patients who completed treatment were prospectively recruited through the regional multidisciplinary team (MDT). Treatment response was categorised as complete response (CR), partial response (PR) or progressive disease on 12-week post-treatment imaging. Pre- and post-treatment blood samples were assessed for HPV cfDNA through droplet digital PCR (ddPCR).
    Results: Eight patients had an isolated partial response in the neck. One (12.5%) had detectable HPV cfDNA (22.96 copies/ml) at ∼12 weeks post-treatment with positive disease on subsequent neck dissection (positive predictive value; PPV = 100%). Of the seven patients with undetectable HPV cfDNA, two patients had evidence of regional disease recurrence at 23.9 and 27.4 months respectively (negative predictive value; NPV = 71%).
    Conclusion: The detection of HPV cfDNA may help target salvage therapy in patients with a partial response in the neck. Follow-up studies in larger cohorts would be required to further validate the use of post-treatment HPV cfDNA in the management of OPSCC.
    MeSH term(s) Humans ; Papillomavirus Infections/complications ; Carcinoma, Squamous Cell/diagnostic imaging ; Carcinoma, Squamous Cell/therapy ; Carcinoma, Squamous Cell/pathology ; Neoplasm Recurrence, Local/pathology ; Oropharyngeal Neoplasms/diagnostic imaging ; Oropharyngeal Neoplasms/therapy ; Oropharyngeal Neoplasms/pathology ; Squamous Cell Carcinoma of Head and Neck/diagnostic imaging ; Squamous Cell Carcinoma of Head and Neck/therapy ; Liquid Biopsy ; Head and Neck Neoplasms/diagnostic imaging ; Head and Neck Neoplasms/therapy ; Cell-Free Nucleic Acids
    Chemical Substances Cell-Free Nucleic Acids
    Language English
    Publishing date 2022-09-29
    Publishing country England
    Document type Journal Article ; Comment
    ZDB-ID 632519-1
    ISSN 1532-2157 ; 0748-7983
    ISSN (online) 1532-2157
    ISSN 0748-7983
    DOI 10.1016/j.ejso.2022.09.016
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    Zs.A 1149: Show issues Location:
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  6. Article ; Online: Longitudinal measurement of HPV copy number in cell-free DNA is associated with patient outcomes in HPV-positive oropharyngeal cancer.

    Warlow, Sophie J / Adamowicz, Martyna / Thomson, John P / Wescott, Robert A / Robert, Christelle / Carey, Lara M / Thain, Helen / Cuschieri, Kate / Li, Lucy Q / Conn, Brendan / Hay, Ashley / Nixon, Iain J / Aitman, Timothy J

    European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology

    2022  Volume 48, Issue 6, Page(s) 1224–1234

    Abstract: Introduction: Oropharyngeal squamous cell carcinoma (OPSCC) is increasing in global prevalence and is divided into two types dependent on association with human papillomavirus (HPV). Assay of HPV copy number in plasma cell-free DNA (cfDNA) provides a ... ...

    Abstract Introduction: Oropharyngeal squamous cell carcinoma (OPSCC) is increasing in global prevalence and is divided into two types dependent on association with human papillomavirus (HPV). Assay of HPV copy number in plasma cell-free DNA (cfDNA) provides a minimally invasive method for detecting and monitoring tumour-derived HPV, with potential for enhancing clinical care.
    Materials and methods: In a prospectively recruited cohort of 104 OPSCC patients, we evaluate the utility of cfDNA droplet digital PCR (ddPCR) as a method for characterisation and longitudinal monitoring of patients with OPSCC.
    Results: ddPCR assay of pre-treatment plasma cfDNA for five HPV types showed overall 95% concordance with p16 immunohistochemistry and PCR analysis of tumour tissue. Longitudinal sampling in 48 HPV+ve patients, with median follow-up of 20 months, was strongly associated with patient outcomes. Persistently elevated cfDNA-HPV post-treatment was associated with treatment failure (2/2 patients) and an increase of cfDNA-HPV in patients whose HPV levels were initially undetectable post-treatment was associated with disease recurrence (5/6 patients). No recurrence was observed in patients in whom cfDNA-HPV was undetectable in all post-treatment samples. In two patients, sequential HPV measurement could have avoided surgical intervention which did not confirm recurrence.
    Conclusion: The high concordance of pre-treatment plasma cfDNA-HPV analysis with tissue-based assays, together with the clinical associations of sequentially measured post-treatment cfDNA-HPV copy number add to a growing body of evidence that suggest utility of cfDNA-HPV ddPCR in management of OPSCC. Standardised clinical trials based on these data are now needed to assess the impact of such testing on overall patient outcomes.
    MeSH term(s) Cell-Free Nucleic Acids ; DNA Copy Number Variations ; Humans ; Neoplasm Recurrence, Local ; Oropharyngeal Neoplasms/diagnosis ; Oropharyngeal Neoplasms/virology ; Papillomaviridae/genetics ; Papillomavirus Infections/complications ; Squamous Cell Carcinoma of Head and Neck/diagnosis ; Squamous Cell Carcinoma of Head and Neck/virology
    Chemical Substances Cell-Free Nucleic Acids
    Language English
    Publishing date 2022-04-06
    Publishing country England
    Document type Journal Article
    ZDB-ID 632519-1
    ISSN 1532-2157 ; 0748-7983
    ISSN (online) 1532-2157
    ISSN 0748-7983
    DOI 10.1016/j.ejso.2022.03.232
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    Zs.A 1149: Show issues Location:
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  7. Article ; Online: Ventilator-associated events, not ventilator-associated pneumonia, is associated with higher mortality in trauma patients.

    Meagher, Ashley D / Lind, Margaret / Senekjian, Lara / Iwuchukwu, Chinenye / Lynch, John B / Cuschieri, Joseph / Robinson, Bryce R H

    The journal of trauma and acute care surgery

    2019  Volume 87, Issue 2, Page(s) 307–314

    Abstract: Background: Ventilator-associated events (VAE), using objective diagnostic criteria, are the preferred quality indicator for patients requiring mechanical ventilation (MV) for greater than 48 hours. We aim to identify the occurrence of VAE in our trauma ...

    Abstract Background: Ventilator-associated events (VAE), using objective diagnostic criteria, are the preferred quality indicator for patients requiring mechanical ventilation (MV) for greater than 48 hours. We aim to identify the occurrence of VAE in our trauma population, the impact on survival, and length of stay, as compared to the traditional definition of ventilator-associated pneumonia (VAP).
    Methods: This retrospective review included adult trauma patients, who were Washington residents, admitted between 2012 and 2017, and required at least 3 days of MV. Exclusions included patients with Abbreviated Injury Scale head score greater than 4 and burn related mechanisms of injury. We matched trauma registry data with our institutional, physician-adjudicated, and culture-confirmed ventilator event database. We compared the clinical outcomes of ventilator-free days, intensive care unit length of stay, hospital length of stay, and likelihood of death between VAE and VAP.
    Results: One thousand five hundred thirty-three trauma patients met criteria; 124 (8.1%) patients developed VAE, 114 (7.4%) patients developed VAP, and 63 (4.1%) patients met criteria for both VAE and VAP. After adjusted analyses, patients with VAE were more likely to die (hazard ratio [HR], 2.86; 95% confidence interval [CI], 1.44-5.68), than those with VAP, as well those patients with neither diagnosis (HR, 2.83; 95% CI, 1.83-4.38). Patients with VAP were no more likely to die (HR, 1.55; 95% CI, 0.91-2.68) than those with neither diagnosis. Patients with VAE had fewer ventilator-free days than those with VAP (HR, -2.71; 95% CI, -4.74 to -0.68).
    Conclusion: Critically injured trauma patients who develop VAE are three times more likely to die and utilize almost 3 days more MV than those that develop VAP. The objective criteria of VAE make it a promising indicator on which quality indicator efforts should be focused. Future studies should be aimed at identification of modifiable risk factors for VAE and their impact on outcome, as these patients are at high risk for death.
    Level of evidence: Retrospective cohort study, level III.
    MeSH term(s) Female ; Humans ; Length of Stay/statistics & numerical data ; Male ; Middle Aged ; Pneumonia, Ventilator-Associated/mortality ; Quality Indicators, Health Care ; Registries ; Respiration, Artificial/adverse effects ; Respiration, Artificial/mortality ; Retrospective Studies ; Wounds and Injuries/mortality ; Wounds and Injuries/therapy
    Language English
    Publishing date 2019-04-02
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2651070-4
    ISSN 2163-0763 ; 2163-0755
    ISSN (online) 2163-0763
    ISSN 2163-0755
    DOI 10.1097/TA.0000000000002294
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    Zs.A 127: Show issues Location:
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  8. Article ; Online: Control at the cell center: the role of spindle poles in cytoskeletal organization and cell cycle regulation.

    Cuschieri, Lara / Nguyen, Thao / Vogel, Jackie

    Cell cycle (Georgetown, Tex.)

    2007  Volume 6, Issue 22, Page(s) 2788–2794

    Abstract: Microtubule organizing centres (MTOCs), which include fungal spindle pole bodies and centrosome in higher eukaryotes, are a structurally diverse group of organelles that share a conserved role in microtubule nucleation and spindle formation. However, ... ...

    Abstract Microtubule organizing centres (MTOCs), which include fungal spindle pole bodies and centrosome in higher eukaryotes, are a structurally diverse group of organelles that share a conserved role in microtubule nucleation and spindle formation. However, recent studies propose that the function of MTOC components extends far beyond these established roles. Numerous cell cycle regulators, checkpoint proteins and microtubule plus tip binding proteins localize to MTOCs during the cell cycle, suggesting that these organelles serve as cellular scaffolds. In addition, several MTOC components such as gamma-tubulin and its associating proteins have been directly implicated in the control of cell cycle progression, activation of checkpoint responses and the regulation of microtubule organization and dynamics. Collectively, these findings implicate MTOCs as cellular control centers that coordinate events at both microtubule minus ends and plus ends with the cell cycle. In this review, we discuss recent studies that support a role for MTOC components, in particular gamma-tubulin, in cell cycle progression, checkpoint response and the coordination of microtubule organization and dynamics.
    MeSH term(s) Animals ; Cell Cycle/physiology ; Centrioles/chemistry ; Centrioles/physiology ; Cytoskeleton/chemistry ; Cytoskeleton/physiology ; Humans ; Microtubules/chemistry ; Microtubules/physiology ; Spindle Apparatus/chemistry ; Spindle Apparatus/physiology
    Language English
    Publishing date 2007-08-27
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2146183-1
    ISSN 1551-4005 ; 1538-4101 ; 1554-8627
    ISSN (online) 1551-4005
    ISSN 1538-4101 ; 1554-8627
    DOI 10.4161/cc.6.22.4941
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  9. Article: Gamma-tubulin is required for proper recruitment and assembly of Kar9-Bim1 complexes in budding yeast.

    Cuschieri, Lara / Miller, Rita / Vogel, Jackie

    Molecular biology of the cell

    2006  Volume 17, Issue 10, Page(s) 4420–4434

    Abstract: Microtubule plus-end-interacting proteins (+TIPs) promote the dynamic interactions between the plus ends (+ends) of astral microtubules and cortical actin that are required for preanaphase spindle positioning. Paradoxically, +TIPs such as the EB1 ... ...

    Abstract Microtubule plus-end-interacting proteins (+TIPs) promote the dynamic interactions between the plus ends (+ends) of astral microtubules and cortical actin that are required for preanaphase spindle positioning. Paradoxically, +TIPs such as the EB1 orthologue Bim1 and Kar9 also associate with spindle pole bodies (SPBs), the centrosome equivalent in budding yeast. Here, we show that deletion of four C-terminal residues of the budding yeast gamma-tubulin Tub4 (tub4-delta dsyl) perturbs Bim1 and Kar9 localization to SPBs and Kar9-dependent spindle positioning. Surprisingly, we find Kar9 localizes to microtubule +ends in tub4-delta dsyl cells, but these microtubules fail to position the spindle when targeted to the bud. Using cofluorescence and coaffinity purification, we show Kar9 complexes in tub4-delta dsyl cells contain reduced levels of Bim1. Astral microtubule dynamics is suppressed in tub4-delta dsyl cells, but it are restored by deletion of Kar9. Moreover, Myo2- and F-actin-dependent dwelling of Kar9 in the bud is observed in tub4-delta dsyl cells, suggesting defective Kar9 complexes tether microtubule +ends to the cortex. Overproduction of Bim1, but not Kar9, restores Kar9-dependent spindle positioning in the tub4-delta dsyl mutant, reduces cortical dwelling, and promotes Bim1-Kar9 interactions. We propose that SPBs, via the tail of Tub4, promote the assembly of functional +TIP complexes before their deployment to microtubule +ends.
    MeSH term(s) Actins ; Cell Cycle Proteins/metabolism ; Cell Cycle Proteins/physiology ; Cells, Cultured ; Microtubule Proteins/metabolism ; Microtubule Proteins/physiology ; Microtubules/metabolism ; Myosin Heavy Chains/metabolism ; Myosin Type V/metabolism ; Nuclear Proteins/metabolism ; Nuclear Proteins/physiology ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism ; Saccharomyces cerevisiae Proteins/physiology ; Saccharomycetales/metabolism ; Signal Transduction ; Spindle Apparatus/metabolism ; Spindle Apparatus/ultrastructure ; Tubulin/genetics ; Tubulin/physiology
    Chemical Substances Actins ; BIM1 protein, S cerevisiae ; Cell Cycle Proteins ; KAR9 protein, S cerevisiae ; MYO2 protein, S cerevisiae ; Microtubule Proteins ; Nuclear Proteins ; Saccharomyces cerevisiae Proteins ; TUB4 protein, S cerevisiae ; Tubulin ; Myosin Type V (EC 3.6.1.-) ; Myosin Heavy Chains (EC 3.6.4.1)
    Language English
    Publishing date 2006-10
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 1098979-1
    ISSN 1939-4586 ; 1059-1524
    ISSN (online) 1939-4586
    ISSN 1059-1524
    DOI 10.1091/mbc.E06-03-0245
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  10. Article: Spc24 and Stu2 promote spindle integrity when DNA replication is stalled.

    Ma, Lina / McQueen, Jennifer / Cuschieri, Lara / Vogel, Jackie / Measday, Vivien

    Molecular biology of the cell

    2007  Volume 18, Issue 8, Page(s) 2805–2816

    Abstract: The kinetochore, a protein complex that links chromosomes to microtubules (MTs), is required to prevent spindle expansion during S phase in budding yeast, but the mechanism of how the kinetochore maintains integrity of the bipolar spindle before mitosis ... ...

    Abstract The kinetochore, a protein complex that links chromosomes to microtubules (MTs), is required to prevent spindle expansion during S phase in budding yeast, but the mechanism of how the kinetochore maintains integrity of the bipolar spindle before mitosis is not well understood. Here, we demonstrate that a mutation of Spc24, a component of the conserved Ndc80 kinetochore complex, causes lethality when cells are exposed to the DNA replication inhibitor hydroxyurea (HU) due to premature spindle expansion and segregation of incompletely replicated DNA. Overexpression of Stu1, a CLASP-related MT-associated protein or a truncated form of the XMAP215 orthologue Stu2 rescues spc24-9 HU lethality and prevents spindle expansion. Truncated Stu2 likely acts in a dominant-negative manner, because overexpression of full-length STU2 does not rescue spc24-9 HU lethality, and spindle expansion in spc24-9 HU-treated cells requires active Stu2. Stu1 and Stu2 localize to the kinetochore early in the cell cycle and Stu2 kinetochore localization depends on Spc24. We propose that mislocalization of Stu2 results in premature spindle expansion in S phase stalled spc24-9 mutants. Identifying factors that restrain spindle expansion upon inhibition of DNA replication is likely applicable to the mechanism by which spindle elongation is regulated during a normal cell cycle.
    MeSH term(s) Anaphase/drug effects ; Cell Polarity/drug effects ; Chromosomal Proteins, Non-Histone/metabolism ; DNA Replication/drug effects ; Genes, Fungal ; Hydroxyurea/pharmacology ; Kinetochores/drug effects ; Kinetochores/metabolism ; Microbial Viability/drug effects ; Microtubule-Associated Proteins/metabolism ; Mutation/genetics ; Nuclear Proteins/metabolism ; Protein Transport/drug effects ; Saccharomyces cerevisiae/cytology ; Saccharomyces cerevisiae/drug effects ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/metabolism ; Spindle Apparatus/drug effects ; Spindle Apparatus/metabolism
    Chemical Substances Chromosomal Proteins, Non-Histone ; Microtubule-Associated Proteins ; NDC80 protein, S cerevisiae ; Nuclear Proteins ; STU2 protein, S cerevisiae ; Saccharomyces cerevisiae Proteins ; Spc24 protein, S cerevisiae ; Hydroxyurea (X6Q56QN5QC)
    Language English
    Publishing date 2007-08
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1098979-1
    ISSN 1939-4586 ; 1059-1524
    ISSN (online) 1939-4586
    ISSN 1059-1524
    DOI 10.1091/mbc.E06-09-0882
    Database MEDical Literature Analysis and Retrieval System OnLINE

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