National survey of occupational advice for lower limb arthroplasty patients.

BACKGROUND: Little is known what advice or support patients are given about return to work (RTW) after hip or knee replacement surgery. AIMS: This study aims to understand the delivery, timing and content of 'RTW' advice currently delivered by surgical teams offering hip and knee replacements across the UK. METHODS: National online survey exploring five specific areas relating to 'RTW' advice: (i) timings of interactions between hospital orthopaedic teams and patients prior to surgery, (ii) routine delivery of 'RTW' advice, (iii) methods used to deliver 'RTW' advice, (iv) confidence delivering advice and (v) need for an occupational 'RTW' advice intervention. RESULTS: A total of 152 participants including surgeons, physiotherapists, occupational therapists and nurses from 59 different public and private health providers responded. Only 20% (n = 30) of respondents reported that working patients were identified as a specific subgroup in need of additional support. Overall, 62% (n = 92) stated that they did not routinely offer 'RTW' advice. When given, 'RTW' advice was almost always verbal, generic advice using blanket timescales and based on the respondent's anecdotal experience rather than the patients individualized needs. Overall, 116 (78%) felt an occupational advice intervention was needed. CONCLUSIONS: This national survey demonstrated wide variation in the timing, content and delivery of information and advice for patients in work and intending to RTW after hip and knee replacement surgery. Current RTW advice provided to hip and knee replacement patients is inadequate.

Implementation and adoption of advanced care planning in the elderly trauma patient.

Background: Geriatric trauma has high morbidity and mortality, often requiring extensive hospital stays and interventions. The number of geriatric trauma patients is also increasing significantly and accounts for a large proportion of trauma care. Specific geriatric trauma protocols exist to improve care for this complex patient population, who often have various comorbidities, pre-existing medications, and extensive injury within a trauma perspective. These guidelines for geriatric trauma care often suggest early advanced care planning (ACP) discussions and documentation to guide patient and family-centered care. Methods: A provincial ACP program was implemented in April of 2012, which has since been used by our level 1 trauma center. We applied a before and after study design to assess the documentation of goals of care in elderly trauma patients following implementation of the standardized provincial ACP tool on April 1, 2012. Results: Documentation of ACP in elderly major trauma patients following the implementation of this tool increased significantly from 16 to 35%. Additionally, secondary outcomes demonstrated that many more patients received goals of care documentation within 24 h of admission, and 93% of patients had goals of care documented prior to intensive care unit (ICU) admission. The number of trauma patients that were admitted to the ICU also decreased from 17 to 5%. Conclusion: Early advanced care planning is crucial for geriatric trauma patients to improve patient and family-centered care. Here, we have outlined our approach with modest improvements in goals of care documentation for our geriatric population at a level 1 trauma center. We also outline the benefits and drawbacks of this approach and identify the areas for improvement to support improved patient-centered care for the injured geriatric patient. Here, we have provided a framework for others to implement and further develop.

Antiglycine receptor antibody related disease: a case series and literature review.

BACKGROUND AND PURPOSE: Antibodies to glycine receptors (GlyR-Abs) were first defined in progressive encephalopathy with rigidity and myoclonus (PERM) but were subsequently identified in other clinical presentations. Our aim was to assess the clinical associations of all patients identified with GlyR-Abs in Queensland, Australia, between April 2014 and May 2017 and to compare these to cases reported in the literature. METHODS: A literature review identified the clinical features of all published GlyR-Ab-positive cases through online databases. A case series was undertaken via collection of clinical information from all patients diagnosed or known to immunology, pathology or neurological services in Queensland during the study period of 3 years. RESULTS: In all, 187 GlyR-Ab-positive cases were identified in the literature. The majority (47.6%) had PERM, 22.4% had epilepsy, but the remaining 30% included mixed phenotypes consisting of cerebellar ataxia, movement disorders, demyelination and encephalitis/cognitive dysfunction. By contrast, in our series of 14 cases, eight had clinical presentations consistent with seizures and epilepsy and only three cases had classical features of PERM. There was one case each of global fatiguable weakness with sustained clonus, laryngeal dystonia and movement disorder with hemiballismus and tics. The rate of response to immune therapy was similar in all groups. CONCLUSION: Antibodies to glycine receptors are linked to a spectrum of neurological disease. The results of the literature review and our case series suggest a greater relationship between GlyR-Abs and epilepsy than previously reported.

Dose optimisation of intravenous tranexamic acid for elective hip and knee arthroplasty: The effectiveness of a single pre-operative dose.

OBJECTIVES: We have increased the dose of tranexamic acid (TXA) in our enhanced total joint recovery protocol at our institution from 15 mg/kg to 30 mg/kg (maximum 2.5 g) as a single, intravenous (IV) dose. We report the clinical effect of this dosage change. METHODS: We retrospectively compared two cohorts of consecutive patients undergoing total hip arthroplasty (THA) or total knee arthroplasty (TKA) surgery in our unit between 2008 and 2013. One group received IV TXA 15 mg/kg, maximum 1.2 g, and the other 30 mg/kg, maximum 2.5 g as a single pre-operative dose. The primary outcome for this study was the requirement for blood transfusion within 30 days of surgery. Secondary measures included length of hospital stay, critical care requirements, re-admission rate, medical complications and mortality rates. RESULTS: A total of 1914 THA and 2537 TKA procedures were evaluated. In THA, the higher dose of TXA was associated with a significant reduction in transfusion (p = 0.02, risk ratio (RR) 0.74, 95% confidence interval (CI) 0.58 to 0.96) and rate of re-admission (p < 0.001, RR 0.50, 95% CI 0.35 to 0.71). There were reductions in the requirement for critical care (p = 0.06, RR 0.55, 95% CI 0.31 to 1.00), and in the length of stay from 4.7 to 4.3 days (p = 0.02). In TKA, transfusion requirements (p = 0.049, RR 0.64, 95% CI 0.41 to 0.99), re-admission rate (p = 0.001, RR 0.56, 95% CI 0.39 to 0.80) and critical care requirements (p < 0.003, RR 0.34, 95% CI 0.16 to 0.72) were reduced with the higher dose. Mean length of stay reduced from 4.6 days to 3.6 days (p < 0.01). There was no difference in the incidence of deep vein thrombosis, pulmonary embolism, gastrointestinal bleed, myocardial infarction, stroke or death in THA and TKA between cohorts. CONCLUSION: We suggest that a single pre-operative dose of TXA, 30 mg/kg, maximum 2.5g, results in a lower transfusion requirement compared with a lower dose in patients undergoing elective primary hip and knee arthroplasty. However, these findings should be interpreted in the context of the retrospective non-randomised study design.Cite this article: R. J. M. Morrison, B. Tsang, W. Fishley, I. Harper, J. C. Joseph, M. R. Reed. Dose optimisation of intravenous tranexamic acid for elective hip and knee arthroplasty: The effectiveness of a single pre-operative dose. Bone Joint Res 2017;6:499-505. DOI: 10.1302/2046-3758.68.BJR-2017-0005.R1.

DLX1 acts as a crucial target of FOXM1 to promote ovarian cancer aggressiveness by enhancing TGF-ß/SMAD4 signaling.

Recent evidence from a comprehensive genome analysis and functional studies have revealed that FOXM1 is a crucial metastatic regulator that drives cancer progression. However, the regulatory mechanism by which FOXM1 exerts its metastatic functions in cancer cells remains obscure. Here, we report that DLX1 acts as a FOXM1 downstream target, exerting pro-metastatic function in ovarian cancers. Both FOXM1 isoforms (FOXM1B or FOXM1C) could transcriptionally upregulate DLX1 through two conserved binding sites, located at +61 to +69bp downstream (TFBS1) and -675 to -667bp upstream (TFBS2) of the DLX1 promoter, respectively. This regulation was further accentuated by the significant correlation between the nuclear expression of FOXM1 and DLX1 in high-grade serous ovarian cancers. Functionally, the ectopic expression of DLX1 promoted ovarian cancer cell growth, cell migration/invasion and intraperitoneal dissemination of ovarian cancer in mice, whereas small interfering RNA-mediated DLX1 knockdown in FOXM1-overexpressing ovarian cancer cells abrogated these oncogenic capacities. In contrast, depletion of FOXM1 by shRNAi only partially attenuated tumor growth and exerted almost no effect on cell migration/invasion and the intraperitoneal dissemination of DLX1-overexpressing ovarian cancer cells. Furthermore, the mechanistic studies showed that DLX1 positively modulates transforming growth factor-ß (TGF-ß) signaling by upregulating PAI-1 and JUNB through direct interaction with SMAD4 in the nucleus upon TGF-ß1 induction. Taken together, these data strongly suggest that DLX1 has a pivotal role in FOXM1 signaling to promote cancer aggressiveness through intensifying TGF-ß/SMAD4 signaling in high-grade serous ovarian cancer cells.

An integrative review of standardized clinical evaluation tool utilization in anticholinergic drug trials for neurogenic lower urinary tract dysfunction.

STUDY DESIGN: To review prospective and randomized trials studying anticholinergic therapy for neurogenic bladder in SCI to identify whether trials included standardized clinical evaluation tools and reporting measures now recognized to enhance clinical trial data. METHODS: A systematic search via EMBASE, MEDLINE, CENTRAL, CINAHL (Cumulative Index to Nursing and Allied Health Literature), HTA (Health Technology Assessment), CMR (Comprehensive Microbial Resource), HAPI (Health and Psychosocial Instruments) and PsycINFO using the key term spinal cord injury crossed with oxybutynin, tolterodine, darifenacin, solifenacin, fesoterodine, trospium chloride, propiverine, propantheline and anticholinergic(s) for 1946-2015 inclusive. We then collated whether standardized clinical tools, measures and descriptors were used within each study identified: American Spine Injury Association (ASIA) impairment scale; symptom scores validated in SCI; technical methodology for urodynamics/video urodynamics; urinary diaries; and standardized urologic terminology. RESULTS: A total of 1225 entries with 610 unique articles were identified, 14 randomized and 16 prospective studies. In 6/30 the population comprised SCI patients with neurogenic bladder alone; the remainder included mixed neurogenic etiologies. Classification using the ASIA impairment scale was used in <10% of studies; none used symptom scores validated in SCI; <50% reported urodynamic test methodology fully, incorporated urinary diaries or used International Continence Society Standardization Subcommittee urinary tract terminology. CONCLUSION: Integrative review of trials from 1946 to 2015 identified infrequent use of standardized clinical evaluation tools and reporting measures. Data from future trials evaluating therapies for neurogenic bladder would likely be more applicable to specific SCI patients if current standardized classification and descriptors now available were used consistently: for example, the ASIA scale, symptom scores validated in SCI, standardized urodynamic methodology, urinary diaries and urinary tract terminology. Studies recruiting SCI patients exclusively would also provide additional benefit.

A systematic review and comparison of questionnaires in the management of spinal cord injury, multiple sclerosis and the neurogenic bladder.

AIMS: Validated questionnaires are increasingly the preferred method used to obtain historical information. Specialized questionnaires exist validated for patients with neurogenic disease including neurogenic bladder. Those currently available are systematically reviewed and their potential for clinical and research use are described. METHODS: A systematic search via Medline and PubMed using the key terms questionnaire(s) crossed with Multiple Sclerosis (MS) and Spinal Cord Injury (SCI) for the years 1946 to January 22, 2014 inclusive. Additional articles were selected from review of references in the publications identified. Only peer reviewed articles published in English were included. RESULTS: 18 questionnaires exist validated for patients with neurogenic bladder; 14 related to MS, 3 for SCI, and 1 for neurogenic bladder in general; with 4 cross-validated in both MS and SCI. All 18 are validated for both male and female patients; 59% are available only in English. The domains of psychological impact and physical function are represented in 71% and 76% of questionnaires, respectively. None for the female population included elements to measure symptoms of prolapse. CONCLUSION: The last decade has seen an expansion of validated questionnaires to document bladder symptoms in neurogenic disease. Disease specific instruments are available for incorporation into the clinical setting for MS and SCI patients with neurogenic bladder. The availability of caregiver and interview options enhances suitability in clinical practice as they can be adapted to various extents of disability. Future developments should include expanded language validation to the top 10 global languages reported by the World Health Organization.

Case of syndrome of headache with neurological deficits and cerebrospinal fluid lymphocytosis (HaNDL) with focal slowing on electroencephalogram.

We describe a case of headache and neurological deficits with cerebrospinal fluid (CSF) lymphocytosis in a patient presenting with a 3-week history of recurrent severe headaches associated with negative sensory symptoms and dysphasia. The patient had no cardiovascular risk factors and no family history of migraines. Neurological examination was unremarkable. Cerebral magnetic resonance imaging was unremarkable. CSF analysis revealed lymphocytosis (leucocytes 84 × 10(6)/L, 100% lymphocytes). Extensive laboratory investigations of CSF and serum did not reveal an infectious, autoimmune or metabolic cause. Visual evoked potentials were normal. Awake electroencephalogram revealed intermittent 3-5 Hz generalised slowing and frontal intermittent rhythmic delta activity, without epileptiform discharges. Repeat CSF analysis showed marked reduction of the total leucocyte count and remained negative for infectious aetiology. Propranolol was commenced, and no recurrence of headache or neurological symptoms was observed at follow-up. An extensive literature review on the topic is discussed.

Recurrent Transmission of a 17q12 Microdeletion and a Variable Clinical Spectrum.

The relatively rare proximal microdeletion of 17q12 (including deletion of the HNF1B gene) is associated with the renal cysts and diabetes syndrome. Recent reports have suggested that there may also be an association between this microdeletion and learning difficulties/autism. This case report describes one of only a few reported families segregating the 17q12 microdeletion, but which highlights the nonpenetrance and variable expressivity of multiple features of this condition.

The oncogenic phosphatase PPM1D confers cisplatin resistance in ovarian carcinoma cells by attenuating checkpoint kinase 1 and p53 activation.

Cisplatin (CDDP: cis-diamminedichloroplatinum) resistance is a major hurdle in the treatment of human ovarian cancer (OVCA). A better understanding of the mechanisms of CDDP resistance can greatly improve therapeutic outcome for patients. A determinant of CDDP sensitivity in OVCA, p53, is activated by checkpoint kinase 1 (Chk1) in response to DNA damage. Although the oncogenic phosphatase protein phosphatase magnesium-dependent 1 (PPM1D) can deactivate both p53 and Chk1 through site-specific dephosphorylation, whether PPM1D has a role in CDDP resistance is unknown. Here, using pair-matched wild-type p53 CDDP-sensitive (OV2008) and -resistant (C13*) cells, and p53-compromised CDDP-resistant cells (A2780cp, OCC-1, OVCAR-3 and SKOV3), we have demonstrated (i) the existence of site-specific differences in phospho-Ser-Chk1 content between sensitive and resistant cells in response to CDDP; (ii) PPM1D, but not phosphoinositide-3-kinase-related kinase Ataxia Telangiectasia and Rad3 related protein (ATR), is important in the regulation of CDDP-induced Chk1 activation and OVCA cell chemosensitivity; (iii) PPM1D downregulation sensitizes resistant cells to CDDP primarily by activating Chk1 and p53. Our findings establish for the first time that PPM1D confers CDDP resistance in OVCA cells through attenuating CDDP-induced, Chk1-mediated, p53-dependent apoptosis. These findings extend the current knowledge on the molecular and cellular basis of cisplatin resistance and offer the rationale for PPMID as a potential target for treatment of chemoresistant OVCA.

Characterization and role of NUMB in the human extravillous trophopblast.

NUMB is a multifunctional protein involved in asymmetric cell differentiation, proliferation and maintenance. Four mammalian NUMB isoforms have been identified, which utilize the phosphotyrosine binding (PTB) domain and the proline rich region (PRR) domain to regulate cell growth and differentiation in the developing nervous system. The observation that a decrease in spongiotrophoblast number and thickness of placentae of null (Numb(-/-)) mouse embryos, which died at E10.5, suggests NUMB may play a role in placental development. In this study, we demonstrated for the first time, that NUMB isoforms 1, 2, 3, and 4 are present in the human placenta and the human extravillous trophoblast (EVT) cell line HTR8/SVneo. We report three novel isoforms, NUMB 7, 8, and 9, identified by cloning of RT-PCR products and sequencing. Corresponding sequences of novel isoforms were submitted to genebank (accession numbers for each new isoform: NUMB 7- EU265736, NUMB 8- EU265737 and NUMB 9-EU265738). Western blot analysis confirmed the presence of all NUMB isofoms in human placental samples in all trimesters and in EVT cells. NUMB immunosignals were extensively localized in human extravillous trophoblasts and decidual cells at the maternal-fetal interface. NUMB 8 appeared to be the predominant isoform in placental villi. Furthermore, cell migration studies revealed NUMB isoform 1 to be involved in EVT cell migration and NUMB isoforms 2 and 4 to induce EVT apoptosis.

P73 regulates cisplatin-induced apoptosis in ovarian cancer cells via a calcium/calpain-dependent mechanism.

P73 is important in drug-induced apoptosis in some cancer cells, yet its role in the regulation of chemosensitivity in ovarian cancer (OVCA) is poorly understood. Furthermore, if and how the deregulation of p73-mediated apoptosis confers resistance to cisplatin (CDDP) treatment is unclear. Here we demonstrate that TAp73α over-expression enhanced CDDP-induced PARP cleavage and apoptosis in both chemosensitive (OV2008 and A2780s) and their resistant counterparts (C13* and A2780cp) and another chemoresistant OVCA cells (Hey); in contrast, the effect of ΔNp73α over-expression was variable. P73α downregulation attenuated CDDP-induced PUMA and NOXA upregulation and apoptosis in OV2008 cells. CDDP decreased p73α steady-state protein levels in OV2008, but not in C13*, although the mRNA expression was identical. CDDP-induced p73α downregulation was mediated by a calpain-dependent pathway. CDDP induced calpain activation and enhanced its cytoplasmic interaction and co-localization with p73α in OV2008, but not C13* cells. CDDP increased the intracellular calcium concentration ([Ca(2+)](i)) in OV2008 but not C13* whereas cyclopiazonic acid (CPA), a Ca(2+)-ATPase inhibitor, caused this response and calpain activation, p73α processing and apoptosis in both cell types. CDDP-induced [Ca(2+)](i) increase in OV2008 cells was not effected by the elimination of extracellular Ca(2+), but this was attenuated by the depletion of internal Ca(2+) store, indicating that mobilization of intracellular Ca(2+]) stores was potentially involved. These findings demonstrate that p73α and its regulation by the Ca(2+)-mediated calpain pathway are involved in CDDP-induced apoptosis in OVCA cells and that dysregulation of Ca(2+)/calpain/p73 signaling may in part be the pathophysiology of CDDP resistance. Understanding the cellular and molecular mechanisms of chemoresistance will direct the development of effective strategies for the treatment of chemoresistant OVCA.

Cochrane reviews on the benefits/risks of fluoride toothpastes.

This concise review presents two Cochrane Reviews undertaken to determine: (1) the relative effectiveness of fluoride toothpastes of different concentrations in preventing dental caries in children and adolescents; and (2) the relationship between the use of topical fluorides in young children and their risk of developing dental fluorosis. To determine the relative effectiveness of fluoride toothpastes of different concentrations, we undertook a network meta-analysis utilizing both direct and indirect comparisons from randomized controlled trials (RCTs). The review examining fluorosis included evidence from experimental and observational studies. The findings of the reviews confirm the benefits of using fluoride toothpaste, when compared with placebo, in preventing caries in children and adolescents, but only significantly for fluoride concentrations of 1000 ppm and above. The relative caries-preventive effects of fluoride toothpastes of different concentrations increase with higher fluoride concentration. However, there is weak, unreliable evidence that starting the use of fluoride toothpaste in children under 12 months of age may be associated with an increased risk of fluorosis. The decision of what fluoride levels to use for children under 6 years should be balanced between the risk of developing dental caries and that of mild fluorosis.

Reversible posterior leukoencephalopathy syndrome: diagnosis and management in the setting of lung transplantation.

Reversible posterior leukoencephalopathy syndrome (RPLS) is a potentially devastating early complication of calcineurin inhibitor (CNI) therapy in solid organ transplantation. Management centres on cessation of CNI therapy; however, this strategy is complicated in lung transplantation because of the threat of allograft rejection, or, if CNI is replaced with mammalian target of rapamycin-based immunosuppression, poor wound healing and bronchial dehiscence. We describe four cases of RPLS after lung transplantation, emphasizing the diagnostic and management approach required to maintain a healthy allograft and ensure that RPLS is, as the name suggests, reversible.

Akt promotes chemoresistance in human ovarian cancer cells by modulating cisplatin-induced, p53-dependent ubiquitination of FLICE-like inhibitory protein.

Although Akt is a determinant of cisplatin (cis-diaminedichloroplatinum (CDDP)) resistance in ovarian cancer cells, which is related in part to its inhibitory action on p53 activation, precisely how Akt confers CDDP resistance is unclear. In this study, we show that CDDP induced p53-dependent Fas-associated death domain-like interleukin-1beta-converting enzyme (FLICE)-like inhibitory protein (FLIP) degradation in chemosensitive ovarian cancer cells but not their resistant counterparts. CDDP induced FLIP-p53-Itch interaction, colocalization and FLIP ubiquitination in chemosensitive but not chemoresistant ovarian cancer cells. Moreover, although activated Akt inhibited CDDP-induced FLIP degradation and apoptosis in sensitive cells, these responses were facilitated by dominant-negative Akt expression in chemoresistant cells. Inhibition of Akt function also facilitated p53-FLIP interaction and FLIP ubiquitination, which were attenuated by p53 silencing. These results suggest that Akt confers resistance, in part, by modulating CDDP-induced, p53-dependent FLIP ubiquitination. Understanding the precise etiology of chemoresistance may improve treatment for ovarian cancer.

Low molecular mass polypeptide-2 in human trophoblast: over-expression in hydatidiform moles and possible role in trophoblast cell invasion.

Embryo implantation involves invasion of placental extravillous trophoblast cell (EVTs) into the uterus. Hyperactive EVT invasion occurs in hydatidiform moles and choriocarcinomas. We have previously demonstrated that the 20S proteasome is involved in mouse embryo implantation and its action is mediated via regulating the expression and activities of matrix metalloproteinase (MMP)-2 and MMP-9 in the EVTs. Our objective was to investigate whether low molecular mass polypeptide-2 (LMP2), a beta subunit of the 20S proteasome, is involved in the regulation of human trophoblast invasion. Normal human placentas or placentas from hydatidiform mole patients were collected and the expression of LMP2 in different cell types including trophoblastic column (TC), cytotrophoblast cells (CTB) and syncytiotrophoblast (STB) under different pathological states were studied by immunohistochemical analysis. Furthermore, the effect of LMP2 or proteasome on cell invasion was measured by using RNAi and inhibitors in a Matrigel invasion assay system in HTR-8/SVneo cells, a human invasive extravillous trophoblast cell line. Changes in the invasion-related molecules including MMP-2 and MMP-9 were also examined by using real time PCR and gelatin zymography. We demonstrated that the expression of LMP2 in TC of partial hydatidiform mole and complete hydatidiform mole, is higher than that in TC of normal human placentas. Besides, LMP2 knockdown significantly attenuated IL-1beta-induced cell invasion in vitro, a response readily induced by proteasome inhibitors. In summary, over-expression of the 20S proteasome beta-subunit LMP2 in trophoblast cells of hydatidiform moles may contribute to its highly invasive phenotype.

Cisplatin alters nitric oxide synthase levels in human ovarian cancer cells: involvement in p53 regulation and cisplatin resistance.

The present study determines if (1) basal protein levels of nitric oxide (NO) synthases (eNOS, iNOS, and nNOS) are different in cisplatin-sensitive (OV2008) and counterpart cisplatin-resistant (C13(*)) human ovarian cancer cells, (2) cisplatin alters NOS levels, (3) NO donor causes apoptosis and p53 upregulation, (4) NO donor sensitizes C13(*) cells to cisplatin via p53 upregulation (determined by p53 siRNA gene-knockdown), and (5) inhibition of endogenous NOS alters cisplatin-induced apoptosis. Basal iNOS levels were higher in OV2008 cells than in C13(*) cells. Cisplatin upregulated iNOS, but dramatically reduced eNOS and nNOS, in OV2008 cells only. Failure of cisplatin to upregulate iNOS and downregulate eNOS/nNOS in cisplatin-resistant C13(*) cells may be an aetiological factor in the development of resistance. The NO donor S-nitroso-N-acetylpenicillamine (SNAP) increased p53 protein levels and induced apoptosis in both cell types, and enhanced cisplatin-induced apoptosis in C13(*) cells in a p53-dependent manner (i.e., enhancement blocked by p53 siRNA). Specific iNOS inhibitor 1400W partially blocked cisplatin-induced apoptosis in OV2008 cells. In cisplatin-resistant C13(*) cells, blocking all NOSs with N(G)-amino-L-arginine dramatically changed these cells from cisplatin-resistant to cisplatin-sensitive, greatly potentiating cisplatin-induced apoptosis. The data suggest important roles for the three NOSs in regulating chemoresistance to cisplatin in ovarian cancer cells.

Regulation of apoptosis-inducing factor-mediated, cisplatin-induced apoptosis by Akt.

Cisplatin is a first-line chemotherapeutic for ovarian cancer, although chemoresistance limits treatment success. Apoptosis, an important determinant of cisplatin sensitivity, occurs via caspase-dependent and -independent mechanisms. Activation of the protein kinase Akt, commonly observed in ovarian tumours, confers resistance to ovarian cancer cells via inhibition of caspase-dependent apoptosis. However, the effect of Akt on cisplatin-induced, caspase-independent apoptosis remains unclear. We show that in chemosensitive ovarian cancer cells, cisplatin induces the mitochondrial release and nuclear translocation of apoptosis-inducing factor (AIF), a mediator of caspase-independent apoptosis, and AIF-dependent apoptosis. Cisplatin failed to induce these effects in the chemoresistant variant cells. Overexpression of AIF sensitised resistant cells to cisplatin-induced apoptosis. Finally, activation of Akt attenuated the cisplatin-induced mitochondrial release and nuclear accumulation of AIF and apoptosis in chemosensitive cells, whereas inhibition of Akt activity facilitated these effects and sensitised chemoresistant cells to AIF-dependent, cisplatin-induced apoptosis. These results suggest that cisplatin-induced apoptosis proceeds, in part, via a caspase-independent mechanism involving AIF, and that Akt activation confers resistance to cisplatin-induced apoptosis by blocking this pathway. These results provide insights into the molecular mechanism of chemoresistance, and suggest that inhibition of Akt activity may represent a novel therapeutic approach to the treatment of cisplatin-resistant ovarian cancer.