Pretreatment malnutrition and quality of life - association with prolonged length of hospital stay among patients with gynecological cancer: A cohort study

Background Length of hospital stay (LOS) is a surrogate marker for patients' well-being during hospital treatment and is associated with health care costs. Identifying pretreatment factors associated with LOS in surgical patients may enable early intervention in order to reduce postoperative LOS. Methods This cohort study enrolled 157 patients with suspected or proven gynecological cancer at a tertiary cancer centre (2004-2006). Before commencing treatment, the scored Patient Generated - Subjective Global Assessment (PG-SGA) measuring nutritional status and the Functional Assessment of Cancer Therapy-General (FACT-G) scale measuring quality of life (QOL) were completed. Clinical and demographic patient characteristics were prospectively obtained. Patients were grouped into those with prolonged LOS if their hospital stay was greater than the median LOS and those with average or below average LOS. Results Patients' mean age was 58 years (SD 14 years). Preoperatively, 81 (52%) patients presented with suspected benign disease/pelvic mass, 23 (15%) with suspected advanced ovarian cancer, 36 (23%) patients with suspected endometrial and 17 (11%) with cervical cancer, respectively. In univariate models prolonged LOS was associated with low serum albumin or hemoglobin, malnutrition (PG-SGA score and PG-SGA group B or C), low pretreatment FACT-G score, and suspected diagnosis of cancer. In multivariable models, PG-SGA group B or C, FACT-G score and suspected diagnosis of advanced ovarian cancer independently predicted LOS. Conclusions Malnutrition, low quality of life scores and being diagnosed with advanced ovarian cancer are the major determinants of prolonged LOS amongst gynecological cancer patients. Interventions addressing malnutrition and poor QOL may decrease LOS in gynecological cancer patients.

Osteopontin expression correlates with melanoma invasion

Melanoma is one of the most aggressive cancers affecting humans. Although early melanomas are curable with surgical excision, metastatic melanomas are associated with high mortality. The mechanism of melanoma development, progression, and metastasis is largely unknown. In order to uncover genes unique to melanoma cells, we used high-density DNA microarrays to examine the gene expression profiles of metastatic melanoma nodules using benign nevi as controls. Over 190 genes were significantly overexpressed in metastatic melanomas compared with normal nevi by at least 2-fold. One of the most abundantly expressed genes in metastatic melanoma nodules is osteopontin (OPN). Immunohistochemistry staining on tissue microarrays and individual skin biopsies representing different stages of melanoma progression revealed that OPN expression is first acquired at the step of melanoma tissue invasion. In addition, blocking of OPN expression by RNA interference reduced melanoma cell numbers in vitro. Our observations suggest that OPN may be acquired early in melanoma development and progression, and may enhance tumor cell growth in invasive melanoma.

Differential roles of the pRb and Arf/p53 pathways in murine naevus and melanoma genesis

We report on a systematic analysis of genotype-specific melanocyte (MC) UVR responses in transgenic mouse melanoma models along with tumour penetrance and comparative histopathology. pRb or p53 pathway mutations cooperated with NrasQ61K to transform MCs. We previously reported that MCs migrate from the follicular outer root sheath into the epidermis after neonatal UVR. Here, we found that Arf or p53 loss markedly diminished this response. Despite this, mice carrying these mutations developed melanoma with very early age of onset after neonatal UVR. Cdk4R24C did not affect the MC migration. Instead, independent of UVR exposure, interfollicular dermal MCs were more prevalent in Cdk4R24C mice. Subsequently, in adulthood, these mutants developed dermal MC proliferations reminiscent of superficial congenital naevi. Two types of melanoma were observed in this model. The location and growth pattern of the first was consistent with derivation from the naevi, while the second appeared to be of deep dermal origin. In animals carrying the Arf or p53 defects, no naevi were detected, with all tumours ostensibly skipping the benign precursor stage in progression.

Making sense of brain tumour: A qualitative investigation of personal and social processes of adjustment

This study investigated personal and social processes of adjustment at different stages of illness for individuals with brain tumour. A purposive sample of 18 participants with mixed tumour types (9 benign and 9 malignant) and 15 family caregivers was recruited from a neurosurgical practice and a brain tumour support service. In-depth semi-structured interviews focused on participants’ perceptions of their adjustment, including personal appraisals, coping and social support since their brain tumour diagnosis. Interview transcripts were analysed thematically using open, axial and selective coding techniques. The primary theme that emerged from the analysis entailed “key sense making appraisals”, which was closely related to the following secondary themes: (1) Interactions with those in the healthcare system, (2) reactions and support from the personal support network, and (3) a diversity of coping efforts. Adjustment to brain tumour involved a series of appraisals about the illness that were influenced by interactions with those in the healthcare system, reactions and support from people in their support network, and personal coping efforts. Overall, the findings indicate that adjustment to brain tumour is highly individualistic; however, some common personal and social processes are evident in how people make sense of and adapt to the illness over time. A preliminary framework of adjustment based on the present findings and its clinical relevance are discussed. In particular, it is important for health professionals to seek to understand and support individuals’ sense-making processes following diagnosis of brain tumour.

Streptococcus pneumoniae infection suppresses allergic airways disease by inducing regulatory T cells

An inverse association exists between some bacterial infections and the prevalence of asthma. We investigated whether Streptococcus pneumoniae infection protects against asthma using mouse models of ovalbumin (OVA)-induced allergic airway disease (AAD). Mice were intratracheally infected or treated with killed S. pneumoniae before, during or after OVA sensitisation and subsequent challenge. The effects of S. pneumoniae on AAD were assessed. Infection or treatment with killed S. pneumoniae suppressed hallmark features of AAD, including antigen-specific T-helper cell (Th) type 2 cytokine and antibody responses, peripheral and pulmonary eosinophil accumulation, goblet cell hyperplasia, and airway hyperresponsiveness. The effect of infection on the development of specific features of AAD depended on the timing of infection relative to allergic sensitisation and challenge. Infection induced significant increases in regulatory T-cell (Treg) numbers in lymph nodes, which correlated with the degree of suppression of AAD. Tregs reduced T-cell proliferation and Th2 cytokine release. The suppressive effects of infection were reversed by anti-CD25 treatment. Respiratory infection or treatment with S. pneumoniae attenuates allergic immune responses and suppresses AAD. These effects may be mediated by S. pneumoniae-induced Tregs. This identifies the potential for the development of therapeutic agents for asthma from S. pneumoniae.

The psychosocial factors influencing aggressive driving behaviour

Many drivers in highly motorised countries believe that aggressive driving is increasing. While the prevalence of the behaviour is difficult to reliably identify, the consequences of on-road aggression can be severe, with extreme cases resulting in property damage, injury and even death. This research program was undertaken to explore the nature of aggressive driving from within the framework of relevant psychological theory in order to enhance our understanding of the behaviour and to inform the development of relevant interventions. To guide the research a provisional ‘working’ definition of aggressive driving was proposed encapsulating the recurrent characteristics of the behaviour cited in the literature. The definition was: “aggressive driving is any on-road behaviour adopted by a driver that is intended to cause physical or psychological harm to another road user and is associated with feelings of frustration, anger or threat”. Two main theoretical perspectives informed the program of research. The first was Shinar’s (1998) frustration-aggression model, which identifies both the person-related and situational characteristics that contribute to aggressive driving, as well as proposing that aggressive behaviours can serve either an ‘instrumental’ or ‘hostile’ function. The second main perspective was Anderson and Bushman’s (2002) General Aggression Model. In contrast to Shinar’s model, the General Aggression Model reflects a broader perspective on human aggression that facilitates a more comprehensive examination of the emotional and cognitive aspects of aggressive behaviour. Study One (n = 48) examined aggressive driving behaviour from the perspective of young drivers as an at-risk group and involved conducting six focus groups, with eight participants in each. Qualitative analyses identified multiple situational and person-related factors that contribute to on-road aggression. Consistent with human aggression theory, examination of self-reported experiences of aggressive driving identified key psychological elements and processes that are experienced during on-road aggression. Participants cited several emotions experienced during an on-road incident: annoyance, frustration, anger, threat and excitement. Findings also suggest that off-road generated stress may transfer to the on-road environment, at times having severe consequences including crash involvement. Young drivers also appeared quick to experience negative attributions about the other driver, some having additional thoughts of taking action. Additionally, the results showed little difference between males and females in the severity of behavioural responses they were prepared to adopt, although females appeared more likely to displace their negative emotions. Following the self-reported on-road incident, evidence was also found of a post-event influence, with females being more likely to experience ongoing emotional effects after the event. This finding was evidenced by ruminating thoughts or distraction from tasks. However, the impact of such a post-event influence on later behaviours or interpersonal interactions appears to be minimal. Study Two involved the quantitative analysis of n = 926 surveys completed by a wide age range of drivers from across Queensland. The study aimed to explore the relationships between the theoretical components of aggressive driving that were identified in the literature review, and refined based on the findings of Study One. Regression analyses were used to examine participant emotional, cognitive and behavioural responses to two differing on-road scenarios whilst exploring the proposed theoretical framework. A number of socio-demographic, state and trait person-related variables such as age, pre-study emotions, trait aggression and problem-solving style were found to predict the likelihood of a negative emotional response such as frustration, anger, perceived threat, negative attributions and the likelihood of adopting either an instrumental or hostile behaviour in response to Scenarios One and Two. Complex relationships were found to exist between the variables, however, they were interpretable based on the literature review findings. Factor analysis revealed evidence supporting Shinar’s (1998) dichotomous description of on-road aggressive behaviours as being instrumental or hostile. The second stage of Study Two used logistic regression to examine the factors that predicted the potentially hostile aggressive drivers (n = 88) within the sample. These drivers were those who indicated a preparedness to engage in direct acts of interpersonal aggression on the road. Young, male drivers 17–24 years of age were more likely to be classified as potentially hostile aggressive drivers. Young drivers (17–24 years) also scored significantly higher than other drivers on all subscales of the Aggression Questionnaire (Buss & Perry, 1992) and on the ‘negative problem orientation’ and ‘impulsive careless style’ subscales of the Social Problem Solving Inventory – Revised (D’Zurilla, Nezu & Maydeu-Olivares, 2002). The potentially hostile aggressive drivers were also significantly more likely to engage in speeding and drink/drug driving behaviour. With regard to the emotional, cognitive and behavioural variables examined, the potentially hostile aggressive driver group also scored significantly higher than the ‘other driver’ group on most variables examined in the proposed theoretical framework. The variables contained in the framework of aggressive driving reliably distinguished potentially hostile aggressive drivers from other drivers (Nagalkerke R2 = .39). Study Three used a case study approach to conduct an in-depth examination of the psychosocial characteristics of n = 10 (9 males and 1 female) self-confessed hostile aggressive drivers. The self-confessed hostile aggressive drivers were aged 24–55 years of age. A large proportion of these drivers reported a Year 10 education or better and average–above average incomes. As a group, the drivers reported committing a number of speeding and unlicensed driving offences in the past three years and extensive histories of violations outside of this period. Considerable evidence was also found of exposure to a range of developmental risk factors for aggression that may have contributed to the driver’s on-road expression of aggression. These drivers scored significantly higher on the Aggression Questionnaire subscales and Social Problem Solving Inventory Revised subscales, ‘negative problem orientation’ and ‘impulsive/careless style’, than the general sample of drivers included in Study Two. The hostile aggressive driver also scored significantly higher on the Barrett Impulsivity Scale – 11 (Patton, Stanford & Barratt, 1995) measure of impulsivity than a male ‘inmate’, or female ‘general psychiatric’ comparison group. Using the Carlson Psychological Survey (Carlson, 1982), the self-confessed hostile aggressive drivers scored equal or higher scores than the comparison group of incarcerated individuals on the subscale measures of chemical abuse, thought disturbance, anti-social tendencies and self-depreciation. Using the Carlson Psychological Survey personality profiles, seven participants were profiled ‘markedly anti-social’, two were profiled ‘negative-explosive’ and one was profiled as ‘self-centred’. Qualitative analysis of the ten case study self-reports of on-road hostile aggression revealed a similar range of on-road situational factors to those identified in the literature review and Study One. Six of the case studies reported off-road generated stress that they believed contributed to the episodes of aggressive driving they recalled. Intense ‘anger’ or ‘rage’ were most frequently used to describe the emotions experienced in response to the perceived provocation. Less frequently ‘excitement’ and ‘fear’ were cited as relevant emotions. Notably, five of the case studies experienced difficulty articulating their emotions, suggesting emotional difficulties. Consistent with Study Two, these drivers reported negative attributions and most had thoughts of aggressive actions they would like to take. Similarly, these drivers adopted both instrumental and hostile aggressive behaviours during the self-reported incident. Nine participants showed little or no remorse for their behaviour and these drivers also appeared to exhibit low levels of personal insight. Interestingly, few incidents were brought to the attention of the authorities. Further, examination of the person-related characteristics of these drivers indicated that they may be more likely to have come from difficult or dysfunctional backgrounds and to have a history of anti-social behaviours on and off the road. The research program has several key theoretical implications. While many of the findings supported Shinar’s (1998) frustration-aggression model, two key areas of difference emerged. Firstly, aggressive driving behaviour does not always appear to be frustration driven, but can also be driven by feelings of excitation (consistent with the tenets of the General Aggression Model). Secondly, while the findings supported a distinction being made between instrumental and hostile aggressive behaviours, the characteristics of these two types of behaviours require more examination. For example, Shinar (1998) proposes that a driver will adopt an instrumental aggressive behaviour when their progress is impeded if it allows them to achieve their immediate goals (e.g. reaching their destination as quickly as possible); whereas they will engage in hostile aggressive behaviour if their path to their goal is blocked. However, the current results question this assertion, since many of the hostile aggressive drivers studied appeared prepared to engage in hostile acts irrespective of whether their goal was blocked or not. In fact, their behaviour appeared to be characterised by a preparedness to abandon their immediate goals (even if for a short period of time) in order to express their aggression. The use of the General Aggression Model enabled an examination of the three components of the ‘present internal state’ comprising emotions, cognitions and arousal and how these influence the likelihood of a person responding aggressively to an on-road situation. This provided a detailed insight into both the cognitive and emotional aspects of aggressive driving that have important implications for the design of relevant countermeasures. For example, the findings highlighted the potential value of utilising Cognitive Behavioural Therapy with aggressive drivers, particularly the more hostile offenders. Similarly, educational efforts need to be mindful of the way that person-related factors appear to influence one’s perception of another driver’s behaviour as aggressive or benign. Those drivers with a predisposition for aggression were more likely to perceive aggression or ‘wrong doing’ in an ambiguous on-road situation and respond with instrumental and/or hostile behaviour, highlighting the importance of perceptual processes in aggressive driving behaviour.

Melanoma mouse model implicates metabotropic glutamate signaling in melanocytic neoplasia

To gain insight into melanoma pathogenesis, we characterized an insertional mouse mutant, TG3, that is predisposed to develop multiple melanomas. Physical mapping identified multiple tandem insertions of the transgene into intron 3 of Grm1 (encoding metabotropic glutamate receptor 1) with concomitant deletion of 70 kb of intronic sequence. To assess whether this insertional mutagenesis event results in alteration of transcriptional regulation, we analyzed Grm1 and two flanking genes for aberrant expression in melanomas from TG3 mice. We observed aberrant expression of only Grm1. Although we did not detect its expression in normal mouse melanocytes, Grm1 was ectopically expressed in the melanomas from TG3 mice. To confirm the involvement of Grm1 in melanocytic neoplasia, we created an additional transgenic line with Grm1 expression driven by the dopachrome tautomerase promoter. Similar to the original TG3, the Tg(Grm1)EPv line was susceptible to melanoma. In contrast to human melanoma, these transgenic mice had a generalized hyperproliferation of melanocytes with limited transformation to fully malignant metastasis. We detected expression of GRM1 in a number of human melanoma biopsies and cell lines but not in benign nevi and melanocytes. This study provides compelling evidence for the importance of metabotropic glutamate signaling in melanocytic neoplasia.

p53 prevents progression of nevi to melanoma predominantly through cell cycle regulation

p53 is the central member of a critical tumor suppressor pathway in virtually all tumor types, where it is silenced mainly by missense mutations. In melanoma, p53 predominantly remains wild type, thus its role has been neglected. To study the effect of p53 on melanocyte function and melanomagenesis, we crossed the 'high-p53'Mdm4+/- mouse to the well-established TP-ras0/+ murine melanoma progression model. After treatment with the carcinogen dimethylbenzanthracene (DMBA), TP-ras0/+ mice on the Mdm4+/- background developed fewer tumors with a delay in the age of onset of melanomas compared to TP-ras0/+ mice. Furthermore, we observed a dramatic decrease in tumor growth, lack of metastasis with increased survival of TP-ras0/+: Mdm4+/- mice. Thus, p53 effectively prevented the conversion of small benign tumors to malignant and metastatic melanoma. p53 activation in cultured primary melanocyte and melanoma cell lines using Nutlin-3, a specific Mdm2 antagonist, supported these findings. Moreover, global gene expression and network analysis of Nutlin-3-treated primary human melanocytes indicated that cell cycle regulation through the p21WAF1/CIP1 signaling network may be the key anti-melanomagenic activity of p53.

A novel duplication polymorphism in the FANCA promoter and its association with breast and ovarian cancer

The FANCA gene is one of the genes in which mutations lead to Fanconi anaemia, a rare autosomal recessive disorder characterised by congenital abnormalities, bone marrow failure, and predisposition to malignancy. FANCA is also a potential breast and ovarian cancer susceptibility gene. A novel allele was identified which has a tandem duplication of a 13 base pair sequence in the promoter region. Methods: We screened germline DNA from 352 breast cancer patients, 390 ovarian cancer patients and 256 normal controls to determine if the presence of either of these two alleles was associated with an increased risk of breast or ovarian cancer. Results: The duplication allele had a frequency of 0.34 in the normal controls. There was a nonsignificant decrease in the frequency of the duplication allele in breast cancer patients. The frequency of the duplication allele was significantly decreased in ovarian cancer patients. However, when malignant and benign tumours were considered separately, the decrease was only significant in benign tumours. Conclusion: The allele with the tandem duplication does not appear to modify breast cancer risk but may act as a low penetrance protective allele for ovarian cancer.

Performance evaluation of eight contemporary passive solar homes in subtropical Australia

Subtropical south-east Queensland’s expanding population is expected to lead to a demand for an additional 754,000 dwellings by 2031. A legacy of poor housing design, minimal building regulations, an absence of building performance evaluation and various social and market factors has lead to a high and growing penetration of, and reliance on, air conditioners to provide comfort in this relatively benign climate. This reliance impacts on policy goals to adapt to and mitigate against global warming, electricity infrastructure investment and household resilience. Based on the concept of bioclimatic design, this field study scrutinizes eight non-air conditioned homes to develop a deeper understanding of the role of contemporary passive solar architecture in the delivery of thermally comfortable and resilient homes in the subtropics. These homes were found to provide inhabitants with an acceptable level of thermal comfort (18-28oC) for 77 – 97% of the year. Family expectations and experiences of comfort, and the various design strategies utilized were compared against the measured performance outcomes. This comparison revealed issues that limited quantification and implementation of design intent and highlighted factors that constrained system optimisation.

Removal of toxic metals in a multi metal system using sorbents for potential application to urban stormwater treatment

In the context of increasing demand for potable water and the depletion of water resources, stormwater is a logical alternative. However, stormwater contains pollutants, among which metals are of particular interest due to their toxicity and persistence in the environment. Hence, it is imperative to remove toxic metals in stormwater to the levels prescribed by drinking water guidelines for potable use. Consequently, various techniques have been proposed, among which sorption using low cost sorbents is economically viable and environmentally benign in comparison to other techniques. However, sorbents show affinity towards certain toxic metals, which results in poor removal of other toxic metals. It was hypothesised in this study that a mixture of sorbents that have different metal affinity patterns can be used for the efficient removal of a range of toxic metals commonly found in stormwater. The performance of six sorbents in the sorption of Al, Cr, Cu, Pb, Ni, Zn and Cd, which are the toxic metals commonly found in urban stormwater, was investigated to select suitable sorbents for creating the mixtures. For this purpose, a multi criteria analytical protocol was developed using the decision making methods: PROMETHEE (Preference Ranking Organisation METHod for Enrichment Evaluations) and GAIA (Graphical Analysis for Interactive Assistance). Zeolite and seaweed were selected for the creation of trial mixtures based on their metal affinity pattern and the performance on predetermined selection criteria. The metal sorption mechanisms employed by seaweed and zeolite were defined using kinetics, isotherm and thermodynamics parameters, which were determined using the batch sorption experiments. Additionally, the kinetics rate-limiting steps were identified using an innovative approach using GAIA and Spearman correlation techniques developed as part of the study, to overcome the limitation in conventional graphical methods in predicting the degree of contribution of each kinetics step in limiting the overall metal removal rate. The sorption kinetics of zeolite was found to be primarily limited by intraparticle diffusion followed by the sorption reaction steps, which were governed mainly by the hydrated ionic diameter of metals. The isotherm study indicated that the metal sorption mechanism of zeolite was primarily of a physical nature. The thermodynamics study confirmed that the energetically favourable nature of sorption increased in the order of Zn < Cu < Cd < Ni < Pb < Cr < Al, which is in agreement with metal sorption affinity of zeolite. Hence, sorption thermodynamics has an influence on the metal sorption affinity of zeolite. On the other hand, the primary kinetics rate-limiting step of seaweed was the sorption reaction process followed by intraparticle diffusion. The boundary layer diffusion was also found to limit the metal sorption kinetics at low concentration. According to the sorption isotherm study, Cd, Pb, Cr and Al were sorbed by seaweed via ion exchange, whilst sorption of Ni occurred via physisorption. Furthermore, ionic bonding is responsible for the sorption of Zn. The thermodynamics study confirmed that sorption by seaweed was energetically favourable in the order of Zn < Cu < Cd < Cr . Al < Pb < Ni. However, this did not agree with the affinity series derived for seaweed suggesting a limited influence of sorption thermodynamics on metal affinity for seaweed. The investigation of zeolite-seaweed mixtures indicated that mixing sorbents have an effect on the kinetics rates and the sorption affinity. Additionally, the theoretical relationships were derived to predict the boundary layer diffusion rate, intraparticle diffusion rate, the sorption reaction rate and the enthalpy of mixtures based on that of individual sorbents. In general, low coefficient of determination (R2) for the relationships between theoretical and experimental data indicated that the relationships were not statistically significant. This was attributed to the heterogeneity of the properties of sorbents. Nevertheless, in relative terms, the intraparticle diffusion rate, sorption reaction rate and enthalpy of sorption had higher R2 values than the boundary layer diffusion rate suggesting that there was some relationship between the former set of parameters of mixtures and that of sorbents. The mixture, which contained 80% of zeolite and 20% of seaweed, showed similar affinity for the sorption of Cu, Ni, Cd, Cr and Al, which was attributed to approximately similar sorption enthalpy of the metal ions. Therefore, it was concluded that the seaweed-zeolite mixture can be used to obtain the same affinity for various metals present in a multi metal system provided the metal ions have similar enthalpy during sorption by the mixture.

Experimenting with affirmative action : the Coate and Loury Model

Coate and Loury (1993) suggest the impact of affirmative action on a negative stereotype is theoretically ambiguous leading to either: a benign equilibrium in which affirmative action eradicates the negative stereotype and leads to equal proportional representation of the two groups; or alternatively a patronising equilibrium in which the stereotype persists. The current paper examines this theoretical ambiguity within the context of a laboratory experiment. Although benign and patronising equilibria are equally plausible in theory, the laboratory experiments easily replicate most features of the benign equilibrium, but diverge from the theoretically predicted patronising equilibrium.

Human Kallikrein 4 signal peptide induces cytotoxic T cell responses in healthy donors and prostate cancer patients.

Immunotherapy is a promising new treatment for patients with advanced prostate and ovarian cancer, but its application is limited by the lack of suitable target antigens that are recognized by CD8+ cytotoxic T lymphocytes (CTL). Human kallikrein 4 (KLK4) is a member of the kallikrein family of serine proteases that is significantly overexpressed in malignant versus healthy prostate and ovarian tissue, making it an attractive target for immunotherapy. We identified a naturally processed, HLA-A*0201-restricted peptide epitope within the signal sequence region of KLK4 that induced CTL responses in vitro in most healthy donors and prostate cancer patients tested. These CTL lysed HLA-A*0201+ KLK4 + cell lines and KLK4 mRNA-transfected monocyte-derived dendritic cells. CTL specific for the HLA-A*0201-restricted KLK4 peptide were more readily expanded to a higher frequency in vitro compared to the known HLA-A*0201-restricted epitopes from prostate cancer antigens; prostate-specific antigen (PSA), prostate-specific membrane antigen (PSMA) and prostatic acid phosphatase (PAP). These data demonstrate that KLK4 is an immunogenic molecule capable of inducing CTL responses and identify it as an attractive target for prostate and ovarian cancer immunotherapy.