Women's cardiovascular health - the cardio-oncologic jigsaw.

Improvements in cancer care have led to an exponential increase in cancer survival. This is particularly the case for breast cancer, where 5-year survival in Australia exceeds 90%. Cardiovascular disease (CVD) has emerged as one of the competing causes of morbidity and mortality among cancer survivors, both as a complication of cancer therapies and because the risk factors for cancer are shared with those for CVD. In this review we cover the key aspects of cardiovascular care for women throughout their cancer journey: the need for baseline cardiovascular risk assessment and management, a crucial component of the cardiovascular care; the importance of long-term surveillance for ongoing maintenance of cardiovascular health; and strong evidence for the beneficial effects of physical exercise to improve both cancer and cardiovascular outcomes. There is general disparity in cardiovascular outcomes for women, which is further exacerbated when both CVD and cancer co-exist. Collaboration between oncology and cardiac services, with an emergence of the whole field of cardio-oncology, allows for expedited investigation and treatment for these patients. This collaboration as well as a holistic approach to patient care and key role of patients' general practitioners are essential to ensure long-term health of people living with, during and beyond cancer.

Prevalence and genotype distribution of JC polyomavirus in urine from patients with hematological malignancies in Vietnam.

JC virus (JCV) causes progressive multifocal leukoencephalopathy in immunocompromised patients. The prevalence and genotype patterns of JCV vary between different geographical regions. This study was done to investigate the prevalence and genotype distribution of JCV in patients with hematological malignancies in Vietnam. A total of 48 urine samples were collected from patients with hematological malignancies. DNA was extracted and detection of JCV was by nested-polymerase chain reaction. Sequence analysis was obtained and a phylogenetic tree was constructed for genotyping of JCV. Twenty-seven (56.25%) urine samples tested positive for JCV. JCV genotype 7 was only observed in this study. Subtype analysis showed that JCV subtype 7A was the most commonly prevalent, followed by 7B1 and 7C1. Other subtypes were not detected in this population. There were no significant differences associated with age, gender, and biochemical parameters between patients with JCV and without JCV excretion in urine. The present study showed a high prevalence of JCV in the urine of patients with hematologic malignancies. The most common genotype found in this population was JCV subtype 7A.

Cardiotoxicity of Radiation Therapy: Mechanisms, Management, and Mitigation.

OPINION STATEMENT: Radiation therapy is a key component of modern-day cancer therapy and can reduce the rates of recurrence and death from cancer. However, it can increase risk of cardiovascular (CV) events, and our understanding of the timeline associated with that risk is shorter than previously thought. Risk mitigation strategies, such as different positioning techniques, and breath hold acquisitions as well as baseline cardiovascular risk stratification that can be undertaken at the time of radiotherapy planning should be implemented, particularly for patients receiving chest radiation therapy. Primary and secondary prevention of cardiovascular disease (CVD), as appropriate, should be used before, during, and after radiation treatment in order to minimize the risks. Opportunistic screening for subclinical coronary disease provides an attractive possibility for primary/secondary CVD prevention and thus mitigation of long-term CV risk. More data on long-term clinical usefulness of this strategy and development of appropriate management pathways would further strengthen the evidence for the implementation of such screening. Clear guidelines in initial cardiovascular screening and cardiac aftercare following radiotherapy need to be formulated in order to integrate these measures into everyday clinical practice and policy and subsequently improve post-treatment morbidity and mortality for these patients.

BCL11A enhancer haplotypes and fetal hemoglobin in sickle cell anemia.

BACKGROUND: Fetal hemoglobin (HbF) levels in sickle cell anemia patients vary. We genotyped polymorphisms in the erythroid-specific enhancer of BCL11A to see if they might account for the very high HbF associated with the Arab-Indian (AI) haplotype and Benin haplotype of sickle cell anemia. METHODS AND RESULTS: Six BCL112A enhancer SNPs and their haplotypes were studied in Saudi Arabs from the Eastern Province and Indian patients with AI haplotype (HbF ~20%), African Americans (HbF ~7%), and Saudi Arabs from the Southwestern Province (HbF ~12%). Four SNPs (rs1427407, rs6706648, rs6738440, and rs7606173) and their haplotypes were consistently associated with HbF levels. The distributions of haplotypes differ in the 3 cohorts but not their genetic effects: the haplotype TCAG was associated with the lowest HbF level and the haplotype GTAC was associated with the highest HbF level and differences in HbF levels between carriers of these haplotypes in all cohorts were approximately 6%. CONCLUSIONS: Common HbF BCL11A enhancer haplotypes in patients with African origin and AI sickle cell anemia have similar effects on HbF but they do not explain their differences in HbF.

Measurement of the full distribution of persistent current in normal-metal rings.

We have measured the persistent current in individual normal metal rings over a wide range of magnetic fields. From this data, we extract the first six cumulants of the single-ring persistent current distribution. Our results are consistent with the prediction that this distribution should be nearly Gaussian for diffusive metallic rings. This measurement highlights the sensitivity of persistent current to the mesoscopic fluctuations within a single isolated coherent volume.

The nitric oxide redox sibling nitroxyl partially circumvents impairment of platelet nitric oxide responsiveness.

Impaired platelet responsiveness to nitric oxide (NO resistance) is a common characteristic of many cardiovascular disease states and represents an independent risk factor for cardiac events and mortality. NO resistance reflects both scavenging of NO by superoxide (O2(-)), and impairment of the NO receptor, soluble guanylate cyclase (sGC). There is thus an urgent need for circumvention of NO resistance in order to improve clinical outcomes. Nitroxyl (HNO), like NO, produces vasodilator and anti-aggregatory effects, largely via sGC activation, but is not inactivated by O2(-). We tested the hypothesis that HNO circumvents NO resistance in human platelets. In 57 subjects with or without ischemic heart disease, platelet responses to the HNO donor isopropylamine NONOate (IPA/NO) and the NO donor sodium nitroprusside (SNP) were compared. While SNP (10µM) induced 29±3% (p<0.001) inhibition of platelet aggregation, IPA/NO (10µM) caused 75±4% inhibition (p<0.001). In NO-resistant subjects (n=28), the IPA/NO:SNP response ratio was markedly increased (p<0.01), consistent with partial circumvention of NO resistance. Similarly, cGMP accumulation in platelets was greater (p<0.001) with IPA/NO than with SNP stimulation. The NO scavenger carboxy-PTIO (CPTIO, 200µM) inhibited SNP and IPA/NO responses by 92±7% and 17±4% respectively (p<0.001 for differential inhibition), suggesting that effects of IPA/NO are only partially NO-mediated. ODQ (10µM) inhibited IPA/NO responses by 36±8% (p<0.001), consistent with a contribution of sGC/haem to IPA/NO inhibition of aggregation. There was no significant relationship between whole blood ROS content and IPA/NO responses. Thus the HNO donor IPA/NO substantially circumvents platelet NO resistance while acting, at least partially, as a haem-mediated sGC activator.

Implications of tropical cyclones on damage and potential recovery and restoration of logged forests in Vietnam.

Many natural forests in Southeast Asia are degraded following decades of logging. Restoration of these forests is delayed by ongoing logging and tropical cyclones, but the implications for recovery are largely uncertain. We analysed meteorological, satellite and forest inventory plot data to assess the effect of Typhoon Doksuri, a major tropical cyclone, on the forest landscapes of central Vietnam consisting of natural forests and plantations. We estimated the return period for a cyclone of this intensity to be 40 years. Plantations were almost twice as likely to suffer cyclone damage compared to natural forests. Logged natural forests (9-12 years after cessation of government-licensed logging) were surveyed before and after the storm with 2 years between measurements and remained a small biomass carbon sink (0.1 ± 0.3 Mg C ha-1 yr-1) over this period. The cyclone reduced the carbon sink of recovering natural forests by an average of 0.85 Mg C ha-1 yr-1, less than the carbon loss due to ongoing unlicensed logging. Restoration of forest landscapes in Southeast Asia requires a reduction in unlicensed logging and prevention of further conversion of degraded natural forests to plantations, particularly in landscapes prone to tropical cyclones where natural forests provide a resilient carbon sink. This article is part of the theme issue 'Understanding forest landscape restoration: reinforcing scientific foundations for the UN Decade on Ecosystem Restoration'.

Determinants of insulin responsiveness in young women: Impact of polycystic ovarian syndrome, nitric oxide, and vitamin D.

BACKGROUND: Polycystic ovary syndrome (PCOS) is associated with incremental risk of atherosclerosis and possibly of cardiovascular events. Insulin resistance (IR) occurs frequently in PCOS subjects, which might be one of the mechanisms involved in engendering such risk. We sought to evaluate whether the impact of other factors potentially associated both with PCOS and with IR might differentially modulate degree of IR in women with and without PCOS. METHODS AND RESULTS: We measured body mass index (BMI), hs-CRP, plasma concentrations of asymmetric dimethylarginine (ADMA), vitamin D (25(OH)D3) levels and platelet responsiveness to nitric oxide donor sodium nitroprusside (NO responsiveness) in 47 young women (n=27 with PCOS and n=20 weight-matched controls) without metabolic syndrome, hypertension or overt cardiovascular disease. We performed univariate and multivariate regression analyses to establish correlates of the quantitative insulin-sensitivity check index (QUICKI), as a marker of IR. On univariate analysis, plasma 25(OH)D3 levels and low NO responsiveness tended to be direct correlates with QUICKI in the entire subject group. BMI, hs-CRP, and ADMA levels were significant inverse correlates of QUICKI in PCOS subjects, but not in subjects without PCOS. On multivariate analysis, NO responsiveness, and 25(OH)D3 levels, but not PCOS per se were significant correlates of QUICKI. CONCLUSIONS: In the entire cohort of young women, low NO responsiveness and vitamin D deficiency are associated with low QUICKI, while elevated ADMA, inflammatory activation and obesity are selectively associated with low QUICKI in PCOS subjects; this may contribute to the increased cardiovascular risk associated with this syndrome.

The endogenous NOS inhibitor asymmetric dimethylarginine (ADMA) predicts LV mass independent of afterload.

BACKGROUND: Nitric oxide (NO) is a modulator of left ventricular hypertrophy (LVH) and myocardial relaxation. The impact of NO availability on development of LVH has never been demonstrated in humans. We tested the hypotheses that elevation of asymmetric dimethylarginine (ADMA) concentrations (biochemical marker of decreased NO generation), and impairment of vascular responsiveness to NO donor GTN, would each predict the presence of LVH and associated LV diastolic dysfunction in a normal aging population. METHODS AND RESULTS: In 74 subjects aged 68±6 years, LV volumes and mass indexed to height(2.7) (LVMI) were calculated from cardiac MRI. Despite the absence of clinically-defined LVH, there was a relationship (r=0.29; p=0.01) between systolic BP and LVMI. Both elevation of ADMA levels to the highest quartile or impairment of GTN responsiveness (determined by applanation tonometry) to the lowest quartile were determinants of LVMI independent of systolic BP (p=0.01 and p=0.03, respectively). Filling pressure (E/E' ratio from echocardiography) was increased in patients with impaired vascular NO responsiveness (p<0.05) irrespective of LVMI. ADMA remained a significant determinant of LVMI on multivariate analysis. CONCLUSIONS: These data imply that NO bioavailability within the myocardium modulates earliest stages of LVH development and facilitates development of diastolic dysfunction at a given LV mass.

Endogenous estrogen regulation of inflammatory arthritis and cytokine expression in male mice, predominantly via estrogen receptor alpha.

OBJECTIVE: A number of experimental observations have associated elevated estrogen levels with amelioration of inflammation. The involvement of estrogen and estrogen receptor (ER) isotypes in the regulation of inflammation in males is not well understood. In this study, we used specific ERalpha and ERbeta agonists in male mice deficient in estrogen because of a deletion of aromatase (aromatase-knockout [ArKO] mice) to investigate ER isotype utilization in estrogen regulation of inflammation. METHODS: Lipopolysaccharide (LPS)-induced cytokine expression and antigen-induced arthritis (AIA) were investigated in male ArKO and WT littermate mice, as well as in response to selective agonists of ERalpha (16alpha-LE2) and ERbeta (8beta-VE2). The therapeutic effect of selective ER agonists was also examined in mice with collagen-induced arthritis (CIA). RESULTS: Estrogen deficiency in ArKO mice was associated with significant increases in LPS-induced serum interleukin-6 (IL-6), tumor necrosis factor, monocyte chemotactic protein 1, and interferon-gamma levels, which were significantly abrogated by administration of 16alpha-LE2, but not 8beta-VE2. In contrast, both 16alpha-LE2 and 8beta-VE2 significantly increased LPS-induced IL-10 levels. Estrogen deficiency was also associated with significant exacerbation of AIA and antigen-specific T cell proliferation, which was reversed by administration of either 16alpha-LE2 or 8beta-VE2. ArKO mice showed increased antigen-specific T cell proliferation in response to immunization with type II collagen (CII). Administration of 16alpha-LE2, but not 8beta-VE2, significantly reduced the severity of CIA, which was associated with inhibition of anti-CII-specific IgG. CONCLUSION: These data indicate that endogenous estrogen plays an essential inhibitory role in inflammation in male mice and that ERalpha is the dominant receptor that mediates these effects.

The effect of dry needling on gastrocnemius muscle stiffness and strength in participants with latent trigger points.

Abnormal muscle stiffness is a potential complication after injury and identifying interventions that modify muscle stiffness may be useful to promote recovery. The purpose of this study was to identify the short-term effects of dry needling (DN) on resting and contracted gastrocnemius muscle stiffness and strength of the triceps surae in individuals with latent myofascial trigger points (MTrPs). In this randomized controlled trial, 52 individuals received two DN treatment sessions to latent MTrPs and 50 individuals received two sham needling sessions. Resting and contracted muscle stiffness were assessed both at the treatment site and a standardized central site in the medial gastrocnemius head immediately post-treatment and one week after the last session. There were significant group by time interactions for resting muscle stiffness at the site of the MTrP (p = .03), but not at the central site (p = .29). Post-needling between group comparison indicated that the DN group had significantly lower resting muscle stiffness at the site of the MTrP than the sham group after adjusting for baseline differences. There were no significant between group differences in contracted muscle stiffness or muscle strength. Identifying strategies that can reduce aberrant muscle stiffness may help to guide management of individuals with neuromuscular pain-related conditions. Level of evidence: Therapy, level 2.

Identification of parasporin genes in Vietnamese isolates of Bacillus thuringiensis.

Four genes encoding parasporins, cytotoxins preferentially killing human cancer cells in vitro, were isolated from four Vietnamese strains of Bacillus thuringiensis. Nucleotide sequence analysis revealed that: (1) three genes fall into the two known classes, ps1Aa and ps1Ab, and (2) another one belongs to ps1Ac, a novel gene class established in this study. Upon proteolytic activation, parasporal protein of the organism with ps1Ac exhibited strong cytocidal activity against human cancer cells, HeLa and Hep G2, but not to non-cancer normal cells, UtSMC and HC.

Tumor-targeted gene therapy for nasopharyngeal carcinoma.

The unique feature of human nasopharyngeal carcinoma (NPC) is its almost universal association with the EBV, which is expressed in a latent form exclusively in cancer cells, and not in the surrounding tissues. We have exploited this differential by constructing a novel replication-deficient adenovirus vector (ad5.oriP) in which transgene expression is under the transcriptional regulation of the family of repeats domain of the origin of replication (oriP) of EBV. When EBNA1, one of the latent gene products of EBV, binds to the family of repeats sequence, this activates transcription of downstream genes. Vector constructs were made using the beta-galactosidase and luciferase reporter genes (ad5oriP.betagal and ad5oriP.luc) or the p53 tumor suppressor gene (ad5oriP.p53). 5-Bromo-4-chloro-3-indolyl-beta-D-galactopyranoside staining demonstrated extensive expression only in EBV-positive NPC cells, specifically in response to the presence of EBNA1. The relative difference in expression between EBV-positive and -negative cell lines is approximately 1000-fold. This selective expression was corroborated in EBV-positive and -negative tumor models, along with an absence of transgene expression in the host liver. Significant cytotoxicity was achieved using the adv.oriP.p53 therapeutic gene only in EBV-positive NPC cells, which was enhanced with the addition of ionizing radiation. Cytotoxicity was mediated primarily by induction of apoptosis. These results demonstrate that the oriP sequence can achieve high levels of gene expression targeted specifically to EBV-positive NPC cells in the context of the adv vector. This has now provided the tumor-specific expression system from which additional interventions can be evaluated in future treatment strategies for patients with nasopharyngeal cancers.

Differential chemosensitivity of breast cancer cells to ganciclovir treatment following adenovirus-mediated herpes simplex virus thymidine kinase gene transfer.

The development of resistance to radiation and chemotherapeutic agents that cause DNA damage is a major problem for the treatment of breast and other cancers. The p53 tumor suppressor gene plays a direct role in the signaling of cell cycle arrest and apoptosis in response to DNA damage, and p53 gene mutations have been correlated with increased resistance to DNA-damaging agents. Herpes simplex virus thymidine kinase (HSV-tk) gene transfer followed by ganciclovir (GCV) treatment is a novel tumor ablation strategy that has shown good success in a variety of experimental tumor models. However, GCV cytotoxicity is believed to be mediated by DNA damage-induced apoptosis, and the relationship between p53 gene status, p53-mediated apoptosis, and the sensitivity of human tumors to HSV-tk/GCV treatment has not been firmly established. To address this issue, we compared the therapeutic efficacy of adenovirus-mediated HSV-tk gene transfer and GCV treatment in two human breast cancer cell lines: MCF-7 cells, which express wild-type p53, and MDA-MB-468 cells, which express high levels of a mutant p53 (273 Arg-His). Treating MCF-7 cells with AdHSV-tk/GCV led to the predicted increase in endogenous p53 and p21WAF1/CIP1 protein levels, and apoptosis was observed in a significant proportion of the target cell population. However, treating MDA-MB-468 cells under the same conditions resulted in a much stronger apoptotic response in the absence of induction in p21WAF1/CIP1 protein levels. This latter result suggested that HSV-tk/GCV treatment can activate a strong p53-independent apoptotic response in tumor cells that lack functional p53. To confirm this observation, four additional human breast cancer cell lines expressing mutant p53 were examined. Although a significant degree of variability in GCV chemosensitivity was observed in these cell lines, all displayed a greater reduction in cell viability than MCF-7 or normal mammary cells treated under the same conditions. These results suggest that endogenous p53 status does not correlate with chemosensitivity to HSV-tk/GCV treatment. Furthermore, evidence for a p53-independent apoptotic response serves to extend the potential of this therapeutic strategy to tumors that express mutant p53 and that may have developed resistance to conventional genotoxic agents.

Heat-directed gene targeting of adenoviral vectors to tumor cells.

Targeting therapeutic gene expression to tumor cells represents a major challenge for cancer gene therapy. The strong transcriptional response exhibited by heat shock genes, along with the beneficial therapeutic effects of hyperthermia have led us to develop a heat-directed gene-targeting strategy for cancer treatment. Heat shock gene expression is mediated in large part by the interaction of heat shock factor 1 with specific binding sites (heat shock elements; HSE) found in the promoters of heat-inducible genes. Here we present a quantitative analysis of heat-inducible gene expression mediated by the wild-type hsp70b gene promoter, as well as a modified hsp70b promoter containing additional HSE sequences. Beta-galactosidase (beta-gal) expression was induced between 50- and 800-fold in a panel of human breast cancer cell lines infected with an adenoviral vector containing the wild-type hsp70b promoter (Ad.70b.betag) following treatment at 43 degrees C for 30 minutes. Infection with an adenoviral vector containing the modified hsp70b promoter (Ad.HSE.70b.betag) resulted in a 200- to 950-fold increase in beta-gal expression under the same conditions, and also provided a 1-2 degrees C decrease in the threshold of activation. Significant increases in the heat responsiveness of the Ad.HSE.70b.betag construct were observed in five of six tumor cell lines tested, as well as under thermotolerant conditions. Finally, we demonstrate that localized heating of a HeLa cell xenograft can effectively target beta-gal gene expression following intratumoral injection of Ad.70b.betag. Adenoviral vectors incorporating heat-inducible therapeutic genes may provide useful adjuncts for clinical hyperthermia.

Forest malaria in Vietnam: a challenge for control.

Forest malaria is a complex but common phenomenon occurring in southeast Asia. We studied its epidemiology through a prospective community-based study in central Vietnam. A total of 585 individuals were followed for two years by active case detection and biannual cross-sectional surveys. The prevalence of antibodies to Plasmodium falciparum was constantly about 20% across surveys and the incidence rate of clinical episodes of P. falciparum malaria was 0.11/person-year. Multivariate analysis showed that regular forest activity was the main risk factor for clinical malaria and malaria infections. Untreated bed nets had a significant protective effect (60%), except for people regularly sleeping in the forest. The population-attributable fraction for regular forest activity was estimated to be 53%. Our results confirm the major role played by forest activity on the malaria burden in this area and provide the basis for targeting control activities to forest workers. New interventions based on insecticide-treated materials need to be urgently evaluated.

Light scattering multipole solution for a cell.

We derive a multipole scattering solution for a system resembling a simple cell. In the model, a spherical cytoplasm is surrounded by a concentric cell membrane. Contained within the cytoplasm is a nonconcentric spherical nucleus. Because of the nature of the (multipole expansion) solution, numerical results can be acquired quite rapidly. We show that the resulting scatter is very sensitive to the system geometry and optical properties. Such a solution may also be used to calculate the scatter from fluorescing molecules located within the cell. © 1998 Society of Photo-Optical Instrumentation Engineers.

Use of flexible intermediate and intensive care to reduce multiple transfers of patients.

OBJECTIVE: To test an alternative flexible approach to traditional fixed intermediate and intensive care to minimize transfers of patients. METHODS: Patients admitted to a 28-bed nursing unit with intermediate care potential and a 12-bed intensive care unit at a 300-bed teaching community hospital were studied. The group included 524 patients with a discharge diagnosis code for mechanical ventilation. During eight 3-week cycles, 1073 transfers of patients were tabulated. A plan-do-study-act method was used to improve weaning from mechanical ventilation and reduce the number of inappropriate days in intensive care. Admissions and transfers to the 2 units for all patients during the eight 3-week cycles were compared over time. Length of stay and mortality were noted for all patients treated with conventional and noninvasive ventilation. RESULTS: Direct admissions to the flexible intermediate unit increased with no overall change in admissions to the intensive care unit. Fewer patients needed conventional ventilation, and more in both units were treated with noninvasive ventilation. The median number of transfers per patient treated with mechanical ventilation decreased from 1.94 to 1.20. Length of stay and mortality also decreased among such patients. Some cost savings were attributable to the decrease in the number of transfers. Transfers out of the hospital directly from the intensive care unit increased from 2.24% to 4.43%. CONCLUSIONS: In a community teaching hospital, flexible care policies decreased the number of in-hospital transfers of patients treated with mechanical ventilation.