'Iron-saturated' lactoferrin is a potent natural adjuvant for augmenting cancer chemotherapy

Bovine lactoferrin (bLf), an iron-containing natural defence protein found in bodily secretions, has been reported to inhibit carcinogenesis and the growth of tumours. Here, we investigated whether natural bLf and iron-saturated forms of bLf differ in their ability to augment cancer chemotherapy. bLf was supplemented into the diet of C57BL/6 mice that were subsequently challenged subcutaneously with tumour cells, and treated by chemotherapy. Chemotherapy eradicated large (0.6 cm diameter) EL-4 lymphomas in mice that had been fed iron-saturated bLf (here designated Lf(+)) for 6 weeks prior to chemotherapy, but surprisingly not in mice that were fed lesser iron-saturated forms of bLf, including apo-bLf (4% iron saturated), natural bLf (approximately 15% iron saturated) and 50% iron-saturated bLf. Lf(+)-fed mice bearing either EL-4, Lewis lung carcinoma or B16 melanoma tumours completely rejected their tumours within 3 weeks following a single injection of either paclitaxel, doxorubicin, epirubicin or fluorouracil, whereas mice fed the control diet were resistant to chemotherapy. Lf(+) had to be fed to mice for more than 2 weeks prior to chemotherapy to be wholly effective in eradicating tumours from all mice, suggesting that it acts as a competence factor. It significantly reduced tumour vascularity and blood flow, and increased antitumour cytotoxicity, tumour apoptosis and the infiltration of tumours by leukocytes. Lf(+) bound to the intestinal epithelium and was preferentially taken up within Peyer's patches. It increased the production of Th1 and Th2 cytokines within the intestine and tumour, including TNF, IFN-gamma, as well as nitric oxide that have been reported to sensitize tumours to chemotherapy. Importantly, it restored both red and white peripheral blood cell numbers depleted by chemotherapy, potentially fortifying the mice against cancer. In summary, bLf is a potent natural adjuvant and fortifying agent for augmenting cancer chemotherapy, but needs to be saturated with iron to be effective.

Oxidised mannan as a novel adjuvant inducing mucosal IgA production.

Mannan, oxidatively coupled to recombinant protein antigens, has here been tested as a possible adjuvant for the production of antibody on the mucosa. Given intranasally, but not intraperitoneally, mannan markedly enhanced the production of IgA, IgG1 and IgG2a in the serum, and IgA locally in the lung and at remote mucosal sites, including tears, vaginal and salivary secretions. Oxidative coupling was critical to its action, since neither mannan simply mixed with protein nor mannan–protein conjugates which had been reduced by treatment with sodium borohydride, acted as adjuvants. Oxidatively coupled mannan was compared with the widely studied mucosal adjuvant, cholera toxin (CT). The use of oxidised mannan as an adjuvant induced better responses than CT judged by the induction of IgA in serum, vaginal washings and saliva. Thus, oxidised mannan, which is non-toxic and can be administered without injection, is a suitable adjuvant coupled with protective antigens for vaccinating against a number of infections that occur via the mucous membranes.

Immune thrombocytopenic purpura (ITP) and breast cancer. Does adjuvant therapy for breast cancer improve platelet counts in ITP?

Although both breast cancer and immune thrombocytopenic purpura (ITP) are common conditions, the simultaneous coexistence of these two diseases is rare. ITP is an autoimmune disease in which the presence of autoantibodies against platelets results in splenic sequestration and thrombocytopenia that may be associated with lymphoid neoplasms [1]. Except for an observational case series of 10 patients [2], only a few individual case reports of ITP coinciding with breast cancer have been reported [3–8]. We are reporting two cases with simultaneous confirmed ITP and breast cancer. The platelet counts in both women have improved during adjuvant breast cancer chemotherapy.

Adjuvant therapy, not mammographic screening, accounts for most of the observed breast cancer specific mortality reductions in Australian women since the national screening program began in 1991

There has been a 28% reduction in age-standardised breast cancer mortality in Australia since 1991 when the free national mammographic program (BreastScreen) began. Therefore, a comparative study between BreastScreen participation and breast cancer age specific mortality trends in Australia was undertaken for two time periods between 1991 and 2007, where women aged 50–59 and 60–69 years, who were invited to screen, were compared to women aged 40–49 and 70–79 years who were not invited, but who did have access to the program. There were mortality reductions in all four age groups between 1991–1992 and 2007, resulting in 5,849 (95% CI 4,979 to 6,718) fewer women dying of breast cancer than would have otherwise been the case. Women aged 40–49 years, who had the lowest BreastScreen participation (approximately 20%), had the largest mortality reduction: 44% (95% CI 34.8–51.2). Women aged 60–69 years, who had the highest BreastScreen participation (approximately 60%), had the smallest mortality reduction: 19% (95% CI 10.5–26.9). As BreastScreen participation by invited women aged 50–69 years only reached a maximum of about 55–60% in 1998–1999, a decline in mortality in Australian women cannot be attributed to BreastScreen prior to this time. Thus, almost 60% of the Australian decline in breast cancer mortality since 1991 cannot be attributed to BreastScreen. Therefore, mammographic screening cannot account for most of the reductions in breast cancer mortality that have occurred in Australian women since 1991 and may have contributed to over-diagnosis. Most, if not all, of the reductions can be attributed to the adjuvant hormonal and chemotherapy, which Australian women have increasingly received since 1986.

A prospective cohort study of the effects of adjuvant breast cancer chemotherapy on taste function, food liking, appetite and associated nutritional outcomes

'Taste' changes are commonly reported during chemotherapy. It is unclear to what extent this relates to actual changes in taste function or to changes in appetite and food liking and how these changes affect dietary intake and nutritional status.

Kinetic resolution of the interactions between agrochemical products and adjuvant systems upon mixing

The addition of an adjuvant to a pesticide usually occurs in a mix-tank, before spray application to the crop. Their interaction is potentially crucial to overall efficacy but has received little attention from a physical-chemical perspective. Study was undertaken by laser diffraction, Raman spectroscopy, and small-angle X-ray scattering to resolve these physical processes. It was shown that migration of the pesticide into the adjuvant droplet occurred in all cases studied. The level of transfer was dependent upon adjuvant level, adjuvant solubility, and surfactant level. For suspension pesticides, dissolution of crystallites within the droplet occurred to a degree limited by solubility. The results directly demonstrate the transfer of the pesticide into the adjuvant carrier. This indicates that for emulsion-based pesticides, application to the target is likely as a homogeneously mixed droplet, whereas for suspension pesticides, solubility may limit transfer and dissolution, leading to heterogeneity in the applied particles.

Review of the role of emergency nurses in management of chemotherapy-related complications

Aims and objectives : To examine the role of emergency nurses in caring for patients who receive chemotherapy in ambulatory oncology settings. Reasons for emergency department presentations are examined, specific sources of clinical risk for patients receiving chemotherapy who require emergency care are discussed and cost implications of emergency department presentations related to chemotherapy are analysed.

Background : Given the increased administration of chemotherapy in ambulatory settings, emergency nurses play an important role in the management of patients undergoing adjuvant chemotherapy. Emergency departments are the major entry point for acute inpatient hospital care of complications arising from chemotherapy.

Design : Systematic review.

Results : Chemotherapy-related emergency department presentations have considerable clinical and cost implications for patients and the healthcare system. Strategies to improve emergency department management of chemotherapy complications and reduction in preventable emergency department presentations has significant implications for improving cancer patients' quality of life and reducing the cost of cancer care.

Conclusions : Nurses are well placed to play a pivotal role in chemotherapy management and lead interventions such as a specialist oncology nursing roles that provide information and support to guide patients through their chemotherapy cycles. These interventions may prevent emergency department presentations for patients receiving chemotherapy in ambulatory settings.

Relevance to clinical practice : Patients receiving chemotherapy require access to specialised care to manage distressing symptoms, as they are at significant clinical risk because of immunosuppression and may not exhibit the usual signs of critical illness. A team approach both within and across nursing specialities may improve care for patients receiving chemotherapy and increase effective use of healthcare resources.

The relationship between primary and secondary control and eating behaviour

Two studies were conducted investigating Australian women's management of their life goals. Although engagement with goals was generally positive for psychological well-being, the propensity to disengage from appearance-related goals was beneficial for body image and protective against disordered eating, suggesting strategies for promoting goal disengagement in women with eating disordered behaviour. The portfolio presents four case studies reviewing empirical research demonstrating the efficacy of adjuvant psychological therapy in relieving psychological distress in cancer patients.

Long lived multi-isotype anti-HIV antibody responses following a prime-double boost immunization strategy

Despite decades of work, an effective HIV vaccine remains elusive. In an effort to elicit protective immunity, investigators have sought to define vaccines able to elicit durable HIV-specific B-cell and T-cell activities. Additionally, vaccines are sought which can induce antibodies of a variety of isotypes, as each isotype possesses unique attributes in terms of opsonization, Fc receptor binding capacity, complement fixation and location. One prominent new vaccine strategy, applied to numerous distinct antigenic systems is the prime boost-regimen, with DNA, vaccinia virus (VV), and/or purified recombinant protein. To examine the durability, location and isotype distribution of responses induced by prime-boost regimens, we tested successive immunizations with DNA, VV and protein (D-V-P), comparing three forms of protein inoculations: (i) purified protein administered intramuscularly with complete Freunds adjuvant, (ii) purified protein administered intranasally, and (iii) purified protein conjugated to oxidized mannan, administered intranasally. We found that all three protocols elicited serum antibodies of multiple isotypes, with serum IgA being most prominent among mice immunized with mannan-conjugated protein. All D-V-P protocols, regardless of protein form or route, also elicited antibody responses at mucosal surfaces. In bronchoalveolar lavage, a tendency toward IgA production was again most prominent in mice boosted with the protein–mannan conjugate. Both B-cell and T-cell responses were sustained for more than 1 year post-immunization following each form of vaccination. Contemporaneous with long-lasting serum and mucosal antibodies were antibody forming cells in the bone marrow of primed animals. Results highlight the D-V-P vaccination strategy as a promising approach for attaining durable, multi-isotype B-cell and T-cell activities toward HIV.

Oxidised mannan-listeriolysin O conjugates induce Th1/Th2 cytokine responses after intranasal immunisation

Clearance of infectious organisms does not always require polarised Th1 or Th2 responses and it may be advantageous for both Th1 and Th2 responses to be elicited for effective protection against an invading pathogen. It was the aim of this study to investigate oxidised mannan as a possible Th1/Th2 adjuvant. Oxidised mannan was conjugated to two candidate antigens and delivered intranasally to mice. Immunisation with the oxidised conjugate resulted in significant antigen specific proliferative responses, IL-2, IFN-γ and IL-4 production when compared to unconjugated controls.

A nurse-assisted screening and referral program for depression among survivors of colorectal cancer : feasibility study

Objective: To test the feasibility and acceptability of a telephone-based program to screen survivors of colorectal cancer (CRC) for distress, and to refer distressed patients to their treating health service.

Design, setting and participants: A prospective, multicentre study involving 59 patients with CRC recruited from six public and private health services in Melbourne, Victoria, from 15 June 2008 to 22 September 2009. Patients who had completed adjuvant chemotherapy for CRC were contacted (7–10 days after recruitment [outcall one] and again 4 weeks later [outcall two]) by the Cancer Council Victoria’s helpline nurse, and screened for distress with the Distress and Impact Thermometer (DIT); participants were given tailored information and support and those with distress scores of ≥5, and impact scores of ≥4, were referred for follow-up. Telephone interviews were conducted 4 weeks after outcall two. Participating helpline and health service staff were surveyed on the feasibility and acceptability of the service. Main outcome measure: Anxiety and depression, measured by the Hospital Anxiety and Depression Scale (HADS).

Results: Of the 59 patients (87%) who agreed to participate, 63% were men; their mean age was 59 years (SD, 9.5 years). HADS depression decreased significantly from baseline (mean score, 4.93; SD, 4.22) to follow-up (mean score, 3.84; SD, 4.10; Z = −2.375; P= 0.02). However, there was no significant difference in HADS anxiety between baseline (mean score, 5.29; SD, 4.11) and follow-up (mean score, 4.78; SD, 3.65). Outcall one generated two referrals (4% of participants) and outcall two generated four referrals
(8%); five of these six participants took up the referrals. Satisfaction with the program among participants was high; 82% found outcall one “quite or very helpful” and 79% found outcall two “quite or very helpful”. Helpline and health service staff reported a straightforward process that did not adversely affect workloads.

Conclusion: This model of care carries the potential to meet ongoing psychosocial needs of survivors of CRC.

Unintentional needlestick injuries in livestock production : a case series and review

Livestock producers and their employees sometimes experience unintentional needlestick injury (NSI) while vaccinating or injecting medications into animals. There is little published regarding the medical complications that can develop from this occupational exposure. The objectives of this study were to (1) perform a retrospective review of animal-related NSIs treated at a tertiary medical center of a rural state; and (2) review the risks of NSI and measures to decrease their occurrence. Medical records of patients with NSI related to animal injection were identified from the University of Iowa Hospitals and Clinics database from 2002 to 2008 and reviewed. Nine patients received medical care for NSI that occurred while vaccinating farm animals. Most common NSI site was the nondominant hand and most occurred while attempting to inject the animal. Soft tissue infection was common and all nine received oral and/or intravenous antibiotics. Two thirds required hospital admission. Three required surgery and one had a bedside incision and drainage procedure. One patient had a serious inflammatory reaction with necrosis in the leg due to the oil adjuvant in the animal vaccine. Another case had a probable mycetoma with osteomyelitis and soft tissue infection due to the bacteria Streptomyces, which is a NSI complication not previously reported. Although medical complications from farm-related NSIs do not appear to be common, this case series illustrates how these injuries can be debilitating, costly, and lead to loss of work time and productivity. Producers and employees who inject livestock need to be aware of the risks and utilize measures to decrease unintentional NSI.

Effect of selenium-saturated bovine lactoferrin (Se-bLF) on antioxidant enzyme activities in human gut epithelial cells under oxidative stress

Cancer and many chronic inflammatory diseases are associated with increased amounts of reactive oxygen species (ROS). The potential cellular and tissue damage created by ROS has significant impact on many disease and cancer states and natural therapeutics are becoming essential in regulating altered redox states. We have shown recently that iron content is a critical determinant in the antitumour activity of bovine milk lactoferrin (bLF). We found that 100% iron-saturated bLF (Fe-bLF) acts as a potent natural adjuvant and fortifying agent for augmenting cancer chemotherapy and thus has a broad utility in the treatment of cancer. Furthermore, we also studied the effects of iron saturated bLF's ability as an antioxidant in the human epithelial colon cancer cell line HT29, giving insights into the potential of bLF in its different states. Thus, metal saturated bLF could be implemented as anti-cancer neutraceutical. In this regard, we have recently been able to prepare a selenium (Se) saturated form of bLF, being up to 98% saturated. Therefore, the objectives of this study were to determine how oxidative stress induced by hydrogen peroxide (H₂O₂) alters antioxidant enzyme activity within HT29 epithelial colon cancer cells, and observe changes in this activity by treatments with different antioxidants ascorbic acid (AA), Apo (iron free)-bLF and selenium (Se)-bLF. The states of all antioxidant enzymes (glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-s-transferase (GsT), catalase and superoxide dismutase (SOD)) demonstrated high levels within untreated HT29 cells compared to the majority of other treatments being used, even prior to H₂O₂ exposure. All enzymes showed significant alterations in activity when cells were treated with antioxidants AA, Apo-bLF or Se-bLF, with and/or without H₂O₂ exposure. Obvious indications that the Se content of the bLF potentially interacted with the glutathione (GSH)/GPx/GR/GsT associated redox system could be observed immediately, showing capability of Se-bLF being highly beneficial in helping to maintain a balance between the oxidant/antioxidant systems within cells and tissues, especially in selenium deficient systems. In conclusion, the antioxidative defence activity of Se-bLf, investigated in this study for the first time, shows dynamic adaptations that may allow for essential protection from the imbalanced oxidative conditions. Because of its lack of toxicity and the availability of both selenium and bLF in whole milk, Se-bLF offers a promise for a prospective natural dietary supplement, in addition to being an immune system enhancement, or a potential chemopreventive agent for cancers.

HSP72 preserves muscle function and slows progression of severe muscular dystrophy

Duchenne muscular dystrophy (DMD) is a severe and progressive muscle wasting disorder caused by mutations in the dystrophin gene that result in the absence of the membrane-stabilizing protein dystrophin¹, ², ³. Dystrophin-deficient muscle fibres are fragile and susceptible to an influx of Ca²⁺, which activates inflammatory and muscle degenerative pathways⁴, ⁵, ⁶. At present there is no cure for DMD, and existing therapies are ineffective. Here we show that increasing the expression of intramuscular heat shock protein 72 (Hsp72) preserves muscle strength and ameliorates the dystrophic pathology in two mouse models of muscular dystrophy. Treatment with BGP-15 (a pharmacological inducer of Hsp72 currently in clinical trials for diabetes) improved muscle architecture, strength and contractile function in severely affected diaphragm muscles in mdx dystrophic mice. In dko mice, a phenocopy of DMD that results in severe spinal curvature (kyphosis), muscle weakness and premature death⁷, ⁸, BGP-15 decreased kyphosis, improved the dystrophic pathophysiology in limb and diaphragm muscles and extended lifespan. We found that the sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase (SERCA, the main protein responsible for the removal of intracellular Ca²⁺) is dysfunctional in severely affected muscles of mdx and dko mice, and that Hsp72 interacts with SERCA to preserve its function under conditions of stress, ultimately contributing to the decreased muscle degeneration seen with Hsp72 upregulation. Treatment with BGP-15 similarly increased SERCA activity in dystrophic skeletal muscles. Our results provide evidence that increasing the expression of Hsp72 in muscle (through the administration of BGP-15) has significant therapeutic potential for DMD and related conditions, either as a self-contained therapy or as an adjuvant with other potential treatments, including gene, cell and pharmacological therapies.

The role of informal caregivers during cancer patients’ recovery from chemotherapy

Aims:  (i) To investigate the availability, perceived importance and roles of informal caregivers in the recovery of patients treated at day oncology centres and (ii) identify differences between patients with and without informal caregivers in the extent to which they experienced symptoms, and the level of bother symptoms caused.

Method:  Patients from three Australian hospitals (n = 122) were recruited during cycles 1 or 2 of adjuvant chemotherapy. Participants completed a modified version of the Rotterdam Symptom Checklist (RSCL) each day for 5 days after chemotherapy. A telephone interview conducted 10 days post-treatment explored the availability, importance and roles of caregivers. During the interview, participants also completed the modified RSCL in which they were asked about the extent to which they experienced, and were bothered by, each symptom over the prior 5 days combined.

Results:  Overall, 71% of participants had an informal caregiver in the 5 days postchemotherapy, commonly a partner. More women (71%) than men (48%) had a caregiver (p < 0.05). Caregivers were perceived to be highly important; they were more important for women than men (U = 213.50, p < 0.01). The most common assistance caregivers provided was meal preparation and emotional support and companionship. On days 6–10 postchemotherapy, the extent to which overall physical symptoms were experienced was higher for patients with a caregiver than without (U = 987.50, p < 0.05); similarly their symptoms caused more bother (U = 966.00, p < 0.01).

Conclusions:  These findings highlighted the importance of informal caregivers to patients postchemotherapy. It is imperative that patients are informed of the importance of this support so a caregiver can be arranged, if possible. Understanding the needs of patients following chemotherapy would enable health professionals to advise patients, with or without caregivers, how to best prepare for and manage their recovery at home.