Influence of Selective Carbon 1s Excitation on Auger-Meitner Decay in the ESCA Molecule.

Two-dimensional spectral mapping is used to visualize how resonant Auger-Meitner spectra are influenced by the site of the initial core-electron excitation and the symmetry of the core-excited state in the trifluoroethyl acetate molecule (ESCA). We observe a significant enhancement of electron yield for excitation of the COO 1s → π* and CF3 1s → σ* resonances unlike excitation at resonances involving the CH3 and CH2 sites. The CF3 1s → π* and CF3 1s → σ* resonance spectra are very different from each other, with the latter populating most valence states equally. Two complementary electronic structure calculations for the photoelectron cross section and Auger-Meitner intensity are shown to effectively reproduce the site- and state-selective nature of the resonant enhancement features. The site of the core-electron excitation and the respective final state hole locality increase the sensistivity of the photoelectron signal at specific functional group sites. This showcases resonant Auger-Meitner decay as a potentially powerful tool for selectively probing structural changes at specific functional group sites of polyatomic molecules.

Resonant Inelastic X-Ray Scattering Reveals Hidden Local Transitions of the Aqueous OH Radical.

Resonant inelastic x-ray scattering (RIXS) provides remarkable opportunities to interrogate ultrafast dynamics in liquids. Here we use RIXS to study the fundamentally and practically important hydroxyl radical in liquid water, OH(aq). Impulsive ionization of pure liquid water produced a short-lived population of OH(aq), which was probed using femtosecond x-rays from an x-ray free-electron laser. We find that RIXS reveals localized electronic transitions that are masked in the ultraviolet absorption spectrum by strong charge-transfer transitions-thus providing a means to investigate the evolving electronic structure and reactivity of the hydroxyl radical in aqueous and heterogeneous environments. First-principles calculations provide interpretation of the main spectral features.

Observation of the fastest chemical processes in the radiolysis of water.

Elementary processes associated with ionization of liquid water provide a framework for understanding radiation-matter interactions in chemistry and biology. Although numerous studies have been conducted on the dynamics of the hydrated electron, its partner arising from ionization of liquid water, H2O+, remains elusive. We used tunable femtosecond soft x-ray pulses from an x-ray free electron laser to reveal the dynamics of the valence hole created by strong-field ionization and to track the primary proton transfer reaction giving rise to the formation of OH. The isolated resonance associated with the valence hole (H2O+/OH) enabled straightforward detection. Molecular dynamics simulations revealed that the x-ray spectra are sensitive to structural dynamics at the ionization site. We found signatures of hydrated-electron dynamics in the x-ray spectrum.

Risk of death from cardiovascular disease following breast cancer in Southeast Asia: a prospective cohort study.

Breast cancer incidence and survival is high in Southeast Asia. As such, many women diagnosed with breast cancer are at risk of dying of other causes. Given the increased risk of cardiotoxicity induced by breast cancer treatments, it is important to identify patients at high risk of cardiovascular disease (CVD) mortality. The aim of this study was to investigate if this risk varies by age and ethnicity. Patient details were obtained from 5,868 Chinese, Malay, and Indian women diagnosed with in situ or non-metastasized invasive breast cancer at the National University Hospital of Singapore and KK Women's and Children's Hospital in Singapore. Death causes were obtained from the National Registry of Births and Deaths. Flexible parametric survival models estimated CVD mortality rates and hazard ratios. During a median follow-up of six years, 1,010 deaths occurred of which 6.8% were due to CVD. CVD mortality rates of older women peaked within the first year following diagnosis and increased over time since diagnosis. Indian had more than double the risk of CVD mortality than Chinese, independent of age at diagnosis and stage. Taking ethnicity and age into account may promote CVD risk stratification and management in (Southeast Asian) women with breast cancer.

Risk of death from cardiovascular disease following breast cancer: a systematic review.

PURPOSE: Breast cancer incidence and survival is high, which results in high prevalence of breast cancer survivors. The risk of (death from) cardiovascular disease (CVD) is higher in patients exposed to cardiotoxic treatments, in particular if they have pre-existing CVD risk factors. This study systematically summarized the risk of death from CVD following breast cancer. METHODS: Databases of Medline, Embase, and the Cochrane Library were systematically searched using the following terms and synonyms: breast cancer, cardiovascular disease, and cause of death. Articles reporting on both risk and risk factors of CVD mortality following breast cancer were eligible for inclusion. The methodological quality of each article was assessed using the Newcastle Ottawa quality assessment scale for cohort studies. RESULTS: Fourteen articles were included assessing the risk of CVD mortality among 1,217,910 women with breast cancer. The methodological quality was high for the majority of the studies. Studies were heterogeneous in design, study population, length of follow-up, CVD outcomes, and risk factors. 1.6-10.4% of all women with breast cancer died of CVD. Women with breast cancer had a higher risk of CVD mortality than women from the general population. The risk of CVD mortality was higher among women with breast cancer with older age at diagnosis, left-sided tumor, diagnosis in an earlier calendar period, and black ethnic origin. CONCLUSIONS: CVD is an important cause of death following breast cancer. Identification of patients at high risk of CVD is important to optimize CVD prevention and tailor breast cancer treatment.

Hetero-site-specific X-ray pump-probe spectroscopy for femtosecond intramolecular dynamics.

New capabilities at X-ray free-electron laser facilities allow the generation of two-colour femtosecond X-ray pulses, opening the possibility of performing ultrafast studies of X-ray-induced phenomena. Particularly, the experimental realization of hetero-site-specific X-ray-pump/X-ray-probe spectroscopy is of special interest, in which an X-ray pump pulse is absorbed at one site within a molecule and an X-ray probe pulse follows the X-ray-induced dynamics at another site within the same molecule. Here we show experimental evidence of a hetero-site pump-probe signal. By using two-colour 10-fs X-ray pulses, we are able to observe the femtosecond time dependence for the formation of F ions during the fragmentation of XeF2 molecules following X-ray absorption at the Xe site.

Haemoglobin disorders in Australia: where are we now and where will we be in the future?

Inherited disorders of haemoglobin (Hb), such as thalassaemia and sickle cell disease (SCD) are common and responsible for significant morbidity and mortality on a global scale. As Australia becomes increasingly ethnically diverse, their prevalence will increase. However, we lack important demographic and epidemiological data to manage these disorders and their consequences and to support affected individuals and communities. Thalassaemia and SCD are lifelong conditions. Affected individuals have reduced life expectancies, poorer quality of life and complex healthcare needs. Treatment strategies currently focus on prenatal diagnosis, red blood cell transfusion, iron chelation, management of iron-related complications, haemopoietic stem cell transplantation (HSCT) and hydroxyurea. Currently, the only curative therapy is HSCT; however, gene therapy offers the possibility of cure and trials are currently underway. These therapies are associated with significant complications and substantial costs; there is also evidence of variation in approaches to diagnosis and care. Optimal strategies for many aspects of management are not yet defined and more research is necessary to inform clinical care and health service delivery.

Multiple myeloma causes clonal T-cell immunosenescence: identification of potential novel targets for promoting tumour immunity and implications for checkpoint blockade.

Tumour-induced dysfunction of cytotoxic T cells in patients with multiple myeloma (MM) may contribute to immune escape and be responsible for the lack of therapeutic efficacy of immune checkpoint blockade. We therefore investigated dysfunctional clonal T cells in MM and demonstrated immunosenescence but not exhaustion as a predominant feature. T-cell clones were detected in 75% of MM patients and their prognostic significance was revalidated in a new post-immunomodulatory drug cohort. The cells exhibited a senescent secretory effector phenotype: KLRG-1+/CD57+/CD160+/CD28-. Normal-for-age telomere lengths indicate that senescence is telomere independent and potentially reversible. p38-mitogen-activated protein kinase, p16 and p21 signalling pathways known to induce senescence were not elevated. Telomerase activity was found to be elevated and this may explain how normal telomere lengths are maintained in senescent cells. T-cell receptor signalling checkpoints were normal but elevated SMAD levels associated with T-cell inactivation were detected and may provide a potential target for the reversal of clonal T-cell dysfunction in MM. Low programmed death 1 and cytotoxic T-lymphocyte-associated antigen 4 expression detected on T-cell clones infers that these cells are not exhausted but suggests that there would be a suboptimal response to immune checkpoint blockade in MM. Our data suggest that other immunostimulatory strategies are required in MM.

Practical management of myelofibrosis with ruxolitinib.

Treatment for the majority of patients with myelofibrosis is primarily based on symptom control as curative allogeneic stem cell transplantation is typically offered only to younger patients, especially those with poor prognosis disease. Around 50% of patients with myelofibrosis have the JAK2(V617F) mutation, but almost all patients have aberrant activation of the JAK-STAT signalling pathway. Recent efforts have focussed on the clinical use of JAK2 inhibitors to treat myelofibrosis. In this article, we present our recommendations for the practical management of myelofibrosis with ruxolitinib, a selective inhibitor of both JAK1 and JAK2. Ruxolitinib can significantly improve the quality of life of patients with myelofibrosis. There is also increasing evidence of a positive impact on survival. Consistent with the physiological role of JAK signalling the major toxicity of ruxolitinib is cytopenia. Managing cytopenia is key to maximising the therapeutic benefit of ruxolitinib. Further research into the safety of ruxolitinib in patients with thrombocytopenia is warranted, as is its role in special subgroups of patients, such as those undergoing stem cell transplantation and those experiencing thrombosis as a major manifestation of myelofibrosis.

Management of systemic AL amyloidosis: recommendations of the Myeloma Foundation of Australia Medical and Scientific Advisory Group.

Systemic AL amyloidosis is a plasma cell dyscrasia with a characteristic clinical phenotype caused by multi-organ deposition of an amyloidogenic monoclonal protein. This condition poses a unique management challenge due to the complexity of the clinical presentation and the narrow therapeutic window of available therapies. Improved appreciation of the need for risk stratification, standardised use of sensitive laboratory testing for monitoring disease response, vigilant supportive care and the availability of newer agents with more favourable toxicity profiles have contributed to the improvement in treatment-related mortality and overall survival seen over the past decade. Nonetheless, with respect to the optimal management approach, there is a paucity of high-level clinical evidence due to the rarity of the disease, and enrollment in clinical trials is still the preferred approach where available. This review will summarise the Clinical Practice Guidelines on the Management of Systemic Light Chain (AL) Amyloidosis recently prepared by the Medical Scientific Advisory Group of the Myeloma Foundation of Australia. It is hoped that these guidelines will assist clinicians in better understanding and optimising the management of this difficult disease.

Phospho-flow detection of constitutive and cytokine-induced pSTAT3/5, pAKT and pERK expression highlights novel prognostic biomarkers for patients with multiple myeloma.

Identifying check points in cell signal transduction pathways has led to the development of new cancer therapies; however, relatively few studies have determined the diagnostic and prognostic significance of analysing phosphorylated signaling proteins in patient blood and bone marrow (BM) samples. This is the first comprehensive phospho-flow study of both constitutive and cytokine-induced pSTAT3, pSTAT5, pAKT and phosphorylated extracellular signal-regulated kinase (pERK) expression in malignant plasma cells of patients with monoclonal gammopathies. In diagnostic BM samples from 65 patients with multiple myeloma (MM), interleukin (IL)-6-induced pSTAT3 proved to be a new and independent prognostic biomarker for improved survival. When combined with the International Staging System, 6 subgroups demonstrated stratified median survivals from 9 to 72 months (χ(2)=34.3; P<0.0001). In contrast, constitutive expression of pSTAT3, pSTAT5, pAKT and pERK did not assist the differential diagnosis nor determine prognosis. High pSTAT3 expression was dependent on existing CD45 expression and pSTAT5 appeared to regulate IgG production. Phospho-flow cytometry could be used to screen for personalized therapy, although the lack of clinical significance of constitutive pSTAT3 levels suggests that pSTAT3 blockade may not be clinically relevant in MM. This study has revealed novel prognostic biomarkers and insights into the biology of signaling pathways in patients with MM.

Long-term survival in multiple myeloma is associated with a distinct immunological profile, which includes proliferative cytotoxic T-cell clones and a favourable Treg/Th17 balance.

Despite improved outcomes in multiple myeloma (MM), a cure remains elusive. However, even before the current therapeutic era, 5% of patients survived >10 years and we propose that immune factors contribute to this longer survival. We identified patients attending our clinic, who had survived >10 years (n=20) and analysed their blood for the presence of T-cell clones, T-regulatory cells (Tregs) and T helper 17 (Th17) cells. These results were compared with MM patients with shorter follow-up and age-matched healthy control donors. The frequency of cytotoxic T-cell clonal expansions in patients with <10 years follow-up (MM patients) was 54% (n=144), whereas it was 100% (n=19/19) in the long-survivors (LTS-MM). T-cell clones from MM patients proliferated poorly in vitro, whereas those from LTS-MM patients proliferated readily (median proliferations 6.1% and 61.5%, respectively (P<0.0001)). In addition, we found significantly higher Th17 cells and lower Tregs in the LTS-MM group when compared with the MM group. These results indicate that long-term survival in MM is associated with a distinct immunological profile, which is consistent with decreased immune suppression.

Health of adults living with a clinically significant haemoglobinopathy in New South Wales, Australia.

AIM: To comprehensively review the health needs of patients living with clinically significant haemoglobinopathies (thalassaemia and sickle-cell disease (SCD)) in New South Wales, Australia. METHODS: A survey-based health needs assessment was undertaken in outpatients cared for at five tertiary institutions in metropolitan and regional centres. Sixty-three of 121 adults (approximately 80-90% of adult patients with transfusion-requiring haemoglobinopathies in New South Wales) completed an in-house and commercial health-related quality assessment survey (SF-36v2). RESULTS: Subjects came from more than eight world regions, with those with SCD being more likely to be born outside of Australia than subjects with thalassaemia (P < 0.001, likelihood ratio 20.64) as well as more likely to have been refugees (26% vs 2%). The population contained socially disadvantaged subjects with 13 subjects (20.6%) having incomes below the Australian poverty line. Complications of thalassaemia were comparable to previous international reports although our subjects had a high rate of secondary amenorrhea (>12 months = 27%) and surgical splenectomy (55.6%). Use of hydroxyurea in SCD was less than expected with only 46.6% of subjects having prior use. Lack of universal access to magnetic resonance imaging-guided chelation (international best practice) was evident, although 65.5% had been able to access magnetic resonance imaging through clinical trial, or self-funding. CONCLUSIONS: Patients with SCD and thalassaemia experience considerable morbidity and mortality and require complex, multidisciplinary care. This study revealed both variance from international best practice and between specialist units. The results of this research may provide the impetus for the development of clinical and research networks to enable the uniform delivery of health services benchmarked against international standards.

Australian guidelines for the assessment of iron overload and iron chelation in transfusion-dependent thalassaemia major, sickle cell disease and other congenital anaemias.

Iron overload is the most important cause of mortality in patients with thalassaemia major. Iron chelation is therefore a critical issue in the management of these patients and others with transfusion-dependent haemoglobinopathies and congenital anaemias. In recent years, significant developments have been made in the assessment of iron overload, including the use of magnetic resonance imaging for measuring liver and cardiac iron. Advances in the modalities available for iron chelation, with the advent of oral iron chelators including deferiprone and deferasirox in addition to parenteral desferrioxamine, have expanded treatment options. A group of Australian haematologists has convened to formulate guidelines for managing iron overload on the basis of available evidence, and to describe best consensus practice as undertaken in major Australian Haemoglobinopathy units. The results of their discussions are described in this article, with the aim of providing guidance in the management of iron overload in these patients.

Overview of endocrinopathies associated with ß-thalassaemia major.

BACKGROUND: Thalassaemia major is a common and serious medical problem worldwide that is associated with a range of complications, including effects on multiple endocrine pathways. Minimizing or preventing comorbidities is important for these individuals who need life-long multidisciplinary care and treatment. However, there are limited overviews of the endocrine complications associated with this illness, nor any consensus regarding management guidelines. METHOD: A retrospective cohort analysis of ß-thalassaemia patients attending an ambulatory transfusion clinic at Royal Prince Alfred Hospital was conducted from June 2008. RESULTS: All of our subjects (n=29) had at least one endocrinopathy present with 16 patients (55%) having three or more (≥3) endocrinopathies. Hypogonadism was the most prevalent followed by osteoporosis and growth failure (less than 3rd centile) with a frequency of 16/29 (55%), 14/29 (48%) and 10/29 (35%) patients respectively. Those with more endocrinopathies (≥3) had a longer duration of transfusion therapy when compared with those with fewer endocrinopathies. CONCLUSION: A summary of our clinical guidelines, which have been used to monitor and manage these complications, is presented along with a discussion on the results and pathophysiology of the associated endocrinopathies.

Characterisation and relevance of CD138-negative plasma cells in plasma cell myeloma.

INTRODUCTION: The use of CD138 to isolate CD138(+) plasma cells (PCs) from plasma cell myeloma (PCM) patients' bone marrow samples has been used extensively in myeloma research. We sought to highlight the problem with this selection process, by demonstrating that a subpopulation of CD138⁻ plasma cells exists which is not included in these analyses. METHODS: Retrospective analysis of a patient database was carried out on all PCM patient bone marrow biopsies taken between 4/9/07 and 18/2/09 (n = 218). CD138(+) and CD138⁻ cell populations were separated using flow cytometry cell sorter then analyzed for percentage of cells in S phase using plasma cell labeling index as an indicator of proliferation. RESULTS: Database results indicated a CD138⁻ PC population in all PCM patient samples which also had a significantly increased (r = 0.53; P < 0.0001) CD45 expression, an indicator or immaturity. Flow cytometric analysis demonstrated the presence of a more immature, higher proliferating CD138⁻ PC population through a significantly (t = 3.26; P < 0.02) higher number of CD138⁻ PCs in S phase compared with the CD138(+) cells. CONCLUSION: We have characterised the CD138⁻ PCs as more immature and with a significantly higher proliferative potential. The current trend to ignore this more immature and proliferative subpopulation of malignant PCs may have serious implications when determining gene expression, classifications and drug sensitivity of the malignancy.

Molecular structure determination from x-ray scattering patterns of laser-aligned symmetric-top molecules.

We investigate the molecular structure information contained in the x-ray diffraction patterns of an ensemble of rigid CF(3)Br molecules aligned by an intense laser pulse at finite rotational temperature. The diffraction patterns are calculated at an x-ray photon energy of 20 keV to probe molecular structure at angstrom-scale resolution. We find that a structural reconstruction algorithm based on iterative phase retrieval fails to extract a reliable structure. However, the high atomic number of Br compared with C or F allows each diffraction pattern to be treated as a hologram. Using this approach, the azimuthal projection of the molecular electron density about the alignment axis may be retrieved.

Evolving transplant options for multiple myeloma: autologous and nonmyeloablative allogenic.

High-dose chemotherapy supported by a single autologous hemopoietic stem cell transplant is considered by many to be the "standard of care" for suitable newly diagnosed patients with multiple myeloma. The majority of myeloma patients, however, still die from their disease. Approaches to improve response and overall survival rates include tandem autologous transplants, nonmyeloablative allogenic transplants, and posttransplant maintenance and immunotherapy strategies. Support for tandem autologous transplantation comes from single-center studies as well as the recently reported large IMF94 trial that demonstrated a statistically significant increase in both event-free and overall survival for the double transplant arm. A number of subsequent, but as yet less mature, studies have been presented recently. Although there is some support for the conclusions of the IMF94 trial, the exact place of this therapy is yet to be resolved. Reduced intensity allogeneic transplantation has been proposed as an alternative to conventional allogenic transplantation as a means of reducing the high transplant-related morbidity and mortality of the latter procedure while still retaining the advantages of the allogeneic graft. Preliminary reports suggest a reduction of acute transplant-related complications, although graft-versus-host disease remains a significant issue. Finally, a variety of posttransplant strategies and novel therapeutic agents are in active development.