EV71:TLLcho virus murine model of enterovirus A71 neurological disease does not exhibit neurogenic pulmonary oedema.

Small animal models play an important role in investigating and revealing the molecular determinants and mechanisms underlying neuro-virulence of enterovirus A71 (EV-A71). In our previous study, we successfully developed two mouse cell-line replication competent EV-A71 strains (EV71:TLLm and EV71:TLLmv) which were capable of inducing neuro-invasion in BALB/c mice. The more virulent EV71:TLLmv exhibited ability to induce acute encephalomyelitis accompanied by neurogenic pulmonary oedema. EV71:TLLcho virus strain was generated from EV71:TLLm by a series of passages in CHO-K1 cells. EV71:TLLcho demonstrated a broader range of infectivity across various mammalian cell lines and exhibited complete cytopathic effects (CPE) within 48 hours post-inoculation in comparison to EV71:TLLm or EV71:TLLmv. EV71:TLLcho consistently yielded higher levels of viral replication at all time points examined. In comparison to EV71:TLLm, EV71:TLLcho consistently induced more severe disease and increased mortality in one-week old BALB/c mice. However, unlike mice challenged with EV71:TLLmv, none of the mice challenged with EV71:TLLcho progressed to severe acute encephalomyelitis and developed neurogenic pulmonary oedema.

TROG 14.04: Multicentre Study of Feasibility and Impact on Anxiety of DIBH in Breast Cancer Patients.

AIMS: The aim of TROG 14.04 was to assess the feasibility of deep inspiration breath hold (DIBH) and its impact on radiation dose to the heart in patients with left-sided breast cancer undergoing radiotherapy. Secondary end points pertained to patient anxiety and cost of delivering a DIBH programme. MATERIALS AND METHODS: The study comprised two groups - left-sided breast cancer patients engaging DIBH and right-sided breast cancer patients using free breathing through radiotherapy. The primary end point was the feasibility of DIBH, defined as left-sided breast cancer patients' ability to breath hold for 15 s, decrease in heart dose in DIBH compared with the free breathing treatment plan and reproducibility of radiotherapy delivery using mid-lung distance (MLD) assessed on electronic portal imaging as the surrogate. The time required for treatment delivery, patient-reported outcomes and resource requirement were compared between the groups. RESULTS: Between February and November 2018, 32 left-sided and 30 right-sided breast cancer patients from six radiotherapy centres were enrolled. Two left-sided breast cancer patients did not undergo DIBH (one treated in free breathing as per investigator choice, one withdrawn). The mean heart dose was reduced from 2.8 Gy (free breathing) to 1.5 Gy (DIBH). Set-up reproducibility in the first week of treatment assessed by MLD was 1.88 ± 1.04 mm (average ± 1 standard deviation) for DIBH and 1.59 ± 0.93 mm for free breathing patients. Using a reproducibility cut-off for MLD of 2 mm (1 standard deviation) as per study protocol, DIBH was feasible for 67% of DIBH patients. Radiotherapy delivery using DIBH took about 2 min longer than for free breathing. Anxiety was not significantly different in DIBH patients and decreased over the course of treatment in both groups. CONCLUSION: Although DIBH was shown to require about 2 min longer per treatment slot, it has the potential to reduce heart dose in left-sided breast cancer patients by nearly a half, provided careful assessment of breath hold reproducibility is carried out.

Determining tolerance levels for quality assurance of 3D printed bolus for modulated arc radiotherapy of the nose.

Given the existing literature on the subject, there is obviously a need for specific advice on quality assurance (QA) tolerances for departments using or implementing 3D printed bolus for radiotherapy treatments. With a view to providing initial suggested QA tolerances for 3D printed bolus, this study evaluated the dosimetric effects of changes in bolus geometry and density, for a particularly common and challenging clinical situation: specifically, volumetric modulated arc therapy (VMAT) treatment of the nose. Film-based dose verification measurements demonstrated that both the AAA and the AXB algorithms used by the Varian Eclipse treatment planning system (Varian Medical Systems, Palo Alto, USA) were capable of providing sufficiently accurate dose calculations to allow this planning system to be used to evaluate the effects of bolus errors on dose distributions from VMAT treatments of the nose. Thereafter, the AAA and AXB algorithms were used to calculate the dosimetric effects of applying a range of simulated errors to the design of a virtual bolus, to identify QA tolerances that could be used to avoid clinically significant effects from common printing errors. Results were generally consistent, whether the treatment target was superficial and treated with counter-rotating coplanar arcs or more-penetrating and treated with noncoplanar arcs, and whether the dose was calculated using the AAA algorithm or the AXB algorithm. The results of this study suggest the following QA tolerances are advisable, when 3D printed bolus is fabricated for use in photon VMAT treatments of the nose: bolus relative electron density variation within [Formula: see text] (although an action level at [Formula: see text] may be permissible); bolus thickness variation within [Formula: see text] mm (or 0.5 mm variation on opposite sides); and air gap between bolus and skin [Formula: see text] mm. These tolerances should be investigated for validity with respect to other treatment modalities and anatomical sites. This study provides a set of baselines for future comparisons and a useful method for identifying additional or alternative 3D printed bolus QA tolerances.

The utility of postoperative radiotherapy in intermediate-risk oral squamous cell carcinoma.

The effectiveness of postoperative radiotherapy (PORT) in improving outcomes remains debatable for oral squamous cell carcinoma (OSCC) patients with pathological intermediate-risk factors (IRFs) after surgery. A retrospective analysis was conducted on 432 intermediate-risk OSCC patients defined by histological reporting of close margin (<5mm), early nodal disease (pN1), depth of invasion/tumour thickness ≥5mm, perineural invasion, and/or lymphovascular invasion. Outcomes measured were disease-free survival (DFS), disease-specific survival (DSS), and overall survival (OS). PORT was associated with an improvement in 5-year DFS on univariable analysis (80% vs 71%; P=0.044), but this did not remain significant on multivariable analysis. PORT was not associated with differences in DSS or OS. The surgical salvage rate was similar in the PORT and surgery-only groups (41% vs 47%; P=0.972). Perineural invasion was found to be an independent predictor of inferior DSS (hazard ratio (HR) 2.19), DFS (HR 1.89), and OS (HR 1.97). Significantly worse outcomes were observed for patients with ≥4 concurrent IRFs. The application of PORT was associated with lower rates of recurrence, but the benefit was less apparent on mortality. Patients with perineural invasion and multiple concurrent IRFs were found to be at greatest risk, representing a subset of intermediate-risk OSCC patients who may benefit from PORT.

Tracking the mental health of a nation: prevalence and correlates of mental disorders in the second Singapore mental health study.

AIMS: The second Singapore Mental Health Study (SMHS) - a nationwide, cross-sectional, epidemiological survey - was initiated in 2016 with the intent of tracking the state of mental health of the general population in Singapore. The study employed the same methodology as the first survey initiated in 2010. The SMHS 2016 aimed to (i) establish the 12-month and lifetime prevalence and correlates of major depressive disorder (MDD), dysthymia, bipolar disorder, generalised anxiety disorder (GAD), obsessive compulsive disorder (OCD) and alcohol use disorder (AUD) (which included alcohol abuse and dependence) and (ii) compare the prevalence of these disorders with reference to data from the SMHS 2010. METHODS: Door-to-door household surveys were conducted with adult Singapore residents aged 18 years and above from 2016 to 2018 (n = 6126) which yielded a response rate of 69.0%. The subjects were randomly selected using a disproportionate stratified sampling method and assessed using World Health Organization Composite International Diagnostic Interview version 3.0 (WHO-CIDI 3.0). The diagnoses of lifetime and 12-month selected mental disorders including MDD, dysthymia, bipolar disorder, GAD, OCD, and AUD (alcohol abuse and alcohol dependence), were based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. RESULTS: The lifetime prevalence of at least one mood, anxiety or alcohol use disorder was 13.9% in the adult population. MDD had the highest lifetime prevalence (6.3%) followed by alcohol abuse (4.1%). The 12-month prevalence of any DSM-IV mental disorders was 6.5%. OCD had the highest 12-month prevalence (2.9%) followed by MDD (2.3%). Lifetime and 12-month prevalence of mental disorders assessed in SMHS 2016 (13.8% and 6.4%) was significantly higher than that in SMHS 2010 (12.0% and 4.4%). A significant increase was observed in the prevalence of lifetime GAD (0.9% to 1.6%) and alcohol abuse (3.1% to 4.1%). The 12-month prevalence of GAD (0.8% vs. 0.4%) and OCD (2.9% vs. 1.1%) was significantly higher in SMHS 2016 as compared to SMHS 2010. CONCLUSIONS: The high prevalence of OCD and the increase across the two surveys needs to be tackled at a population level both in terms of creating awareness of the disorder and the need for early treatment. Youth emerge as a vulnerable group who are more likely to be associated with mental disorders and thus targeted interventions in this group with a focus on youth friendly and accessible care centres may lead to earlier detection and treatment of mental disorders.

Immunological responses following administration of a genotype 1a/1b/2/3a quadrivalent HCV VLP vaccine.

The significant public health problem of Hepatitis C virus (HCV) has been partially addressed with the advent of directly acting antiviral agents (DAAs). However, the development of an effective preventative vaccine would have a significant impact on HCV incidence and would represent a major advance towards controlling and possibly eradicating HCV globally. We previously reported a genotype 1a HCV viral-like particle (VLP) vaccine that produced neutralizing antibodies (NAb) and T cell responses to HCV. To advance this approach, we produced a quadrivalent genotype 1a/1b/2a/3a HCV VLP vaccine to produce broader immune responses. We show that this quadrivalent vaccine produces antibody and NAb responses together with strong T and B cell responses in vaccinated mice. Moreover, selective neutralizing human monoclonal antibodies (HuMAbs) targeting conserved antigenic domain B and D epitopes of the E2 protein bound strongly to the HCV VLPs, suggesting that these critical epitopes are expressed on the surface of the particles. Our findings demonstrate that a quadrivalent HCV VLP based vaccine induces broad humoral and cellular immune responses that will be necessary for protection against HCV. Such a vaccine could provide a substantial addition to highly active antiviral drugs in eliminating HCV.

The Singaporean public beliefs about the causes of mental illness: results from a multi-ethnic population-based study.

AIMS: To identify the common causal beliefs of mental illness in a multi-ethnic Southeast Asian community and describe the sociodemographic associations to said beliefs. The factor structure to the causal beliefs scale is explored. The causal beliefs relating to five different mental illnesses (alcohol abuse, depression, obsessive-compulsive disorder (OCD), dementia and schizophrenia) and desire for social distance are also investigated. METHODS: Data from 3006 participants from a nationwide vignette-based study on mental health literacy were analysed using factor analysis and multiple logistic regression to address the aims. Participants answered questions related to sociodemographic information, causal beliefs of mental illness and their desire for social distance towards those with mental illness. RESULTS: Physical causes, psychosocial causes and personality causes were endorsed by the sample. Sociodemographic differences including ethnic, gender and age differences in causal beliefs were found in the sample. Differences in causal beliefs were shown across different mental illness vignettes though psychosocial causes was the most highly attributed cause across vignettes (endorsed by 97.9% of respondents), followed by personality causes (83.5%) and last, physical causes (37%). Physical causes were more likely to be endorsed for OCD, depression and schizophrenia. Psychosocial causes were less often endorsed for OCD. Personality causes were less endorsed for dementia but more associated with depression. CONCLUSIONS: The factor structure of the causal beliefs scale is not entirely the same as that found in previous research. Further research on the causal beliefs endorsed by Southeast Asian communities should be conducted to investigate other potential causes such as biogenetic factors and spiritual/supernatural causes. Mental health awareness campaigns should address causes of mental illness as a topic. Lay beliefs in the different causes must be acknowledged and it would be beneficial for the public to be informed of the causes of some of the most common mental illnesses in order to encourage help-seeking and treatment compliance.

Characterization of a hepatitis C virus-like particle vaccine produced in a human hepatocyte-derived cell line.

An effective immune response against hepatitis C virus (HCV) requires the early development of multi-specific class 1 CD8+ and class II CD4+ T-cells together with broad neutralizing antibody responses. We have produced mammalian-cell-derived HCV virus-like particles (VLPs) incorporating core, E1 and E2 of HCV genotype 1a to produce such immune responses. Here we describe the biochemical and morphological characterization of the HCV VLPs and study HCV core-specific T-cell responses to the particles. The E1 and E2 glycoproteins in HCV VLPs formed non-covalent heterodimers and together with core protein assembled into VLPs with a buoyant density of 1.22 to 1.28 g cm-3. The HCV VLPs could be immunoprecipited with anti-ApoE and anti-ApoC. On electron microscopy, the VLPs had a heterogeneous morphology and ranged in size from 40 to 80 nm. The HCV VLPs demonstrated dose-dependent binding to murine-derived dendritic cells and the entry of HCV VLPs into Huh7 cells was blocked by anti-CD81 antibody. Vaccination of BALB/c mice with HCV VLPs purified from iodixanol gradients resulted in the production of neutralizing antibody responses while vaccination of humanized MHC class I transgenic mice resulted in the prodution of HCV core-specific CD8+ T-cell responses. Furthermore, IgG purified from the sera of patients chronically infected with HCV genotypes 1a and 3a blocked the binding and entry of the HCV VLPs into Huh7 cells. These results show that our mammalian-cell-derived HCV VLPs induce humoral and HCV-specific CD8+ T-cell responses and will have important implications for the development of a preventative vaccine for HCV.

Portable lysis apparatus for rapid single-step DNA extraction of Bacillus subtilis.

AIMS: To demonstrate and characterize a portable lysis apparatus for rapid single-step bacterial DNA extraction. METHODS AND RESULTS: Our portable lysis apparatus employed a novel design consisting of an annular piezo-element with perforated diaphragm. Using Bacillus subtilis as target bacteria, our portable lysis apparatus was able to achieve a normalized percent lysis as high as 66% within 30 s. This is comparable to that by microprobe ultrasonication and almost 7 times higher than that by conventional bead beating. The effect from adding glass beads was predictable. However, the results from the addition of sodium dodecyl sulphate (SDS) were counter-intuitive because a further increase from 0·5 to 1% concentration reduced the lysis performance. The portable lysis apparatus is also at least 1·5-5 times more power efficient than microprobe ultrasonication. CONCLUSIONS: Our portable lysis apparatus is capable of rapidly extracting bacterial DNA and is more power efficient than microprobe ultrasonication. The addition of glass beads or SDS concentration (up to 0·5%) improves its performance. SIGNIFICANCE AND IMPACT OF THE STUDY: The portable lysis apparatus provides a standalone, rapid, low cost and power efficient way of obtaining genomic constituents prior to a variety of bioassays used in the field of environmental, biomedical and other applied microbiology.

The roller coaster flight strategy of bar-headed geese conserves energy during Himalayan migrations.

The physiological and biomechanical requirements of flight at high altitude have been the subject of much interest. Here, we uncover a steep relation between heart rate and wingbeat frequency (raised to the exponent 3.5) and estimated metabolic power and wingbeat frequency (exponent 7) of migratory bar-headed geese. Flight costs increase more rapidly than anticipated as air density declines, which overturns prevailing expectations that this species should maintain high-altitude flight when traversing the Himalayas. Instead, a "roller coaster" strategy, of tracking the underlying terrain and discarding large altitude gains only to recoup them later in the flight with occasional benefits from orographic lift, is shown to be energetically advantageous for flights over the Himalayas.

The effect of carbon dioxide flow rate on the euthanasia of laboratory mice.

Laboratory rodents are commonly euthanized by exposure to gradually increasing concentrations of carbon dioxide (CO2). Current recommended flow rates range between 10 and 30% chamber vol/min and result in insensibility before exposure to painful concentrations (<40%). However, this method causes dyspnea, indicated by deep, rapid breathing. In humans dyspnea is associated with a negative affective experience. Sensations of dyspnea may explain why rodents find CO2 concentrations >3% aversive. This study aimed to assess the effect of CO2 flow rates on time between the onset of dyspnea and various measures of insensibility (recumbency, loss of the righting reflex and loss of the pedal withdrawal reflex) to identify flow rates that minimize the potential experience of dyspnea. The results of this study indicate that a flow rate of 50% chamber vol/min, while holding the CO2 cage concentration just below 40%, minimizes the interval between the onset of labored breathing and recumbency. Using a 50% flow rate this interval averaged (± SE) 30.3 ± 2.9 s versus 49.7 ± 2.9 s at 20% chamber vol/min (F3,22 = 7.83, P = 0.0013). Similarly, the interval between the onset of labored breathing and loss of the righting reflex averaged 38.2 ± 2.4 s at a flow rate of 50% versus 59.2 ± 2.4 s at 20% chamber vol/min of CO2 (F3,22 = 13.62, P < 0.0001). We conclude that higher flow rates reduce the duration of dyspnea, but even at the highest flow rate mice experience more than 30 s between the onset of dyspnea and the most conservative estimate of insensibility.

A review of the management of ductal carcinoma in situ following breast conserving surgery.

Ductal carcinoma in situ (DCIS) is a heterogeneous, pre-malignant disease accounting for 10-20% of all new breast tumours. Evidence shows a statistically significant local control benefit for adjuvant radiotherapy (RT) following breast conserving surgery (BCS) for all patients. The baseline recurrence risk of individual patients varies according to clinical-pathological criteria and in selected patients, omission of RT may be considered, following a discussion with the patient. The role of adjuvant endocrine therapy remains uncertain. Ongoing studies are attempting to define subgroups of patients who are at sufficiently low risk of recurrence that RT may be safely omitted; investigating RT techniques and dose fractionation schedules; and defining the role of endocrine therapy. Future directions in the management of patients with DCIS will include investigation of prognostic and predictive biomarkers to inform individualised therapy tailored to the risk of recurrence.

Stroke atlas: a 3D interactive tool correlating cerebrovascular pathology with underlying neuroanatomy and resulting neurological deficits.

Understanding stroke-related pathology with underlying neuroanatomy and resulting neurological deficits is critical in education and clinical practice. Moreover, communicating a stroke situation to a patient/family is difficult because of complicated neuroanatomy and pathology. For this purpose, we created a stroke atlas. The atlas correlates localized cerebrovascular pathology with both the resulting disorder and surrounding neuroanatomy. It also provides 3D display both of labeled pathology and freely composed neuroanatomy. Disorders are described in terms of resulting signs, symptoms and syndromes, and they have been compiled for ischemic stroke, hemorrhagic stroke, and cerebral aneurysms. Neuroanatomy, subdivided into 2,000 components including 1,300 vessels, contains cerebrum, cerebellum, brainstem, spinal cord, white matter, deep grey nuclei, arteries, veins, dural sinuses, cranial nerves and tracts. A computer application was developed comprising: 1) anatomy browser with the normal brain atlas (created earlier); 2) simulator of infarcts/hematomas/aneurysms/stenoses; 3) tools to label pathology; 4) cerebrovascular pathology database with lesions and disorders, and resulting signs, symptoms and/or syndromes. The pathology database is populated with 70 lesions compiled from textbooks. The initial view of each pathological site is preset in terms of lesion location, size, surrounding surface and sectional neuroanatomy, and lesion and neuroanatomy labeling. The atlas is useful for medical students, residents, nurses, general practitioners, and stroke clinicians, neuroradiologists and neurologists. It may serve as an aid in patient-doctor communication helping a stroke clinician explain the situation to a patient/family. It also enables a layman to become familiarized with normal brain anatomy and understand what happens in stroke.

Bridging neuroanatomy, neuroradiology and neurology: three-dimensional interactive atlas of neurological disorders.

Understanding brain pathology along with the underlying neuroanatomy and the resulting neurological deficits is of vital importance in medical education and clinical practice. To facilitate and expedite this understanding, we created a three-dimensional (3D) interactive atlas of neurological disorders providing the correspondence between a brain lesion and the resulting disorder(s). The atlas contains a 3D highly parcellated atlas of normal neuroanatomy along with a brain pathology database. Normal neuroanatomy is divided into about 2,300 components, including the cerebrum, cerebellum, brainstem, spinal cord, arteries, veins, dural sinuses, tracts, cranial nerves (CN), white matter, deep gray nuclei, ventricles, visual system, muscles, glands and cervical vertebrae (C1-C5). The brain pathology database contains 144 focal and distributed synthesized lesions (70 vascular, 36 CN-related, and 38 regional anatomy-related), each lesion labeled with the resulting disorder and associated signs, symptoms, and/or syndromes compiled from materials reported in the literature. The initial view of each lesion was preset in terms of its location and size, surrounding surface and sectional (magnetic resonance) neuroanatomy, and labeling of lesion and neuroanatomy. In addition, a glossary of neurological disorders was compiled and for each disorder materials from textbooks were included to provide neurological description. This atlas of neurological disorders is potentially useful to a wide variety of users ranging from medical students, residents and nurses to general practitioners, neuroanatomists, neuroradiologists and neurologists, as it contains both normal (surface and sectional) brain anatomy and pathology correlated with neurological disorders presented in a visual and interactive way.

Three-dimensional interactive atlas of cranial nerve-related disorders.

Anatomical knowledge of the cranial nerves (CN) is fundamental in education, research and clinical practice. Moreover, understanding CN-related pathology with underlying neuroanatomy and the resulting neurological deficits is of vital importance. To facilitate CN knowledge anatomy and pathology understanding, we created an atlas of CN-related disorders, which is a three-dimensional (3D) interactive tool correlating CN pathology with the underlying surface and sectional neuroanatomy as well as the resulting neurological deficits. A computer platform was developed with: 1) anatomy browser along with the normal brain atlas (built earlier); 2) simulator of CN lesions; 3) tools to label CN-related pathology; and 4) CN pathology database with lesions and disorders, and the resulting signs, symptoms and/or syndromes. The normal neuroanatomy comprises about 2,300 3D components subdivided into modules. Cranial nerves contain more than 600 components: all 12 pairs of cranial nerves (CN I - CN XII) and the brainstem CN nuclei. The CN pathology database was populated with 36 lesions compiled from clinical textbooks. The initial view of each disorder was preset in terms of lesion location and size, surrounding surface and sectional neuroanatomy, and disorder and neuroanatomy labeling. Moreover, path selection from a CN nucleus to a targeted organ further enhances pathology-anatomy relationships. This atlas of CN-related disorders is potentially useful to a wide variety of users ranging from medical students and residents to general practitioners, neuroradiologists and neurologists, as it contains both normal brain anatomy and CN-related pathology correlated with neurological disorders presented in a visual and interactive way.

Preoperative vascular screening in the presence of aortic, carotid and peripheral pathology for patients undergoing their first arterial intervention: 18 month follow-up.

BACKGROUND: The aim of this paper was to determine prevalence and incidence of intervention required for concomitant Asymptomatic Vascular Disease (AVD) on patients undergoing their first elective peripheral arterial intervention. METHODS: This is a prospective observational study Data was obtained on patients undergoing peripheral revascularisation, abdominal aortic aneurysmal (AAA) repair or carotid procedure from 2006 to 2009. Of 542 complex arterial procedures, 328 patients had their first vascular intervention. (PAD=127, AAA=97, CAD=83, concomitant AAA and PAD=21). Primary endpoint is detection of any concomitant asymptomatic AAA, CAS or PAD. Secondary endpoints are need for intervention of AVD detected on screening, and major adverse clinical events during follow-up. RESULTS: Prevalence of AVD detected was 13% PAD, 51% CAS and 8%AAA. Symptomatic and Asymptomatic PolyVasBed patients had 11.4- and 8.16-fold increased likelihood for detection of asymptomatic CAS respectively (P<0.0001) relative to the remaining study population. Asymptomatic PolyVasBed patients had 8.2 fold increased likelihood of asymptomatic AAA, P<0.0001, compared to the remaining study population. Likelihood for intervention in Asymptomatic PolyVasBed is OR 5.740 (P=0.044) and Symptomatic PolyVasBed is OR 4.500 (P<0.001). Asymptomatic AAA detected in both symptomatic and asymptomatic vascular disease patients, is the strongest predicting factor of intervention in 18 months follow-up. In Asymptomatic PolyVasBed patients, CAS and AAA have the highest prevalence. CONCLUSIONS: Screening for AVD is mandatory prior to any vascular intervention.

Developing FGFR4 inhibitors as potential anti-cancer agents via in silico design, supported by in vitro and cell-based testing.

Fibroblast growth factor receptor-4 (FGFR4) is a tyrosine kinase with a range of important physiological functions. However, it is also frequently mutated in various cancers and is now generating significant interest as a potential therapeutic target. Unfortunately, biochemical characterization of its role in disease, and further evaluation as a drug target is hampered by lack of a specific inhibitor. We aimed to discover new inhibitors for FGFR4 ab initio using a strategy combining in silico, in vitro and cell-based assays. We used the homologous FGFR1 to calculate docking scores of a chemically-diverse library of approximately 2000 potential kinase inhibitors. Nineteen potential inhibitors and ten randomly- selected negative controls were taken forward for in vitro FGFR4 kinase assays. All compounds with good docking scores significantly inhibited FGFR4 kinase activity, some with sub-micromolar (most potent being V4-015 with an IC(50) of 0.04 µM). Four of these compounds also demonstrated substantial activity in cellular assays using the FGFR4- overexpressing breast carcinoma cell line, MDA-MB453. Through immunoblot assays, these compounds were shown to block the phosphorylation of the FGFR4 adaptor protein, FGFR substrate protein-2α (FRS2α). The most potent compound to date, V4-015, suppressed proliferation of MDA-MB453 cells at sub-micromolar concentrations, activated the pro-apoptotic caspases 3/7 and inhibited cellular migration. While achieving complete selectivity of this compound for FGFR4 will require further lead optimization, this study has successfully identified new chemical scaffolds with unprecedented FGFR4 inhibition capacities that will support mechanism of action studies and future anti-cancer drug design.

The paradox of extreme high-altitude migration in bar-headed geese Anser indicus.

Bar-headed geese are renowned for migratory flights at extremely high altitudes over the world's tallest mountains, the Himalayas, where partial pressure of oxygen is dramatically reduced while flight costs, in terms of rate of oxygen consumption, are greatly increased. Such a mismatch is paradoxical, and it is not clear why geese might fly higher than is absolutely necessary. In addition, direct empirical measurements of high-altitude flight are lacking. We test whether migrating bar-headed geese actually minimize flight altitude and make use of favourable winds to reduce flight costs. By tracking 91 geese, we show that these birds typically travel through the valleys of the Himalayas and not over the summits. We report maximum flight altitudes of 7290 m and 6540 m for southbound and northbound geese, respectively, but with 95 per cent of locations received from less than 5489 m. Geese travelled along a route that was 112 km longer than the great circle (shortest distance) route, with transit ground speeds suggesting that they rarely profited from tailwinds. Bar-headed geese from these eastern populations generally travel only as high as the terrain beneath them dictates and rarely in profitable winds. Nevertheless, their migration represents an enormous challenge in conditions where humans and other mammals are only able to operate at levels well below their sea-level maxima.

Patterns and risk factors for locoregional failures after mastectomy for breast cancer: an International Breast Cancer Study Group report.

BACKGROUND: Rates and risk factors of local, axillary and supraclavicular recurrences can guide patient selection and target for postmastectomy radiotherapy (PMRT). PATIENTS AND METHODS: Local, axillary and supraclavicular recurrences were evaluated in 8106 patients enrolled in 13 randomized trials. Patients received chemotherapy and/or endocrine therapy and mastectomy without radiotherapy. Median follow-up was 15.2 years. RESULTS: Ten-year cumulative incidence for chest wall recurrence of >15% was seen in patients aged <40 years (16.1%), with ≥4 positive nodes (16.5%) or 0-7 uninvolved nodes (15.1%); for supraclavicular failures >10%: ≥4 positive nodes (10.2%); for axillary failures of >5%: aged <40 years (5.1%), unknown primary tumor size (5.2%), 0-7 uninvolved nodes (5.2%). In patients with 1-3 positive nodes, 10-year cumulative incidence for chest wall recurrence of >15% were age <40, peritumoral vessel invasion or 0-7 uninvolved nodes. Age, number of positive nodes and number of uninvolved nodes were significant parameters for each locoregional relapse site. CONCLUSION: PMRT to the chest wall and supraclavicular fossa is supported in patients with ≥4 positive nodes. With 1-3 positive nodes, chest wall PMRT may be considered in patients aged <40 years, with 0-7 uninvolved nodes or with vascular invasion. The findings do not support PMRT to the dissected axilla.

Association of intronic single-nucleotide polymorphisms in the EMILIN1 gene with essential hypertension in a Chinese population.

Studies in mice suggest that the elastin microfibril interfacer-1 gene (EMILIN1), the gene encoding elastin microfibril interfacer-1 protein, contributes to the pathogenesis of essential hypertension (EH) in humans. EMILIN1 in part maintains elastic fibres in vessel walls, and hence peripheral arterial compliance. In a case-control study, we assessed 942 non-obese non-diabetic Chinese, comprising 467 patients with EH and 475 normotensive control subjects (166 without, and 309 with, family history of hypertension in first-degree relatives (FHH)). Hypertension in first-degree relatives occurred in 88%, 65% and 0% of cases, all controls and controls without FHH, respectively. We scanned for single-nucleotide polymorphisms (SNPs) and genotyped them in the EMILIN1 gene using high-resolution melt-curve analysis. No exonic variants were detected. We assessed the association of SNPs and their haplotypes with EH. Three SNPs in introns 1 and 5 (rs2289360, rs2011616 and rs7424556) were in strong pair-wise linkage disequilibrium (r(2)>0.89). All three SNPs were significantly associated with hypertension. Genotypic frequencies at the three SNPs differed significantly between cases and only those controls without FHH. Healthy controls with FHH should be excluded to increase the odds of detecting association. All the G alleles of rs2289360 (odds ratio = 1.69, P = 0.010), rs2011616 (odds ratio = 1.52, P = 0.038) and rs7424556 (odds ratio = 1.59, P = 0.023) were high-risk alleles in the recessive genetic model. We observed significant overall haplotypic association with EH (empirical P = 0.0072); GGG is a risk haplotype (P = 0.043). The overall results support EMILIN1 as a candidate gene for human EH.