Low-dose ipilimumab plus nivolumab combined with IL-2 and hyperthermia in cancer patients with advanced disease: exploratory findings of a case series of 131 stage IV cancers - a retrospective study of a single institution.

The 3-year overall survival (OS) rate of patients with previously treated or untreated stage III or IV melanoma has by now reached 63% using ipilimumab and nivolumab therapy. However, immune-related adverse events (irAEs) of grade 3 or 4 occurred in 59% of patients leading to discontinuation of therapy in 24.5% of patients and one death. Therapy with checkpoint inhibitors could be safer and more effective in combination with hyperthermia and fever inducing therapies. We conducted a retrospective analysis to test the safety and efficacy of a new combination immune therapy in 131 unselected stage IV solid cancer patients with 23 different histological types of cancer who exhausted all conventional treatments. Treatment consisted of locoregional- and whole-body hyperthermia, individually dose adapted interleukin 2 (IL-2) combined with low-dose ipilimumab (0.3 mg/kg) plus nivolumab (0.5 mg/kg). The objective response rate (ORR) was 31.3%, progression-free survival (PFS) was 10 months, survival probabilities at 6 months was 86.7% (95% CI, 81.0-92.8%), at 9 months was 73.5% (95% CI, 66.2-81.7%), at 12 months was 66.5% (95% CI, 58.6-75.4%), while at 24 months survival was 36.6% (95% CI:28.2%; 47.3%). irAEs of World Health Organization (WHO) Toxicity Scale grade 1, 2, 3, and 4 were observed in 23.66%, 16.03%, 6.11%, and 2.29% of patients, respectively. Our results suggest that the irAEs profile of the combined treatment is safer than that of the established protocols without compromising efficacy.

Development of a bio-optical model for the Barents Sea to quantitatively link glider and satellite observations.

A bio-optical model for the Barents Sea is determined from a set of in situ observations of inherent optical properties (IOPs) and associated biogeochemical analyses. The bio-optical model provides a pathway to convert commonly measured parameters from glider-borne sensors (CTD, optical triplet sensor-chlorophyll and CDOM fluorescence, backscattering coefficients) to bulk spectral IOPs (absorption, attenuation and backscattering). IOPs derived from glider observations are subsequently used to estimate remote sensing reflectance spectra that compare well with coincident satellite observations, providing independent validation of the general applicability of the bio-optical model. Various challenges in the generation of a robust bio-optical model involving dealing with partial and limited quantity datasets and the interpretation of data from the optical triplet sensor are discussed. Establishing this quantitative link between glider-borne and satellite-borne data sources is an important step in integrating these data streams and has wide applicability for current and future integrated autonomous observation systems. This article is part of the theme issue 'The changing Arctic Ocean: consequences for biological communities, biogeochemical processes and ecosystem functioning'.

What might Brexit mean for British tourists travelling to the rest of Europe?

Brexit will have profound implications for British tourists visiting the rest of the European Union, in particular because of the likely loss of coverage of healthcare should they be injured or fall ill. This paper compares the cost of travel insurance within the EU and in comparable countries outside it, asking how it varies by age and pre-existing conditions. Fictitious patients, differing by age, pre-existing condition, and destination (France, an EU Member State; Israel and Canada, two high income non-EU frequent destinations) were entered into an insurance price comparison website to assess the influence of these characteristics on prices quoted. Cost of travel insurance increases with age, pre-existing health conditions and by destination. In those with no pre-existing conditions, there is a marked difference between France, where the cost rises steadily with age, and Israel and Canada, where there is a sharp increase after age 75. For individuals with any one pre-existing condition, there is no similar jump in cost but rather a progressive increase with age, although the rate of increase accelerates as the individuals concerned get older. For all travellers, the cost of insurance is highest for Canada and lowest for France. At present, pre-existing health conditions in British tourists travelling in the rest of the EU are covered by the European Health Insurance Card. With the UK's probable exit from the EU and almost certain loss of this coverage, travellers in the older age groups may have to pay much more for their travel insurance, with some possibly tempted to forgo travel insurance coverage because of the cost. It is essential that health professionals understand how leaving the EU may impact on those seeking their advice.

Preventing caries in young children of immigrant Bangladeshi families in New York: perspectives of mothers and paediatricians.

OBJECTIVE: Childhood caries is common in South Asian immigrant families. Few children visit a dentist by 12 months, as recommended by current guidelines. The paediatric visit has important potential for linking children to preventive care. The aim of this study was to understand the barriers and facilitators to caries prevention for young children of immigrant Bangladeshi families in New York. Qualitative data were collected as a preliminary step in the development of an oral health counselling intervention for South Asian children. BASIC DESIGN: Qualitative interviews on child feeding and oral health prevention were conducted with Bangladeshi mothers. Qualitative interviews were conducted with paediatricians regarding their experiences with providing care. The data were analysed using standard qualitative approaches. SETTING: Paediatric practices serving low income Bangladeshi immigrants in New York City. PARTICIPANTS: 26 mothers of children aged 6-24 months receiving services in five paediatric settings and 15 paediatricians providing care in these settings. RESULTS: Both mothers and their paediatricians described risky feeding practices, communication problems and a lack of compliance. Oral health for young children was a low priority for some mothers. Most, however, were concerned about childhood caries but lacked skills or resources to decrease caries risk. CONCLUSIONS: Results support our plan to develop an empowerment-based counselling intervention to address caries risk in children. Paediatric dentists should be aware of the barriers to caries prevention in this group.

Separated response function ratios in exclusive, forward π(±) electroproduction.

The study of exclusive π(±) electroproduction on the nucleon, including separation of the various structure functions, is of interest for a number of reasons. The ratio RL=σL(π-)/σL(π+) is sensitive to isoscalar contamination to the dominant isovector pion exchange amplitude, which is the basis for the determination of the charged pion form factor from electroproduction data. A change in the value of RT=σT(π-)/σT(π+) from unity at small -t, to 1/4 at large -t, would suggest a transition from coupling to a (virtual) pion to coupling to individual quarks. Furthermore, the mentioned ratios may show an earlier approach to perturbative QCD than the individual cross sections. We have performed the first complete separation of the four unpolarized electromagnetic structure functions above the dominant resonances in forward, exclusive π(±) electroproduction on the deuteron at central Q(2) values of 0.6, 1.0, 1.6 GeV(2) at W=1.95 GeV, and Q(2)=2.45 GeV(2) at W=2.22 GeV. Here, we present the L and T cross sections, with emphasis on RL and RT, and compare them with theoretical calculations. Results for the separated ratio RL indicate dominance of the pion-pole diagram at low -t, while results for RT are consistent with a transition between pion knockout and quark knockout mechanisms.

First measurements of inclusive muon neutrino charged current differential cross sections on argon.

The ArgoNeuT Collaboration presents the first measurements of inclusive muon neutrino charged current differential cross sections on argon. Obtained in the NuMI neutrino beam line at Fermilab, the flux-integrated results are reported in terms of outgoing muon angle and momentum. The data are consistent with the Monte Carlo expectation across the full range of kinematics sampled, 0°<θ(µ)<36° and 0

Oxytocin: an emerging regulator of prolactin secretion in the female rat.

In the female rat, a complex interplay of both stimulatory and inhibitory hypothalamic factors controls the secretion of prolactin. Prolactin regulates a large number of physiological processes from immunity to stress. Here, we have chosen to focus on the control of prolactin secretion in the female rat in response to suckling, mating and ovarian steroids. In all three of these states, dopamine, released from neurones in the mediobasal hypothalamus, is a potent inhibitory signal regulating prolactin secretion. Early research has determined that the relief of dopaminergic tone is not sufficent to account for the full surge of prolactin secretion observed in response to the suckling stimulus, launching a search for possible prolactin-releasing factors. This research has subsequently broadened to include searching for prolactin-releasing factors controlling prolactin secretion after mating or ovarian steroids. A great deal of literature has suggested that this prolactin-releasing factor may include oxytocin. Oxytocin receptors are present on lactotrophs. These oxytocin receptors respond to exogenous oxytocin and antagonism of endogenous oxytocin inhibits lactotroph activity. In addition, the pattern of oxytocin neuronal activity and oxytocin release correlate with the release of prolactin. Here, we suggest not only that oxytocin is stimulating prolactin secretion, but also that prolactin secretion is controlled by a complex network of positive (oxytocin) and negative (dopamine) feedback loops. We discuss the available literature and attempt to describe the circuitry we believe may be responsible for controlling prolactin secretion.

A stromal cell-derived factor-1 releasing matrix enhances the progenitor cell response and blood vessel growth in ischaemic skeletal muscle.

Although many regenerative cell therapies are being developed to replace or regenerate ischaemic muscle, the lack of vasculature and poor persistence of the therapeutic cells represent major limiting factors to successful tissue restoration. In response to ischaemia, stromal cell-derived factor-1 (SDF-1) is up-regulated by the affected tissue to stimulate stem cell-mediated regenerative responses. Therefore, we encapsulated SDF-1 into alginate microspheres and further incorporated these into an injectable collagen-based matrix in order to improve local delivery. Microsphere-matrix impregnation reduced the time for matrix thermogelation, and also increased the viscosity reached. This double-incorporation prolonged the release of SDF-1, which maintained adhesive and migratory bioactivity, attributed to chemotaxis in response to SDF-1. In vivo, treatment of ischaemic hindlimb muscle with microsphere-matrix led to increased mobilisation of bone marrow-derived progenitor cells, and also improved recruitment of angiogenic cells expressing the SDF-1 receptor (CXCR4) from bone marrow and local tissues. Both matrix and SDF-1-releasing matrix were successful at restoring perfusion, but SDF-1 treatment appeared to play an earlier role, as evidenced by arterioles that are phenotypically older and by increased angiogenic cytokine production, stimulating the generation of a qualitative microenvironment for a rapid and therefore more efficient regeneration. These results support the release of implanted SDF-1 as a promising method for enhancing progenitor cell responses and restoring perfusion to ischaemic tissues via neovascularisation.

The small GTPase Cdc42 promotes membrane protrusion during polar body emission via ARP2-nucleated actin polymerization.

Polar body emission is a specialized cell division throughout the animal kingdom, serving to reduce chromosome ploidy while preserving the egg cytoplasm. Critical to polar body emission are the asymmetric positioning of the meiotic spindle prior to anaphase, with one pole attached to the oocyte cortex, and the simultaneous membrane protrusion during subsequent cytokinesis. We have shown that, during Xenopus oocyte maturation, the small GTPase Cdc42 promotes membrane protrusion while a classical RhoA contractile ring forms and constricts at the base of the protrusion. We report here that treating oocytes with low concentrations of nocodazole diminished the size of metaphase I spindles and prevented polar body emission, and yet an active Cdc42 cap of correspondingly diminished size still developed, on time, atop of the spindle pole. Conversely, treating oocytes with low concentrations of taxol resulted in a spindle with multiple poles attached to the cortex, but still each of these poles were associated with activated cortical Cdc42 at the appropriate time. Therefore, the asymmetric positioning of the meiotic spindle with one pole anchored to the cortex is a prerequisite for Cdc42 activation. Furthermore, we demonstrated that the Cdc42-regulated F-actin nucleator ARP2/3 complex was similarly localized at the cortex of the protruding polar body membrane, suggesting that Cdc42 promotes membrane protrusion through an F-actin meshwork mechanism. Finally, we demonstrated that Cdc42 and RhoA formed similarly complementary activity zones during egg activation and that inhibition of Cdc42 prevented second polar body emission. Therefore, Cdc42 activation likely promotes membrane protrusion during polar body emission in widespread systems.

Initial experience with a rapid access blackouts triage clinic.

Transient loss of consciousness (T-LOC), or blackout, is common in acute medicine. Clinical skills are not done well, with at least 74,000 patients misdiagnosed and mistreated for epilepsy in England alone. The aim of this study was to provide a rapid, structured assessment and an electrocardiogram (ECG) for patients with blackouts, aiming to identify high risk, reduce misdiagnoses, reduce hospital admission rates for low-risk patients, diagnose and treat where appropriate, and also provide onward specialist referral. The majority of patients had syncope, and very few had epilepsy. A high proportion had an abnormal ECG. A specialist-nurse-led rapid access blackouts triage clinic (RABTC) provided rapid effective triage for risk, a comprehensive assessment format, direct treatment for many patients, and otherwise a prompt appropriate onward referral. Rapid assessment through a RABTC reduced re-admissions with blackouts. Widespread use of the web-based blackouts tool could provide the NHS with a performance map. The U.K. has low rates of pacing compared to Western Europe, which RABTCs might help correct. The RABTC sits between first responders and specialist referral, providing clinical assessment and ECG in all cases, and referral where appropriate.

Hepatitis C testing practices and prevalence in a high-risk urban ambulatory care setting.

Approximately 3.2 million persons are chronically infected with the hepatitis C virus (HCV) in the U.S.; most are not aware of their infection. Our objectives were to examine HCV testing practices to determine which patient characteristics are associated with HCV testing and positivity, and to estimate the prevalence of HCV infection in a high-risk urban population. The study subjects were all patients included in the baseline phase of the Hepatitis C Assessment and Testing Project (HepCAT), a serial cross-sectional study of HCV screening strategies. We examined all patients with a clinic visit to Montefiore Medical Center from 1/1/08 to 2/29/08. Demographic information, laboratory data and ICD-9 diagnostic codes from 3/1/97-2/29/08 were extracted from the electronic medical record. Risk factors for HCV were defined based on birth date, ICD-9 codes and laboratory data. The prevalence of HCV infection was estimated assuming that untested subjects would test positive at the same rate as tested subjects, based on risk-factors. Of 9579 subjects examined, 3803 (39.7%) had been tested for HCV and 438 (11.5%) were positive. The overall prevalence of HCV infection was estimated to be 7.7%. Risk factors associated with being tested and anti-HCV positivity included: born in the high-prevalence birth-cohort (1945-64), substance abuse, HIV infection, alcohol abuse, diagnosis of cirrhosis, end-stage renal disease, and alanine transaminase elevation. In a high-risk urban population, a significant proportion of patients were tested for HCV and the prevalence of HCV infection was high. Physicians appear to use a risk-based screening strategy to identify HCV infection.

Precision measurement of neutrino oscillation parameters with KamLAND.

The KamLAND experiment has determined a precise value for the neutrino oscillation parameter Deltam21(2) and stringent constraints on theta12. The exposure to nuclear reactor antineutrinos is increased almost fourfold over previous results to 2.44 x 10(32) proton yr due to longer livetime and an enlarged fiducial volume. An undistorted reactor nu[over]e energy spectrum is now rejected at >5sigma. Analysis of the reactor spectrum above the inverse beta decay energy threshold, and including geoneutrinos, gives a best fit at Deltam21(2)=7.58(-0.13)(+0.14)(stat) -0.15+0.15(syst) x 10(-5) eV2 and tan2theta12=0.56(-0.07)+0.10(stat) -0.06+0.10(syst). Local Deltachi2 minima at higher and lower Deltam21(2) are disfavored at >4sigma. Combining with solar neutrino data, we obtain Deltam21(2)=7.59(-0.21)+0.21 x 10(-5) eV2 and tan2theta12=0.47(-0.05)+0.06.

Case report: severe acute Parkinsonism associated with streptococcal infection and antibasal ganglia antibodies.

We report the case of a young man who presented with a severe acute akinetic-rigid disorder 2 weeks after complete recovery from an episode of pharyngitis. Magnetic resonance imaging scan abnormalities strikingly localized to the basal ganglia were accompanied by serological evidence of recent streptococcal infection and the presence of anti-basal ganglia antibodies in the serum. The case represents an unusually clear example in the spectrum of inflammatory neurological disorders associated with streptococcal infection, an etiology that should be considered in the differential diagnosis of all acute onset movement disorders.

Sarcoidosis and HTLV-1 infection.

An asymptomatic, homosexual, white man was found to have an abnormal chest x ray. A presumptive diagnosis of sarcoidosis was made, but pulmonary function tests and a transbronchial biopsy were normal. He then remained asymptomatic for 10 years until he developed a progressive spastic paraparesis. At this point, antibodies to human T cell lymphotropic virus type 1 (HTLV-1) were identified in the serum and cerebrospinal fluid, and the diagnosis of HTLV-1 associated myelopathy was made, the history suggesting sexual exposure to HTLV-1 many years previously. HTLV-1 is associated with a spectrum of immune related disorders, including a pulmonary sarcoid-like syndrome. Infection with this chronic proinflammatory retrovirus should be considered in the differential diagnosis of all immune disorders in at risk individuals.

High-dose vitamin E supplementation does not diminish ribavirin-associated haemolysis in hepatitis C treatment with combination standard alpha-interferon and ribavirin.

BACKGROUND: Ribavirin is associated with haemolytic anaemia. Antioxidants have been reported to decrease severity of this anaemia. AIM: To determine effect of vitamin E supplementation on ribavirin-associated haemolysis in chronic hepatitis C treated with standard alpha-interferon and ribavirin. METHODS: Fifty-one naive chronic hepatitis C patients were randomized to receive either alpha-interferon/ribavirin therapy (control) or therapy plus vitamin E 800 IU b.d. with 24-week follow-up. Alanine aminotransferase ALT, haemoglobin and reticulocyte percentage were monitored. Symptoms and health-related quality of life were also monitored at each visit. RESULTS: Forty-seven subjects were treated (27 vitamin E /20 controls). Thirteen withdrew because of adverse effects or non-compliance. Groups were similar in demographics, genotype and baseline lab indices. Comparison with baseline, treatment and follow-up values showed a significant haemoglobin and ALT reduction in both groups. There was no significant difference in haemoglobin and reticulocyte percentage between groups. Sustained viral response was not significantly different between vitamin E (11/18) and control (6/16) groups. Three patients required ribavirin dose-reduction in the vitamin E group compared with two controls. Health-related quality of life during and end-of-treatment was not different between groups. CONCLUSIONS: Vitamin E supplementation alone during standard alpha-interferon and ribavirin therapy does not appear to diminish ribavirin-associated haemolysis.

Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors.

The peroxisome proliferator-activated receptors (PPARs) are transcriptional regulators of glucose, lipid, and cholesterol metabolism. We report the x-ray crystal structure of the ligand binding domain of PPAR alpha (NR1C1) as a complex with the agonist ligand GW409544 and a coactivator motif from the steroid receptor coactivator 1. Through comparison of the crystal structures of the ligand binding domains of the three human PPARs, we have identified molecular determinants of subtype selectivity. A single amino acid, which is tyrosine in PPAR alpha and histidine in PPAR gamma, imparts subtype selectivity for both thiazolidinedione and nonthiazolidinedione ligands. The availability of high-resolution cocrystal structures of the three PPAR subtypes will aid the design of drugs for the treatments of metabolic and cardiovascular diseases.

Longitudinal electroproduction of charged pions from (1)H, (2)H, and (3)He.

Separated longitudinal and transverse cross sections for charged pion electroproduction from (1)H, (2)H, and (3)He were measured at Q(2) = 0.4 (GeV/c)(2) for two values of the invariant mass, W = 1.15 GeV and W = 1.60 GeV, in a search for a mass dependence which would signal the effect of nuclear pions. This is the first such study that includes recoil momenta significantly above the Fermi surface. The longitudinal cross section, if dominated by the pion-pole process, should be sensitive to nuclear pion currents. Comparisons of the longitudinal cross section target ratios to a quasifree calculation reveal a significant suppression in (3)He at W = 1.60 GeV. The W = 1.15 GeV results are consistent with simple estimates of the effect of nuclear pion currents, but are also consistent with pure quasifree production.

Comparison of complete nuclear receptor sets from the human, Caenorhabditis elegans and Drosophila genomes.

BACKGROUND: The availability of complete genome sequences enables all the members of a gene family to be identified without limitations imposed by temporal, spatial or quantitative aspects of mRNA expression. Using the nearly completed human genome sequence, we combined in silico and experimental approaches to define the complete human nuclear receptor (NR) set. This information was used to carry out a comparative genomic study of the NR superfamily. RESULTS: Our analysis of the human genome identified two novel NR sequences. Both these contained stop codons within the coding regions, indicating that both are pseudogenes. One (HNF4 gamma-related) contained no introns and expressed no detectable mRNA, whereas the other (FXR-related) produced mRNA at relatively high levels in testis. If translated, the latter is predicted to encode a short, non-functional protein. Our analysis indicates that there are fewer than 50 functional human NRs, dramatically fewer than in Caenorhabditis elegans and about twice as many as in Drosophila. Using the complete human NR set we made comparisons with the NR sets of C. elegans and Drosophila. Searches for the >200 NRs unique to C. elegans revealed no human homologs. The comparative analysis also revealed a Drosophila member of NR subfamily NR3, confirming an ancient metazoan origin for this subfamily. CONCLUSIONS: This work provides the basis for new insights into the evolution and functional relationships of NR superfamily members.

Regulation of the human CYP2B6 gene by the nuclear pregnane X receptor.

Cytochromes P450 (P450s) are involved in the oxidative metabolism of a plethora of structurally unrelated compounds, including therapeutic drugs. Two orphan members of the nuclear receptor superfamily, the pregnane X receptor (PXR; NR1I2) and constitutive androstane receptor (CAR; NR1I3) have been implicated in this phenomenon. In the present study, we examined the transcriptional regulation of the human CYP2B6 gene. In primary cultures of human hepatocytes, CYP2B6 was highly inducible by a number of compounds known to be human PXR ligands, including rifampicin and hyperforin. PXR was shown to be capable of activating the phenobarbital-responsive enhancer module (PBREM) region of the CYP2B6 gene, a 51-base-pair enhancer element that mediates induction of CYP2B6 expression by CAR. The two nuclear receptor-binding motifs within the PBREM effectively bound PXR as a heterodimer with the 9-cis retinoic acid receptor alpha (NR2B1). Taken together, these observations demonstrate that the CYP2B6 gene is directly regulated by PXR and further establish this receptor as a key regulator of drug-metabolizing P450s.