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'.

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.

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.

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

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.

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.

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.

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.

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.

The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions.

The cytochrome P-450 monooxygenase 3A4 (CYP3A4) is responsible for the oxidative metabolism of a wide variety of xenobiotics including an estimated 60% of all clinically used drugs. Although expression of the CYP3A4 gene is known to be induced in response to a variety of compounds, the mechanism underlying this induction, which represents a basis for drug interactions in patients, has remained unclear. We report the identification of a human (h) orphan nuclear receptor, termed the pregnane X receptor (PXR), that binds to a response element in the CYP3A4 promoter and is activated by a range of drugs known to induce CYP3A4 expression. Comparison of hPXR with the recently cloned mouse PXR reveals marked differences in their activation by certain drugs, which may account in part for the species-specific effects of compounds on CYP3A gene expression. These findings provide a molecular explanation for the ability of disparate chemicals to induce CYP3A4 levels and, furthermore, provide a basis for developing in vitro assays to aid in predicting whether drugs will interact in humans.

Structure of the Tie2 RTK domain: self-inhibition by the nucleotide binding loop, activation loop, and C-terminal tail.

BACKGROUND: Angiogenesis, the formation of new vessels from the existing vasculature, is a critical process during early development as well as in a number of disease processes. Tie2 (also known as Tek) is an endothelium-specific receptor tyrosine kinase involved in both angiogenesis and vasculature maintenance. RESULTS: We have determined the crystal structure of the Tie2 kinase domain to 2.2 A resolution. The structure contains the catalytic core, the kinase insert domain (KID), and the C-terminal tail. The overall fold is similar to that observed in other serine/threonine and tyrosine kinase structures; however, several unique features distinguish the Tie2 structure from those of other kinases. The Tie2 nucleotide binding loop is in an inhibitory conformation, which is not seen in other kinase structures, while its activation loop adopts an "activated-like" conformation in the absence of phosphorylation. Tyr-897, located in the N-terminal domain, may negatively regulate the activity of Tie2 by preventing dimerization of the kinase domains or by recruiting phosphatases when it is phosphorylated. CONCLUSION: Regulation of the kinase activity of Tie2 is a complex process. Conformational changes in the nucleotide binding loop, activation loop, C helix, and the C-terminal tail are required for ATP and substrate binding.

Expression of wild-type estrogen receptor beta and variant isoforms in human breast cancer.

It has been shown in previous studies that a variety of estrogen receptor (ER) beta mRNA transcripts are expressed in human breast cancer cell lines and tumors. To complement the RNA expression studies, we have developed ER-beta-specific antibodies to characterize ER-beta protein expression in breast cancer cell lines and tumors. Monoclonal antibodies were made against a peptide representing the first 18 amino acids of the longest ER-beta open reading frame reported to date, and polyclonal antibodies were made against a peptide within the ER-beta B domain. By Western blot analysis, we show that ER-beta protein is expressed in all cancer cell lines tested and in three of five breast tumor samples. The breast cancer cell lines showed variation in the size of the expressed ER-beta protein. The longest form detected was consistent with the 530-amino acid, full-length ER-beta sequence. Shorter ER-beta isoforms were detected in the ER-alpha-negative MDA-MB-231 and MDA-MB-435 breast cancer cell lines, likely corresponding to previously described COOH-terminal RNA variant isoforms.

Randomized, double-blind, placebo-controlled dose-ranging study of tirofiban (MK-383) platelet IIb/IIIa blockade in high risk patients undergoing coronary angioplasty.

OBJECTIVES: The objectives of this double-blind, placebo-controlled, randomized dose-ranging study were 1) to examine the safety and tolerability of tirofiban (MK-383), a new nonpeptide platelet IIb/IIIa receptor antagonist, on a background of intravenous heparin and aspirin therapy; 2) to study the pharmacodynamics and pharmacokinetics of tirofiban; and 3) to evaluate the incidence of adverse cardiac outcomes (urgent repeat revascularization, myocardial infarction and death) with tirofiban versus placebo in a high risk subset of patients undergoing coronary angioplasty. BACKGROUND: Abrupt vessel closure complicates 4% to 8% of angioplasty procedures. Recent data have suggested that agents that antagonize the platelet glycoprotein IIb/IIIa receptor may reduce the incidence of adverse ischemic outcomes after coronary angioplasty. METHODS: Seventy-three patients received tirofiban in three sequential dose panels and 20 patients received placebo. Patients within each panel were randomized to receive either tirofiban or placebo in a 3:1 randomization design. Bolus doses of 5, 10 and 10 microg/kg and continuous infusion (16 to 24 h) doses of 0.05, 0.10 and 0.15 microg/kg per min were administered in panels I, II and III, respectively. Patients received concomitant heparin and aspirin for the angioplasty procedure. Data on patients receiving placebo (heparin and aspirin only) were pooled across panels for comparisons. The pharmacodynamic effect of tirofiban on ex vivo platelet aggregation to 5 micromol/liter adenosine diphosphate (ADP) and bleeding times were measured. Clinical outcomes were assessed in all patients, but the power to detect clinically meaningful differences (a one-third reduction in clinical events) between groups was limited (5%). RESULTS: Tirofiban was associated with a dose-dependent inhibition of ex vivo ADP-mediated platelet aggregation that was sustained during intravenous infusion and resolved rapidly after drug cessation. Adverse bleeding events, largely related to vascular access site hemorrhage, were slightly increased at the highest dose. Adverse clinical outcomes were infrequent in all patients and were not different among the small number of patients within each group. CONCLUSIONS: This study establishes a rational and generally well tolerated dosing regimen for administration of tirofiban as adjunctive therapy in high risk angioplasty patients. The impact of tirofiban on adverse clinical outcomes after angioplasty awaits definition by a larger clinical trial.

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.

The pregnane X receptor: a promiscuous xenobiotic receptor that has diverged during evolution.

Transcription of genes encoding cytochrome P450 3A (CYP3A) monooxygenases is induced by a variety of xenobiotics and natural steroids. There are marked differences in the compounds that induce CYP3A gene expression between species. Recently, the mouse and human pregnane X receptor (PXR) were shown to be activated by compounds that induce CYP3A expression. However, most studies of CYP3A regulation have been performed using rabbit and rat hepatocytes. Here, we report the cloning and characterization of PXR from these two species. PXR is remarkably divergent between species, with the rabbit, rat, and human receptors sharing only approximately 80% amino acid identity in their ligand-binding domains. This sequence divergence is reflected by marked pharmacological differences in PXR activation profiles. For example, the macrolide antibiotic rifampicin, the antidiabetic drug troglitazone, and the hypocholesterolemic drug SR12813 are efficacious activators of the human and rabbit PXR but have little activity on the rat and mouse PXR. Conversely, pregnane 16alpha-carbonitrile is a more potent activator of the rat and mouse PXR than the human and rabbit receptor. The activities of xenobiotics in PXR activation assays correlate well with their ability to induce CYP3A expression in primary hepatocytes. Through the use of a novel scintillation proximity binding assay, we demonstrate that many of the compounds that induce CYP3A expression bind directly to human PXR. These data establish PXR as a promiscuous xenobiotic receptor that has diverged during evolution.

Short-term behavioral effects of beta-adrenergic medications in men with mild hypertension.

beta-Adrenergic-inhibiting drugs are widely prescribed for the treatment of hypertension. These drugs have previously been found to influence a variety of psychologic and behavioral functions and have, in some cases, been associated with serious psychiatric side effects. The present study examined psychologic changes associated with beta-blockade therapy. Twenty-six men with mild hypertension (diastolic blood pressure 90 to 110 mm Hg) were randomly assigned to receive either a selective beta 1-antagonist (atenolol), a nonselective beta 1- and beta 2-antagonist (propranolol), or a placebo. Both before and after a 2-week period of drug administration, subjects completed a comprehensive assessment of quality of life including measures of mood, memory performance, and side effects. In general, beta-blocker therapy was associated with relatively few adverse symptoms, particularly when compared with control subjects taking placebo. Reductions in negative emotional states (tension and anger) were observed for subjects receiving atenolol, and the largest improvements in memory performance were observed for subjects receiving propranolol. These results suggest that beta-blocker therapy is not invariably associated with negative side effects and that some behavioral functions may actually be improved.

Fear of pain in orofacial pain patients.

In the present study, we examined whether fear of pain, dental fear, general indices of psychological distress, and self-reported stress levels differed between 40 orofacial pain patients and 40 gender and age matched control general dental patients. We also explored how fear of pain, as measured by the Fear of Pain Questionnaire-III (J Behav Med 21 (1998) 389), relates to established measures of psychological problems in our sample of patients. Finally, we examined whether fear of pain uniquely and significantly predicts dental fear and psychological distress relative to other theoretically-relevant psychological factors. Our results indicate that fear of severe pain and anxiety-related distress, broadly defined, are particularly elevated in orofacial pain patients relative to matched controls. Additionally, fear of pain shares a significant relation with dental fear but not other general psychological symptomology, and uniquely and significantly predicts dental fear relative to other theoretically-relevant variables. Taken together, these data, in conjunction with other recent studies, suggest greater attention be placed on understanding the fear of pain in orofacial pain patients and its relation to dental fear and anxiety.

(1-Pyrenylmethyl)amino alcohols, a new class of antitumor DNA intercalators. Discovery and initial amine side chain structure-activity studies.

In the series of 1-pyrenylmethylamines studied in this work the relationships among structure, interaction with DNA, and murine antitumor activity were examined. Binding studies show that all of these 1-pyrenylmethylamine derivatives bind to some extent to DNA by intercalation. The presence of additional basic amine groups in the side chain enhances DNA binding due to electrostatic interactions. Those compounds containing only a single basic benzylic amine bind similarly to DNA. Only the presence of bulky side chains appears to decrease the DNA interactions in the compounds examined. Although antitumor activity is seen for (1-pyrenylmethyl)amino alcohols, useful antitumor activity in the series is limited to those congeners bearing the 2-amino-1,3-propanediol-type side chain. These derivatives bind moderately to DNA. DNA binding is a necessary but not sufficient criterion for antitumor activity in the series. In addition, the strength of DNA binding does not correlate with the antitumor activity in the group of active compounds. Three related 2-[(arylmethyl)amino]-1,3-propanediol derivatives (AMAPs) [crisnatol (770U82), 773U82, and 502U83] are currently in clinical trials as potential antitumor agents.

2-[(arylmethyl) amino]-2-methyl-1,3-propanediol DNA intercalators. An examination of the effects of aromatic ring variation on antitumor activity and DNA binding.

The effects of variation of aromatic ring size, shape, and side-chain position on antitumor activity and DNA binding in a series of carbocyclic 2-[(arylmethyl)amino]-2-methyl-1,3-propanediols (AMAPs) were examined. In general, the interaction of AMAPs with DNA increases as the intercalating ring system grows in area, with three distinct binding levels evident. Isomers from a specific ring system appear to bind DNA similarly. DNA binding is not the sole criterion for antitumor activity for the AMAPs studied; the magnitude of the delta Tm does not correlate with the antitumor activity observed. Significant in vivo P388 activity was seen for AMAP congeners from several tetracyclic ring systems. However, isomers from each of the specific ring systems produced a wide range of in vivo P388 activity. Thus, AMAP antitumor activity is not a function of the ring system per se, but rather appears to be related to the shape of the specific molecule. Three AMAP congeners (crisnatol (770U82, 773U82, and 502U83) are currently in clinical trials.