Immunotherapies for hepatocellular carcinoma

Cases of hepatocellular carcinoma (HCC) are rapidly rising. This is particularly the case in the Western world, as a result of increasing rates of chronic liver disease, secondary to lifestyle-associated risk factors and the lack of an established screening programme for the general population. Traditionally, radical/curative treatment options for HCC, including liver transplantation and surgical resection are reserved for the minority of patients, presenting with an early stage cancer. For patients with advanced disease, Sorafenib and Lenvatinib were, until recently, the only licensed systemic treatments, and provided only limited survival benefits at the cost of a multitude of potential side effects. Recent scientific advances in the field of cancer immunotherapy have renewed significant interest in advanced HCC, in order to fulfil this apparent area of unmet clinical need. This has led to the success and recent regulatory approval of an Atezolizumab/Bevacizumab combination for the first-line treatment of advanced HCC following results from the IMbrave150 clinical trial in 2019, with further immune checkpoint inhibitors currently undergoing testing in advanced clinical trials. Furthermore, other cancer immunotherapies, including chimeric antigen receptor T-cells, dendritic cell vaccines and oncolytic viruses are also in early stage clinical trials, for the treatment of advanced HCC. This review will summarise the major approaches that have been and are currently in development for the systemic treatment of advanced HCC, their advantages, drawbacks, and predictions of where this revolutionary treatment field will continue to travel for the foreseeable future

Sr-Nd isotope geochemistry of the early Precambrian sub-alkaline mafic igneous rocks from the southern Bastar craton, Central India

Sr–Nd isotope data are reported for the early Precambrian sub-alkaline mafic igneous rocks of the southern Bastar craton, central India. These mafic rocks are mostly dykes but there are a few volcanic exposures. Field relationships together with the petrological and geochemical characteristics of these mafic dykes divide them into two groups; Meso-Neoarchaean sub-alkaline mafic dykes (BD1) and Paleoproterozoic (1.88 Ga) sub-alkaline mafic dykes (BD2). The mafic volcanics are Neoarchaean in age and have very close geochemical relationships with the BD1 type. The two groups have distinctly different concentrations of high-field strength (HFSE) and rare earth elements (REE). The BD2 dykes have higher concentrations of HFSE and REE than the BD1 dykes and associated volcanics and both groups have very distinctive petrogenetic histories. These rocks display a limited range of initial 143Nd/144Nd but a wide range of apparent initial 87Sr/86Sr. Initial 143Nd/144Nd values in the BD1 dykes and associated volcanics vary between 0.509149 and 0.509466 and in the BD2 dykes the variation is between 0.510303 and 0.510511. All samples have positive εNd values the BD1 dykes and associated volcanics have εNd values between +0.3 and +6.5 and the BD2 dykes between +1.9 to +6.0. Trace element and Nd isotope data do not suggest severe crustal contamination during the emplacement of the studied rocks. The positive εNd values suggest their derivation from a depleted mantle source. Overlapping positive εNd values suggest that a similar mantle source tapped by variable melt fractions at different times was responsible for the genesis of BD1 (and associated volcanics) and BD2 mafic dykes. The Rb–Sr system is susceptible to alteration and resetting during post-magmatic alteration and metamorphism. Many of the samples studied have anomalous apparent initial 87Sr/86Sr suggesting post-magmatic changes of the Rb–Sr system which severely restricts the use of Rb–Sr for petrogenetic interpretation

Predictive value of less than moderate residual mitral regurgitation as assessed by transesophageal echocardiography for the short-term outcomes of patients with mitral regurgitation treated with mitral valve repair

<p>Abstract</p> <p>Background</p> <p>Traditionally, in patients with mitral regurgitation (MR) a successful mitral valve repair is considered when residual MR by post-pump transesophageal echocardiography (TEE) is less than moderate or absent. Little is known about the prognostic value of less than moderate (mild or mild-to-moderate) residual MR for the early outcome of patients treated with mitral valve repair.</p> <p>Methods</p> <p>Eligible for this study were patients undergoing isolated mitral valve repair. Patients with moderate or severe residual MR after valve repair were excluded. The primary endpoint of the study was the composite of death or need of reintervention.</p> <p>Results</p> <p>A total of 98 patients (54 with no residual MR-Group 1, and 44 with less than moderate residual MR-Group 2) were analyzed. Of these, 72% presented with New York Heart Association (NYHA) 3/4, and 38% were women. The primary endpoint of the study occurred in 3 (5.5%) patients in Group 1 and 6 (13.6%) patients in Group 2 MR (<it>P </it>= 0.31). There was a trend toward a higher incidence of use of inotropic drugs post-interventional (<it>P </it>= 0.12), and a longer hospital stay among patients with less than moderate residual MR (<it>P </it>= 0.18).</p> <p>Conclusion</p> <p>In our study population, patients with less than moderate residual MR had a trend toward a higher risk of early adverse outcomes as compared with patients with no residual MR by post-pump TEE. Studies with a larger patient population and longer follow-up data may be useful to better define the clinical significance of residual mild MR after mitral vale repair.</p

Inflammatory cytokines and biofilm production sustain Staphylococcus aureus outgrowth and persistence: A pivotal interplay in the pathogenesis of Atopic Dermatitis

Individuals with Atopic dermatitis (AD) are highly susceptible to Staphylococcus aureus colonization. However, the mechanisms driving this process as well as the impact of S. aureus in AD pathogenesis are still incompletely understood. In this study, we analysed the role of biofilm in sustaining S. aureus chronic persistence and its impact on AD severity. Further we explored whether key inflammatory cytokines overexpressed in AD might provide a selective advantage to S. aureus. Results show that the strength of biofilm production by S. aureus correlated with the severity of the skin lesion, being significantly higher (P < 0.01) in patients with a more severe form of the disease as compared to those individuals with mild AD. Additionally, interleukin (IL)-β and interferon γ (IFN-γ), but not interleukin (IL)-6, induced a concentration-dependent increase of S. aureus growth. This effect was not observed with coagulase-negative staphylococci isolated from the skin of AD patients. These findings indicate that inflammatory cytokines such as IL1-β and IFN-γ, can selectively promote S. aureus outgrowth, thus subverting the composition of the healthy skin microbiome. Moreover, biofilm production by S. aureus plays a relevant role in further supporting chronic colonization and disease severity, while providing an increased tolerance to antimicrobials

Global Assessment of Extinction Risk to Populations of Sockeye Salmon Oncorhynchus nerka

BACKGROUND: Concern about the decline of wild salmon has attracted the attention of the International Union for the Conservation of Nature (IUCN). The IUCN applies quantitative criteria to assess risk of extinction and publishes its results on the Red List of Threatened Species. However, the focus is on the species level and thus may fail to show the risk to populations. The IUCN has adapted their criteria to apply to populations but there exist few examples of this type of assessment. We assessed the status of sockeye salmon Oncorhynchus nerka as a model for application of the IUCN population-level assessments and to provide the first global assessment of the status of an anadromous Pacific salmon. METHODS/PRINCIPAL FINDINGS: We found from demographic data that the sockeye salmon species is not presently at risk of extinction. We identified 98 independent populations with varying levels of risk within the species' range. Of these, 5 (5%) are already extinct. We analyzed the risk for 62 out of 93 extant populations (67%) and found that 17 of these (27%) are at risk of extinction. The greatest number and concentration of extinct and threatened populations is in the southern part of the North American range, primarily due to overfishing, freshwater habitat loss, dams, hatcheries, and changing ocean conditions. CONCLUSIONS/SIGNIFICANCE: Although sockeye salmon are not at risk at the species-level, about one-third of the populations that we analyzed are at risk or already extinct. Without an understanding of risk to biodiversity at the level of populations, the biodiversity loss in salmon would be greatly underrepresented on the Red List. We urge government, conservation organizations, scientists and the public to recognize this limitation of the Red List. We also urge recognition that about one-third of sockeye salmon global population diversity is at risk of extinction or already extinct

Retuning of Inferior Colliculus Neurons Following Spiral Ganglion Lesions: A Single-Neuron Model of Converging Inputs

Lesions of spiral ganglion cells, representing a restricted sector of the auditory nerve array, produce immediate changes in the frequency tuning of inferior colliculus (IC) neurons. There is a loss of excitation at the lesion frequencies, yet responses to adjacent frequencies remain intact and new regions of activity appear. This leads to immediate changes in tuning and in tonotopic progression. Similar effects are seen after different methods of peripheral damage and in auditory neurons in other nuclei. The mechanisms that underlie these postlesion changes are unknown, but the acute effects seen in IC strongly suggest the “unmasking” of latent inputs by the removal of inhibition. In this study, we explore computational models of single neurons with a convergence of excitatory and inhibitory inputs from a range of characteristic frequencies (CFs), which can simulate the narrow prelesion tuning of IC neurons, and account for the changes in CF tuning after a lesion. The models can reproduce the data if inputs are aligned relative to one another in a precise order along the dendrites of model IC neurons. Frequency tuning in these neurons approximates that seen physiologically. Removal of inputs representing a narrow range of frequencies leads to unmasking of previously subthreshold excitatory inputs, which causes changes in CF. Conversely, if all of the inputs converge at the same point on the cell body, receptive fields are broad and unmasking rarely results in CF changes. However, if the inhibition is tonic with no stimulus-driven component, then unmasking can still produce changes in CF

Measurements of neutrino oscillation in appearance and disappearance channels by the T2K experiment with 6.6 x 10(20) protons on target

111 pages, 45 figures, submitted to Physical Review D. Minor revisions to text following referee comments111 pages, 45 figures, submitted to Physical Review D. Minor revisions to text following referee comments111 pages, 45 figures, submitted to Physical Review D. Minor revisions to text following referee commentsWe thank the J-PARC staff for superb accelerator performance and the CERN NA61/SHINE Collaboration for providing valuable particle production data. We acknowledge the support of MEXT, Japan; NSERC, NRC, and CFI, Canada; CEA and CNRS/IN2P3, France; DFG, Germany; INFN, Italy; National Science Centre (NCN), Poland; RSF, RFBR and MES, Russia; MINECO and ERDF funds, Spain; SNSF and SER, Switzerland; STFC, UK; and the U. S. Deparment of Energy, USA. We also thank CERN for the UA1/NOMAD magnet, DESY for the HERA-B magnet mover system, NII for SINET4, the WestGrid and SciNet consortia in Compute Canada, GridPP, UK, and the Emerald High Performance Computing facility in the Centre for Innovation, UK. In addition, participation of individual researchers and institutions has been further supported by funds from ERC (FP7), EU; JSPS, Japan; Royal Society, UK; and DOE Early Career program, USA

Measurement of the electron neutrino charged-current interaction rate on water with the T2K ND280 pi(0) detector

10 pages, 6 figures, Submitted to PRDhttp://journals.aps.org/prd/abstract/10.1103/PhysRevD.91.112010© 2015 American Physical Society11 pages, 6 figures, as accepted to PRD11 pages, 6 figures, as accepted to PRD11 pages, 6 figures, as accepted to PR

A general scenario of Hox gene inventory variation among major sarcopterygian lineages

<p>Abstract</p> <p>Background</p> <p><it>H</it>ox genes are known to play a key role in shaping the body plan of metazoans. Evolutionary dynamics of these genes is therefore essential in explaining patterns of evolutionary diversity. Among extant sarcopterygians comprising both lobe-finned fishes and tetrapods, our knowledge of the <it>Hox </it>genes and clusters has largely been restricted in several model organisms such as frogs, birds and mammals. Some evolutionary gaps still exist, especially for those groups with derived body morphology or occupying key positions on the tree of life, hindering our understanding of how <it>Hox </it>gene inventory varied along the sarcopterygian lineage.</p> <p>Results</p> <p>We determined the <it>Hox </it>gene inventory for six sarcopterygian groups: lungfishes, caecilians, salamanders, snakes, turtles and crocodiles by comprehensive PCR survey and genome walking. Variable <it>Hox </it>genes in each of the six sarcopterygian group representatives, compared to the human <it>Hox </it>gene inventory, were further validated for their presence/absence by PCR survey in a number of related species representing a broad evolutionary coverage of the group. Turtles, crocodiles, birds and placental mammals possess the same 39 <it>Hox </it>genes. <it>HoxD12 </it>is absent in snakes, amphibians and probably lungfishes. <it>HoxB13 </it>is lost in frogs and caecilians. Lobe-finned fishes, amphibians and squamate reptiles possess <it>HoxC3</it>. <it>HoxC1 </it>is only present in caecilians and lobe-finned fishes. Similar to coelacanths, lungfishes also possess <it>HoxA14</it>, which is only found in lobe-finned fishes to date. Our <it>Hox </it>gene variation data favor the lungfish-tetrapod, turtle-archosaur and frog-salamander relationships and imply that the loss of <it>HoxD12 </it>is not directly related to digit reduction.</p> <p>Conclusions</p> <p>Our newly determined <it>Hox </it>inventory data provide a more complete scenario for evolutionary dynamics of <it>Hox </it>genes along the sarcopterygian lineage. Limbless, worm-like caecilians and snakes possess similar <it>Hox </it>gene inventories to animals with less derived body morphology, suggesting changes to their body morphology are likely due to other modifications rather than changes to <it>Hox </it>gene numbers. Furthermore, our results provide basis for future sequencing of the entire <it>Hox </it>clusters of these animals.</p