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Sitravatinib is an immunomodulatory tyrosine kinase inhibitor that can augment responses when combined with programmed death-1 inhibitors such as nivolumab. We report a single-arm, interventional, phase 2 study of neoadjuvant sitravatinib in combination with nivolumab in patients with locally advanced clear cell renal cell carcinoma (ccRCC) prior to curative nephrectomy (NCT03680521). The primary endpoint was objective response rate (ORR) prior to surgery with a null hypothesis ORR = 5% and the alternative hypothesis set at ORR = 30%. Secondary endpoints were safety; pharmacokinetics (PK) of sitravatinib; immune effects, including changes in programmed cell death–ligand 1 expression; time-to-surgery; and disease-free survival (DFS). Twenty patients were evaluable for safety and 17 for efficacy. The ORR was 11.8%, and 24-month DFS probability was 88·0% (95% CI 61.0 to 97.0). There were no grade 4/5 treatment-related adverse events. Sitravatinib PK did not change following the addition of nivolumab. Correlative blood and tissue analyses showed changes in the tumour microenvironment resulting in an immunologically active tumour by the time of surgery (median time-to-surgery: 50 days). The primary endpoint of this study was not met as short-term neoadjuvant sitravatinib and nivolumab did not substantially increase ORR. In patients with locally advanced clear cell renal cell carcinoma (ccRCC), neoadjuvant therapy prior to curative nephrectomy has been shown to improve patient outcomes. Here, the authors report the safety and radiological efficacy of a phase II clinical trial investigating neoadjuvant sitravatinib (tyrosine kinase inhibitor) and nivolumab (PD-1 inhibitor) in locally advanced ccRCC. [ABSTRACT FROM AUTHOR]

Chimaeras, or ratfishes, are the only extant group of holocephalan fishes and are the sole host group of gyrocotylidean cestodes, which represent a sister group of the true tapeworms (Eucestoda). These unique, non-segmented cestodes have been known since the 1850s and multiple species and genera have been erected despite a general agreement that the delineation of species on the basis of morphology is effectively impossible. Thus, in the absence of molecular studies, the validity of gyrocotylid taxa and their specific host associations has remained highly speculative. Here we report the presence of Gyrocotyle spp. from rarely-caught deep-sea chimaeras collected in the North-East Atlantic, and describe two new species: G. haffii n. sp. from the bent-nose chimaera, Harriota raleighana Goode & Bean, and G. discoveryi n. sp. from the large-eyed rabbit fish, Hydrolagus mirabilis (Collett). Nuclear ribosomal sequence data were generated for individual parasites taken from different host species collected on different dates and from different localities and were combined with previously published sequences. Phylogenetic analyses supported the recognition of independent lineages and clusters, indicative of species, but were indecisive in recovering the root of the tree in analyses that included non-gyrocotylid outgroup taxa. The molecular data reveal variation not reflected in morphology and point to a complex picture of genetic divergence shaped by both isolation and migration in the deep-sea environment. [ABSTRACT FROM AUTHOR]

Checkpoint inhibitor therapy has led to major treatment advances for several cancers including non-small cell lung cancer (NSCLC). Despite this, a significant percentage of patients do not respond or develop resistance. Potential mechanisms of resistance include lack of expression of programmed death ligand 1 (PD-L1), decreased capacity to present tumor antigens, and the presence of an immunosuppressive tumor microenvironment. Mocetinostat is a spectrum-selective inhibitor of class I/IV histone deacetylases (HDACs), a family of proteins implicated in epigenetic silencing of immune regulatory genes in tumor and immune cells. Mocetinostat upregulated PD-L1 and antigen presentation genes including class I and II human leukocyte antigen (HLA) family members in a panel of NSCLC cell lines in vitro. Mocetinostat target gene promoters were occupied by a class I HDAC and exhibited increased active histone marks after mocetinostat treatment. Mocetinostat synergized with interferon γ (IFN-γ) in regulating class II transactivator (CIITA), a master regulator of class II HLA gene expression. In a syngeneic tumor model, mocetinostat decreased intratumoral T-regulatory cells (Tregs) and potentially myeloid-derived suppressor cell (MDSC) populations and increased intratumoral CD8+ populations. In ex vivo assays, patient-derived, mocetinostat-treated Tregs also showed significant down regulation of FOXP3 and HELIOS. The combination of mocetinostat and a murine PD-L1 antibody antagonist demonstrated increased anti-tumor activity compared to either therapy alone in two syngeneic tumor models. Together, these data provide evidence that mocetinostat modulates immune-related genes in tumor cells as well as immune cell types in the tumor microenvironment and enhances checkpoint inhibitor therapy. [ABSTRACT FROM AUTHOR]

The success of any population translocation programme relies heavily on the measures implemented to control and monitor the spread of disease. Without these measures, programmes run the risk of releasing immunologically naïve species or, more dangerously, introducing novel infectious agents to native populations. As a precaution, a reintroduction programme for the common or hazel dormouse, Muscardinus avellanarius, in England screens dormice before release following captive breeding. Using PCR sequencing of a range of genes, we tested whether the same species of tapeworm(s) were present in captive and free-living dormice. Whilst only Rodentolepis straminea were identified in free-living dormice, cestode ova found in a captive individual produced a molecular match closely related to Hymenolepis microstoma and a previously unrecorded Rodentolepis species. To prevent putting at risk the free-living population, we recommended the continued treatment of dormice showing tapeworm infection before release. Our work demonstrates how molecular techniques can be used to inform reintroduction programmes, reduce risk from disease and increase chances of reintroduction success. [ABSTRACT FROM AUTHOR]

Wnt genes encode secreted glycoproteins that act in cell-cell signalling to regulate a wide array of developmental processes, ranging from cellular differentiation to axial patterning. Discovery that canonical Wnt/β-catenin signalling is responsible for regulating head/tail specification in planarian regeneration has recently highlighted their importance in flatworm (phylum Platyhelminthes) development, but examination of their roles in the complex development of the diverse parasitic groups has yet to be conducted. Here, we characterise Wnt genes in the model tapeworm Hymenolepis microstoma and mine genomic resources of free-living and parasitic species for the presence of Wnts and downstream signalling components. We identify orthologs through a combination of BLAST and phylogenetic analyses, showing that flatworms have a highly reduced and dispersed complement that includes orthologs of only five subfamilies (Wnt1, Wnt2, Wnt4, Wnt5 and Wnt11) and fewer paralogs in parasitic flatworms (5-6) than in planarians (9). All major signalling components are identified, including antagonists and receptors, and key binding domains are intact, indicating that the canonical (Wnt/β-catenin) and non-canonical (planar cell polarity and Wnt/Ca) pathways are functional. RNA-Seq data show expression of all Hymenolepis Wnts and most downstream components in adults and larvae with the notable exceptions of wnt1, expressed only in adults, and wnt2 expressed only in larvae. The distribution of Wnt subfamilies in animals corroborates the idea that the last common ancestor of the Cnidaria and Bilateria possessed all contemporary Wnts and highlights the extent of gene loss in flatworms. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDA) is a lethal disease. Overall survival is typically 6 months from diagnosis. Numerous phase 3 trials of agents effective in other malignancies have failed to benefit unselected PDA populations, although patients do occasionally respond. Studies in other solid tumors have shown that heterogeneity in response is determined, in part, by molecular differences between tumors. Furthermore, treatment outcomes are improved by targeting drugs to tumor subtypes in which they are selectively effective, with breast and lung cancers providing recent examples. Identification of PDA molecular subtypes has been frustrated by a paucity of tumor specimens available for study. We have overcome this problem by combined analysis of transcriptional profiles of primary PDA samples from several studies, along with human and mouse PDA cell lines. We define three PDA subtypes: classical, quasimesenchymal and exocrine-like, and we present evidence for clinical outcome and therapeutic response differences between them. We further define gene signatures for these subtypes that may have utility in stratifying patients for treatment and present preclinical model systems that may be used to identify new subtype specific therapies. [ABSTRACT FROM AUTHOR]

Seismic waves sampling the top 100 km of the Earth's inner core reveal that the eastern hemisphere (40° E–180° E) is seismically faster, more isotropic and more attenuating than the western hemisphere. The origin of this hemispherical dichotomy is a challenging problem for our understanding of the Earth as a system of dynamically coupled layers. Previously, laboratory experiments have established that thermal control from the lower mantle can drastically affect fluid flow in the outer core, which in turn can induce textural heterogeneity on the inner core solidification front. The resulting texture should be consistent with other expected manifestations of thermal mantle control on the geodynamo, specifically magnetic flux concentrations in the time-average palaeomagnetic field over the past 5 Myr, and preferred eddy locations in flows imaged below the core–mantle boundary by the analysis of historical geomagnetic secular variation. Here we show that a single model of thermochemical convection and dynamo action can account for all these effects by producing a large-scale, long-term outer core flow that couples the heterogeneity of the inner core with that of the lower mantle. The main feature of this thermochemical ‘wind’ is a cyclonic circulation below Asia, which concentrates magnetic field on the core–mantle boundary at the observed location and locally agrees with core flow images. This wind also causes anomalously high rates of light element release in the eastern hemisphere of the inner core boundary, suggesting that lateral seismic anomalies at the top of the inner core result from mantle-induced variations in its freezing rate. [ABSTRACT FROM AUTHOR]

The dipole moment of Earth’s magnetic field has decreased by nearly % MathType!Translator!2!1!AMS LaTeX.tdl!TeX -- AMS-LaTeX!% MathType!MTEF!2!1!+-% feaaeaart1ev0aaatCvAUfeBSjuyZL2yd9gzLbvyNv2CaerbuLwBLn% hiov2DGi1BTfMBaeXatLxBI9gBaerbd9wDYLwzYbItLDharqqtubsr% 4rNCHbGeaGqiVu0Je9sqqrpepC0xbbL8F4rqqrFfpeea0xe9Lq-Jc9% vqaqpepm0xbba9pwe9Q8fs0-yqaqpepae9pg0FirpepeKkFr0xfr-x% fr-xb9adbaqaaeGaciGaaiaabeqaamaabaabaaGcbaGaaGyoaiaacw% caaaa!3755! $$9\% $$ over the past 150 years and by about 30% over the past 2,000 years according to archeomagnetic measurements. Here, we explore the causes and the implications of this rapid change. Maps of the geomagnetic field on the core–mantle boundary derived from ground-based and satellite measurements reveal that most of the present episode of dipole moment decrease originates in the southern hemisphere. Weakening and equatorward advection of normal polarity magnetic field by the core flow, combined with proliferation and growth of regions where the magnetic polarity is reversed, are reducing the dipole moment on the core–mantle boundary. Growth of these reversed flux regions has occurred over the past century or longer and is associated with the expansion of the South Atlantic Anomaly, a low-intensity region in the geomagnetic field that presents a radiation hazard at satellite altitudes. We address the speculation that the present episode of dipole moment decrease is a precursor to the next geomagnetic polarity reversal. The paleomagnetic record contains a broad spectrum of dipole moment fluctuations with polarity reversals typically occurring during dipole moment lows. However, the dipole moment is stronger today than its long time average, indicating that polarity reversal is not likely unless the current episode of moment decrease continues for a thousand years or more. [ABSTRACT FROM AUTHOR]

New collections were made of Ditrachybothridium macrocephalum Rees, 1959 from the deep-sea elasmobranchs Apristurus laurussonii (Saemundsson) and cf. Rajella bigelowi (Stehmann) in the northern Atlantic Ocean, allowing studies of the morphology of its plerocercus. The material has also allowed an estimate of its position within the Diphyllidea inferred from molecular data for the first time. The plerocercus is withdrawn, but not invaginated, within a cyst with a thick vacuolated wall. The encysted strobila is distinct, with several putative segments and advanced genital anlagen, and the scolex is fully developed with a distinct apical pad. 28S rDNA (D1-D3 regions) sequences were generated from both encysted and excysted D. macrocephalum, as well as from other diphyllidean and pseudophyllidean (outgroup) taxa for use in phylogenetic analyses. Maximum parsimony and Bayesian inference analyses both showed that the diphyllidean genus Echinobothrium is paraphyletic without inclusion of the only two other diphyllidean genera, Ditrachybothridium Rees, 1959 and Macrobothridium Khalil & Abdul-Salam, 1989. A list of published records of larval diphyllideans, their hosts and localities is included. [ABSTRACT FROM AUTHOR]

Thiazolidinediones (TZDs) are insulin-sensitizing drugs and are potent agonists of the nuclear peroxisome proliferator-activated receptor-? (PPAR-?). Although muscle is the major organ responsible for insulin-stimulated glucose disposal, PPAR-? is more highly expressed in adipose tissue than in muscle. To address this issue, we used the Cre-loxP system to knock out Pparg, the gene encoding PPAR-?, in mouse skeletal muscle. As early as 4 months of age, mice with targeted disruption of PPAR-? in muscle showed glucose intolerance and progressive insulin resistance. Using the hyperinsulinemic-euglycemic clamp technique, the in vivo insulin-stimulated glucose disposal rate (IS-GDR) was reduced by ~80% and was unchanged by 3 weeks of TZD treatment. These effects reveal a crucial role for muscle PPAR-? in the maintenance of skeletal muscle insulin action, the etiology of insulin resistance and the action of TZDs. [ABSTRACT FROM AUTHOR]

Reports a study which examines the origin of the Earth's magnetic field. Role of the polar vortices beneath the core-mantle boundary in each hemisphere; How numerical dynamos have been used to detect secular variations; Use of the observed structure of the Earth's magnetic field and its variation since 1870 to show the existence of vortices.

The role of the nuclear peroxisome proliferator-activated receptor (PPAR)-? in cancer has been a subject of debate. The identification of loss-of-function mutations in PPARG in colon and prostate tumors has led to the idea that this gene may function as a tumor suppressor. We have directly tested this notion using a mouse model of prostate cancer. Neither hemizygous deletion of Pparg nor complete ablation of Ppara influenced the development of prostate cancer in our experimental context. [ABSTRACT FROM AUTHOR]

Discusses research which reports on numerical models of convection-driven dynamos that reproduce many observed characteristics of Earth's magnetic field. Planetary magnetism a common phenomenon; Research by Kuang and Bloxham in September 25, 1997 edition of `Nature'; Comparison with model by Glatzmaier and Roberts; Role of solid iron inner core; Barriers to flow in atmosphere and ocean; Question of barrier at inner-core tangent cylinder.