In this first-in-human phase 1 study (NCT02964013; MK-7684-001), we investigated the safety and efficacy of the anti-TIGIT (T cell immunoglobulin and ITIM domain) antibody vibostolimab as monotherapy ...or in combination with pembrolizumab.
Part A enrolled patients with advanced solid tumors, and part B enrolled patients with non-small-cell lung cancer (NSCLC). Patients received vibostolimab 2.1-700 mg alone or with pembrolizumab 200 mg in part A and vibostolimab 200 mg alone or with pembrolizumab 200 mg in part B. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics and objective response rate (ORR) per RECIST v1.1.
Part A enrolled 76 patients (monotherapy, 34; combination therapy, 42). No dose-limiting toxicities were reported. Across doses, 56% of patients receiving monotherapy and 62% receiving combination therapy had treatment-related adverse events (TRAEs); grade 3-4 TRAEs occurred in 9% and 17% of patients, respectively. The most common TRAEs were fatigue (15%) and pruritus (15%) with monotherapy and pruritus (17%) and rash (14%) with combination therapy. Confirmed ORR was 0% with monotherapy and 7% with combination therapy. In part B, 39 patients had anti-PD-1 (programmed cell death protein 1)/PD-L1 (programmed death-ligand 1)-naive NSCLC (all received combination therapy), and 67 had anti-PD-1/PD-L1-refractory NSCLC (monotherapy, 34; combination therapy, 33). In patients with anti-PD-1/PD-L1-naive NSCLC: 85% had TRAEs–the most common were pruritus (38%) and hypoalbuminemia (31%); confirmed ORR was 26%, with responses occurring in both PD-L1-positive and PD-L1-negative tumors. In patients with anti-PD-1/PD-L1-refractory NSCLC: 56% receiving monotherapy and 70% receiving combination therapy had TRAEs–the most common were rash and fatigue (21% each) with monotherapy and pruritus (36%) and fatigue (24%) with combination therapy; confirmed ORR was 3% with monotherapy and 3% with combination therapy.
Vibostolimab plus pembrolizumab was well tolerated and demonstrated antitumor activity in patients with advanced solid tumors, including patients with advanced NSCLC.
•First-in-human phase 1 study in patients with advanced solid tumors who received vibostolimab alone or with pembrolizumab.•Vibostolimab plus pembrolizumab was well tolerated in advanced solid tumors.•Vibostolimab plus pembrolizumab demonstrated antitumor activity in patients with advanced solid tumors.
Three principal granite provinces are defined across SE Asia, as follows. (1) The Western Thailand-Myanmar/Burma province consists of hornblende-biotite I-type granodiorite-granites and felsic ...biotite-K-feldspar (± garnet ± tourmaline) granites associated with abundant tin mineralization in greisen-type veins. New ion microprobe U-Pb dating results from Phuket Island show zircon core ages of 212 ± 2 and 214 ± 2 Ma and a thermal overprint with rims of 81.2 ± 1.2 and 85-75 Ma. (2) The North Thailand-West Malaya Main Range province has mainly S-type biotite granites and abundant tin mineralization resulting from crustal thickening following collision of the Sibumasu plate with Indochina during the Mid-Triassic. Biotite granites around Kuala Lumpur contain extremely U-rich zircons (up to 38000 ppm) that yield ages of 215 ± 7 and 210 ± 7 Ma. (3) The East Malaya province consists of dominantly Permian-Triassic I-type hornblende-biotite granites but with subordinate S-type plutons and A-type syenite-gabbros. Biotite-K-feldspar granites from Tioman Island off the east coast of Malaysia also yield a zircon age of 80 ± 1 Ma, showing Cretaceous magmatism in common with province 1. Geological and U-Pb geochronological data suggest that two east-dipping (in present-day coordinates) subduction zones are required during the Triassic, one along the Bentong-Raub Palaeo-Tethyan suture, and the other west of the Phuket-Burma province 1 belt. SUPPLEMENTARY MATERIAL: A full description of U-Pb analytical methods used and data tables are available at www.geolsoc.org.uk/SUP18523.
Background and purpose
We analyzed the incidence and causes of oral anticoagulant (OAC) cessation and subsequent stroke after OAC withdrawal in a cohort of Korean stroke patients with atrial ...fibrillation.
Methods
The Korean Atrial Fibrillation Evaluation Registry in Ischemic Stroke patients (K‐ATTENTION) is a multicenter cohort study, merging stroke registries from 11 tertiary centers in Korea. The number of OAC interruption episodes and the reasons were reviewed from hospital records. Stroke after OAC withdrawal was defined when a patient experienced ischaemic stroke within 31 days after OAC withdrawal. Clinical variables were compared between patients who experienced stroke recurrence during OAC interruption and those who did not experience recurrence.
Results
Among 3213 stroke patients with atrial fibrillation, a total of 329 episodes of OAC interruption were detected in 229 patients after index stroke (mean age 72.9 ± 8.3 years, 113 female patients). The most frequent reason for OAC withdrawal was poor compliance 103 episodes (31.3%) followed by extracranial bleeding 96 episodes (29.2%). Stroke after OAC withdrawal was noted in 13 patients. Mean age, vascular risk factor profile and mean CHA2DS2‐VASc score were not significantly different between patients with and without recurrent stroke.
Conclusions
A considerable number of stroke patients with atrial fibrillation experienced temporary interruption of OAC after index stroke, which was associated with stroke recurrence of 4.0 cases per 100 interruption episodes.
Macromolecular crowding has a profound impact on reaction rates and the physical properties of the cell interior, but the mechanisms that regulate crowding are poorly understood. We developed ...genetically encoded multimeric nanoparticles (GEMs) to dissect these mechanisms. GEMs are homomultimeric scaffolds fused to a fluorescent protein that self-assemble into bright, stable particles of defined size and shape. By combining tracking of GEMs with genetic and pharmacological approaches, we discovered that the mTORC1 pathway can modulate the effective diffusion coefficient of particles ≥20 nm in diameter more than 2-fold by tuning ribosome concentration, without any discernable effect on the motion of molecules ≤5 nm. This change in ribosome concentration affected phase separation both in vitro and in vivo. Together, these results establish a role for mTORC1 in controlling both the mesoscale biophysical properties of the cytoplasm and biomolecular condensation.
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•GEMs enable high-throughput microrheology in unperturbed living cells•mTORC1 controls diffusion by tuning ribosome concentration•Diffusion can be accurately predicted as a function of ribosome concentration•Crowding of the cytoplasm by ribosomes increases phase separation
mTORC1 signaling controls phase transitions in the cytoplasm through its effects on molecular crowding.
Background
Exposure to environmental pollutants promotes Th2 cell responses. Aryl hydrocarbon receptor (AhR) activation aggravates allergic responses. Epithelium‐derived thymic stromal lymphopoietin ...(TSLP), interleukin (IL)‐25, and IL‐33 are implicated in the dysregulation of Th2 immune responses in severe allergic asthma.
Methods
Bronchial biopsies of 28 allergic severe asthma and 6 mild asthma subjects from highly polluted areas were analyzed for AhR nuclear translocation (NT), cytokine expression, and gene activation. Cultured primary epithelial cells were stimulated with diesel exhausted particles (DEP) to determine AhR‐mediated IL‐33, Il‐25, and TSLP synthesis and release.
Results
Primary bronchial epithelial cells exposed to DEP showed upregulation of IL‐33, IL‐25, and TSLP. These effects were abolished by knockdown of AhR by siRNA. Increased AhR/ARNT binding to promoters of IL‐33, IL‐25, and TSLP was found using chromatin immunoprecipitation (ChIP) assay. Allergic severe asthma with high AhR NT had higher bronchial gene and protein expression of IL‐33, IL‐25, and TSLP. These patients derived clinical benefit from anti‐IgE treatment.
Conclusion
Aryl hydrocarbon receptor activation by DEP mediates upregulation of IL‐33, IL‐25, and TSLP with Th2 activation, potentially linking environmental pollution and allergic severe asthma.
Environmental diesel exhaust particles (DEP) exposed to airway epithelium ligate cytoplasmic aryl hydrocarbon receptor (AhR), translocate to the nucleus with aryl hydrocarbon receptor nuclear translocator (ARNT), and then transactivate IL‐33, Il‐25, and TSLP gene expression. Patients with high AhR nucleus translocation overexpressed IL‐33, Il‐25, and TSLP cytokines compared to those with low. Patients with high AhR nucleus translocation are more response to anti‐IgE therapy compared to those with low.
Lead halide perovskites exhibit structural instabilities and large atomic fluctuations thought to impact their optical and thermal properties, yet detailed structural and temporal correlations of ...their atomic motions remain poorly understood. Here, these correlations are resolved in CsPbBr3 crystals using momentum-resolved neutron and X-ray scattering measurements as a function of temperature, complemented with first-principles simulations. We uncover a striking network of diffuse scattering rods, arising from the liquid-like damping of low-energy Br-dominated phonons, reproduced in our simulations of the anharmonic phonon self-energy. These overdamped modes cover a continuum of wave vectors along the edges of the cubic Brillouin zone, corresponding to two-dimensional sheets of correlated rotations in real space, and could represent precursors to proposed two-dimensional polarons. Further, these motions directly impact the electronic gap edge states, linking soft anharmonic lattice dynamics and optoelectronic properties. These results provide insights into the highly unusual atomic dynamics of halide perovskites, relevant to further optimization of their optical and thermal properties.Neutron and X-ray scattering measurements provide further insight into the anharmonic behaviour of lead halide perovskites, revealing that rotations of PbBr6 octahedra in CsPbBr3 crystals occur in a correlated fashion along two-dimensional planes.
The nuclear-encoded Krebs cycle enzymes, fumarate hydratase (FH) and succinate dehydrogenase (SDHB, -C and -D), act as tumour suppressors. Germline mutations in FH predispose individuals to ...leiomyomas and renal cell cancer (HLRCC), whereas mutations in SDH cause paragangliomas and phaeochromocytomas (HPGL). In this study, we have shown that FH-deficient cells and tumours accumulate fumarate and, to a lesser extent, succinate. SDH-deficient tumours principally accumulate succinate. In situ analyses showed that these tumours also have over-expression of hypoxia-inducible factor 1α (HIF1α), activation of HIF1αtargets (such as vascular endothelial growth factor) and high microvessel density. We found no evidence of increased reactive oxygen species in our cells. Our data provide in vivo evidence to support the hypothesis that increased succinate and/or fumarate causes stabilization of HIF1α a plausible mechanism, inhibition of HIF prolyl hydroxylases, has previously been suggested by in vitro studies. The basic mechanism of tumorigenesis in HPGL and HLRCC is likely to be pseudo-hypoxic drive, just as it is in von Hippel–Lindau syndrome.
Aging is a biological process characterized by time-dependent functional declines that are influenced by changes in redox status and by oxidative stress-induced inflammatory reactions. An organism’s ...pro-inflammatory status may underlie the aging process and age-related diseases. In this review, we explore the molecular basis of low-grade, unresolved, subclinical inflammation as a major risk factor for exacerbating the aging process and age-related diseases. We focus on the redox-sensitive transcription factors, NF-κB and FOXO, which play essential roles in the expression of pro-inflammatory mediators and anti-oxidant enzymes, respectively. Major players in molecular inflammation are discussed with respect to the age-related up-regulation of pro-inflammatory cytokines and adhesion molecules, cyclo-oxygenase-2, lipoxygenase, and inducible nitric oxide synthase. The molecular inflammation hypothesis proposed by our laboratory is briefly described to give further molecular insights into the intricate interplay among redox balance, pro-inflammatory gene activation, and chronic age-related inflammatory diseases. The final section discusses calorie restriction as an aging-retarding intervention that also exhibits extraordinarily effective anti-inflammatory activity by modulating GSH redox, NF-κB, SIRT1, PPARs, and FOXOs.
Hesperidin, a known flavonoid constituent of citrus, reduces the proliferation of many cancer cells. The apoptotic effects of hesperidin on human colon cancer cells, SNU-C4, were determined at ...concentrations of 1–100
μM. At 100
μM, hesperidin reduced cell viability to 65.00±0.05% of control values in a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cell death induced by hesperidin showed apoptotic features in 4,6-diamidino-2-phenylindole (DAPI) staining and in terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assays. Examination of the expression of apoptosis-regulating genes indicated that hesperidin treatment decreased the expression of B-cell CLL/lymphoma 2 (
BCL2) mRNA, and increased the expression of BCL2-associated X protein (
BAX). The expression and activity of the major apoptotic factor caspase3 (CASP3) was increased significantly with hesperidin treatment. Hesperidin down-regulated the protein expression of pro-CASP3, and up-regulated the level of active CASP3. Thus, these results suggest that hesperidin could induce apoptosis in human colon cancer cells through CASP3 activation.
Outputs from new state‐of‐the‐art climate models under the Coupled Model Inter‐comparison Project phase 6 (CMIP6) promise improvement and enhancement of climate change projections information for ...Australia. Here we focus on three key aspects of CMIP6: what is new in these models, how the available CMIP6 models evaluate compared to CMIP5, and their projections of the future Australian climate compared to CMIP5 focussing on the highest emissions scenario. The CMIP6 ensemble has several new features of relevance to policymakers and others, for example, the integrated matrix of socioeconomic and concentration pathways. The CMIP6 models show incremental improvements in the simulation of the climate in the Australian region, including a reduced equatorial Pacific cold tongue bias, slightly improved rainfall teleconnections with large‐scale climate drivers, improved representation of atmosphere and ocean extreme heat events, as well as dynamic sea level. However, important regional biases remain, evident in the excessive rainfall over the Maritime Continent and rainfall pattern biases in the nearby tropical convergence zones. Projections of Australian temperature and rainfall from the available CMIP6 ensemble broadly agree with those from CMIP5, except for a group of CMIP6 models with higher climate sensitivity and greater warming and increase in some extremes after 2050. CMIP6 rainfall projections are similar to CMIP5, but the ensemble examined has a narrower range of rainfall change in austral summer in Northern Australia and austral winter in Southern Australia. Overall, future national projections are likely to be similar to previous versions but perhaps with some areas of improved confidence and clarity.
Key Points
CMIP6 shows incremental improvement of the simulation of Australian climate compared to CMIP5
CMIP6 climate projections are similar to CMIP5 except for a group of higher sensitivity models with warmer projected change
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