Adsorption kinetics of NO2 gas on oxyfluorinated graphene film.

We report the fabrication of high-performance NO2 gas sensors based on oxyfluorinated graphene (OFG) layers. At room temperature, the times of adsorption/desorption of NO2 on/from the surface of thin OFG films are less than 1200 s and can be reduced by increasing the operation temperature. The sensors are capable of detecting NO2 molecules at sub-ppm level with a sensitivity of 0.15 ppm-1 at 348 K. The temperature dependence of the rate constants shows that the simultaneous presence of a large number of fluorine- and oxygen-containing groups on the graphene surface provides the formation of low-energy sites (ΔHa < 0.1 eV) for NO2 adsorption. The combination of the high sensitivity of the sensor and a reasonable adsorption/desorption time of the analyte is promising for on-line monitoring.

On the taxonomy of the genus Isochlora Staudinger with descriptions of two new species from Mongolia and Qinghai, China (Lepidoptera: Noctuidae: Noctuinae).

Two new species of the genus Isochlora Staudinger, 1882 are described: I. hreblayi Volynkin, Tth, Titov & Saldaitis, sp. n. (western Mongolia) and I. kozlovi Volynkin, Titov, Matov & Saldaitis, sp. n. (Qinghai Province, China). The type species of the genus-group names Chamyla Staudinger, 1900 and Grumia Alphraky, 1892 (I. arctomys Alphraky, 1897 and I. flora (Alphraky, 1892), respectively) are examined, and their synonymy with Isochlora is revised. The synonymy of Chamyla idia Staudinger, 1900 with Isochlora arctomys Alphraky, 1897 is revised as junior synonymies. Lectotypes are designated for Isochlora arctomys Alphraky, 1897, Chamyla idia Staudinger, 1900 and Grumia flora Alphraky, 1892. Isochlora intricans (Alphraky, 1882) is reported from Kazakhstan for the first time. Adults as well as male and female genitalia are illustrated.

Analysis of Polarization Images in the Microphysical Blood Parameters Research for the Hematocrit Diagnostics.

The development of non-invasive optoelectronic technologies for human blood monitoring is one of the important research areas for medicine. A critical analysis of optoelectronic methods of blood research and the micromechanical systems based on them is carried out in this article. A design realization of a polarizing portable system for non-invasive monitoring of hematocrit as one of the basic homeostatic constants of the human body containing information about the microphysical parameters of blood cells has been substantiated. A physical model of polarized radiation conversion in a video information system of laser sensing of a biological research object has been formed. Visual and quantitative differences in the spatial distribution of polarization parameters of the scattered radiation for the states of the body with different hematocrit levels have been revealed. A scheme of a multichannel imaging portable system, based on a smartphone using miniature optical and microelectronic components of information conversion for non-invasive monitoring of microphysical blood parameters, has been created. The system implements the principle of polarimetric blood photometry and a multiparametric analysis of the polarization properties of the laser radiation scattered by blood. The developed portable optoelectronic system, based on a smartphone, can be used for rapid blood diagnostics in disaster medicine and the presence of clinical contraindications to the formation of invasive tests. The proposed polarization-based approach is a promising automated alternative to traditional devices and systems for the research of microphysical blood parameters.

Estimating the neutron component of radiation properties of the IVG.1M research reactor irradiated low-enriched fuel.

Safe irradiated nuclear fuel (INF) storage of research reactors is ensured by solving issues of protection against γ-irradiation while the neutron component is usually without consideration due to significantly lower intensity. Regarding the low-enriched composite uranium fuel of the IVG.1M reactor that is characterized by a set of elements with low and mean atomic weight where reaction is possible (α, n), evaluation of the neutron component is an indispensable procedure for ensuring radiation safety INF storage. This research suggests a method for neutron component calculation of radiation properties of fresh and irradiated fuel of the IVG.1M reactor, the α-n-component was evaluated. The research results will be useful when choosing a technology for INF storage and for analysis of feasibility to use neutron irradiation with a purpose to control fuel burnout.

Endorsing a Hidden Plasmonic Mode for Enhancement of LSPR Sensing Performance in Evolved Metal-insulator Geometry Using an Unsupervised Machine Learning Algorithm.

Large-area nanoplasmonic structures with pillared metal-insulator geometry, also called nanomushrooms (NM), consist of an active spherical-shaped plasmonic material such as gold as its cap and silicon dioxide as its stem. NM is a geometry which evolves from its precursor, nanoislands (NI) consisting of aforementioned spherical structures on flat silicon dioxide substrates, via selective physical or chemical etching of the silicon dioxide. The NM geometry is well-known to provide enhanced localized surface plasmon resonance (LSPR) sensitivity in biosensing applications as compared to NI. However, precise optical phenomenon behind this enhancement is unknown and often associated with the existence of electric fields in the large fraction of the spatial region between the pillars of NM, usually accessible by the biomolecules. Here, we uncover the association of LSPR enhancement in such geometries with a hidden plasmonic mode by conducting magneto-optics measurements and by deconvoluting the absorbance spectra obtained during the local refractive index change of the NM and NI geometries. By the virtue of principal component analysis, an unsupervised machine learning technique, we observe an explicit relationship between the deconvoluted modes of LSPR, the differential absorption of left and right circular polarized light, and the refractive index sensitivity of the LSPR sensor. Our findings may lead to the development of new approaches to extract unknown properties of plasmonic materials or establish new fundamental relationships between less understood photonic properties of nanomaterials.

Trivial Indirect Trauma Causing Recurrent Bilateral Quadriceps Tendon Rupture in End Stage Renal Failure Patient: A Case Report.

Recurrent bilateral quadriceps tendon rupture in a young patient is a very rare incident. The underlying medical condition is always present and may have contributed to this injury. We report a recurrent bilateral quadricep tendon rupture in a 28-year-old man with underlying end-stage renal failure that occurred 10 months after the first repair. Injuries were indirect and trivial during the first and second events. Surgical repair was performed with similar technique for both incidents and he was advised to exercise extreme cautions after the second repair. He could return to his daily activities with no further recurrence at 30 months follow-up.

Effects of Alpha-2 Adrenergic Agonist Mafedine on Brain Electrical Activity in Rats after Traumatic Brain Injury.

The search for and development of new neuroprotective (or cerebroprotective) drugs, as well as suitable methods for their preclinical efficacy evaluation, are priorities for current biomedical research. Alpha-2 adrenergic agonists, such as mafedine and dexmedetomidine, are a highly appealing group of drugs capable of reducing neurological deficits which result from brain trauma and vascular events in both experimental animals and human patients. Thus, our aim was to assess the effects of mafedine and dexmedetomidine on the brain's electrical activity in a controlled cortical-impact model of traumatic brain injury (TBI) in rats. The functional status of the animals was assessed by electrocorticography (ECoG), using ECoG electrodes which were chronically implanted in different cortical regions. The administration of intraperitoneal mafedine sodium at 2.5 mg∙kg-1 at 1 h after TBI induction, and daily for the following 6 days, restored interhemispheric connectivity in remote brain regions and intrahemispheric connections within the unaffected hemisphere at post-TBI day 7. Animals that had received mafedine sodium also demonstrated an improvement in cortical responses to photic and somatosensory stimulation. Dexmedetomidine at 25 µg∙kg-1 did not affect the brain's electrical activity in brain-injured rats. Our results confirm the previously described neuroprotective effects of mafedine sodium and suggest that ECoG registration and analysis are a viable method evaluating drug efficacy in experimental animal models of TBI.

Fluorine patterning of graphene: effects of fluorine content and temperature.

In this paper we present a successful approach for the generation of partially fluorinated graphene structures. A computationally simple model optimized on a large density functional theory dataset quickly and precisely predicts experimentally observed structures. From the analysis of the structural diversity of fluorinated graphene in a wide range of synthesis temperatures, the general structural patterns are identified and the conditions for their achievement are determined. In addition, to facilitate further studies of fluorinated graphene, we present a ready-to-use GenCF code that implements the described structure generator.

Trivial Indirect Trauma Causing Recurrent Bilateral Quadriceps Tendon Rupture in End Stage Renal Failure Patient: A Case Report

@#Recurrent bilateral quadriceps tendon rupture in a young patient is a very rare incident. The underlying medical condition is always present and may have contributed to this injury. We report a recurrent bilateral quadricep tendon rupture in a 28-year-old man with underlying end-stage renal failure that occurred 10 months after the first repair. Injuries were indirect and trivial during the first and second events. Surgical repair was performed with similar technique for both incidents and he was advised to exercise extreme cautions after the second repair. He could return to his daily activities with no further recurrence at 30 months follow-up.

SITC cancer immunotherapy resource document: a compass in the land of biomarker discovery.

Since the publication of the Society for Immunotherapy of Cancer's (SITC) original cancer immunotherapy biomarkers resource document, there have been remarkable breakthroughs in cancer immunotherapy, in particular the development and approval of immune checkpoint inhibitors, engineered cellular therapies, and tumor vaccines to unleash antitumor immune activity. The most notable feature of these breakthroughs is the achievement of durable clinical responses in some patients, enabling long-term survival. These durable responses have been noted in tumor types that were not previously considered immunotherapy-sensitive, suggesting that all patients with cancer may have the potential to benefit from immunotherapy. However, a persistent challenge in the field is the fact that only a minority of patients respond to immunotherapy, especially those therapies that rely on endogenous immune activation such as checkpoint inhibitors and vaccination due to the complex and heterogeneous immune escape mechanisms which can develop in each patient. Therefore, the development of robust biomarkers for each immunotherapy strategy, enabling rational patient selection and the design of precise combination therapies, is key for the continued success and improvement of immunotherapy. In this document, we summarize and update established biomarkers, guidelines, and regulatory considerations for clinical immune biomarker development, discuss well-known and novel technologies for biomarker discovery and validation, and provide tools and resources that can be used by the biomarker research community to facilitate the continued development of immuno-oncology and aid in the goal of durable responses in all patients.

Bispecific Targeting of PD-1 and PD-L1 Enhances T-cell Activation and Antitumor Immunity.

The programmed cell death protein 1 receptor (PD-1) and programmed death ligand 1 (PD-L1) coinhibitory pathway suppresses T-cell-mediated immunity. We hypothesized that cotargeting of PD-1 and PD-L1 with a bispecific antibody molecule could provide an alternative therapeutic approach, with enhanced antitumor activity, compared with monospecific PD-1 and PD-L1 antibodies. Here, we describe LY3434172, a bispecific IgG1 mAb with ablated Fc immune effector function that targets both human PD-1 and PD-L1. LY3434172 fully inhibited the major inhibitory receptor-ligand interactions in the PD-1 pathway. LY3434172 enhanced functional activation of T cells in vitro compared with the parent anti-PD-1 and anti-PD-L1 antibody combination or respective monotherapies. In mouse tumor models reconstituted with human immune cells, LY3434172 therapy induced dramatic and potent antitumor activity compared with each parent antibody or their combination. Collectively, these results demonstrated the enhanced immunomodulatory (immune blockade) properties of LY3434172, which improved antitumor immune response in preclinical studies, thus supporting its evaluation as a novel bispecific cancer immunotherapy.

Characterization of 7A5: A Human CD137 (4-1BB) Receptor Binding Monoclonal Antibody with Differential Agonist Properties That Promotes Antitumor Immunity.

The CD137 receptor plays a key role in mediating immune response by promoting T cell proliferation, survival, and memory. Effective agonism of CD137 has the potential to reinvigorate potent antitumor immunity either alone or in combination with other immune-checkpoint therapies. In this study, we describe the discovery and characterization of a unique CD137 agonist, 7A5, a fully human IgG1 Fc effector-null monoclonal antibody. The biological properties of 7A5 were investigated through in vitro and in vivo studies. 7A5 binds CD137, and the binding epitope overlaps with the CD137L binding site based on structure. 7A5 engages CD137 receptor and activates NF-κB cell signaling independent of cross-linking or Fc effector function. In addition, T cell activation measured by cytokine IFNγ production is induced by 7A5 in peripheral blood mononuclear cell costimulation assay. Human tumor xenograft mouse models reconstituted with human immune cells were used to determine antitumor activity in vivo. Monotherapy with 7A5 inhibits tumor growth, and this activity is enhanced in combination with a PD-L1 antagonist antibody. Furthermore, the intratumoral immune gene expression signature in response to 7A5 is highly suggestive of enhanced T cell infiltration and activation. Taken together, these results demonstrate 7A5 is a differentiated CD137 agonist antibody with biological properties that warrant its further development as a cancer immunotherapy. GRAPHICAL ABSTRACT: http://mct.aacrjournals.org/content/molcanther/19/4/988/F1.large.jpg.

Genomic characterization of intrinsic and acquired resistance to cetuximab in colorectal cancer patients.

Anti-EGFR antibodies are effective in therapies for late-stage colorectal cancer (CRC); however, many tumours are unresponsive or develop resistance. We performed genomic analysis of intrinsic and acquired resistance to anti-EGFR therapy in prospectively collected tumour samples from 25 CRC patients receiving cetuximab (an EGFR inhibitor). Of 25 CRC patients, 13 displayed intrinsic resistance to cetuximab; 12 were intrinsically sensitive. We obtained six re-biopsy samples at acquired resistance from the intrinsically sensitive patients. NCOA4-RET and LMNA-NTRK1 fusions and NRG1 and GNAS amplifications were found in intrinsic-resistant patients. In cetuximab-sensitive patients, we found KRAS K117N and A146T mutations in addition to BRAF V600E, AKT1 E17K, PIK3CA E542K, and FGFR1 or ERBB2 amplifications. The comparison between baseline and acquired-resistant tumours revealed an extreme shift in variant allele frequency of somatic variants, suggesting that cetuximab exposure dramatically selected for rare resistant subclones that were initially undetectable. There was also an increase in epithelial-to-mesenchymal transition at acquired resistance, with a reduction in the immune infiltrate. Furthermore, characterization of an acquired-resistant, patient-derived cell line showed that PI3K/mTOR inhibition could rescue cetuximab resistance. Thus, we uncovered novel genomic alterations that elucidate the mechanisms of sensitivity and resistance to anti-EGFR therapy in metastatic CRC patients.

The Folate Pathway Inhibitor Pemetrexed Pleiotropically Enhances Effects of Cancer Immunotherapy.

PURPOSE: Combination strategies leveraging chemotherapeutic agents and immunotherapy have held the promise as a method to improve benefit for patients with cancer. However, most chemotherapies have detrimental effects on immune homeostasis and differ in their ability to induce immunogenic cell death (ICD). The approval of pemetrexed and carboplatin with anti-PD-1 (pembrolizumab) for treatment of non-small cell lung cancer represents the first approved chemotherapy and immunotherapy combination. Although the clinical data suggest a positive interaction between pemetrexed-based chemotherapy and immunotherapy, the underlying mechanism remains unknown. EXPERIMENTAL DESIGN: Mouse tumor models (MC38, Colon26) and high-content biomarker studies (flow cytometry, Quantigene Plex, and nCounter gene expression analysis) were deployed to obtain insights into the mechanistic rationale behind the efficacy observed with pemetrexed/anti-PD-L1 combination. ICD in tumor cell lines was assessed by calreticulin and HMGB-1 immunoassays, and metabolic function of primary T cells was evaluated by Seahorse analysis. RESULTS: Pemetrexed treatment alone increased T-cell activation in mouse tumors in vivo, robustly induced ICD in mouse tumor cells and exerted T-cell-intrinsic effects exemplified by augmented mitochondrial function and enhanced T-cell activation in vitro. Increased antitumor efficacy and pronounced inflamed/immune activation were observed when pemetrexed was combined with anti-PD-L1. CONCLUSIONS: Pemetrexed augments systemic intratumor immune responses through tumor intrinsic mechanisms including immunogenic cell death, T-cell-intrinsic mechanisms enhancing mitochondrial biogenesis leading to increased T-cell infiltration/activation along with modulation of innate immune pathways, which are significantly enhanced in combination with PD-1 pathway blockade.See related commentary by Buque et al., p. 6890.

Randomised phase II study of second-line olaratumab with mitoxantrone/prednisone versus mitoxantrone/prednisone alone in metastatic castration-resistant prostate cancer.

INTRODUCTION: Platelet-derived growth factor receptor-α (PDGFRα) is expressed in primary prostate adenocarcinoma and in associated skeletal metastases. Olaratumab is a fully human monoclonal antibody that binds PDGFRα and blocks downstream signalling. This phase II study assessed the efficacy and safety of olaratumab in combination with mitoxantrone and prednisone (M/P) versus M/P alone in patients with metastatic castration-resistant prostate cancer (mCRPC) who progressed after docetaxel. METHODS: Patients were randomised to receive 21-d cycles of olaratumab (15 mg/kg, Days 1 and 8) plus mitoxantrone (12 mg/m2, Day 1) and prednisone (5 mg, twice daily) or M/P alone. Progression-free survival (PFS) was the primary end-point. Secondary end-points included overall survival (OS), safety, and circulating tumour cell (CTC) counts. RESULTS: A total of 123 patients were randomised, 63 to olaratumab + M/P and 60 to M/P. Median PFS was 2.3 months for olaratumab + M/P and 2.4 months for M/P (hazard ratio [HR] = 1.29; 95% confidence interval [CI] = 0.87-1.90). Median OS was 14.2 months for olaratumab + M/P and 12.8 months for M/P (HR = 1.08; 95% CI = 0.72-1.61). Both treatment arms had similar toxicity profiles; neutropenia (24% versus 15%), anaemia (13% versus 14%) and fatigue (11% versus 9%) (olaratumab + M/P versus M/P, respectively) were the most common grade ≥3 events. High CTC count was associated with poorer OS in both arms. Patients with very high cell counts (>37 cells/7.5 ml) exhibited improved OS with olaratumab + M/P (interaction P = 0.043). CONCLUSIONS: Olaratumab + M/P had an acceptable safety profile but did not improve the efficacy of M/P chemotherapy. Further study with selected patient populations and earlier in the disease course might be considered.

Targeting the TGFß pathway with galunisertib, a TGFßRI small molecule inhibitor, promotes anti-tumor immunity leading to durable, complete responses, as monotherapy and in combination with checkpoint blockade.

BACKGROUND: TGFß signaling plays a pleotropic role in tumor biology, promoting tumor proliferation, invasion and metastasis, and escape from immune surveillance. Inhibiting TGFß's immune suppressive effects has become of particular interest as a way to increase the benefit of cancer immunotherapy. Here we utilized preclinical models to explore the impact of the clinical stage TGFß pathway inhibitor, galunisertib, on anti-tumor immunity at clinically relevant doses. RESULTS: In vitro treatment with galunisertib reversed TGFß and regulatory T cell mediated suppression of human T cell proliferation. In vivo treatment of mice with established 4T1-LP tumors resulted in strong dose-dependent anti-tumor activity with close to 100% inhibition of tumor growth and complete regressions upon cessation of treatment in 50% of animals. This effect was CD8+ T cell dependent, and led to increased T cell numbers in treated tumors. Mice with durable regressions rejected tumor rechallenge, demonstrating the establishment of immunological memory. Consequently, mice that rejected immunogenic 4T1-LP tumors were able to resist rechallenge with poorly immunogenic 4 T1 parental cells, suggesting the development of a secondary immune response via antigen spreading as a consequence of effective tumor targeting. Combination of galunisertib with PD-L1 blockade resulted in improved tumor growth inhibition and complete regressions in colon carcinoma models, demonstrating the potential synergy when cotargeting TGFß and PD-1/PD-L1 pathways. Combination therapy was associated with enhanced anti-tumor immune related gene expression profile that was accelerated compared to anti-PD-L1 monotherapy. CONCLUSIONS: Together these data highlight the ability of galunisertib to modulate T cell immunity and the therapeutic potential of combining galunisertib with current PD-1/L1 immunotherapy.

Correction to: Discovery and preclinical characterization of the antagonist anti-PD-L1 monoclonal antibody LY3300054.

Unfortunately, after publication of this article [1], it was noticed that corrections to the legends of Figs. 1 and 2 were not correctly incorporated. The correct legends can be seen below.

Discovery and preclinical characterization of the antagonist anti-PD-L1 monoclonal antibody LY3300054.

BACKGROUND: Modulation of the PD-1/PD-L1 axis through antagonist antibodies that block either receptor or ligand has been shown to reinvigorate the function of tumor-specific T cells and unleash potent anti-tumor immunity, leading to durable objective responses in a subset of patients across multiple tumor types. RESULTS: Here we describe the discovery and preclinical characterization of LY3300054, a fully human IgG1λ monoclonal antibody that binds to human PD-L1 with high affinity and inhibits interactions of PD-L1 with its two cognate receptors PD-1 and CD80. The functional activity of LY3300054 on primary human T cells is evaluated using a series of in vitro T cell functional assays and in vivo models using human-immune reconstituted mice. LY3300054 is shown to induce primary T cell activation in vitro, increase T cell activation in combination with anti-CTLA4 antibody, and to potently enhance anti-tumor alloreactivity in several xenograft mouse tumor models with reconstituted human immune cells. High-content molecular analysis of tumor and peripheral tissues from animals treated with LY3300054 reveals distinct adaptive immune activation signatures, and also previously not described modulation of innate immune pathways. CONCLUSIONS: LY3300054 is currently being evaluated in phase I clinical trials for oncology indications.

The CDK4/6 Inhibitor Abemaciclib Induces a T Cell Inflamed Tumor Microenvironment and Enhances the Efficacy of PD-L1 Checkpoint Blockade.

Abemaciclib, an inhibitor of cyclin dependent kinases 4 and 6 (CDK4/6), has recently been approved for the treatment of hormone receptor-positive breast cancer. In this study, we use murine syngeneic tumor models and in vitro assays to investigate the impact of abemaciclib on T cells, the tumor immune microenvironment and the ability to combine with anti-PD-L1 blockade. Abemaciclib monotherapy resulted in tumor growth delay that was associated with an increased T cell inflammatory signature in tumors. Combination with anti-PD-L1 therapy led to complete tumor regressions and immunological memory, accompanied by enhanced antigen presentation, a T cell inflamed phenotype, and enhanced cell cycle control. In vitro, treatment with abemaciclib resulted in increased activation of human T cells and upregulated expression of antigen presentation genes in MCF-7 breast cancer cells. These data collectively support the clinical investigation of the combination of abemaciclib with agents such as anti-PD-L1 that modulate T cell anti-tumor immunity.

Snap-through transition of buckled graphene membranes for memcapacitor applications.

Using computational and theoretical approaches, we investigate the snap-through transition of buckled graphene membranes. Our main interest is related to the possibility of using the buckled membrane as a plate of capacitor with memory (memcapacitor). For this purpose, we performed molecular-dynamics (MD) simulations and elasticity theory calculations of the up-to-down and down-to-up snap-through transitions for membranes of several sizes. We have obtained expressions for the threshold switching forces for both up-to-down and down-to-up transitions. Moreover, the up-to-down threshold switching force was calculated using the density functional theory (DFT). Our DFT results are in general agreement with MD and analytical theory findings. Our systematic approach can be used for the description of other structures, including nanomechanical and biological ones, experiencing the snap-through transition.