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Targeted inhibition of the PD-L1–PD-1 pathway might be further amplified through combination of PD-1 or PD-L1 inhibitors with novel anti-TIGIT inhibitory immune checkpoint agents, such as tiragolumab. In the CITYSCAPE trial, we aimed to assess the preliminary efficacy and safety of tiragolumab plus atezolizumab (anti-PD-L1) therapy as first-line treatment for non-small-cell lung cancer (NSCLC). CITYSCAPE is a phase 2, randomised, double-blind, placebo-controlled trial. Patients with chemotherapy-naive, PD-L1-positive (defined as a tumour proportion score of ≥1% by 22C3 immunohistochemistry pharmDx assay; Dako, Agilent Technologies, Santa Clara, CA, USA) recurrent or metastatic NSCLC with measurable disease, Eastern Cooperative Oncology Group performance status of 0 or 1, and no EGFR or ALK alterations were enrolled from 41 clinics in Europe, Asia, and the USA. Patients were randomly assigned (1:1), via an interactive voice or web-based response system, to receive tiragolumab (600 mg) plus atezolizumab (1200 mg) or placebo plus atezolizumab intravenously once every 3 weeks. Investigators and patients were masked to treatment assignment. The co-primary endpoints were investigator-assessed objective response rate and progression-free survival as per Response Evaluation Criteria in Solid Tumors version 1.1 in the intention-to-treat population, analysed after approximately 80 progression-free survival events had been observed in the primary population. Safety was assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT03563716, and is ongoing. Patients were enrolled between Aug 10, 2018, and March 20, 2019. At data cutoff for the primary analysis (June 30, 2019), 135 of 275 patients assessed for eligibility were randomly assigned to receive tiragolumab plus atezolizumab (67 [50%]) or placebo plus atezolizumab (68 [50%]). In this primary analysis, after a median follow-up of 5·9 months (4·6–7·6, in the intention-to-treat population, 21 patients (31·3% [95% CI 19·5–43·2]) in the tiragolumab plus atezolizumab group versus 11 patients (16·2% [6·7–25·7]) in the placebo plus atezolizumab group had an objective response (p=0·031). Median progression-free survival was 5·4 months (95% CI 4·2–not estimable) in the tiragolumab plus atezolizumab group versus 3·6 months (2·7–4·4) in the placebo plus atezolizumab group (stratified hazard ratio 0·57 [95% CI 0·37–0·90], p=0·015). 14 (21%) patients receiving tiragolumab plus atezolizumab and 12 (18%) patients receiving placebo plus atezolizumab had serious treatment-related adverse events. The most frequently reported grade 3 or worse treatment-related adverse event was lipase increase (in six [9%] patients in the tiragolumab plus atezolizumab group vs two [3%] in the placebo plus atezolizumab group). Two treatment-related deaths (of pyrexia and infection) occurred in the tiragolumab plus atezolizumab group. Tiragolumab plus atezolizumab showed a clinically meaningful improvement in objective response rate and progression-free survival compared with placebo plus atezolizumab in patients with chemotherapy-naive, PD-L1-positive, recurrent or metastatic NSCLC. Tiragolumab plus atezolizumab was well tolerated, with a safety profile generally similar to that of atezolizumab alone. These findings demonstrate that tiragolumab plus atezolizumab is a promising immunotherapy combination for the treatment of previously untreated, locally advanced unresectable or metastatic NSCLC. F Hoffmann-La Roche and Genentech.

Tocopheramines are a class of antioxidants which are distinguished from tocopherols (vitamin E) by the presence of an amino group instead of the phenolic hydroxyl group. α-Tocopheramine is intensively studied for biomedical applications but also as a stabilizer for synthetic and natural polymers, in particular for cellulose solutions and spinning dopes for cellulosic fibers. This study addresses a fundamental difference in the oxidation chemistry of α-tocopheramine and its tocopherol counterpart: while the formation of the ortho-quinone methide (o-QM) involving C-5a is one of the most fundamental reactions of α-tocopherol, the corresponding ortho-iminoquinone methide (o-IQM) derived from α-tocopheramine has been elusive so far. Synthesis of the transient intermediate succeeded initially via 5a-hydroxy-α-tocopheramine, and its occurrence was confirmed by dimerization to the corresponding spiro-dimer and by trapping with ethyl vinyl ether. Eventually, suitable oxidation conditions were found which allowed for the generation of the o-IQM directly from α-tocopheramine. The underlying oxidation chemistry of α-tocopherol and α-tocopheramine is concisely discussed.

α-Tocopheramine and N-methyl-α-tocopheramine are used as stabilizers in the spinning of cellulosic fibers from solutions in 1,3-dialkylimidazolium ionic liquids. Upon aging, they form chromophoric degradation products, among which the spiro-dimers are major components. These compounds have proved to be otherwise inaccessible so far, although they are urgently needed as chromatographic standards in spinning baths and fiber analysis. In this work, the spiro-dimers of α-tocopheramine and N-methyl-α-tocopheramine have been synthesized. Extensive optimization of reaction conditions, solvents and oxidants resulted in a sustainable one-pot protocol that provided quantitative yields without the need for product purification and with the easy recycling of the solvent.

It has always been a challenge for civil engineers to lay roads in the areas covered by expansive soil. The expansive soil undergoes extreme phase changes from being hard in hot summer to being slushy and without strength in monsoon season. Thus, the engineering properties of the expansive soil must be improved before laying the roads. This paper presents the results of experimental work carried out to improve the engineering properties of an expansive clay i.e. black cotton soil (BCS) by using fly ash geopolymer. Sodium hydroxide (NaOH) and sodium silicate (Na 2 SiO 3 ) solutions were mixed in different ratios (0.5, 1, 1.5, and 2) and used for synthesizing the geopolymer. The stabilized BCS samples were characterized in the laboratory for various properties viz., Atterberg’s limits, free swell ratio, and unconfined compressive strength. The untreated and treated BCS samples were also analyzed for their microstructural and morphological properties by using the SEM (scanning electron microscope) images and the XRD (X-ray fiffractometer) and FTIR (Fourier-transform infrared spectroscopy) spectra. An increase in the unconfined compressive strength and reduction in free swell ratio as well as shrinkage limit was observed after stabilization with geopolymer. Results also indicate binding of soil particles and formation of dense microstructure resulting in higher strength and less swelling and shrinkage characteristics. Furthermore, the bender element test was used to indicate the improvement in stiffness of the geopolymer stabilized expansive soil in terms of shear wave velocity.

Geotechnical infrastructures, like slopes and embankments, retaining walls, foundations, engineered landfills, overburden dumps, and pavements, get continuously exposed to various environmental factors which are climate dependent. Fate/stability of these infrastructures due to extreme and abrupt change in precipitation, temperatures, humidity, and wind/airflow is quite questionable. Some of the issues related to climate change on soils include increase in infiltration rate, high pore-water pressure, decrease in effective stress, soil liquefaction, seepage failures, frost heaving, changes in soil suction potential, swelling and shrinkage in fine-grained soils, differential settlement, and damage to vegetation cover and thereby causing slope failures, waterlogged conditions, floods, soil erosion and/or internal erosion of fines, damage to landfill liners and soil covers, desertification, desiccation cracks on the ground surface, and groundwater table pollution due to contaminant migration. Therefore, studies on the impact of climate change on geotechnical infrastructures have gained attention of many researchers in the recent times. In present study, an up-to-date review of the works related to the influence of various climatic factors on geotechnical properties and thereby on geotechnical projects is carried out. Topics related to climate data downscaling using global climate models (GCM), climate change–induced slope instability, acid rains, desiccation cracking in soils with changing temperatures, impacts of dry–wet cycles and freeze–thaw cycles, and vegetation effects on soils are emphasized in this paper. Furthermore, to address the challenges, need-based research related to resilient infrastructures, thermo-hydro-mechanical models, bioremediation methods, innovative sustainable composite materials, and incorporation of climatic factors in design is highlighted and discussed.

Mountain erosion mapping is one of the important aspects for monitoring environmental degradation. Global climate change coupled with human activities is eroding the mountain regions of the world at an alarming rate. The various types of erosion can be classified as water erosion, aeolian erosion, glaciered erosion, gravity erosion and man-made erosion. Tectonic activity also plays a major role towards mountain erosion. Soil erosion along with debris flow and rock falling not only causes loss of human life and property, but also affects the climatic condition of the mountain regions. Mountain erosion mitigation and protection methods include wire mesh fencing with inclusion of brush layers and brush mats on fascines, constructing check dams and slope benches and application of bioengineering works such as plantation and vegetation growth. This study consists of the global scenario with some of the state-of-the-art methods for mitigation and mappings of mountain erosion. The erosion in mountainous regions can be controlled with the help of suitable vegetation and plant growth, with installation of special bioengineered materials. However, public awareness is also considered as an important factor. Moreover, it is found that mapping the rate of erosion greatly helps to make proper action plan against the erosion process.

Demand for infrastructure development in coastal regions where the subsurface is often composed of soft clays, results from the desire for rapid industrialization. The frequently encountered coastal soil conditions often call for suitable ground improvement and modification techniques to prepare soft deposits for foundation construction. For appropriate site improvement, several engineering soil properties are desired which require expensive and time consuming field and laboratory testing. Under such circumstances, empirical correlations based on routinely determined soil properties would be very useful and economical in planning of the project. With this as a goal, undisturbed samples from three on-shore and off-shore sites of the coastal regions in India, where major infrastructure projects are being executed, were collected. These samples were tested for physical, chemical, mineralogical and geotechnical characteristics. In addition, shear wave velocity of specimens of these soils was determined by using bender elements. Based on this data, empirical correlations between void ratio, compression index and undrained shear strength with shear wave velocity of clays were developed. Because shear wave velocity can be easily determined in the laboratory, these correlations are found to be valuable for preliminary planning of the project. The utility of these correlations for preliminary characterization of the soft soil has also been demonstrated.

Thrombotic thrombocytopenic purpura (TTP) is a coagulation disorder caused by a deficiency in ADAMTS13. Patients classically present with symptoms of end-organ damage as well as anemia and thrombocytopenia. Treatment is therapeutic plasma exchange (TPE) in the acute setting, with systemic immunosuppression for refractory cases. A 48-year-old female diagnosed with TTP at age 42 presented initially with altered mental status (AMS), severe anemia, and thrombocytopenia requiring intensive care unit (ICU) admission. The patient was treated acutely and discharged from the hospital. During subsequent years, multiple relapses requiring hospitalization prompted scheduled maintenance with rituximab. Since maintenance therapy, the patient remained relapse-free while ADAMTS13 levels escalated. Untreated, TTP is fatal. The treatment goal in the acute setting is the repletion of ADAMTS13 coupled with immunosuppression in refractory cases. Rituximab typically is reserved for patients who do not improve with initial TPE. Albeit unusual in TTP, rituximab maintenance in our patient induced remission. Maintenance therapy with rituximab in patients with a history of relapsing TTP can blunt or obviate the frequency of relapses and hospital admissions. More research is required to establish the effectiveness of rituximab in the chronic treatment of TTP.

The oxidative effect of carbanilation mixtures containing dimethylsulfoxide (DMSO) was demonstrated by means of alcohol model substances in which competitive carbanilation was prevented due to steric hindrance of the hydroxyl function, rendering those compounds specific probes for oxidation effects. Dimethylsulfonium ions and derived ylide species were shown to be the actually oxidizing species according to trapping methodology using lipophilic olefins which were converted into the corresponding cyclopropane and epoxide derivatives. The experimental data were in good agreement with DFT computations carried out on the B3LYP/6-311+G(d,p) level of theory. The direct interaction of cellulose and sulfoxide solvent was proven by means of methyl-(2-naphthyl)sulfoxide (MNSO) as a model for DMSO, which caused introduction of UV-detectable methylthionaphthyl ether moieties into the cellulose, formed in Pummerer-type side reaction paralleling the chemical behavior of DMSO. A facile color test--responding to sulfoxide-derived oxidizing species--was developed to assess the suitability of carbanilation conditions with regard to cellulose oxidation and degradation. DMSO-based carbanilation systems have to be used with great caution for determination of molecular weight parameters and for similar purposes which require complete maintenance of the cellulose integrity. Cellulose oxidation/degradation by DMSO-derived intermediates upon carbanilation can be minimized but cannot be avoided completely. Thus, if cellulose integrity is an issue as it is in cellulose analytics, it is recommended to replace DMSO by solvent components of similar solution behavior but without the inherent danger of generating oxidants, such as pyridine or DMAc, whenever possible.

Shear and compression wave velocities (Vs and Vp, respectively) have been demonstrated to be quite useful for determining basic engineering properties of the soil mass by earlier researchers. To achieve this, resonant column, cyclic triaxial and tortional shear tests have been employed. However, these methods are not only quite elaborate and expensive but require skilled manpower, are cumbersome and time consuming. This calls for development of an alternate methodology that can be employed for characterizing the soil mass, which is not very intricate and is cost-effective. In this situation, usage of piezoceramic elements (i.e., bender and extender elements, which can be employed for measuring Vs and Vp, respectively) seems to be a good option.With this in view, an attempt has been made in this study to develop a simple and costeffective methodology for measuring Vs and Vp in different types of soils, compacted to different compaction states. This methodology incorporates in it the optimal performance of different bender and extender pairs. The suitability of the methodology has been demonstrated for characterization of the soil mass for engineering purpose. Using this methodology, Vs and Vp were measured in the laboratory for different types of soils in their dry and wet conditions corresponding to different various compaction states. Based on the results, empirical relationships have been developed between Vs and soil specific properties (viz., void ratio, effective stress, and size, shape, roundness and sphericity of the particles). However, for cohesive soils, Vs has also been correlated to the compression index, undrained shear strength and various index properties (viz., plasticity, fine content and moisture content) of the soil mass. Attempts have also been made to develop generalized relationships that can be used for determining basic geotechnical engineering properties of the soil mass, quite easily, just by inputting Vs. Also, a comparison has been made between the Poisson's ratio and elastic modulus of the soil mass obtained from Vs and Vp measurements, and conventional triaxial tests.