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Blends of synthetic rubbers are widely used by rubber product manufacturing industries depending on the end use and product application. The estimation of individual rubber in blends is an important aspect to characterise the correctness of the mixing process. In tyre industry, Styrene butadiene rubber/Polybutadiene rubber (SBR/BR) blend is commonly used to achieve different performance properties, particularly for passenger car tyre. Out of the different quantitative analysis techniques to characterise the blend, one of the widely used techniques Gas Chromatography-Mass Spectrometry (GC-MS) has been used to develop and later validate a method to quantify the SBR/BR blend ratio. Through this GC-MS technique detection capability is measured, with a minimum limit of detection (LOD) of 5.17% and a limit of quantification (LOQ) of 15.67% Styrene butadiene rubber (SBR) in an SBR-BR vulcanizate. It is observed that the bias percentage is highest in case of a lower SBR content sample, i.e. 11.1% while in the case of other sets, it is varying from (–)1.4% to (+)1.5%. During the recovery study, it is observed that with increasing SBR content, recovery is also improving. All requirements for a successful method validation: Accuracy, precision, selectivity, detection capability, calibration range and robustness have been carried out in this entire work.

There is emerging evidence for the use of poly (ADP-ribose) polymerase inhibitors (PARPi) in patients with mCRPC with patients harboring germline or somatic mutations deriving clinical benefit. However, the toxicity profile of PARPi in mCRPC is not well established. In March 2022 a literature search was conducted across 4 databases - Medline, PubMed, Cochrane Library and Embase. In total, 14 relevant studies were identified cumulating in 2066 patients that were treated with PARPi. The overall ORR to PARPi alone or in combination with other therapy was 37% (246/666). In 5trials that investigated PARPi alone, the ORR was 39% (141/361). Treatment emergent adverse events (TEAEs) of any grade were reported in 96% (1034/1080) in PARPi treatment arms. TEAEs of grade= 3 were reported in 57% (611/1080). 45% (457/1006) experienced treatment interruption whilst 31% (310/989) required dose reductions. 11% (114/1006) of patients had their treatment discontinued directly as the result of toxicity associated with the trial medications. The most common hematological toxicity was anemia, reported in 490/1160 (42%) patients. and lowered white blood cell count were the next 2most common toxicities, reported in 186/655 (28%) and 133/729 (18%) respectively. The 3most common non-hematological toxicities reported were nausea, fatigue and anorexia reported in 440/1013 (43%), 340/1013 (34%) and 274/1013 (27%) patients respectively. Overall, TRAEs associated with individual PARPi are still emerging with hematological toxicities being most apparent. Further toxicities will be informed from future clinical trials to allow improved treatment selection, education and management of toxicities in prostate cancer.

Resistance to androgen receptor (AR) blockade in castration-resistant prostate cancer (CRPC) is associated with sustained AR signaling, including through alternative splicing of AR (AR-SV). Inhibitors of transcriptional coactivators that regulate AR activity, including the paralog histone acetyltransferase proteins p300 and CBP, are attractive therapeutic targets for lethal prostate cancer. Herein, we validate targeting p300/CBP as a therapeutic strategy for lethal prostate cancer and describe CCS1477, a novel small-molecule inhibitor of the p300/CBP conserved bromodomain. We show that CCS1477 inhibits cell proliferation in prostate cancer cell lines and decreases AR- and C-MYC–regulated gene expression. In AR-SV–driven models, CCS1477 has antitumor activity, regulating AR and C-MYC signaling. Early clinical studies suggest that CCS1477 modulates KLK3 blood levels and regulates CRPC biopsy biomarker expression. Overall, CCS1477 shows promise for the treatment of patients with advanced prostate cancer.Significance:Treating CRPC remains challenging due to persistent AR signaling. Inhibiting transcriptional AR coactivators is an attractive therapeutic strategy. CCS1477, an inhibitor of p300/CBP, inhibits growth and AR activity in CRPC models, and can affect metastatic CRPC target expression in serial clinical biopsies.See related commentary by Rasool et al., p. 1011.This article is highlighted in the In This Issue feature, p. 995

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Anticancer drug development is a costly and protracted activity, and failure at late phases of clinical testing is common. We have previously proposed the Pharmacological Audit Trail (PhAT) intended to improve the efficiency of drug development, with a focus on the use of tumour tissue-based biomarkers. Blood-based ‘liquid biopsy’ approaches, such as targeted or whole-genome sequencing studies of plasma circulating cell-free tumour DNA (ctDNA) and circulating tumour cells (CTCs), are of increasing relevance to this drug development paradigm. Liquid biopsy assays can provide quantitative and qualitative data on prognostic, predictive, pharmacodynamic and clinical response biomarkers, and can also enable the characterization of disease evolution and resistance mechanisms. In this Perspective, we examine the promise of integrating liquid biopsy analyses into the PhAT, focusing on the current evidence, advances, limitations and challenges. We emphasize the continued importance of analytical validation and clinical qualification of circulating tumour biomarkers through prospective clinical trials. In this Perspective, members of the group that previously proposed the Pharmacological Audit Trail (PhAT) as a tool to improve and accelerate drug development through the use of tissue biomarkers discuss the promise of integrating liquid biopsy approaches into this paradigm. They focus on the potential applications of plasma circulating cell-free tumour DNA and circulating tumour cells as prognostic, predictive, pharmacodynamic, clinical response and resistance biomarkers, while also highlighting key technological considerations, limitations and challenges, and the importance of analytical validation and clinical qualification.

Let X be a tree of proper geodesic spaces with edge spaces strongly contracting and uniformly separated from each other by a number depending on the contraction function of edge spaces. Then we prove that the strongly contracting geodesics in vertex spaces are quasiconvex in X. We further prove that in X if all the vertex spaces are uniformly hyperbolic metric spaces then X is a hyperbolic metric space and vertex spaces are quasiconvex in X., Comment: 15 pages, 5 figures. Main Theorems are proved for more general cases. To appear in Proc. Indian Acad. Sci. (Math. Sci.)

Geometric group theory emerged as a distinct branch of mathematics through the seminal work of Gromov [25] in 1987 and since then it has been a very active area of research intermingling with many other fields of mathematics. This paper is a survey of contributions made in the past decade in Geometric group theory by the Indian mathematicians.

Introduction Immune checkpoint inhibitors (ICIs) are increasingly a standard of care for many cancers; these agents can result in immune-related adverse events (irAEs) including fever, which is common but can rarely be associated with systemic immune activation (SIA or acquired HLH). Methods All consecutive patients receiving ICIs in the Drug Development Unit of the Royal Marsden Hospital between May 2014 and November 2019 were retrospectively reviewed. Patients with fever ≥ 38°C or chills/rigors (without fever) ≤ 6 weeks of commencing ICIs were identified for clinical data collection. Results Three patients met diagnostic criteria for SIA/HLH with median time to onset of symptoms of 10 days. We describe the clinical evolution, treatment used, and outcomes for these patients. High-dose steroids are used first-line with other treatments, such as tocilizumab, immunoglobulin and therapeutic plasmapheresis can be considered for steroid-refractory SIA/HLH. Conclusion SIA/HLH post ICI is a rare but a potentially fatal irAE that presents with fever and a constellation of nonspecific symptoms. Early recognition and timely treatment are key to improving outcomes.

An analytical method is a process or pathway to estimate, determine, or solve any type of measurand or problem...

Anticancer drug development is a costly and protracted activity, and failure at late phases of clinical testing is common. We have previously proposed the Pharmacological Audit Trail (PhAT) intended to improve the efficiency of drug development, with a focus on the use of tumour tissue-based biomarkers. Blood-based 'liquid biopsy' approaches, such as targeted or whole-genome sequencing studies of plasma circulating cell-free tumour DNA (ctDNA) and circulating tumour cells (CTCs), are of increasing relevance to this drug development paradigm. Liquid biopsy assays can provide quantitative and qualitative data on prognostic, predictive, pharmacodynamic and clinical response biomarkers, and can also enable the characterization of disease evolution and resistance mechanisms. In this Perspective, we examine the promise of integrating liquid biopsy analyses into the PhAT, focusing on the current evidence, advances, limitations and challenges. We emphasize the continued importance of analytical validation and clinical qualification of circulating tumour biomarkers through prospective clinical trials.

e18810 Background: The PACIFIC trial established concurrent chemoradiation followed by one year of consolidation durvalumab as the standard of care for unresectable stage III non-small cell lung cancer (NSCLC). However, the data to support the use of durvalumab in patients with EGFR mutations and low PD-L1 expression is less clear. This study adds to the available evidence by describing the survival outcomes for patients with stage III unresectable NSCLC treated with chemoradiation followed by durvalumab with a focus on their EGFR mutation and PD-L1 status. Methods: This retrospective observational study was conducted at six sites across Sydney, Australia. It included patients diagnosed with unresectable stage III NSCLC treated with chemoradiation and at least one cycle of durvalumab between January 2018 to September 2021. Patients were stratified into EGFR wild-type and mutated tumours and PD-L1 tumour proportional score (TPS) greater than or less than 1%. Survival analyses were supplemented with cox proportional hazards regression models which estimated HRs for PFS in treatment group comparisons. The proportional hazards assumption was confirmed for all cox models. All statistical analysis was done using R version 4.1.1. Results: 146 patients were included in the analysis. The median follow-up from the start of Durvalumab was 15.1 months. The median age was 66 years in the EGFR mutated and 65 years in the EGFR wild-type cohorts. 61% (n = 89) of patients were male. 10% (n = 15) of patients had EGFR mutation. 42% (n = 61) of patients had a PD-L1 TPS of < 1%. PD-L1 expression was similar in both cohorts with 47% (n = 7) of EGFR mutated patients having PD-L1 TPS of < 1% compared with 45% (n = 59) in the wild-type group. The median progression-free survival (PFS) was 7.5 months for EGFR mutated patients versus 33.9 months for EGFR wild- type patients (HR: 2.7; 95% CI: 1.2 – 5.7; p = 0.01). There was no statistically significant difference in either PFS (HR 0.7, 95% CI 0.4 – 1.7, p = 0.43) or OS (HR 0.5, 95% CI 0.4 – 4.7, p = 0.16) for patients with PD-L1 TPS of < 1% compared with PD-L1 TPS of > 1%. Conclusions: Our data adds to the growing evidence that suggests consolidation durvalumab after definitive chemoradiation may not be as efficacious in patients with EGFR-mutated tumours. PD-L1 TPS did not affect survival outcomes.

BackgroundData suggest that immunomodulation induced by DNA hypomethylating agents can sensitize tumors to immune checkpoint inhibitors. We conducted a phase 1 dose-escalation trial (NCT02998567) of guadecitabine and pembrolizumab in patients with advanced solid tumors. We hypothesized that guadecitabine will overcome pembrolizumab resistance.MethodsPatients received guadecitabine (45 mg/m2 or 30 mg/m2, administered subcutaneously on days 1–4), with pembrolizumab (200 mg administered intravenously starting from cycle 2 onwards) every 3 weeks. Primary endpoints were safety, tolerability and maximum tolerated dose; secondary and exploratory endpoints included objective response rate (ORR), changes in methylome, transcriptome, immune contextures in pre-treatment and on-treatment tumor biopsies.ResultsBetween January 2017 and January 2020, 34 patients were enrolled. The recommended phase II dose was guadecitabine 30 mg/m2, days 1–4, and pembrolizumab 200 mg on day 1 every 3 weeks. Two dose-limiting toxicities (neutropenia, febrile neutropenia) were reported at guadecitabine 45 mg/m2 with none reported at guadecitabine 30 mg/m2. The most common treatment-related adverse events (TRAEs) were neutropenia (58.8%), fatigue (17.6%), febrile neutropenia (11.8%) and nausea (11.8%). Common, grade 3+ TRAEs were neutropaenia (38.2%) and febrile neutropaenia (11.8%). There were no treatment-related deaths. Overall, 30 patients were evaluable for antitumor activity; ORR was 7% with 37% achieving disease control (progression-free survival) for ≥24 weeks. Of 12 evaluable patients with non-small cell lung cancer, 10 had been previously treated with immune checkpoint inhibitors with 5 (42%) having disease control ≥24 weeks (clinical benefit). Reduction in LINE-1 DNA methylation following treatment in blood (peripheral blood mononuclear cells) and tissue samples was demonstrated and methylation at transcriptional start site and 5’ untranslated region gene regions showed enriched negative correlation with gene expression. Increases in intra-tumoural effector T-cells were seen in some responding patients. Patients having clinical benefit had high baseline inflammatory signature on RNAseq analyses.ConclusionsGuadecitabine in combination with pembrolizumab is tolerable with biological and anticancer activity. Reversal of previous resistance to immune checkpoint inhibitors is demonstrated.

e18773 Background: The neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) has been of prognostic interest in lung cancer. Sustained NLR and PLR after initial chemoradiotherapy (CRT) has been shown to correlate with worse prognosis in other solid organ malignancies. This study aims to add to the available evidence by describing the survival outcomes for patients with stage III NSCLC who are treated with consolidation Durvalumab when stratified by baseline or sustained NLR and PLR. Methods: We conducted a retrospective observational cohort study involving 6 sites across Sydney, Australia, including all patients diagnosed with stage III NSCLC treated with chemoradiation (CRT) and at least one cycle of durvalumab between January 2018 to September 2021. Patients had NLR and PLR collected prior to their first treatment of CRT and prior to their first treatment with Durvalumab. We used NLR and PLR values of 3 and 185 respectively to stratify patients into high and low groups. Patients with sustained NLR or PLR were defined as those with values > = 3 or > = 185 at both pre-CRT and pre-Durvalumab time points. Results: 148 patients were included in the study. The median follow-up from the start of Durvalumab was 15.1 months. The median age was 66 years. 61% (n = 90) of patients were male. The median PFS was 17.6 months in the pre-CRT NLR high cohort and not reached in the pre-CRT NLR low cohort (HR 1.99; 95% CI 1.16 – 3.41; p = 0.01). Median OS was 35.5 months versus 42.0 months in high and low pre-CRT NLR groups respectively (HR 2.62; 95% CI 1.23 – 5.56; p < 0.01). The median PFS was 19.9 months in the pre-CRT high PLR cohort versus and not reached in the pre-CRT low PLR cohort (HR 1.98; 95% CI 1.15 – 3.42; p = 0.02). The median OS was 39.9 months versus 42.0 months in high and low pre-CRT PLR groups respectively (HR 2.29; 95% CI 1.08– 4.88; p = 0.03). Median PFS for sustained NLR elevation was 17.1 months versus NR (HR 1.5, 95% CI 1.1 – 2.2, p < 0.01). Similarly median PFS for sustained PLR elevation was 16.6 months versus NR (HR 1.7, 95% CI 1.1 – 2.4, p < 0.01). Conclusions: Pre-CRT NLR and pre-CRT PLR are associated with OS and PFS outcomes in stage III unresectable NSCLC treated with CRT and Durvalumab. Those with sustained NLR or sustained PLR also have worse progression free survival outcomes.

Clustering-based image segmentation got wide attention for decades. Among various existing clustering techniques, K-means algorithm gained popularity for its better outcome. But the drawback of this algorithm can be found, when it is applied to noisy medical images. So, modification of the standard K-means algorithm is highly desired. This paper proposes an improved version of K-means algorithm called as (IKM) to get more effective and efficient outcomes. The efficiency of the algorithm depends on the speed of forming the clusters. So, in the proposed approach, new idea has been applied to find the minimum distance to generate the clusters. The proposed IKM algorithm has been applied to the set of noisy medical images, and the segmented outcomes have been evaluated by the standard quality measurement metrics, namely Peak-Signal-to-Noise-Ratio (PSNR) and structural similarity index measurement (SSIM). The outcomes have also been compared with the Watershed algorithm for showing the betterment of the proposed approach.

Resistance to androgen receptor (AR) blockade in castration-resistant prostate cancer (CRPC) is associated with sustained AR signaling, including through alternative splicing of AR (AR-SV). Inhibitors of transcriptional coactivators that regulate AR activity, including the paralog histone acetyltransferase proteins p300 and CBP, are attractive therapeutic targets for lethal prostate cancer. Herein, we validate targeting p300/CBP as a therapeutic strategy for lethal prostate cancer and describe CCS1477, a novel small-molecule inhibitor of the p300/CBP conserved bromodomain. We show that CCS1477 inhibits cell proliferation in prostate cancer cell lines and decreases AR- and C-MYC–regulated gene expression. In AR-SV–driven models, CCS1477 has antitumor activity, regulating AR and C-MYC signaling. Early clinical studies suggest that CCS1477 modulates KLK3 blood levels and regulates CRPC biopsy biomarker expression. Overall, CCS1477 shows promise for the treatment of patients with advanced prostate cancer. Significance: Treating CRPC remains challenging due to persistent AR signaling. Inhibiting transcriptional AR coactivators is an attractive therapeutic strategy. CCS1477, an inhibitor of p300/CBP, inhibits growth and AR activity in CRPC models, and can affect metastatic CRPC target expression in serial clinical biopsies. See related commentary by Rasool et al., p. 1011. This article is highlighted in the In This Issue feature, p. 995

In this article, we prove a combination theorem for a complex of relatively hyperbolic groups. It is a generalization of Martin's \cite{martin} work for combination of hyperbolic groups over a finite $M_K$-simplicial complex, where $k\leq 0$., Comment: 17 pages, Major revision done

Effect of different solvents on emission behaviour of oligothiophene (OT) has been explored in this article. OT was synthesized using a modified cationic surfactant assisted polymerization technique. The average molecular weight was 1006 (which indicated an addition of 12 thiophene units) with a wider distribution (solid state crystallinity of 26% from X-ray crystallography). A gradient solubility of OT was obtained in N, N-dimethyl sulphoxide (95%), ethanol (82%) and chloroform (65%) due to descending solvochromatic interaction. A higher emission intensity (blue) and fluorescent quantum yield (11%) was obtained in DMSO than in ethanol (quantum yield 7%) due to a lower HOMO-LUMO transition energy. Conversely, excitation in a high molecular weight solvent like poly (vinyl alcohol) displayed a low emission intensity and fluorescent quantum yield (3%) despite lower HOMO-LUMO transition energy mainly due to quenching effect. Instead, such a system was suited for a capacitative action as demonstrated through cyclic voltametric measurement.

In our present work, we have attempted to develop a low volatile organic containing, ecofriendly resin from a natural resource maintaining the quality and desired properties for printing ink applications. Guar Gum, a natural polysaccharide was used in place of pentaerythritol in the recipe. It was used during trans-esterification reaction to synthesize rosin modified phenolic resin for printing ink. A conventional rosin modified phenolic resin, using pentaerytritol, was also synthesized for comparison. Guar Gum having multiple hydroxyl groups was able to produce resin with higher molecular weight and high solvent tolerance value which makes the ecofriendly resin as potential binder for printing ink application with excellent print quality. The modified resin was characterized using various analytical techniques to find the influence of the polysaccharide on the final properties. A detailed kinetic study was also carried out in order to justify the reaction mechanism.

Acacia nilotica gum (NG) was blended with high hydrolyzed grade biodegradable poly (vinyl alcohol) ( M n ¯ 14,000) in different mass proportions to produce a green and efficient flocculant for separartion of a low concentration of kaolin particles (3 mass%) from its suspension. Flocculation efficacy (settling time and turbidity number) was optimized with respect to flocculant dose, PVA-NG blend composition and pH of the medium. Results showed that PVA-NG73 (70% PVA and 30% NG) was the best performing flocculant at 25 ppm dose when the pH of the medium was maintained at 2.6. Zeta potential (both before and after addition of flocculant), hydrodynamic size, isoelectric point and reduced viscosity number were measured to explain the sedimentation rate and turbidity numbers. The floc size was measured and was found to be comparative to the rate of sedimentation. The amount of water absorbed and lost during operation was found to be proportional with the floc size. Impact of inorganic salts on sedimentation was investigated at a neutral pH which showed a faster settling potential of both bivalent and trivalent salts at an optimized concentration (0.3 M), at the best flocculant dose (25 ppm).

IntroductionEarly phase cancer clinical trials have become increasingly complicated in terms of patient selection and trial procedures—this is reflected in the increasing length of participant information sheets (PIS). Informed consent for early phase clinical trials has been contentious due to the potential ethical issues associated with performing experimental research on a terminally ill population which has exhausted standard treatment options. Empirical studies have demonstrated significant gaps in patient understanding regarding the nature and intent of these trials. This study aims to test whether enhanced informed consent for patient education can improve patient scores on a validated questionnaire testing clinical trial comprehension.Methods and analysisThis is a randomised controlled trial that will allocate patients who are eligible to participate in one of four investigator-initiated clinical trials at the Royal Marsden Drug Development Unit to either a standard arm or an experimental arm, stratified by age and educational level. The standard arm will involve the full length trial PIS, followed by electronic or paper administration of the Quality of Informed Consent Questionnaire Parts A and B (QuIC-A and QuIC-B). The experimental arm will involve the full length trial PIS, exposure to a two-page study aid and 10 online educational videos, followed by administration of the QuIC-A and QuIC-B. The primary endpoint will be the difference (using a one-sided two-sample t-test) in the QuIC-A score, which measures objective understanding, between the standard and experimental arm. Accrual target is at least 17 patients per arm to detect an 8 point difference (80% power, alpha 0.05).Ethics and disseminationEthics approval was granted by the National Health Service Health Research Authority on 15 June 2020—IRAS Project ID 277065, Protocol Number CCR5165, REC Reference 20/EE/0155. Results will be disseminated via publication in a relevant journal.Trial registration numberNCT04407676; Pre-results.

Carboxymethyl guargum-g-poly(acrylic acid)-co-poly(divinyl benzene), bCMGG-g-HBPAA, having an unprecedented hyperbranched architecture is developed. A combination of a polymer grafting technique and “Strathclyde methodology” in emulsion is followed for the first time in the synthesis of bCMGG-g-HBPAA. FTIR, NMR, intrinsic viscosity and linear viscoelasticity studies confirm the microstructure of bCMGG-g-HBPAA. Owing to the unique properties of polysaccharide and hyperbranched chains, bCMGG-g-HBPAA successfully stabilizes monodispersed silver nanoparticles (AgNPs-HB) of size 27 nm and with good optical clarity. AgNPs-HB forms an amalgam in the presence of Hg2+ and thus facilitates colorimetric detection/accurate estimation of Hg2+ (up to 1 ppb). Furthermore, for the first time it is shown that the specificity and sensitivity of AgNPs-HB based sensors towards Hg2+ sensing can be enhanced in the presence of Na salt catalysts. The working principle of AgNPs-HB and AgNPs-HB/Na salt(s) based sensors for Hg2+ is explained through UV-Vis, XRD, HRTEM and CV studies.

Noble copolymers from xanthan gum (XG) and poly(acrylic acid) (PAA) were synthesised through surfactant mediated graft copolymerization. The copolymers were applied as a biosorbent for inorganic Hg(II) at higher concentration level (300ppm). The copolymers were characterized using different analytical techniques which showed, the grafting principally occurred across the amorphous region of XG. Measurement of zeta potential and hydrodynamic size indicated, the copolymers were strong polyanion and possessed greater hydrodynamic size (almost in all cases) than XG, despite a strong molecular degradation that took place simultaneously during grafting. In the dispersed form, all grades of the copolymer displayed higher adsorption capability than XG, however, the grade with maximum grafting produced the highest efficiency (68.03%). Manipulation produced further improvement in efficiency to 72.17% with the same copolymer after 75min at a pH of 5.0. The allowable biosorbent dose, however, was 1000ppm as determined from the experimental evidences.

This article describes the influence of zeta potential and hydrodynamic size of a polyanion, poly (acrylic acid) grafted guar gum (GG-g-PAA) for adsorption of Pb(II). The copolymers were synthesized through surfactant mediated free radical polymerization technique. Aqueous dispersion of the copolymers were directly added to the contaminated water and the parameters such as copolymer grade, pH, adsorbent–adsorbate concentrations, adsorption time and temperature were varied to maximize the adsorption efficiency. The copolymer synthesized with 1:10, GG:AA mole composition and 0.5 wt% initiator content produced maximum adsorption (89.62%) at a pH of 4.5, which was further raised to 95.32% on manipulation. Regression analysis showed the polyanion chemically interacted with Pb(II) and formed a monolayer (Langmuir adsorption) while Chi-square ( χ 2 ) test indicated possibility of multilayer formation (both Langmuir and Freundlich isotherm models as well). The process followed pseudo second order kinetics alike all adsorption processes.

The synthesis and X-ray crystallographic characterization of one antiferromagnetically coupled trinuclear Ni(II) complex, [Ni3(L)2(OAc)2] (1) [L = N,N-(salicyaldene)-1,3-diaminopropan-2-ol], is reported. It effectively catalyses the oxidation of 3,5-ditertiarybutyl catechol to its corresponding quinone in methanol solvent. It follows Michaelis–Menten kinetics with a turnover number of 3.85 × 103 h−1.

In the current context of green mobility and sustainability, the use of new generation natural fillers, namely, &alpha, cellulose, has gained significant recognition. The presence of hydroxyl groups on &alpha, cellulose has generated immense eagerness to map its potency as filler in an elastomeric composite. In the present work, &alpha, cellulose-emulsion-grade styrene butadiene rubber (E-SBR) composite is prepared by conventional rubber processing method by using variable proportions of &alpha, cellulose (1 to 40 phr) to assess its reinforce ability. Rheological, physical, visco-elastic and dynamic-mechanical behavior have clearly established that 10 phr loading of &alpha, cellulose can be considered as an optimized dosage in terms of performance parameters. Morphological characterization with the aid of scanning electron microscope (SEM) and transmission electron microscopy (TEM) also substantiated that composite with 10 phr loading of &alpha, cellulose has achieved the morphological threshold. With this background, synthetic filler (silica) is substituted by green filler (&alpha, cellulose) in an E-SBR-based composite. Characterization of the compound has clearly established the reinforcement ability of &alpha, cellulose.

Early-phase cancer clinical trials are becoming increasingly accessible for patients with advanced cancer who have exhausted standard treatment options and later phase trial options. Many of these trials mandate research tissue biopsies. Research biopsies have been perceived as ethically fraught due to the perception of potential coercion of vulnerable human subjects. We performed an audit of two years of practice to assess the safety of ultrasound (US)-guided research biopsies, and to look at the yield of a simultaneous tumour next-generation sequencing (NGS) and immunohistochemistry (IHC) molecular characterisation programme. We show that in our institution, US-guided research biopsies were safe, produced adequate tumour content and in a selected subset who underwent in-house NGS sequencing, showed a high rate of actionable mutations with 30% having a Tier 1 variant. Nevertheless, these research biopsies may only provide direct benefit for a minority of patients and we conclude with a reflection on the importance of obtaining truly informed consent.

Introduction: We investigated the efficacy and toxicity of pembrolizumab in patients with mesothelioma from a real-world Australian population. We aimed to determine clinical factors and predictive biomarkers that could help select patients who are likely to benefit from pembrolizumab. Method: Patients with mesothelioma who were treated with pembrolizumab as part of the Insurance and Care New South Wales compensation scheme were included. Clinical information was collected retrospectively. Tumor biomarkers such as programmed death-ligand 1 (PD-L1), BAP1, and CD3-positive (CD3+) tumor-infiltrating lymphocytes (TILs) were examined using archival formalin-fixed paraffin-embedded tumor samples. Results: A total of 98 patients were included with a median age of 70 years (range, 46–91 y); 92% were men; 76% had epithelioid subtype; 21% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0. Pembrolizumab was used as second-line or subsequent-line treatment in 94 patients and as first-line treatment in four patients. The overall response rate was 18%, and the disease control rate was 56%. The median progression-free survival (PFS) was 4.8 months (95% confidence interval: 3.6–6.2), and the median overall survival (OS) was 9.5 months (95% confidence interval: 6.6–13.7). Immune-related adverse events occurred in 27% of patients, of which nine (9%) were of grade 3 or higher. In the multivariable analysis, factors independently associated with longer PFS included baseline ECOG status of 0 (median PFS: 12 mo versus 4 mo, p < 0.01) and PD-L1 tumor proportion score of greater than or equal to 1% (median PFS: 6 mo versus 4 mo, p < 0.01). Baseline platelet count of less than or equal to 400 × 109/liter was independently associated with longer PFS and OS (median PFS: 6 mo versus 2 mo, p = 0.05; median OS: 10 mo versus 4 mo, p = 0.01), whereas lack of pretreatment dexamethasone was independently associated with OS but not PFS (median OS: 10 mo versus 3 mo, p = 0.01). The odds of response were higher for patients with baseline ECOG status of 0 (p = 0.02) and with greater than or equal to 5% CD3+ TILs in the tumor (p < 0.01). PD-L1 expression, BAP1 loss, and CD3+ TILs in the stroma were not significantly associated with the overall response rate. Conclusions: Immunotherapy is a reasonable treatment option for patients with mesothelioma. Our results are comparable to other clinical trials investigating pembrolizumab in mesothelioma in terms of response. Good performance status assessment remains the most robust predictor for patient outcomes. CD3+ TILs in the tumor may help select patients that are likely to respond to pembrolizumab, whereas factors such as PD-L1 expression, baseline platelet count, and lack of pretreatment dexamethasone may help predict survival outcomes from pembrolizumab treatment.

Background: Methylation is reported to support cancer immune tolerance. We conducted a phase 1 dose-escalation trial [NCT02998567] of combination guadecitabine (G; DNA hypomethylating agent) and pembrolizumab (P) in patients (pts) with advanced cancers. We hypothesized that G can normalize the expression of epigenetically suppressed immune genes, increase interferon producing tumor-infiltrating lymphocytes (TILs), and enhance the anticancer activity of P. Methods: In dose escalation (Es), pts received G (45 mg/m2 or 30 mg/m2, administered SC on days 1-4) with P (200 mg, administered IV starting from cycle 2 onwards) as outpatient Q3W; in expansion (Ex), the RP2D of G (30 mg/m2) with P (200 mg) Q3W was administered. Pre-treatment and on-treatment tumor biopsies were evaluated for PD-L1 expression, tumor infiltrating lymphocytes, gene expression by RNAseq and methylome studies. Longitudinal analyses of peripheral blood CD3, CD4 and CD8 lymphocytes by flow cytometry were performed. Results: Overall, 34 pts (Es, n = 14; Ex, n = 20) were evaluable for safety. The most common treatment-related adverse events (TRAEs) were neutropenia (n = 21), fatigue (n = 6) and thrombocytopenia (n = 3), diarrhea (n = 2). G3+ TRAEs were neutropenia (n = 14), febrile neutropenia (n = 4), raised ALP (n = 1), raised AST (n=1), colitis (n = 1), diarrhoea (n = 1) and lung infection (n = 1). Two DLTs (neutropenia, febrile neutropenia) were reported at G 45mg/m2 with none reported at G 30mg/m2. There were no treatment-related deaths. In total, 28 pts (Es, n = 12; Ex, n = 16) were evaluable for antitumor activity studies (≥2 scans); ORR (CR+PR) and DCR (CR+PR+SD) were 3% and 57%; 10/15 pts with non-small cell lung cancer (13 pts resistant/refractory to PD-1/PD-L1 targeting agents) were evaluable, with a DCR of 80% and 5 pts having DCR > 6 months with 8 pts remaining on study treatment. Overall, 25 paired biopsies were obtained. Using LINE1 sequences to study global methylation, both tumor biopsies and peripheral blood showed reduced methylation post-G treatment. Preliminary data on tumor-infiltrating lymphocytes assessed by multicolor immunofluorescence in 9 paired biopsies showed a numerical increase in median values of T-helper (CD4+FOXP3-) (10.20 to 19.70, p = 0.5469), T-regulatory (CD4+FOXP3+) (5.1 to 6.7, p=0.8438), and T-cytotoxic (CD8+) cell densities (2.7 to 7.4, p=0.6523) . Comparing with matched pre-treatment, on treatment tumor had numerical increases in interferon alpha and gamma response pathway activation in serial biopsy RNAseq analyses but did not reach significance. Conclusions: G plus P resulted in no unexpected toxicities with evidence suggestive of biological and anti-cancer activity. Citation Format: Dionysis Papadatos-Pastos, Abhijit Pal, Melek Akay, Malaka Ameratunga, Sanjena Mithra, Joo-Ern Ang, Sofia Levva, Reece Caldwell, Ruth Riisnaes, Mateus Crespo, Wei Yuan, George Seed, Bora Gurel, Ines Figueiredo, Rita Pereira, Susana Miranda, Anna Ferreira, Suzanne Carreira, Claudia Bertan, Chloe Baker, Ricardo Morilla, Robert Brown, Nahal Masrour, Toby Prout, Anna Zachariou, Alison Turner, Mona Parmar, Mark Van de Velde, Ben Jenkins, Christina Yap, Nina Tunariu, Udai Banerji, Juanita Lopez, Anna Minchom, Johann De Bono. HyPeR: A phase 1, dose escalation and expansion trial of guadecitabine (SGI-110), a second-generation hypomethylating agent in combination with pembrolizumab (MK3475) in patients with refractory solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT129.

An elastic semi IPN from guar gum (GG), xanthan gum (XG) and poly(acrylic acid) (PAA) was developed and used as a bioadsorbent for soluble Pb(II) and Hg(II) from water. The IPNs were developed using a photo-initiated crosslinking cum polymerization approach (benzophenone was used as an initiator) with a variable composition of the biopolymers (GG:XG fixed at 20:80 by mass) to PAA by mass (Biopolymers: PAA as 90:10, 80:20, 70:30 and 50:50, respectively). The hybrids were extensively characterized for microstructure, morphology, swelling, porosity and rheological behavior, both in dry and swelled conditions. Three grades of biosorbents namely 90:10, 80:20 and 70:30 showed an enhanced adsorption efficiency compared to the remaining ternary grades as well as the crosslinked binary grade of GG:XG (20:80 mass composition, used as a control), respectively. It was primarily due to high network strength (elasticity) cum flexibility (more liquid like behavior) of those three ternary grades under swollen condition followed by their higher swelling capacity and strongly negative zeta potential to attract the positively charged Pb(II) and Hg(II), respectively. The 80:20 grade (80 parts was the mass composed of XG:GG in 80:20 mass ratio and 20 parts was the mass of PAA) exhibited the maximum molecular effect and thus recorded the highest adsorption efficiency (93 % for Pb(II) with an adsorption capacity of 111.6 and 72 % of Hg(II) with an adsorption capacity of 86.4). Nevertheless, all the hybrids showed a strong pH dependant adsorption as the –COOH unit present in the network displayed a pH sensitive ionization. The adsorption was lower below the pH level of 4.0 (pKa of PAA at 4.5) while drastically improved beyond that. On additional note, the adsorbate dose was also found to affect the adsorption efficiency whereby a maximum dose of 300 ppm of both Pb(II) and Hg(II) was found to be most effective for adsorption.