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Fire analysis of reinforced concrete (RC) structures is vital for understanding their behavior under extreme conditions. In real-world scenarios, uncontrolled fires can damage buildings and infrastructure substantially, undermining their structural integrity. Assessing the performance of RC beams under fire exposure is crucial for ensuring the safety and reliability of structures. This study examines the structural performance and residual moment capacity of plastered and unplaster-reinforced concrete (RC) beams subjected to varying durations of fire exposure. Two types of reinforcement configurations in plastered and unplaster beams were evaluated: one with two 10 mm diameter reinforcement bars at the top and bottom and another with two 10 mm diameter bars at the top and three at the bottom. Unplaster and plastered beams were made from concrete with a compressive strength of 20 MPa at ambient temperature. They were exposed to fire for durations of 0, 3, and 6 h, simulating real fire conditions with a peak temperature of 800 °C. Beams exposed to fire showed reductions in moment capacity of about 20–36%, depending on the reinforcement. The findings highlight the importance of considering plaster as a protective layer in RC beam design to enhance fire resistance and post-fire structural performance. The findings emphasize the necessity of incorporating fire-resistant measures, such as plaster coatings, to mitigate structural degradation, thereby enhancing post-fire safety and performance of RC beams.

Revolutionizing construction, the concrete blend seamlessly integrates human hair (HH) fibers and millet husk ash (MHA) as a sustainable alternative. By repurposing human hair for enhanced tensile strength and utilizing millet husk ash to replace sand, these materials not only reduce waste but also create a durable, eco-friendly solution. This groundbreaking methodology not only adheres to established structural criteria but also advances the concepts of the circular economy, representing a significant advancement towards environmentally sustainable and resilient building practices. The main purpose of the research is to investigate the fresh and mechanical characteristics of concrete blended with 10–40% MHA as a sand substitute and 0.5–2% HH fibers by applying response surface methodology modeling and optimization. A comprehensive study involved preparing 225 concrete specimens using a mix ratio of 1:1.5:3 with a water-to-cement ratio of 0.52, followed by a 28 day curing period. It was found that a blend of 30% MHA and 1% HH fibers gave the best compressive and splitting tensile strengths at 28 days, which were 33.88 MPa and 3.47 MPa, respectively. Additionally, the incorporation of increased proportions of MHA and HH fibers led to reductions in both the dry density and workability of the concrete. In addition, utilizing analysis of variance (ANOVA), response prediction models were created and verified with a significance level of 95%. The models' R 2 values ranged from 72 to 99%. The study validated multi-objective optimization, showing 1% HH fiber and 30% MHA in concrete enhances strength, reduces waste, and promotes environmental sustainability, making it recommended for construction.

The landscape of advanced non-small lung cancer (NSCLC) therapies has rapidly been evolving beyond chemotherapy over the last few years. The discovery of oncogenic driver mutations has led to new ways in classifying NSCLC as well as offered novel therapeutic targets for anticancer therapy. Targets such as epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) gene rearrangements have successfully been targeted with appropriate tyrosine kinase inhibitors (TKIs). Other driver mutations such as ROS, MET, RET, BRAF have also been investigated with targeted agents with some success in the early phase clinical setting. Novel strategies in the field of immune-oncology have also led to the development of inhibitors of cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed death-1 receptor (PD-1), which are important pathways in allowing cancer cells to escape detection by the immune system. These inhibitors have been successfully tried in NSCLC and also now bring the exciting possibility of long term responses in advanced NSCLC. In this review recent data on novel targets and therapeutic strategies and their future prospects are discussed.

Background Small cell lung cancer (SCLC) is an aggressive neuroendocrine cancer with an appalling overall survival of less than 5% (Zimmerman et al. J Thor Oncol 14:768-83, 2019). Patients typically respond to front line platinum-based doublet chemotherapy, but almost universally relapse with drug resistant disease. Elevated MYC expression is common in SCLC and has been associated with platinum resistance. This study evaluates the capacity of MYC to drive platinum resistance and through screening identifies a drug capable of reducing MYC expression and overcoming resistance. Methods Elevated MYC expression following the acquisition of platinum resistance in vitro and in vivo was assessed. Moreover, the capacity of enforced MYC expression to drive platinum resistance was defined in SCLC cell lines and in a genetically engineered mouse model that expresses MYC specifically in lung tumors. High throughput drug screening was used to identify drugs able to kill MYC-expressing, platinum resistant cell lines. The capacity of this drug to treat SCLC was defined in vivo in both transplant models using cell lines and patient derived xenografts and in combination with platinum and etoposide chemotherapy in an autochthonous mouse model of platinum resistant SCLC. Results MYC expression is elevated following the acquisition of platinum resistance and constitutively high MYC expression drives platinum resistance in vitro and in vivo. We show that fimepinostat decreases MYC expression and that it is an effective single agent treatment for SCLC in vitro and in vivo. Indeed, fimepinostat is as effective as platinum-etoposide treatment in vivo. Importantly, when combined with platinum and etoposide, fimepinostat achieves a significant increase in survival. Conclusions MYC is a potent driver of platinum resistance in SCLC that is effectively treated with fimepinostat.

Engineered cementitious composites (ECC) boast superior tensile strain capacity and crack resistance compared to traditional concrete. A key contributor to this enhanced behavior is their high fracture energy, reflecting the material's ability to absorb energy before failure. This review paper comprehensively examines the factors influencing ECC fracture energy. It explores the impact of fiber properties (volume, type, aspect ratio), the binding matrix's characteristics, and the crucial fiber–matrix bond quality. The review dives deeper into established methods for measuring ECC fracture energy. It analyzes various test configurations and data analysis techniques used to quantify this vital property. Understanding how critical factors such as fiber volume, aspect ratio, and fiber type can improve or reduce the fracture process is discussed in this review. To optimize the ECC design, different experimental procedures along with their advantages and shortcomings and future testing methods to clearly evaluate the fracture behavior of ECC are discussed as well. This allows for achieving targeted fracture energy levels tailored to specific applications. Additionally, the review identifies promising directions for future research in ECC fracture energy. These include multi-scale modeling for enhanced design, exploration of advanced fiber engineering for improved performance, and the possibility of incorporating self-healing mechanisms for increased durability. Ultimately, this review aims to provide a comprehensive understanding of the factors governing fracture energy in ECC and the methods for its evaluation, paving the way for the development of next-generation ECC with superior functioning and broader applicability.

Safflower is a multipurpose, underutilized annual crop that could be an alternate oilseed crop for normal and marginal lands around the world. Zinc as a nutrient plays a critical role in enzyme activity and nutrient absorption, leading to improved productivity and quality of oilseeds. However, imbalances between NPK and Zn can result in antagonistic interactions, leading to nutrient deficiencies. Therefore, this field experiment at the University of Agriculture, Faisalabad, Pakistan, was conducted to explore the synergistic effects of NPK and Zn on safflower growth, yield, and oil content. Safflower accession (UAF-SAFF-100) was treated with ten different combinations of zinc and NPK having different concentrations, i.e., T0 = control, T1 = NPK at 40:40:40 kg ha−1, T2 = NPK at 50:50:40 kg ha−1, T3 = NPK at 60:60:40 kg ha−1, T4 = NPK at 70:70:40 kg ha−1, T5 = NPK at 80:80:40 kg ha−1, T6 = T1 + zinc at 7.5 kg ha−1, T7 = T2 + zinc at 7.5 kg ha−1, T8 = T3 + zinc at 7.5 kg ha−1, T9 = T4 + zinc at 7.5 kg ha−1, and T10 = T5 + zinc at 7.5 kg ha−1. The results indicated that the application of T9 (NPK @ 70:70:40 kg/ha−1 + zinc @ 7.5 kg/ha−1) showed the most promising results in terms of growth and yield attributes. This treatment significantly improved key metrics such as capitulum diameter, the number of capitula per plant, seed yield, petal yield, and oil content. Thus, this treatment (T9) is proposed as an effective strategy for enhancing safflower growth and productivity, particularly in semi-arid regions. This study underscores the importance of optimizing nutrient management to achieve superior crop performance and suggests that tailored NPK and Zn applications can be a promising approach to maximizing safflower yield and oil quality.

Introduction Concurrent chemoradiotherapy with high‐dose (HD) cisplatin is the standard treatment for locally advanced head and neck squamous cell carcinoma (LA‐HNSCC). Due to the higher treatment‐related adverse effects with standard therapy, alternative regimens (non‐standard therapy), namely, lower dose weekly cisplatin, carboplatin/paclitaxel, or cetuximab are considered. There is, however, no consensus on non‐standard regimens. We aimed to investigate the efficacy and safety profile of these regimens. Methods This single centre retrospective cohort study included all consecutive adult patients with newly diagnosed LA‐HNSCC treated with either standard or non‐standard regimens between January 2016 and April 2021. The primary outcome was 2‐year failure‐free survival (FFS). The secondary outcomes included acute toxicities, hospitalisation rates, dose modifications, treatment failure rates (TFR), and overall survival. Results About 235 patients were included in the final analysis; median age was 61 years (IQR 55–67), and 87% were male. Most had oropharyngeal tumours (85.5%) and p16‐positivity was frequent (80%). About 56% received non‐standard regimens: weekly cisplatin = 79 and non‐cisplatin = 48. These patients had higher Charlson Comorbidity Index (CCI; p < .001) and lower European Cooperative Oncology Group (ECOG)‐0 (p = .003). There was no difference in 2‐year FFS (hazard ratio [HR] = 1.16; 95% confidence interval – [CI] 0.65–2.05), hospitalisation and grade‐3 toxicity rates between the two regimens. Nausea and vomiting were lower in the non‐standard regimen (3.0% vs. 16%, p < .001). Dose reductions, adjusted for age, sex, and CCI, were less likely in the non‐standard regimen (OR = 2.36; 95%‐CI: 1.01–5.49, p = .007). Conclusions We demonstrated similar efficacy of lower dose weekly cisplatin and carboplatin/paclitaxel regimens and better safety profile of weekly cisplatin compared to standard HD cisplatin regimens for LA‐HNSCC. Multicenter randomised control trials are required in HD cisplatin‐ineligible patients.

Patient-derived xenograft (PDX) models generated from surgical specimens are gaining popularity as preclinical models of cancer. However, establishment of PDX lines from small cell lung cancer (SCLC) patients is difficult due to very limited amount of available biopsy material. We asked whether SCLC cells obtained from endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) could generate PDX lines that maintained the phenotypic and genetic characteristics of the primary tumor. Following successful EBUS-TBNA sampling for diagnostic purposes, we obtained an extra sample for cytologic analysis and implantation into the flanks of immunodeficient mice. Animals were monitored for engraftment for up to 6 months. Histopathologic and immunohistochemical analysis, and targeted next-generation re-sequencing, were then performed in both the primary sample and the derivative PDX line. A total of 12 patients were enrolled in the study. EBUS-TBNA aspirates yielded large numbers of viable tumor cells sufficient to inject between 18,750 and 1,487,000 cells per flank, and to yield microgram quantities of high-quality DNA. Of these, samples from 10 patients generated xenografts (engraftment rate 83%) with a mean latency of 104 days (range 63-188). All but one maintained a typical SCLC phenotype that closely matched the original sample. Identical mutations that are characteristic of SCLC were identified in both the primary sample and xenograft line. EBUS-TBNA has the potential to be a powerful tool in the development of new targeting strategies for SCLC patients by providing large numbers of viable tumor cells suitable for both xenografting and complex genomic analysis.

Small cell lung cancer (SCLC) accounts for approximately 10–15% of all lung cancers. The prognosis is poor with median survival in the advanced stage remaining at around 12 months. Despite applying every known therapeutic approach, no major breakthrough has improved the overall survival in the last 30 years. Historically, experiments performed on conventional cell lines may have limitations of not accurately reflecting the complex biological and genomic heterogeneity of this disease. However, additional knowledge gained from recently developed genetically engineered mouse models (GEMMs) and patient derived xenografts (PDXs) have made encouraging inroads. Whole genome sequencing (WGS) data reveals a high mutational burden and a number of genetic alterations but low frequency of targetable mutations. Despite several failures, considerable therapeutic opportunities have recently emerged. Potentially promising therapies include those targeting DNA damage repair, stem cell/renewal and drug resistant mechanisms. Modest success has also been achieved with immune checkpoint inhibitors while therapeutic exploration of various other components of the immune system is underway. However, the complex heterogeneities reflect the need for accurate bio-markers to translate novel discoveries into clinical benefit. Additionally, the molecular mechanisms that differentiate chemo-sensitive from chemo-refractory disease remain unknown. Obtaining reliable tumour samples by utilising novel techniques such as endobronchial ultrasound guided needle aspiration or adopting to liquid biopsies are becoming popular. This review will focus on recent technological and therapeutic advancements to surmount this recalcitrant disease.

BackgroundThe prognosis for advanced and metastatic cutaneous squamous cell carcinoma (CSCC) remains poor for many patients with the disease despite approval of the anti-PD1 antibodies cemiplimab and pembrolizumab.1 2 RP1 is an oncolytic virus (HSV-1) that expresses a fusogenic glycoprotein (GALV-GP R-) and granulocyte macrophage colony stimulating factor (GM-CSF). In preclinical studies, RP1 induced immunogenic tumor cell death and provided potent systemic anti-tumor activity, which is further improved by combining anti-PD-1 therapy.3 Preliminary results from IGNYTE, a phase I/II clinical study of RP1 in combination with nivolumab showed a high rate of deep and durable responses in patients (pts) with CSCC.4 The objective of this trial is to evaluate the safety and efficacy of cemiplimab + RP1 versus cemiplimab alone in advanced CSCC.MethodsThis global, multicenter, randomized phase 2 study is enrolling pts with metastatic or unresectable, locally advanced CSCC who are not candidates for/refuse surgery and/or radiotherapy. Key eligibility criteria include no prior treatment with anti-PD1/PD-L1 antibodies or oncolytic viruses. The clinical trial will enroll approximately 180 pts from centers in the EU, Australia, Canada and USA. Pts will be randomized in a 2:1 ratio favoring the RP1 + cemiplimab arm. Pts will receive 350 mg of cemiplimab intravenously (IV) Q3W for up to 108 weeks. In the RP1 + cemiplimab arm, RP1 will be injected intratumorally at a starting RP1 dose of 1 × 10^6 plaque forming units (PFU)/mL alone, followed by up to 7 doses of RP1 at 1 × 10^7 PFU/mL Q3W together with cemiplimab. Pts in the combination arm may receive up to 8 additional RP1 doses. No crossover will be allowed. Pts will be stratified by disease status and prior systemic therapy. Tumor assessments will be performed every 9 weeks. Primary endpoints are overall response rate and complete response rate by blinded independent review. Secondary endpoints include safety, progression free survival, duration of response and overall survival. Exploratory endpoints include viral shedding and biodistribution, and immune biomarker analyses. This trial is currently enrolling pts.Trial RegistrationNCT04050436ReferencesMigden MR, Rischin D, Schmults CD, Guminski A, Hauschild A, Lewis KD, Chung CH, Hernandez-Aya L, Lim AM, Chang ALS, Rabinowits G, Thai AA, Dunn LA, Hughes BGM, Khushalani NI, Modi B, Schadendorf D, Gao B, Seebach F, Li S, Li J, Mathias M, Booth J, Mohan K, Stankevich E, Babiker HM, Brana I, Gil-Martin M, Homsi J, Johnson ML, Moreno V, Niu J, Owonikoko TK, Papadopoulos KP, Yancopoulos GD, Lowy I, Fury MG. PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma. N Engl J Med 2018;379(4):341–351.Grob JJ, Gonzalez R, Basset-Seguin N, Vornicova O, Schachter J, Joshi A, Meyer N, Grange F, Piulats JM, Bauman JR, Zhang P, Gumuscu B, Swaby RF, Hughes BGM. Pembrolizumab monotherapy for recurrent or metastatic cutaneous squamous cell carcinoma: a single-arm phase II trial (KEYNOTE-629). J Clin Oncol 2020;38(25):2916–2925.Thomas S, Kuncheria L, Roulstone V, Kyula JN, Mansfield D, Bommareddy PK, Smith H, Kaufman HL, Harrington KJ, Coffin RS. Development of a new fusion-enhanced oncolytic immunotherapy platform based on herpes simplex virus type 1. J Immunother Cancer 2019;7(1):214.Middleton M, Aroldi F, Sacco J, Milhem M, Curti B, VanderWalde A, Baum S, Samson A, Pavlick A, Chesney J, Niu J, Rhodes T, Bowles T, Conry R, Olsson-Brown A, Earl Laux D, Kaufman H, Bommareddy P, Deterding A, Samakoglu S, Coffin R, Harrington K. 422 An open-label, multicenter, phase 1/2 clinical trial of RP1, an enhanced potency oncolytic HSV, combined with nivolumab: updated results from the skin cancer cohorts. J Immunother Cancer 2020; 8 (3).Ethics ApprovalThe study was approved by institutional review board or the local ethics committee at each site. Informed consent was obtained from patients before participating into the trial.