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Featured Application: The motor vehicle industry is undergoing continuous action to reduce the weight of transport means. To achieve this, one important method is to use new and composite materials and aluminum alloys for various parts of the vehicle. Towing systems represent one of these very important components, for which alternative materials are being studied to replace steel. The presented conclusions are practically useful and can be used by towing system manufacturers. Towing systems are an important component in the automobile industry, having to meet specific quality and resistance conditions. In most cases, the towbar is made of steel. Decreases in vehicle weight and manufacturing price mean that, in this field, research is also being conducted in order to replace the materials that make up the towbar and replace the steel with composite materials or aluminum alloys. In this paper, research was performed on towing systems built from other materials, and the obtained results were compared with those of steel systems. Theoretical calculations and experimental results made it possible to obtain a database and recommendations for the use of new and composite materials. The experimental tests validated the theoretical results obtained. Five towing systems made of different materials were studied. The results of the research are emphasized through recommendations regarding the manufacturing of towing systems. [ABSTRACT FROM AUTHOR]

We have developed and validated a highly specific, versatile antibody to the extracellular domain of human LGR5 (α-LGR5). α-LGR5 detects LGR5 overexpression in >90% of colorectal cancer (CRC), hepatocellular carcinoma (HCC) and pre-B-ALL tumour cells and was used to generate an Antibody-Drug Conjugate (α-LGR5-ADC), Bispecific T-cell Engager (α-LGR5-BiTE) and Chimeric Antigen Receptor (α-LGR5-CAR). α-LGR5-ADC was the most effective modality for targeting LGR5+ cancer cells in vitro and demonstrated potent anti-tumour efficacy in a murine model of human NALM6 pre-B-ALL driving tumour attrition to less than 1% of control treatment. α-LGR5-BiTE treatment was less effective in the pre-B-ALL cancer model yet promoted a twofold reduction in tumour burden. α-LGR5-CAR-T cells also showed specific and potent LGR5+ cancer cell killing in vitro and effective tumour targeting with a fourfold decrease in pre-B-ALL tumour burden relative to controls. Taken together, we show that α-LGR5 can not only be used as a research tool and a biomarker but also provides a versatile building block for a highly effective immune therapeutic portfolio targeting a range of LGR5-expressing cancer cells. Synopsis: Highly specific antibodies against the extracellular domain of LGR5 were developed as (i) a research tool to study LGR5 biology, (ii) for diagnostic use in multiple cancer types and (iii) as novel immunotherapeutics. A unique antibody toolkit has been validated for high affinity and specific detection of human LGR5. α-LGR5 was established as a diagnostic for discriminating high LGR5 expressing colorectal cancer (CRC), hepatocellular carcinoma (HCC) and pre-B-ALL tumours relative to low expression in healthy human tissues. α-LGR5-derived Antibody Drug Conjugates (ADCs), Bispecific T cell Engagers (BiTEs) and Chimeric Antigen Receptor (CAR) T cells were developed and displayed in vivo efficacy in a pre-B-ALL murine tumour model. Highly specific antibodies against the extracellular domain of LGR5 were developed as (i) a research tool to study LGR5 biology, (ii) for diagnostic use in multiple cancer types and (iii) as novel immunotherapeutics. [ABSTRACT FROM AUTHOR]

Invariant natural killer T (iNKT) cells are immune cells that harness properties of both the innate and adaptive immune system and exert multiple functions critical for the control of various diseases. Prevention of graft-versus-host disease (GVHD) by iNKT cells has been demonstrated in mouse models and in correlative human studies in which high iNKT cell content in the donor graft is associated with reduced GVHD in the setting of allogeneic hematopoietic stem cell transplants. This suggests that approaches to increase the number of iNKT cells in the setting of an allogeneic transplant may reduce GVHD. iNKT cells can also induce cytolysis of tumor cells, and murine experiments demonstrate that activating iNKT cells in vivo or treating mice with ex vivo expanded iNKT cells can reduce tumor burden. More recently, research has focused on testing anti-tumor efficacy of iNKT cells genetically modified to express a chimeric antigen receptor (CAR) protein (CAR-iNKT) cells to enhance iNKT cell tumor killing. Further, several of these approaches are now being tested in clinical trials, with strong safety signals demonstrated, though efficacy remains to be established following these early phase clinical trials. Here we review the progress in the field relating to role of iNKT cells in GVHD prevention and anti- cancer efficacy. Although the iNKT field is progressing at an exciting rate, there is much to learn regarding iNKT cell subset immunophenotype and functional relationships, optimal ex vivo expansion approaches, ideal treatment protocols, need for cytokine support, and rejection risk of iNKT cells in the allogeneic setting. [ABSTRACT FROM AUTHOR]

Simple Summary: The ectopic expression of the master regulator PU.1 could prove detrimental to CAR T cell functionality despite its upregulation of multiple costimulatory receptors on CAR T cells. These data proffer novel insights into CAR T cell biology and highlight the intricate quest for refining CAR T cell functionality. Chimeric antigen receptor (CAR) T cell therapy has achieved extraordinary success in eliminating B cell malignancies; however, so far, it has shown limited efficacy in the treatment of solid tumors, which is thought to be due to insufficient CAR T cell activation. We hypothesized that the transcription factor PU.1, a master regulator of innate cell functionality, may augment pro-inflammatory CAR T cell activation. T cells were engineered with a CEA-specific CAR together with the constitutive expression of PU.1. CAR-redirected T cell activation was recorded for canonical functionality in vitro under conditions of prolonged repetitive antigen exposure. Ectopic PU.1 expression in CAR T cells upregulated the costimulatory receptors CD40, CD80, CD86, and CD70, which, unexpectedly, did not augment effector functions but hampered the upregulation of 4-1BB, decreased IL-2 production, reduced CAR T cell proliferation, and impaired their cytotoxic capacities. Under "stress" conditions of repetitive engagement of cognate tumor cells, CAR T cells with ectopic PU.1 showed reduced persistence, and finally failed to control the growth of cancer cells. Mechanistically, PU.1 caused CAR T cells to secrete IFN-β, a cytokine known to promote CAR T cell attrition and apoptosis. Collectively, PU.1 can polarize the functional capacities of CAR T cells towards innate cells. [ABSTRACT FROM AUTHOR]

For the monitoring of chimeric antigen receptor (CAR) T-cell therapies, antigen-based CAR detection methods are usually applied. However, for each target-antigen, a separate detection system is required. Furthermore, when monitored CAR T-cells in the blood of patients treated with bispecific antibodies or T-cell engagers (bsAbs/BiTEs) recognize the same antigen, these methods produce false-positive results in clinical diagnostics. Anti-CAR-linker monoclonal antibodies (mAbs) targeting the linker sequence between the variable domains of the antigen binding CAR fragment promise a universal and unbiased CAR detection. To test this, we analyzed clinical specimens of all BCMA- and CD19-targeting CAR T-cell products currently approved for clinical use. We found a highly specific and sensitive CAR detection using anti-CAR-linker mAb in blood cells from patients treated with Ide-cel, Tisa-cel, Axi-cel, Brexu-cel, and Liso-cel. For Ide-cel and Tisa-cel, the sensitivity was significantly lower compared to that for antigen-based CAR detection assays. Strikingly, the specificity of anti-CAR linker mAb was not affected by the simultaneous presence of bispecific blinatumomab or teclistamab for Axi-cel, Brexu-cel, Liso-cel, or Ide-cel, respectively. Cilta-cel (containing a monomeric G4S-CAR linker) could not be detected by anti-CAR linker mAb. In conclusion, anti-CAR-linker mAbs are highly specific and useful for CAR T-cell monitoring but are not universally applicable. [ABSTRACT FROM AUTHOR]

Abstract We have developed and validated a highly specific, versatile antibody to the extracellular domain of human LGR5 (α-LGR5). α-LGR5 detects LGR5 overexpression in >90% of colorectal cancer (CRC), hepatocellular carcinoma (HCC) and pre-B-ALL tumour cells and was used to generate an Antibody-Drug Conjugate (α-LGR5-ADC), Bispecific T-cell Engager (α-LGR5-BiTE) and Chimeric Antigen Receptor (α-LGR5-CAR). α-LGR5-ADC was the most effective modality for targeting LGR5+ cancer cells in vitro and demonstrated potent anti-tumour efficacy in a murine model of human NALM6 pre-B-ALL driving tumour attrition to less than 1% of control treatment. α-LGR5-BiTE treatment was less effective in the pre-B-ALL cancer model yet promoted a twofold reduction in tumour burden. α-LGR5-CAR-T cells also showed specific and potent LGR5+ cancer cell killing in vitro and effective tumour targeting with a fourfold decrease in pre-B-ALL tumour burden relative to controls. Taken together, we show that α-LGR5 can not only be used as a research tool and a biomarker but also provides a versatile building block for a highly effective immune therapeutic portfolio targeting a range of LGR5-expressing cancer cells.

This study assessed the effects of vehicle mileage on the floor panel geometry and the upper mounting of the McPherson struts, as well as on the wheel alignment parameters. Geometry changes were determined in cars with the same design parameters, differing only in the type of engine supply system. The cars were van-bodied vehicles with compression ignition engines fuelled with diesel fuel and spark-ignition engines fuelled with LPG. The vehicles differed significantly in the weight distribution on their axles. The study is distinguished by its comprehensive approach to identifying in-service body wear. A detailed analysis covered not only the main causes of changes in body geometry, namely the influence of the vehicles’ mileage and design parameters, but also the effect of identifying the values of changes in the suspension and steering system geometry parameters. The body geometry and wheel alignment testing was carried out at a mileage of approximately 300,000 km. The study determined the relationships between changes in body geometry and wheel alignment. Changes in body geometry were determined by the type of basis point and the type of vehicle under analysis. Major changes in body geometry and wheel alignment were found in diesel-fuelled cars at the front of the vehicles and in LPG-fuelled cars at the rear of the vehicles. The greatest changes in body geometry in both vehicle types were noted within the area of the points associated with the mounting of the front and rear axle suspension system components.

Background: The lack of association between serum testosterone levels and symptoms suggestive of hypogonadism is a significant barrier in the determination of late-onset hypogonadism (LOH) in men. This study explored whether testosterone levels increase after morning awakening, likewise the cortisol awakening response (CA R) in the hypothalamic-pituitary-adrenal (HPA) axis, and whether testosterone levels during the post-awakening period are associated with age and symptoms suggestive of late-onset hypogonadism (LOH) in men. Methods: Testosterone and cortisol levels were determined in saliva samples collected immediately upon awakening and 30 and 60 min after awakening, and scores of the Aging Males' Symptoms (AMS) questionnaire were obtained from 225 healthy adult men. Results: A typical CA R (an increase in cortisol level ≥ 2.5 nmol/L above individual baseline) was observed in 155 participants (the subgroup exhibiting typical CA R). In the subgroup exhibiting CA R, testosterone levels sharply increased during the post-awakening period, showing a significant negative correlation with age, total AMS score, and the scores of 11 items on the somatic, psychological, and sexual AMS subscales. Of these items, three sexual items (AMS items #15-17) were correlated with age. Meanwhile, there was no notable increase in testosterone levels and no significant correlation of testosterone levels with age and AMS score in the subgroup exhibiting no typical CA R (n = 70). Conclusions: The results indicate that the hypothalamus-pituitary-gonad (HPG) axis responds to morning awakening, and determining testosterone levels during the post-awakening period in men with typical CA R may be useful for assessing HPG axis function and LOH. [ABSTRACT FROM AUTHOR]

Classroom Action Research (CAR) is a research type conducted within the classroom environment to enhance the learning process. To collaborates in organizing community service through training to empower the educational community at SMA Negeri 1 Krembung. To assess the community service program's effectiveness, pre-test and post-test analyses were carried out using the t-test. By applying the Wilcoxon Signed Rank Test hypothesis, a significant difference was identified in statistical and data science-based analysis skills before and after the community service program implementation. The ability to analyze based on statistics and data science has improved, evident from the post-test mean rank value surpassing the pre-test mean rank value (11.08 > 6.33). Consequently, it can be concluded that repeating training activities is essential to enhance statistical and data science-based analysis skills in the big data era and to provide a deeper understanding of Classroom Action Research.

AbstractThe car rental contract is one of the contracts that their applications have increased in Iraq and the Kurdistan Region, and many companies have been established that practice this activity, in the absence of a special and comprehensive legislative regulation for this field in Iraq and the Kurdistan Region, and this situation requires depending on the provisions of the Civil Code, although this may not help in providing solutions to all the problems of this type of contracting.Accordingly, this study is an attempt to clarify the concept of the car rental contract and its legal adaptation, going through studying the obligations of its parties and ending with its expiration, in addition to addressing the problems raised by the practical application of this contract, while enhancing the subject by studying several models of car rental contracts. The study presented some suggestions in a context related to its topic.

Chimeric antigen receptor (CAR) therapy has emerged as a ground-breaking advancement in cancer treatment, harnessing the power of engineered human immune cells to target and eliminate cancer cells. The escalating interest and investment in CAR therapy in recent years emphasize its profound significance in clinical research, positioning it as a rapidly expanding frontier in the field of personalized cancer therapies. A crucial step in CAR therapy design is choosing the right target as it determines the therapy's effectiveness, safety and specificity against cancer cells, while sparing healthy tissues. Herein, we propose a suite of tools for the identification and analysis of potential CAR targets leveraging expression data from The Cancer Genome Atlas and Genotype-Tissue Expression Project, which are implemented in CARTAR website. These tools focus on pinpointing tumor-associated antigens, ensuring target selectivity and assessing specificity to avoid off-tumor toxicities and can be used to rationally designing dual CARs. In addition, candidate target expression can be explored in cancer cell lines using the expression data for the Cancer Cell Line Encyclopedia. To our best knowledge, CARTAR is the first website dedicated to the systematic search of suitable candidate targets for CAR therapy. CARTAR is publicly accessible at https://gmxenomica.github.io/CARTAR/. [ABSTRACT FROM AUTHOR]

Indonesia has entered a period of demographic bonus. Human resources must be optimized. The number of children who do not in employment, education or training (NEET) in each province needs attention. Several factors that could contribute to the decline in the NEET percentage are literacy rates and the number of adolescents with computer skills. Increasing these two factors is believed to be able to reduce the percentage of NEET in every province in Indonesia. To find out the relationship between these two factors and how much influence they have on the percentage of NEET, this research is modeled by Cauchy regression and includes spatial effects. The results of the analysis show that the best model is when the spatial effect is modeled by Fernandez Steel Skew Normal conditionally autoregressive (FSSN CAR). This result is seen from the smallest value of the Watanabe Akaike Information Criterion (WAIC) in this model, which is 190.5. The parameter estimated shows that the higher the literacy rate and the number of adolescents with computer skills, the lower the percentage of NEET in each province in Indonesia. The results of this research can be useful for the Indonesian government to increase the number of educational facilities related to these two factors. [ABSTRACT FROM AUTHOR]

Adeno-associated virus (AAV) gene therapy is making rapid strides owing to its wide range of therapeutic applications. However, development of serious immune responses to the capsid antigen or the therapeutic transgene product hinders its full clinical impact. Immune suppressive (IS) drug treatments have been used in various clinical trials to prevent the deleterious effects of cytotoxic T cells to the viral vector or transgene, although there is no consensus on the best treatment regimen, dosage, or schedule. Regulatory T cells (Tregs) are crucial for maintaining tolerance against self or nonself antigens. Of importance, Tregs also play an important role in dampening immune responses to AAV gene therapy, including tolerance induction to the transgene product. Approaches to harness the tolerogenic effect of Tregs include the use of selective IS drugs that expand existing Tregs, and skew activated conventional T cells into antigen-specific peripherally induced Tregs. In addition, Tregs can be expanded ex vivo and delivered as cellular therapy. Furthermore, receptor engineering can be used to increase the potency and specificity of Tregs allowing for suppression at lower doses and reducing the risk of disrupting protective immunity. Because immune-mediated toxicities to AAV vectors are a concern in the clinic, strategies that can enhance or preserve Treg function should be considered to improve both the safety and efficacy of AAV gene therapy. [ABSTRACT FROM AUTHOR]

The current study aimed to assess the effect of timosaponin AⅢ (T-AⅢ) on drug-metabolizing enzymes during anticancer therapy. The in vivo experiments were conducted on nude and ICR mice. Following a 24-day administration of T-AⅢ, the nude mice exhibited an induction of CYP2B10, MDR1, and CYP3A11 expression in the liver tissues. In the ICR mice, the expression levels of CYP2B10 and MDR1 increased after a three-day T-AⅢ administration. The in vitro assessments with HepG2 cells revealed that T-AⅢ induced the expression of CYP2B6, MDR1, and CYP3A4, along with constitutive androstane receptor (CAR) activation. Treatment with CAR siRNA reversed the T-AⅢ-induced increases in CYP2B6 and CYP3A4 expression. Furthermore, other CAR target genes also showed a significant increase in the expression. The up-regulation of murine CAR was observed in the liver tissues of both nude and ICR mice. Subsequent findings demonstrated that T-AⅢ activated CAR by inhibiting ERK1/2 phosphorylation, with this effect being partially reversed by the ERK activator t-BHQ. Inhibition of the ERK1/2 signaling pathway was also observed in vivo. Additionally, T-AⅢinhibited the phosphorylation of EGFR at Tyr1173 and Tyr845, and suppressed EGF-induced phosphorylation of EGFR, ERK, and CAR. In the nude mice, T-AⅢ also inhibited EGFR phosphorylation. These results collectively indicate that T-AⅢ is a novel CAR activator through inhibition of the EGFR pathway. [ABSTRACT FROM AUTHOR]

This research aimed to analyze the possibility of installing an ultrasonic emitter in an already manufactured car and to prove the possibility of cleaning the exhaust gases of an internal combustion engine through the action of an ultrasonic wave due to coagulation and examining the optimal regimes of its work. The existing theoretical solution to describe the proposed process was analyzed. A Mercedes-Benz M-Class ML 270 CDI MT car with the OM 612 DE 27 LA Diesel engine was used for the experiment. An ultrasound generator and an ultrasound emitter were connected to the muffler. The stand was connected to the car via the inlet with a rubber hose that directs the exhaust gases out of the car. The crankshaft speed of the engine was changed in the range of 750 to 1250 rpm, which corresponds to urban conditions when cars are moving in heavy traffic jams. The content of CH, CO, CO2, and O2 in the exhaust gas of the vehicle was determined as a function of the crankshaft speed without ultrasonic exposure and with ultrasonic exposure at an ultrasound frequency of 25, 28, and 40 kHz. The results of the experiment showed that the introduction of an ultrasonic emitter into the muffler reduced the smoke content of the gas, increased the oxygen content, and reduced the amount of carbon dioxide in the exhaust gases. With an increase in the ratio between the ultrasonic frequency and the angular velocity of the engine crankshaft (f/ω), the smoke content of the gas also decreased. At the maximum values of ultrasonic frequency and angular velocity of the engine crankshaft selected in the experimental studies, the minimum value of the ratio of gas smoke indicators was achieved, and the degree of purification was 10–13%. Such results correspond to the condition of optimal operation of the ultrasonic muffler, where the ratio of gas to smoke values should tend to a minimum. These results confirm the potential of using ultrasound as a method for cleaning exhaust gases and underline the need for further research in this area. [ABSTRACT FROM AUTHOR]

Science learning emphasises the provision of direct experience to develop students' competencies in exploring and understanding the natural surroundings scientifically. However, the science learning process in SDN 2 Bulusan, Indonesia, remains directed at students' ability to merely remember various information without relating it to their natural surroundings. This impacted students' ability to understand science only to the extent of rote memorisation. There is a need for an approach that improves students' cognitive skills to achieve the desired ability. The objectives of this study are: (1) to explain the procedures of Project-based Learning (PjBL) in teaching Science, Technology, Engineering, and Mathematics (STEM); and (2) to improve scientific attitudes and students' cognitive learning outcomes. This research employed classroom action research (CAR) with two cycles for 13 fifth graders of SDN 2 Bulusan. The data was obtained through interviews, observation, and tests, which were analysed using source triangulation and technique triangulation. The results showed that: (1) PjBL STEM was carried out through reflection, research, discovery, application, and communication; and (2) students' cognitive learning outcomes have increased as shown through minimum completion criteria, which improved from 76.9% to 92.3%. This finding shows that PjBL STEM potentially improves the cognitive learning outcomes of Indonesian fifth-graders. [ABSTRACT FROM AUTHOR]

Invariant natural killer T (iNKT) cells are immune cells that harness properties of both the innate and adaptive immune system and exert multiple functions critical for the control of various diseases. Prevention of graft-versus-host disease (GVHD) by iNKT cells has been demonstrated in mouse models and in correlative human studies in which high iNKT cell content in the donor graft is associated with reduced GVHD in the setting of allogeneic hematopoietic stem cell transplants. This suggests that approaches to increase the number of iNKT cells in the setting of an allogeneic transplant may reduce GVHD. iNKT cells can also induce cytolysis of tumor cells, and murine experiments demonstrate that activating iNKT cells in vivo or treating mice with ex vivo expanded iNKT cells can reduce tumor burden. More recently, research has focused on testing anti-tumor efficacy of iNKT cells genetically modified to express a chimeric antigen receptor (CAR) protein (CAR-iNKT) cells to enhance iNKT cell tumor killing. Further, several of these approaches are now being tested in clinical trials, with strong safety signals demonstrated, though efficacy remains to be established following these early phase clinical trials. Here we review the progress in the field relating to role of iNKT cells in GVHD prevention and anti- cancer efficacy. Although the iNKT field is progressing at an exciting rate, there is much to learn regarding iNKT cell subset immunophenotype and functional relationships, optimal ex vivo expansion approaches, ideal treatment protocols, need for cytokine support, and rejection risk of iNKT cells in the allogeneic setting.

ABSTRACT This study examines the impact of credit risk, liquidity, and capital adequacy level (CAR) on profitability in the Indonesian banking sector while accounting for bank size moderation. The results of a linear regression study of panel data using annual financial report data from banks listed on the Indonesia Stock Exchange (2017–2022) show that although credit risk has an adverse effect and liquidity does not affect profitability, CAR does not significantly affect profitability. While bank size enhances the beneficial moderation of credit risk on profitability, it does not mitigate the impact of CAR and liquidity. Encouragement of Indonesian banks to enhance credit risk management while taking into account extra elements like operational effectiveness and product innovation are some of the practical ramifications. Additionally, these findings offer theoretical advancements in the field of agency. ABSTRAK Penelitian ini menguji dampak risiko kredit, likuiditas, dan tingkat kecukupan modal (CAR) terhadap profitabilitas di sektor perbankan Indonesia dengan memperhitungkan moderasi ukuran bank. Hasil studi regresi linier data panel dengan menggunakan data laporan keuangan tahunan dari bank-bank yang terdaftar di Bursa Efek Indonesia (2017-2022) menunjukkan bahwa meskipun risiko kredit memiliki pengaruh negatif dan likuiditas tidak berpengaruh terhadap profitabilitas, namun CAR tidak berpengaruh secara signifikan terhadap profitabilitas. Meskipun ukuran bank meningkatkan moderasi yang menguntungkan dari risiko kredit terhadap profitabilitas, namun tidak mengurangi dampak CAR dan likuiditas. Dorongan bagi bank-bank di Indonesia untuk meningkatkan manajemen risiko kredit dengan mempertimbangkan elemen-elemen lain seperti efektivitas operasional dan inovasi produk merupakan beberapa konsekuensi praktisnya. Selain itu, temuan ini juga memberikan kemajuan teoritis mengenai keagenan.

Abstract Background CAR T cell therapy is a promising approach to improve outcomes and decrease toxicities for patients with cancer. While extraordinary success has been achieved using CAR T cells to treat patients with CD19-positive malignancies, multiple obstacles have so far limited the benefit of CAR T cell therapy for patients with solid tumors. Novel manufacturing and engineering approaches show great promise to enhance CAR T cell function against solid tumors. However, similar to single agent chemotherapy approaches, CAR T cell monotherapy may be unable to achieve high cure rates for patients with difficult to treat solid tumors. Thus, combinatorial drug plus CAR T cell approaches are likely required to achieve widespread clinical success. Methods We developed a novel, confocal microscopy based, high-content screen to evaluate 1114 FDA approved drugs for the potential to increase expression of the solid tumor antigen B7-H3 on the surface of osteosarcoma cells. Western blot, RT-qPCR, siRNA knockdown and flow cytometry assays were used to validate screening results and identify mechanisms of drug-induced B7-H3 upregulation. Cytokine and cytotoxicity assays were used to determine if drug pre-treatment enhanced B7-H3-CAR T cell effector function. Results Fifty-five drugs were identified to increase B7-H3 expression on the surface of LM7 osteosarcoma cells using a novel high-content, high-throughput screen. One drug, ingenol-3-angelate (I3A), increased B7-H3 expression by up to 100%, and was evaluated in downstream experiments. Validation assays confirmed I3A increased B7-H3 expression in a biphasic dose response and cell dependent fashion. Mechanistic studies demonstrated that I3A increased B7-H3 (CD276) mRNA, total protein, and cell surface expression via protein kinase C alpha activation. Functionally, I3A induced B7-H3 expression enhanced B7-H3-CAR T cell function in cytokine production and cytotoxicity assays. Conclusions This study demonstrates a novel high-content and high-throughput screen can identify drugs to enhance CAR T cell activity. This and other high-content technologies will pave the way to develop clinical trials implementing rational drug plus CAR T cell combinatorial therapies. Importantly, the technique could also be repurposed for an array of basic and translational research applications where drugs are needed to modulate cell surface protein expression.

Several decades ago, the 1998 financial crisis in ASEAN developing countries had a limited impact on the performance of sharia banking due to its adherence to principles of transparency and fairness in its operations, allowing it to sustain growth under various conditions. This study examines the effect of CAR, ROA, and FDR on the efficiency of Islamic banking in developing countries, specifically the United Arab Emirates, Malaysia, Kuwait, and Qatar. Employing quantitative methods and panel data regression analysis, the findings reveal that CAR does not have a significant individual effect on Sharia banking efficiency, whereas FDR and ROA significantly enhance banking efficiency. This research contributes valuable insights into the role of these financial ratios in shaping the efficiency of Islamic banks in developing countries, providing practical implications for policymakers and banking professionals aiming to improve sharia banking performance.

Abstract: Has Agency Theory Not Been Applied Maximally in State-Owned Banks? Purpose: To determine the impact of Capital Adequacy Ratio (CAR), Non-performing Loans (NPL), and Loan to Deposit Ratio (LDR) on Return on Assets (ROA). Method: Using multiple regression analysis in 4 state-owned bank Indonesia at 2004-2022. Results: CAR has no effect on ROA while NPL and LDR have a significant negative effect on ROA. Simultaneously CAR, NPL, LDR have a significant effect on ROA. Novelty: This research support signaling theory but doesn't support the agency theory because state-owned banks management in Indonesia only giving positive signal to investor by nonperforming loan ratio and loan to deposit ratio. Contribution: This research suggest that management need to act more professionally by considering capital adequacy and not only focusing on nonperforming loan and liquidity. Abstrak: Apakah Teori Agensi Belum Diterapkan Secara maksimal Pada Bank BUMN? Tujuan: Untuk mengetahui pengaruh Capital Adequacy Ratio (CAR), Non-performing Loan (NPL), dan Loan to Deposit Ratio (LDR) terhadap Return on Aset (ROA). Metode: Menggunakan analisis regresi berganda dengan 4 Bank BUMN di Indonesia selama 2004-2022. Hasil: CAR tidak berpengaruh terhadap ROA sementara NPL dan LDR memiliki pengaruh negatif yang signifikan terhadap ROA dan secara simultan CAR, NPL, dan LDR berpengaruh terhadap ROA. Kebaruan: Penelitian ini mendukung teori sinyal dan belum dapat mendukung teori agensi karena kecukupan modal bukan menjadi pertimbangan manajemen Bank BUMN karena mereka hanya mempertimbangkan sinyal positif kepada para investor melalui tingkat kredit macet serta likuiditas. Kontribusi: Penelitian ini menyarankan kepada manajemen bank agar lebih bersikap professional dengan mempertimbangkan kecukupan modal dan tidak hanya berfokus pada kredit macet serta likuiditas.

The article considers the process of developing a simulation model of the road network section of the city of Kazan in order to improve road safety. The choice of modelling tools is carried out and the load of Kazan city roads is studied.

Abstract Background Chimeric antigen receptor (CAR) T cell therapy is associated with high risk of adverse events. Glucocorticoids (GCs) are cornerstone in the management of high-grade cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Given the potentially deleterious effects of GCs on CAR T cells anti-tumor activity, increasing our understanding of GCs impact on CAR T cells is crucial. Methods Using several CAR T cells i.e., CD19, mesothelin (MSLN)-CD28 and MSLN-41BB CAR T cells (M28z and MBBz), we compared phenotypical, functional, changes and anti-tumor activity between i) transduced CD19 CAR T cells with untransduced T cells, ii) M28z with MBBz CAR T cells induced by Dexamethasone (Dx) or Methylprednisolone (MP) exposures. Results Higher levels of GC receptor were found in less differentiated CAR T cells. Overall, Dx and MP showed a similar impact on CAR T cells. Compared to untreated condition, GCs exposure increased the expression of PD-1 and TIM-3 and reduced the expression of LAG3 and function of T cells and CAR T cells. GC exposures induced more exhausted (LAG3 + PD1 + TIM3 +) and dysfunctional (CD107a-INFγ-TNF-IL2-) untransduced T cells in comparison to CD19 CAR T cells. GC exposure impaired more CD4 + than CD8 + CD19 CAR T cells. GC exposures increased more PD-1 expression associated with reduced proliferative capacity and function of M28z as compared to MBBz CAR T cells. CAR T cells anti-tumor activity was greatly affected by repeated GC exposure but partly recovered within 48h after GCs withdrawal. Conclusions In summary, GCs impacted phenotype and function of untransduced and CAR T cell with different magnitude. The nature of the CAR costimulatory domain influenced the magnitude of CAR T cell response to GCs.

The article describes the effect of soil salinization on the level of correlations between quantitative indicators of photosynthetic pigments in vetch varieties. The objects of the study were the varieties of wiki Mirzachul-1 (Vicia villosa Roth) and Mirzachul-3 (Vicia angustifolia. L.). It was found that in highly saline soils, compared with weak ones, the amount of chlorophyll Chl «a» in the Mirzachul-1 variety decreased by 308 mg/g, the amount of chlorophyll Chl «b» and carotenoids (Car) increased by 0.11214 and 0.1300 mg/g.There was a strong positive correlation between Chl «a» and Chl «b» in all variants of the study. The similarity of correlation matrices is studied. At the same time, the similarity of correlation matrices between weakly and strongly saline soils was noted in the Mirzachul-1 variety by more than 90%, in the Mirzachul-3 variety by 69.1%. This indicates that the Mirzachul-1 varieties are stable in terms of the level of correlations according to the studied characteristics, which indicates a tendency to soil salinization.

The automotive industry has always represented a key sector within the economy of any country. Moreover, its significant contribution to the gross domestic product of many countries transformed this industry into one of the main pillars of the global economy. Therefore, numerous countries have built and produced various motor vehicles on different continents. The purpose of the paper is to briefly present and analyze the evolution of the world motor vehicle production on the four continents (Europe, America, Asia-Oceania, and Africa) in the period 2018-2022. The research methodology is based on a qualitative research method. The paper shows that the pre-pandemic period was a better period for the automotive industry than the pandemic period. Also, it demonstrates that AsiaOceania dominates the production hierarchy by continents.

Adoptive T-cell therapies (ACTs) including tumor-infiltrating lymphocytes and engineered T cells (transgenic T-cell receptor and chimeric antigen receptor T cells), have made an important impact in the field of cancer treatment over the past years. Most of these therapies are typically administered systemically in approaches that facilitate the elimination of hematologic malignancies. Therapeutical efficacy against solid tumors, however, with the exception of tumor-infiltrating lymphocytes against melanoma, remains limited due to several barriers preventing lymphocyte access to the tumor bed. Building upon the experience of regional administration in other immunotherapies, the regional administration of adoptive cell therapies is being assessed to overcome this challenge, granting a first round of access of the transferred T cells to the tumor niche and thereby ensuring their activation and expansion. Intralesional and intracavitary routes of delivery have been tested with promising antitumor objective responses in preclinical and clinical studies. Additionally, several strategies are being developed to further improve T-cell activity after reinfusing them back to the patient such as combinations with other immunotherapy agents or direct engineering of the transferred T cells, achieving long-term immune memory. Clinical trials testing different regional adoptive T-cell therapies are ongoing but some issues related to methodology of administration and correct selection of the target antigen to avoid on-target/off-tumor side-effects need to be further evaluated and improved. Herein, we discuss the current preclinical and clinical landscape of intratumoral and locoregional delivery of adoptive T-cell therapies.

Background: The Sonoran Desert region, encompassing most of southern Arizona, has an extreme climate that is famous for dust storms known as haboobs. These storms lead to decreased visibility and potentially hazardous driving conditions. In this study we evaluate the relationship between haboob events and emergency department (ED) visits due to motor vehicle collisions (MVCs) in Phoenix, Arizona.Methods: This study is a retrospective analysis of MVC-related trauma presentations to Phoenix, AZ, hospitals before and following haboob dust storms. These events were identified from 2009–2017 primarily using Phoenix International Airport weather data. De-identified trauma data were obtained from the Arizona Department of Health Services (ADHS) Arizona State Trauma Registry (ASTR) from seven trauma centers within a 10-mile radius of the airport. We compared MVC-related trauma using six- and 24-hour windows before and following the onset of haboob events.Results: There were 31,133 MVC-related trauma encounters included from 2009–2017 and 111 haboob events meeting meteorological criteria during that period. There was a 17% decrease in MVC-related ED encounters in the six hours following haboob onset compared to before onset (235 vs 283, P = 0.04), with proportionally more injuries among males (P < 0.001) and higher mortality (P = 0.02). There was no difference in frequency of presentations (P = 0.82), demographics, or outcomes among the 24-hour pre-and post-haboob groups.Conclusion: Haboob dust storms in Phoenix, Arizona, are associated with a decrease in MVC-related injuries during the six-hour period following storm onset, likely indicating the success of public safety messaging efforts. Males made up a higher proportion of those injured during the storms, suggesting a target for future interventions. Future public-targeted weather-safety initiatives should be accompanied more closely by monitoring and evaluation efforts to assess for effectiveness.

Several anti-mesothelin (MSLN) chimeric antigen receptor (CAR) T cells are in phase 1/2 clinical trials to treat solid-organ malignancies. The effect of MSLN antigen density on MSLN CAR cytotoxicity against tumor cells has not been examined previously, nor are there data regarding the effect of agents that increase MSLN antigen density on anti-MSLN CAR T cell efficacy. MSLN antigen density was measured on a panel of pancreatic cancer and mesothelioma cell lines by flow cytometry. In parallel, the cytotoxicity and specificity of two anti-MSLN CAR T cells (m912 and SS1) were compared against these cell lines using a real-time impedance-based assay. The effect of two MSLN 'sheddase' inhibitors (lanabecestat and TMI-1) that increase MSLN surface expression was also tested in combination with CAR T cells. SS1 CAR T cells were more cytotoxic compared with m912 CAR T cells against cell lines that expressed fewer than ∼170 000 MSLN molecules/cell. A comparison of the m912 and amatuximab (humanized SS1) antibodies identified that amatuximab could detect and bind to lower levels of MSLN on pancreatic cancer and mesothelioma cell lines, suggesting that superior antibody/scFv affinity was the reason for the SS1 CAR's superior cytotoxicity. The cytotoxicity of m912 CAR T cells was improved in the presence of sheddase inhibitors, which increased MSLN antigen density. These data highlight the value of assessing CAR constructs against a panel of cells expressing varying degrees of target tumor antigen as occurs in human tumors. Furthermore, the problem of low antigen density may be overcome by concomitant administration of drugs that inhibit enzymatic shedding of MSLN. [Display omitted] [ABSTRACT FROM AUTHOR]

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Background: Chimeric antigen receptor (CAR) T cell therapy is associated with high risk of adverse events. Glucocorticoids (GCs) are cornerstone in the management of high-grade cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Given the potentially deleterious effects of GCs on CAR T cells anti-tumor activity, increasing our understanding of GCs impact on CAR T cells is crucial. Methods: Using several CAR T cells i.e., CD19, mesothelin (MSLN)-CD28 and MSLN-41BB CAR T cells (M28z and MBBz), we compared phenotypical, functional, changes and anti-tumor activity between i) transduced CD19 CAR T cells with untransduced T cells, ii) M28z with MBBz CAR T cells induced by Dexamethasone (Dx) or Methylprednisolone (MP) exposures. Results: Higher levels of GC receptor were found in less differentiated CAR T cells. Overall, Dx and MP showed a similar impact on CAR T cells. Compared to untreated condition, GCs exposure increased the expression of PD-1 and TIM-3 and reduced the expression of LAG3 and function of T cells and CAR T cells. GC exposures induced more exhausted (LAG3 + PD1 + TIM3 +) and dysfunctional (CD107a-INFγ-TNF-IL2-) untransduced T cells in comparison to CD19 CAR T cells. GC exposure impaired more CD4 + than CD8 + CD19 CAR T cells. GC exposures increased more PD-1 expression associated with reduced proliferative capacity and function of M28z as compared to MBBz CAR T cells. CAR T cells anti-tumor activity was greatly affected by repeated GC exposure but partly recovered within 48h after GCs withdrawal. Conclusions: In summary, GCs impacted phenotype and function of untransduced and CAR T cell with different magnitude. The nature of the CAR costimulatory domain influenced the magnitude of CAR T cell response to GCs. [ABSTRACT FROM AUTHOR]

Addressing the pressing challenge of global warming, reducing greenhouse gas emissions in the transportation sector is a critical imperative. Battery and fuel cell electric vehicles have emerged as promising solutions for curbing emissions in this sector. In this study, we conducted a comprehensive life cycle assessment (LCA) for typical passenger vehicles, heavy-duty trucks, and city buses using either proton-exchange membrane fuel cells or Li-ion batteries with different cell chemistries. To ensure accuracy, we supplemented existing studies with data from the literature, particularly for the recycling phase, as database limitations were encountered. Our results highlight that fuel cell and battery systems exhibit large emissions in the production phase. Recycling can significantly offset some of these emissions, but a comparison of the technologies examined revealed considerable differences. Overall, battery electric vehicles consistently outperform fuel cell electric vehicles regarding absolute greenhouse gas emissions. Hence, we recommend prioritizing battery electric over fuel cell vehicles. However, deploying fuel cell electric vehicles could become attractive in a hydrogen economy scenario where other factors, e.g., the conversion and storage of surplus renewable electricity via electrolysis, become important. [ABSTRACT FROM AUTHOR]

Immunotherapy treatments aim to modulate the host's immune response to either mitigate it in inflammatory/autoimmune disease or enhance it against infection or cancer. Among different immunotherapies reaching clinical application during the last years, chimeric antigen receptor (CAR) immunotherapy has emerged as an effective treatment for cancer where different CAR T cells have already been approved. Yet their use against infectious diseases is an area still relatively poorly explored, albeit with tremendous potential for research and clinical application. Infectious diseases represent a global health challenge, with the escalating threat of antimicrobial resistance underscoring the need for alternative therapeutic approaches. This review aims to systematically evaluate the current applications of CAR immunotherapy in infectious diseases and discuss its potential for future applications. Notably, CAR cell therapies, initially developed for cancer treatment, are gaining recognition as potential remedies for infectious diseases. The review sheds light on significant progress in CAR T cell therapy directed at viral and opportunistic fungal infections. [ABSTRACT FROM AUTHOR]

Science learning emphasises the provision of direct experience to develop students’ competencies in exploring and understanding the natural surroundings scientifically. However, the science learning process in SDN 2 Bulusan, Indonesia, remains directed at students’ ability to merely remember various information without relating it to their natural surroundings. This impacted students’ ability to understand science only to the extent of rote memorisation. There is a need for an approach that improves students’ cognitive skills to achieve the desired ability. The objectives of this study are: (1) to explain the procedures of Project-based Learning (PjBL) in teaching Science, Technology, Engineering, and Mathematics (STEM); and (2) to improve scientific attitudes and students’ cognitive learning outcomes. This research employed classroom action research (CAR) with two cycles for 13 fifth graders of SDN 2 Bulusan. The data was obtained through interviews, observation, and tests, which were analysed using source triangulation and technique triangulation. The results showed that: (1) PjBL STEM was carried out through reflection, research, discovery, application, and communication; and (2) students’ cognitive learning outcomes have increased as shown through minimum completion criteria, which improved from 76.9% to 92.3%. This finding shows that PjBL STEM potentially improves the cognitive learning outcomes of Indonesian fifth-graders.

In this article, the simulation of the braking distance of two cars moving at different speeds is conducted. The first car was moving at 55 km/h and the other at 50 km/h. The simulation was run with the use of V-SIM software. The cars had to come to a standstill in front of a pedestrian and cycle crossing. The simulation confirmed the longer braking distance of the car moving at the higher speed thus leading to a cyclist being knocked down. The braking distance for this vehicle was 19.8 m and for a vehicle traveling at the maximum permissible speed it was 16.6 m. The simulation also showed that in the case of drivers moving at a speed of 55 km/h, eighty percent braking efficiency is achieved after driving 5.33 m from the moment of braking, which extends the braking distance by approximately 0.5 m compared to a car moving at 50 km/h. The aim of this article is to make the reader aware that failure to adjust the vehicle speed to prevailing road conditions or current restrictions increases the braking distance and that the consequences of such behaviour may be tragic, even if the allowable speed is exceeded only slightly.

Abstract Background Chimeric antigen receptor (CAR) T-cells have revolutionized the treatment of CD19- and B-cell maturation antigen-positive haematological malignancies. However, the effect of a CAR construct on the function of T-cells stimulated via their endogenous T-cell receptors (TCRs) has yet to be comprehensively investigated. Methods Experiments were performed to systematically assess TCR signalling and function in CAR T-cells using anti-mesothelin human CAR T-cells as a model system. CAR T-cells expressing the CD28 or 4-1BB costimulatory endodomains were manufactured and compared to both untransduced T-cells and CAR T-cells with a non-functional endodomain. These cell products were treated with staphylococcal enterotoxin B to stimulate the TCR, and in vitro functional assays were performed by flow cytometry. Results Increased proliferation, CD69 expression and IFNγ production were identified in CD8+ 4-1BBζ CAR T-cells compared to control untransduced CD8+ T-cells. These functional differences were associated with higher levels of phosphorylated ZAP70 after stimulation. In addition, these functional differences were associated with a differing immunophenotype, with a more than two-fold increase in central memory cells in CD8+ 4-1BBζ CAR T-cell products. Conclusion Our data indicate that the 4-1BBζ CAR enhances CD8+ TCR-mediated function. This could be beneficial if the TCR targets epitopes on malignant tissues or infectious agents, but detrimental if the TCR targets autoantigens.

The goal of Community Service activities with the theme Writing and Publication of Classroom Action Research (CAR) is to increase educators' competence in the field of CAR, inspire innovation and improve learning, disseminate CAR knowledge and practice in the classroom, and encourage collaboration and knowledge sharing. The activity's goal was to reach 35 junior high school teachers in Kupang Regency, NTT Province. Carried out through the use of andragogy learning methodologies, including needs assessment, content preparation, and interactive training. The end findings demonstrate that the training participants' understanding of CAR has greatly expanded, their desire and self-innovation have developed, and they have continued with a commitment to use the outcomes of the CAR training, as well as subsequent training activities will be carried out in order to improve instructors' capacities to enhance their understanding and skills in CAR-related issues.

The objective of this study was to assess the predictive value of inflammatory biomarkers in COVID-19 patients, namely the CRP/albumin ratio (CAR), interleukin 6 (IL-6), IL-6/lymphocyte ratio (IL-6/LY), and neutrophil/lymphocyte ratio (NLR). A prospective cohort study was conducted between January to June 2021 at Dr. Saiful Anwar General Hospital, Malang, East Java, Indonesia. CRP and albumin levels were measured using COBAS C6000. IL-6 was measured using the enzymatic chemiluminescence immunoassay (ECLIA) method and NLR was calculated based on flow cytometry evaluation of neutrophil and lymphocyte. Patient outcomes were obtained from medical records. Out of the 102 COVID-19 patients, 60 were non-survivors. The findings revealed that the area under the receiver (AUC) for CAR, IL-6, IL-6/LY, and NLR were 0.71, 0.77, 0.75, and 0.65, respectively. Kaplan-Meier curve analysis demonstrated significant differences between the groups stratified by these cut-off values. Notably, CAR and IL-6 exhibited the most accurate predictive values for mortality in COVID-19 patients. These findings suggest that CAR and IL-6 may serve as valuable biomarkers for predicting mortality in COVID-19 patients. Importantly, CAR offers an advantage over IL-6 as it is relatively more affordable, making it a viable option even if COVID-19 becomes endemic.

The purpose of this study was to determine the health level of Bank Muamalat Indonesia (BMI) and Bank Syariah Indonesia (BSI) and to determine the difference in the health level of Bank Muamalat and Bank Syariah Indonesia. The population in this study were BSI and BMI, the sample used BSI and BMI quarterly financial report data from 2015-2022. The analysis technique uses multiple linear regression analysis and independent sample t-test. At BMI, the CR and CAR ratios have no effect on ROA, only the BOPO ratio has an effect on ROA. Then at BSI, the CR and BOPO ratios affect ROA, while the CAR ratio has no effect on ROA. The results of the independent t-test show that there are differences between BMI and BSI on ROA, CR, CAR, and BOPO. The conclusion shows that both in BMI and BSI the CR variable affects ROA and there are differences in performance between BMI and BSI banks where the performance of Bank Syariah Indonesia is better than Bank Muamalat.

Abstract Background Acute myeloid leukemia (AML) is a clonal malignant disorder which originates from a small number of leukemia-initiating cells or leukemic stem cells (LSCs)—the subpopulation that is also the root cause of relapsed/refractory AML. Chimeric antigen receptor (CAR)-T cell therapy has proved successful at combating certain hematologic malignancies, but has several hurdles that limit its widespread applications. CAR-natural killer (NK) cells do not carry the risk of inducing graft-versus-host disease (GvHD) frequently associated with allogeneic T cells, thereby overcoming time-consuming, autologous cell manufacturing, and have relatively safer clinical profiles than CAR-T cells. The present study aimed to generate anti-TIM3 CAR-NK cells targeting LSCs from a clonal master induced pluripotent stem cells engineered with the third-generation anti-TIM3 CAR. Methods A clonal master umbilical cord blood NK-derived induced pluripotent stem cell (iPSC) line, MUSIi013-A, was used as a starting cells for engineering of an anti-TIM3 CAR harboring TIM3 scFv fragment (clone TSR-022), CD28, 4-1BB, and CD3ζ signaling (CAR-TIM3). The established CAR-TIM3 iPSCs were further differentiated under serum- and feeder-free conditions into functional CAR-TIM3 NK cells and tested for its anti-tumor activity against various TIM3-positive AML cells. Results We successfully established a single-cell clone of CAR-TIM3 iPSCs, as validated by genomic DNA sequencing as well as antibody and antigen-specific detection. We performed thorough iPSC characterization to confirm its retained pluripotency and differentiation capacity. The established CAR-TIM3 iPSCs can be differentiated into CAR-TIM3 NK-like cells, which were further proven to have enhanced anti-tumor activity against TIM3-positive AML cells with minimal effect on TIM3-negative cells when compared with wild-type (WT) NK-like cells from parental iPSCs. Conclusions iPSCs engineered with CARs, including the established single-cell clone CAR-TIM3 iPSCs herein, are potential alternative cell source for generating off-the-shelf CAR-NK cells as well as other CAR-immune cells. The feasibility of differentiation of functional CAR-TIM3 NK cells under serum- and feeder-free conditions support that Good Manufacturing Practice (GMP)-compliant protocols can be further established for future clinical applications.

Abstract Background Even acknowledging the game-changing results achieved in the treatment of metastatic melanoma with the use of immune checkpoint inhibitors (ICI), a large proportion of patients (40–60%) still fail to respond or relapse due to the development of resistance. Alterations in the expression of Human Leukocyte Antigen class I (HLA-I) molecules are considered to play a major role in clinical resistance to ICI. Cellular immunotherapy with HLA-independent CAR-redirected lymphocytes is a promising alternative in this challenging setting and dedicated translational models are needed. Methods In this study, we propose an HLA-independent therapeutic strategy with Cytokine Induced Killer lymphocytes (CIK) genetically engineered with a Chimeric Antigen Receptor (CAR) targeting the tumor antigen CSPG4 as effector mechanism. We investigated the preclinical antitumor activity of CSPG4-CAR.CIK in vitro and in a xenograft murine model focusing on patient-derived melanoma cell lines (Mel) with defective expression of HLA-I molecules. Results We successfully generated CSPG4-CAR.CIK from patients with metastatic melanoma and reported their intense activity in vitro against a panel of CSPG4-expressing patient-derived Mel. The melanoma killing activity was intense, even at very low effector to target ratios, and not influenced by the expression level (high, low, defective) of HLA-I molecules on target cells. Furthermore, CAR.CIK conditioned medium was capable of upregulating the expression of HLA-I molecules on melanoma cells. A comparable immunomodulatory effect was replicated by treatment of Mel cells with exogenous IFN-γ and IFN-α. The antimelanoma activity of CSPG4-CAR.CIK was successfully confirmed in vivo, obtaining a significant tumor growth inhibition of an HLA-defective Mel xenograft in immunodeficient mice. Conclusions In this study we reported the intense preclinical activity of CSPG4-CAR.CIK against melanoma, including those with low or defective HLA-I expression. Our findings support CSPG4 as a valuable CAR target in melanoma and provide translational rationale for clinical studies exploring CAR-CIK cellular immunotherapies within the challenging setting of patients not responsive or relapsing to immune checkpoint inhibitors.

Towing systems are an important component in the automobile industry, having to meet specific quality and resistance conditions. In most cases, the towbar is made of steel. Decreases in vehicle weight and manufacturing price mean that, in this field, research is also being conducted in order to replace the materials that make up the towbar and replace the steel with composite materials or aluminum alloys. In this paper, research was performed on towing systems built from other materials, and the obtained results were compared with those of steel systems. Theoretical calculations and experimental results made it possible to obtain a database and recommendations for the use of new and composite materials. The experimental tests validated the theoretical results obtained. Five towing systems made of different materials were studied. The results of the research are emphasized through recommendations regarding the manufacturing of towing systems.

Chimeric antigen receptor (CAR) T cell therapy has achieved extraordinary success in eliminating B cell malignancies; however, so far, it has shown limited efficacy in the treatment of solid tumors, which is thought to be due to insufficient CAR T cell activation. We hypothesized that the transcription factor PU.1, a master regulator of innate cell functionality, may augment pro-inflammatory CAR T cell activation. T cells were engineered with a CEA-specific CAR together with the constitutive expression of PU.1. CAR-redirected T cell activation was recorded for canonical functionality in vitro under conditions of prolonged repetitive antigen exposure. Ectopic PU.1 expression in CAR T cells upregulated the costimulatory receptors CD40, CD80, CD86, and CD70, which, unexpectedly, did not augment effector functions but hampered the upregulation of 4-1BB, decreased IL-2 production, reduced CAR T cell proliferation, and impaired their cytotoxic capacities. Under “stress” conditions of repetitive engagement of cognate tumor cells, CAR T cells with ectopic PU.1 showed reduced persistence, and finally failed to control the growth of cancer cells. Mechanistically, PU.1 caused CAR T cells to secrete IFN-β, a cytokine known to promote CAR T cell attrition and apoptosis. Collectively, PU.1 can polarize the functional capacities of CAR T cells towards innate cells.

Background: Neutrophil-to-lymphocyte ratio (NLR), platelets-to-lymphocyte ratio (PLR) and C-reactive protein-to-albumin ratio (CAR) are believed to be potential inflammatory markers that are closely related to the prognosis and course of cardiovascular diseases. The main goal of this study was the evaluation of NLR, PLR and CAR as factors reflecting the clinical picture and the prognosis of elderly chronic heart failure (CHF) patients. Methods: In 150 elderly patients with newly diagnosed CHF, the NLR, PLR and CAR were correlated with cardiac, laboratory and nutritional parameters. Results: Systemic inflammatory ratios were correlated with selected patient's parameters. CAR was associated with an unfavorable clinical picture of CHF—a reduced EF (p = 0.007), an elevated PASP (p = 0.014), an increased LVESD in both males and females (p = 0.032 and 0.024, respectively) and a decreased TAPSE (p = 0.023). CAR allowed us to distinguish between NYHA I–III and NYHA IV classes with AUC of 0.830. By analyzing the five-year mortality rate in patients with different CAR values, the greater death rate was recorded for patients with high CAR values—one-year death rate (40.3% vs. 17.2%) and five-year death rate (80% vs. 58.3%) (p = 0.002). Both NLR and PLR correlated only with selected parameters. Conclusion: An analysis of inflammatory markers, mainly CAR, allows the management of CHF, because its value can reflect the cardiac and nutritional status of patients with a prognostic value. NLR and PLR can serve as supplementary examinations for CAR evaluation. [ABSTRACT FROM AUTHOR]