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Background: Understanding the pathophysiology of sudden sensorineural hearing loss (SSNHL) and identifying its clinical symptoms and associated risk factors are crucial for doctors in order to create effective prevention and therapeutic methods for this prevalent otolaryngologic emergency. Methods: This study focuses on investigating the correlation between the C-reactive protein/albumin ratio (CAR) and SSNHL complicated by hypertension. In this study, 120 patients diagnosed with SSNHL were divided into groups with and without hypertension, and propensity score matching was used to compare and analyze the severity, type, prognosis, and CAR levels in SSNHL. Results: The results showed that the SSNHL group with hypertension had significantly higher CAR levels, age, hearing curve abnormalities, and more severe hearing loss compared to the control group with isolated SSNHL. These differences were statistically significant (p < 0.001). Among different subtypes of SSNHL, CAR levels increased progressively with the advancement of the condition, and these differences were also statistically significant (p < 0.001). Conclusion: In summary, in patients with SSNHL, those with hypertension had higher CAR levels than those without a history of hypertension, and they experienced more severe hearing loss. Moreover, there was a clear correlation between CAR levels and the extent of SSNHL, indicating that greater CAR levels in patients with SSNHL are connected to more severe hearing loss in various hearing patterns and perhaps indicative of a poorer prognosis. [ABSTRACT FROM AUTHOR]

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.

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]

Data breach incidents are growing by the day and firms struggle to detect, defend, and respond to such breaches. Nowadays, security breaches are considered one of the major concerns for corporate organizations around the world. Hence, it is essential to assess the impact of such breaches on organizations. This article reports stock price reaction due to public disclosure of information security breach (ISB) incidents on publicly traded firms of India. Using the event study methodology on a sample of 120 publicly announced ISB incidents between January 2004 and April 2019 pertaining to 69 publicly listed firms of India, we found that exposure to an ISB incident exacerbates negative stock price reactions based on both one-factor market model and Fama-French three-factor model. On average, breached firms lost 0.55% of their market value within two days post the announcement of ISB incidents. Further, we found some factors that significantly negatively impacted Cumulative Abnormal Return (CAR). Important emerging factors such as type of compromised data, sentiment, subjectivity, and remedial strategy significantly impact CAR. According to our study findings, we suggest that firms should mention remedial measures in terms of apology and/or compensation in the ISB disclosure. Furthermore, the result indicates that investors penalize listed firms for subsequent ISB incidents. Thus, our findings may guide Chief Information Officers (CIOs), information security managers, and IT managers of publicly traded firms to devise various strategies in terms of IT security measures and content of the ISB disclosure. [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]

One of the primary sources of noise and vibration in automobiles is gearboxes. Shafts, gears, and bearings are the main causes of noise and vibration in vehicle gearboxes. Various studies have reported that vibrations' root cause is bearing excitation. Besides bearing fatal defects or extreme structure resonance amplification, gear mesh is the primary source of high-frequency vibration and noise, even in newly built units. Gear damage detection is frequently crucial in automotive gearboxes and vehicle safety. Furthermore, vibrations caused by shaft imbalances, shaft misalignments, and other factors can cause noise and vibrations in the drivetrain's transfer path. In addition, the vibration of an automobile gearbox is closely related to poor design, construction quality, and production accuracy. This paper reviewed previous research and methods on car gearboxes for conventional vehicles. It was obvious that frequency analysis and order analysis were commonly used in noise and vibration analysis on car gearboxes. Envelope analysis is usually used to analyze bearing faults. Finally, rolling-element bearing diagnostic techniques were also reviewed. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptors (CARs) are genetically engineered receptors that recognize antigens and activate signaling cascades in a cell. Signal recognition and transmission are mediated by the CAR domains derived from different proteins. T cells carrying CARs against tumor-associated antigens have been used in the development of the CAR T cell therapy, a new approach to fighting malignant neoplasms. Despite its high efficacy in the treatment of oncohematological diseases, CAR T cell therapy has a number of disadvantages that could be avoided by using other types of leukocytes as effector cells. CARs can be expressed in a wide range of cells of adaptive and innate immunity with the emergence or improvement of cytotoxic properties. This review discusses the features of CAR function in different types of immune cells, with a particular focus on the results of preclinical and clinical efficacy studies and the safety of potential CAR cell products. [ABSTRACT FROM AUTHOR]

Summary: Several products containing chimeric antigen receptor T cells targeting CD19 (CART19) have been approved for the treatment of patients with relapsed/refractory non‐Hodgkin's lymphoma (NHL) and acute lymphoblastic leukaemia (ALL). Despite very impressive response rates, a significant percentage of patients experience disease relapse and die of progressive disease. A major cause of CART19 failure is loss or downregulation of CD19 expression in tumour cells, which has prompted a myriad of novel strategies aimed at targeting more than one antigen (e.g. CD19 and CD20 or CD22). Dual targeting can the accomplished through co‐administration of two separate products, co‐transduction with two different vectors, bicistronic cassettes or tandem receptors. In this manuscript, we review the pros and cons of each strategy and the clinical results obtained so far. [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]

This research examined whether financing growth and CAR affect ROA with NPF as a moderating variable of Sharia commercial banks. To address various potential answers, this research employed a quantitative methodology by analyzing financial data from Islamic commercial banks registered with the OJK during the period of 2011-2020. Sample selection was conducted using the purposive sampling method, resulting in the selection of 6 Islamic commercial banks as the sample. The data were analyzed using moderated regression analysis (MRA). The results of this research indicated that financing growth has a positive and significant impact on ROA,CAR has a positive and significant impact on ROA, NPF is not capable of moderating the influence of financing growth on ROA, and NPF is capable of moderating by weakening the influence of CAR on ROA. These findings contribute to Islamic commercial banks effectively channelling financing and achieving efficiency in CAR, thereby enhancing financial performance. [ABSTRACT FROM AUTHOR]

The human papillomavirus type 16 (HPV16) causes a large fraction of genital and oropharyngeal carcinomas. To maintain the transformed state, the tumor cells must continuously synthesize the E6 and E7 viral oncoproteins, which makes them tumor‐specific antigens. Indeed, specific T cell responses against them have been well documented and CD8+ T cells engineered to express T cell receptors (TCRs) that recognize epitopes of E6 or E7 have been tested in clinical studies with promising results, yet with limited clinical success. Using CD8+ T cells from peripheral blood of healthy donors, we have identified two novel TCRs reactive to an unexplored E618‐26 epitope. These TCRs showed limited standalone cytotoxicity against E618‐26‐HLA‐A*02:01‐presenting tumor cells. However, a single‐signaling domain chimeric antigen receptor (ssdCAR) targeting L1CAM, a cell adhesion protein frequently overexpressed in HPV16‐induced cancer, prompted a synergistic effect that significantly enhanced the cytotoxic capacity of NK‐92/CD3/CD8 cells armored with both TCR and ssdCAR when both receptors simultaneously engaged their respective targets, as shown by live microscopy of 2‐D and 3‐D co‐cultures. Thus, virus‐specific TCRs from the CD8+ T cell repertoire of healthy donors can be combined with a suitable ssdCAR to enhance the cytotoxic capacity of the effector cells and, indirectly, their specificity. [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.

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.

Background The epidemiology of cytomegalovirus (CMV) after chimeric antigen receptor–modified T-cell immunotherapy (CARTx) is poorly understood owing to a lack of routine surveillance. Methods We prospectively enrolled 72 adult CMV-seropositive CD19-, CD20-, or BCMA-targeted CARTx recipients and tested plasma samples for CMV before and weekly up to 12 weeks after CARTx. We assessed CMV-specific cell-mediated immunity (CMV-CMI) before and 2 and 4 weeks after CARTx, using an interferon γ release assay to quantify T-cell responses to IE-1 and pp65. We tested pre-CARTx samples to calculate a risk score for cytopenias and infection (CAR-HEMATOTOX). We used Cox regression to evaluate CMV risk factors and evaluated the predictive performance of CMV-CMI for CMV reactivation in receiver operator characteristic curves. Results CMV was detected in 1 patient (1.4%) before and in 18 (25%) after CARTx, for a cumulative incidence of 27% (95% confidence interval, 16.8–38.2). The median CMV viral load (interquartile range) was 127 (interquartile range, 61–276) IU/mL, with no end-organ disease observed; 5 patients received preemptive therapy based on clinical results. CMV-CMI values reached a nadir 2 weeks after infusion and recovered to baseline levels by week 4. In adjusted models, BCMA-CARTx (vs CD19/CD20) and corticosteroid use for >3 days were significantly associated with CMV reactivation, and possible associations were detected for lower week 2 CMV-CMI and more prior antitumor regimens. The cumulative incidence of CMV reactivation almost doubled when stratified by BCMA-CARTx target and use of corticosteroids for >3 days (46% and 49%, respectively). Conclusions CMV testing could be considered between 2 and 6 weeks in high-risk CARTx recipients. [ABSTRACT FROM AUTHOR]

Researchers have shown how UN stabilization peace operations mix liberal and illiberal goals and strategies. Yet, further research is needed to theorize and comprehend illiberal peacebuilding features of stabilization operations. This article fills this gap by demonstrating how UN stabilization operations wield illiberal peacebuilding practices. Building upon previous scholarship, we understand illiberal peacebuilding both as an approach and outcome which is oriented by and helps diffuse illiberal norms in the societies where illiberal peacebuilding is instrumentalized by local, regional and international actors. We frame UN stabilization operations in the CAR, the DRC, and Mali as illiberal peacebuilding processes infused with illiberal strategies and show that liberal actors can engage with illiberal strategies for peace promotion. We also analyse peace agreements that accompany these missions as illiberal peacebuilding outcomes and show how these are shaped by illiberal norms. Our key finding is that a set of illiberal norms – exclusion, violence, power inequality and authoritarianism – are central for both UN stabilization operations and peace agreements signed in CAR, DRC and Mali. Therefore, we challenge the UN discourse that stabilization is a needed first step towards liberal and inclusive peace agreements. [ABSTRACT FROM AUTHOR]

Older adults (≥55 years old) with B-cell acute lymphoblastic leukemia (B-ALL) have dismal outcomes with standard chemotherapy as the result of low treatment efficacy and considerable risks for treatment-related morbidity and mortality. There has been a recent success with the introduction of novel therapies, such as blinatumomab and inotuzumab, in the frontline therapeutic paradigm in older adults with B-ALL. However, these agents have their own challenges including the limited durability of remission, the need for additional concurrent chemotherapy and the prolonged course of treatment, and limited efficacy in the setting of extramedullary disease. Here, we hypothesize that the incorporation of chimeric antigen receptor (CAR) T cell therapy as a consolidation treatment in older adults with B-cell ALL in their first complete remission is the ideal setting to advance treatment outcomes by reducing treatment toxicity, enhancing remission durability, and expanding the use of this effective therapy in this age population. [ABSTRACT FROM AUTHOR]

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]

This study focuses on three essential concepts – collaboration, action, and research. It was initiated by three former teacher educators (TEs) at Asmara Community College of Education (ACCE), Eritrea (now defunct), and data was drawn from their written accounts and rigorous reflective discussions. It illuminates the lines of development while attempting to improve practices, the tensions this created among individuals, collective agencies, and institutional transformations. It reveals realities about the perpetual and unpredictable challenges the TEs encountered and the outcome of the actions they attempted to execute. Along the way, they uncovered evidence on why and how they could enrich their professional values when they come together and collaborate in exploring the essence of their practices. The findings reveal that TEs who systematize their practices through collaborative action research (CAR) can significantly develop their professional effectiveness. They have established that TEs should collaborate, act, and engage in research to develop enduring professional identities which can adapt to changing educational situations. [ABSTRACT FROM AUTHOR]

Artykuł podejmuje zagadnienie relacji funkcjonalno-przestrzennych między ośrodkiem centralnym a jego otoczeniem. Głównym celem opracowania było zidentyfikowanie zasięgu oddziaływania Słupska jako ośrodka handlowego; przeanalizowano również określone cechy poszczególnych sklepów (lub ich zespołów), takie jak rozmieszczenie w przestrzeni miasta czy popularność. Niezbędne dane zostały pozyskane w ramach terenowych badań, polegających na zanotowaniu liczby pojazdów pozostawionych na parkingach pod badanymi obiektami handlowymi oraz powiatu ich zarejestrowania. Przeprowadzono pomiary w różnych porach dnia i tygodnia w celu uzyskania szerokiego spektrum materiałów. Wykazano, iż zdecydowanie najchętniej odwiedzanym przez zmotoryzowanych klientów obiektem handlowym w Słupsku jest Centrum Handlowe Jantar, zaś wnioskiem generalnym jest większa frekwencja na parkingach w sobotę w porównaniu do dnia roboczego. Najsilniej wyróżniające Słupsk w skali regionu sklepy oraz większe kompleksy handlowo-usługowe odwiedzane są przede wszystkim przez mieszkańców miasta i otaczającego go powiatu ziemskiego, przy zauważalnej obecności osób z powiatów sławieńskiego i bytowskiego. Zasięg dojazdów samochodem do Słupska w celu nabycia dóbr lub usług w badanych obiektach zasadniczo zamyka się w granicach dawnego województwa słupskiego (z lat 1975‑1998), co dowodzi pełnieniu przez miasto funkcji przynajmniej subregionalnych. Ponadto, zauważalne jest pewne rozciągnięcie tego obszaru w kierunku zachodnim (region Pomorza Środkowego). [ABSTRACT FROM AUTHOR]

The prognostic evaluation of the septic patient has recently been enriched by some predictive indices such as albumin concentration, lactate/albumin ratio (LAR) and C-reactive protein/albumin ratio (CAR). The performance of these indices has been evaluated in septic patients in intensive care, but until now their performance in infected patients in the Emergency Department (ED) has not been evaluated. To investigate the potential prognostic role of albumin, LAR and CAR in patients with infection in the ED. Single-centre prospective study performed between 1 January 2021 and 31 December 2021 at the ED of the Merano Hospital (Italy). All patients with infection were enrolled. The study outcome was death within 30 days. The predictive ability of albumin, LAR and CAR was assessed by area under the receiver operating characteristic curves (AUROCs). A multivariate logistic regression model was used to examine the association of the indices with 30-day mortality, with comorbidity, acute urgency and severity of infection as covariates. The study enrolled 962 patients with an infectious status. The overall 30-day mortality rate was 8.9% (86/962). The AUROC of albumin was 0.831 (95% CI 0.795–868), while for LAR this was 0.773 (CI95% 0.719–0.827) and for CAR 0.718 (CI95% 0.664–0.771). The odds ratio for 30-day mortality for albumin was 3.362 (95% CI 1.904–5.936), for ln(LAR) 2.651 (95% CI 1.646–4.270) and for ln(CAR) 1.739 (95% CI 1.326–2.281). All three indices had a good discriminatory ability for the risk of short-term death in patients with infection, indicating their promising use in the ED as well as in the ICU. Further studies are needed to confirm the better performance of albumin compared to LAR and CAR. [ABSTRACT FROM AUTHOR]

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In the Initial Orbit Determination (IOD) context, Admissible Regions are subsets of parameter space of orbital elements that are reckoned as functions of the tracking measurement variables. Physically acceptable orbits, e.g., orbits with negative energies, constitute an Admissible Region. This paper defines sets of orbits that satisfy constraints imposed by the measurement variables. Using a probabilistic representation of constraints on some of the orbital parameters the Admissible Region can be further constrained to give a Probabilistic Admissible Region (PAR). PAR gives a particle cloud representation of the initial probability density function (pdf) of the state of a Resident Space Object (RSO). This paper presents a geometric solution to the Probabilistic Admissible Region (G-PAR). G-PAR is a set of algorithms sharing the same underlying template that geometrically maps postulated statistics on some orbital elements and statistics of the measurement process to the uncertainty in the states. The proposed scheme gives a simple closed-form solution for mapping particles to get the PAR pdf for the first time. This speeds up the PAR initial orbit determination with a single partial state measurement. The effectiveness of the proposed G-PAR is shown on diverse combinations of sensors and prior knowledge. [ABSTRACT FROM AUTHOR]

Copyright of Political Science Studies / Studia Politologiczne is the property of University of Warsaw and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)