Search

Purpose: This study aims to identify the main challenges to achieving humanitarian logistics in the context of United Nations peace missions in sub-Saharan Africa and to present suggestions for overcoming the logistical gaps encountered. Design/methodology/approach: The methodological approach of the work focuses on the comparative case study of the United Nations Mission in South Sudan, the United Nations Multidimensional Integrated Stabilisation Mission in the Central African Republic and The United Nations Organisation Stabilisation Mission in the Democratic Republic of Congo from 2014 to 2021. The approach combined a systematic literature review with the authors' empirical experience as participant observers in each mission, combining theory and practice. Findings: As a result, six common challenges were identified for carrying out humanitarian logistics in the three peace missions. Each challenge revealed a logistical gap for which an appropriate solution was suggested based on the best practices found in the case study of each mission. Research limitations/implications: This paper presents limitations when addressing the logistical analysis based on only three countries under the UN mission as a case study, as well as conceiving that certain flaws in the system, in the observed period, are already in the process of correction with the adoption of the 2016–2021 strategy by the UN Global Logistic Cluster. The authors suggest that further studies can be carried out by expanding the number of cases or using countries where other bodies (AU, NATO or EU) work. Originality/value: To the best of the authors' knowledge, this study is the first comparative case study of humanitarian logistics on the three principal missions of the UN conducted by academics and practitioners. [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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

Copyright of VLC Arquitectura is the property of VLC Arquitectura 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.)

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 Polish Geographical Review / Przegląd Geograficzny is the property of Polska Akademia Nauk, Instytut Geografii i Przestrzennego Zagospodarowania 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.)

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.)

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]

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]

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]

This article examines the role of C-reactive protein/albumin ratio (CAR) and prognostic nutritional index (PNI) in diagnosing complicated acute appendicitis (AA). The study analyzed the medical records of 187 patients with AA and found that CAR levels were higher in the complicated AA group, but neither CAR nor PNI were independent predictors of complicated AA. The article also discusses other diagnostic tools and factors that have been studied in relation to complicated AA, but no significant relationships were found. The study has limitations and further research is needed to determine the clinical significance of CAR and PNI in diagnosing complicated AA. [Extracted from the article]

Purpose. To develop a hybrid method based on ICEEMDAN and OMEDA for high-fidelity detection of the diagnostic features of the technical condition of roller bearing. Methodology. Due to digital signal processing the search was made of the informative components on the broadband spectra, envelope spectra, squared envelope spectra. The usage of the methods of mathematical statistics for the selection of informative IMFs as a result of iterative calculate procedures. The introduction of blind deconvolution method with a proper objective function for the enhancement of impulse fault features. Findings. The use of traditional spectral methods provided an incomplete list of diagnostic features of bearing roller damage. The empirical mode decomposition (EMD) method and its minor versions provide the series of intrinsic mode functions (IMFs). On the broadband vibration spectra of the selected low-frequency IMFs, diagnostic features were not detected in a sufficient number. Further research focused on the development of a hybrid method that takes into account the demodulation procedure of the high-frequency components of those IMFs that were selected according to the complex evaluation index. The Fast Kurtogram technique determined an informative frequency band of 7.2–7.5 kHz for demodulation and construction of the squared envelope spectra, where harmonics of the roller spin frequency and some side bands with a width equal to the separator rotation frequency appeared. The use of OMEDA caused the reduction of residual noise on the squared envelope spectra and bilateral sidebands to appear around all harmonics of the roller spin frequency. Originality. For the first time, the whole list of the diagnostic features of roller faults of the axle-box bearing was identified using the developed hybrid method, which involves steps of noise reduction for enhancing a physical meaning of a proper frequency components, associated with faults. The usage of the optimal minimum entropy deconvolution adjusted method helped to eliminate noise and provide all diagnostic features of the technical condition on the squared envelope spectrum. Practical value. The results of the study help to control the quality of repair of the axle-box rolling bearings on the test rig at the workshop of the freight railway car depot. [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]

Purpose: Air pollutants, such as Asian sand and particulate matter (PM) 2.5, have become a global concern for causing ocular inflammation and allergic symptoms. This study, as part of an international investigation, examined the effects of eyewashes for ocular damage caused by air pollution in Indonesia. Methods: This was a single-center, patient- and-evaluator-blinded, parallel two-arm, nonrandomized trial. In Jakarta, Indonesia, 30 eyes of 15 car commuters and 30 eyes of 15 motorcycle commuters were recruited from healthy volunteers. After commuting to work, both eyes were washed with a commercial eyewash. Before and after eyewashing, eight items of ocular surface symptoms and four items of rhinitis subjective symptoms were scored using a modified Japanese Allergic Conjunctival Disease Quality-of-Life Questionnaire. Results: Five of the 12 subjective symptom scores before eyewashing were higher in motorcycle commuters than in car commuters (p < 0.05). Motorcycle commuters showed improvement in the five symptom scores of "itchy eyes, foreign body sensation, eye mucus, dryness, and eye strain" after eyewashing compared to before eyewashing (p < 0.05). In all patients, sootlike particles and ocular mucus were found in the solutions collected after eyewashing. Conclusion: These findings indicate that eyewashing for ocular symptoms caused by airborne particles may be effective in removing foreign particles from the ocular surface and relieving subjective symptoms. [ABSTRACT FROM AUTHOR]

Objectives: Multiple myeloma (MM) accounts for 10% of hematologic malignancies. However, most of the patients suffered from relapsed/refractory disease. We would like to expand CAR T cell therapy to treat MM using our current platform. Methods: BCMA CAR T lymphocytes were generated for volunteers or MM patients. The transduction efficiency was detected by the ddPCR technique. Immunophenotyping and exhaustion markers were monitored by flow cytometry. The efficacy of BCMA CAR T cells was tested using coculturing with BCMA CAR or mock, and the positive and negative targets, K562/hBCMA‐ECTM and K562, respectively. Results: BCMA CAR T cells were generated from consented volunteers or MM patients and could be detected CAR BCMA expression at a mean of 4.07 ± 1.95 or 4.65 ± 1.21 copies/cell, respectively. Those modified T cells were primarily effector memory T cells. Our BCMA CAR T cells could explicitly eradicate the K562/hBCMA‐ECTM cell line while the K562 cell line survived. Interestingly, the BCMA CAR, mock T cells, and peripheral blood mononuclear cells from MM patients expressed similar levels of the exhaustion makers, TIM‐3, LAG‐3, and PD1. Conclusions: Our BCMA CAR T cells, mainly effector/effector memory, could eliminate BCMA‐expressing cells in vitro and had similar levels of exhaustion markers among different populations. [ABSTRACT FROM AUTHOR]

We have developed a new format of a chimeric antigen receptor for αβ T cells, in which the single-chain variable fragment recognizing the tumor antigen is directly fused to the T cell receptor, called T cell receptor fusion construct (TRuC). Here, we express an anti-CD19 εTRuC in primary γδ T cells that were expanded using zoledronate (Zol) or concanavalin A. We show that the resulting εTRuC γδ T cells were reprogrammed to better recognize CD19-positive B cell tumors and—in case of the Zol-expanded cells—a CD19-expressing colon adenocarcinoma-derived cell line in vitro. This resulted in enhanced tumor killing, upregulation of the activation marker CD25, and secretion of cytokines. We found that the transduction efficiency of the concanavalin A–expanded cells was better than the one of the Zol-expanded ones. Our in vitro cytotoxicity data suggest that the Vδ2 T cells were better killers than the Vδ1 T cells. Finally, addition of vitamin C promoted the recovery of larger γδ T cell numbers after lentiviral transduction, as used for the expression of the εTRuC. In conclusion, the generation and use of γδ εTRuC T cells might be a new approach for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Summary: Varnimcabtagene autoleucel (var‐cel) is an academic anti‐CD19 chimeric antigen receptor (CAR) product used for the treatment of non‐Hodgkin lymphoma (NHL) in the CART19‐BE‐01 trial. Here we report updated outcomes of patients with NHL treated with var‐cel. B‐cell recovery was compared with patients with acute lymphoblastic leukaemia (ALL). Forty‐five patients with NHL were treated. Cytokine release syndrome (any grade) occurred in 84% of patients (4% grade ≥3) and neurotoxicity in 7% (2% grade ≥3). The objective response rate was 73% at Day +100, and the 3‐year duration of response was 56%. The 3‐year progression‐free and overall survival were 40% and 52% respectively. High lactate dehydrogenase was the only covariate with an impact on progression‐free survival. The 3‐year incidence of B‐cell recovery was lower in patients with NHL compared to ALL (25% vs. 60%). In conclusion, in patients with NHL, the toxicity of var‐cel was manageable, while B‐cell recovery was significantly prolonged compared to ALL. This trial was registered as NCT03144583. [ABSTRACT FROM AUTHOR]

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]

Copyright of Progress in Modern Biomedicine is the property of Publishing House of Progress in Modern Biomedicine 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.)

Copyright of Journal of Russian Studies (JORUS) / Rusya Araştırmaları Dergisi is the property of Rusya Arastirmalari Dergisi (RUSAD) 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.)

A braking system in a vehicle has a very important role in maintaining the safety of drivers and passengers, and preventing accidents. The brake system functions to reduce speed (slow down) and stop the vehicle. A good braking system provides safety and comfort for the drivers. Therefore, it is necessary to design the right braking system for "Sakera" car. In this study, an analysis and calculation of the braking system was carried out to determine the required braking force at a speed of 50 km/hour and other speeds in a distance of 15 m. The data taken in this study was the specification of the braking system used in the Sakera car. The braking system analysis was carried out on flat roads with varying speeds, namely 30 km/h, 35 km/h, 40 km/h, 45 km/h, and 50 km/h with a distance of 15 m for braking. The conclusions of the analysis were obtained, namely the greater the speed of Sakera's car, the greater the braking force to stop the car, the hydraulic pressure on the hose, and the force of the driver's feet, as well as the braking force needed on road conditions with a slope angle of 20°, which is 839.362 N. [ABSTRACT FROM AUTHOR]

An analytical review of the methods used to protect car bodies against corrosion is presented. Their positive and negative aspects are revealed. [ABSTRACT FROM AUTHOR]

Copyright of Journal of University Research / Üniversite Araştırmaları Dergisi is the property of Journal of University Research 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.)

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. [ABSTRACT FROM AUTHOR]

Copyright of Progress in Modern Biomedicine is the property of Publishing House of Progress in Modern Biomedicine 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.)

Target-negative relapse after CD19 chimeric antigen receptor engineered (CAR) T cell therapy for patients with B lineage acute lymphoblastic leukemia (B-ALL) presents limited treatment options with dismal outcomes. Although CD22-CAR T cells mediate similarly potent antineoplastic effects in patients with CD19dim or even CD19-negative relapse following CD19-directed immunotherapy, a high rate of relapse associated with diminished CD22 cell surface expression has also been observed. Therefore, it is unclear whether any other therapeutic options are available. Mitoxantrone has shown significant antineoplastic activity in patients with relapsed or refractory leukemia over the past decades, and in some cases, the addition of bortezomib to conventional chemotherapeutic agents has demonstrated improved response rates. However, whether this mitoxantrone and bortezomib combination therapy is effective for those patients who have relapsed B-ALL after receiving CD19-CAR T cell therapy remains to be elucidated. In this study, we established a cellular model system using a CD19-positive B-ALL cell line Nalm-6 to investigate the treatment options for CD19-negative relapsed B-ALL after CD19-CAR T cell therapy. In addition to CD22-CAR T therapy, we observed that the combination of bortezomib and mitoxantrone exhibited effective anti-leukemia activity in the CD19-negative Nalm-6 cell line by downregulating p-AKT and p-mTOR. These results suggest that this combination therapy is a possible option for target-negative refractory leukemia cells after CAR-T cell treatment. [ABSTRACT FROM AUTHOR]

Copyright of RumeliDE Journal of Language & Literature Research / RumeliDE Dil ve Edebiyat Araştırmaları Dergisi is the property of RumeliDE Uluslararasi Hakemli Dil & Edebiyat Arastirmalari Dergisi 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.)

Objective: To determine a methodology for the analysis of real-time driving posture data in the low back pain population. Background: The strength of the relationship between driving posture and low back pain is yet to be defined due to the lack of studies in the field using validated and repeatable posture measurement tools. Reliable and validated real-time measurement tools are now available, yet reliable methods of analysis of these data are yet to be established. Method: Ten occupational drivers completed a typical work shift while wearing an inertial motion sensor system (dorsaVi ViMove). Real-time lumbar flexion data were extracted, with test–retest reliability of mean lumbar flexion, peak lumbar flexion, and standard deviation of lumbar flexion analysed at different times across a work shift, and in different sections within a drive. Results: Mean lumbar flexion was highly repeatable over numerous drives in one day, with greater test–retest reliability if the first five minutes of driving data were excluded. Peak lumbar flexion had acceptable test-retest reliability over numerous drives in one day, while standard deviation of lumbar flexion was not a repeatable measure. Conclusion: Mean lumbar flexion was a reliable outcome for characterising driving posture in drivers with low back pain. Peak lumbar flexion may be used if appropriate to the individual study. S tandard deviation of lumbar flexion is not a reliable posture outcome. Application: This paper provides a reliable methodology for analysis of real-time driving posture data in occupational drivers with low back pain. [ABSTRACT FROM AUTHOR]

This article seeks to tell an emotional history of car use through the genre of life-writing, a source whose use in historical mobility research has recently been advocated by Colin Pooley. It focuses on two diarists, Hugh Miller and Victor Klemperer, to uncover what automobility looked and felt like in interwar Britain and Germany, when modern mass motorisation was emerging. It highlights that experiences of automobility were heterogeneous and dependent on social position, combining the excitement and liberty popularly associated with interwar car use with the banal, frustrating and terrifying. Motorists like Miller and Klemperer felt conflicted about automobility and what it represented. Their inner ambivalence points to a unique emotional engagement with the car, which may help to explain its persistence in twentieth-century society and beyond. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Applied Business & Economics (JABE) is the property of Universitas Indraprasta PGRI 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.)

Per- and poly-fluoroalkyl substances (PFAS) are a large class of fluorinated carbon chains that include legacy PFAS, such as perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorohexane sulfonate (PFHxS). These compounds induce adverse health effects, including hepatotoxicity. Potential alternatives to the legacy PFAS (HFPO-DA (GenX), HFPO4, HFPO-TA, F-53B, 6:2 FTSA, and 6:2 FTCA), as well as a byproduct of PFAS manufacturing (Nafion BP2), are increasingly being found in the environment. The potential hazards of these new alternatives are less well known. To better understand the diversity of molecular targets of the PFAS, we performed a comparative toxicogenomics analysis of the gene expression changes in the livers of mice exposed to these PFAS, and compared these to five activators of PPARα, a common target of many PFAS. Using hierarchical clustering, pathway analysis, and predictive biomarkers, we found that most of the alternative PFAS modulate molecular targets that overlap with legacy PFAS. Only three of the 11 PFAS tested did not appreciably activate PPARα (Nafion BP2, 6:2 FTSA, and 6:2 FTCA). Predictive biomarkers showed that most PFAS (PFHxS, PFOA, PFOS, PFNA, HFPO-TA, F-53B, HFPO4, Nafion BP2) activated CAR. PFNA, PFHxS, PFOA, PFOS, HFPO4, HFPO-TA, F-53B, Nafion BP2, and 6:2 FTSA suppressed STAT5b, activated NRF2, and activated SREBP. There was no apparent relationship between the length of the carbon chain, type of head group, or number of ether linkages and the transcriptomic changes. This work highlights the similarities in molecular targets between the legacy and alternative PFAS. [ABSTRACT FROM AUTHOR]

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 FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]