New horizons in our understanding of precursor multiple myeloma and early interception.

Multiple myeloma is an incurable plasma cell malignancy that evolves over decades through the selection and malignant transformation of monoclonal plasma cells. The evolution from precursor states to symptomatic disease is characterized by an increasing complexity of genomic alterations within the plasma cells and a remodelling of the microenvironment towards an immunosuppressive state. Notably, in patients with advanced disease, similar mechanisms of tumour escape and immune dysfunction mediate resistance to modern T cell-based therapies, such as T cell-engaging bispecific antibodies and chimeric antigen receptor (CAR)-T cells. Thus, an increasing number of clinical trials are assessing the efficiency and safety of these therapies in individuals with newly diagnosed multiple myeloma and high-risk smoldering multiple myeloma. In this Review, we summarize the current knowledge about tumour intrinsic and extrinsic processes underlying progression from precursor states to symptomatic myeloma and discuss the rationale for early interception including the use of T cell-redirecting therapies.

Acute Response of Calcium Lactate Supplementation on the Athletic Performance of Soccer Players Under the Age of 15.

PURPOSE: To determine the acute response of lactate supplementation on athletic performance. METHOD: Fifteen athletes under the age of 15 performed the following 4 sessions in a nonrandomized order: (1) familiarization, (2) control, (3)  participants ingested calcium lactate (21.5 mg·kg-1 body mass), and (4) participants ingested a placebo (PLA, calcium carbonate, 21.5 mg·kg-1 body mass). The capsules were randomly offered and consumed 60 minutes before the physical tests. To assess the physical performance, the athletes executed squat jump, countermovement squat jump, 20-m linear sprint, change of direction test, and running anaerobic sprint test. RESULTS: There were no significant differences between conditions for squat jump, countermovement jump, change of direction, and minimum power obtained in the running anaerobic sprint test (P > .05). Conversely, we observed a worse performance (P < .05) in the 20-m linear sprint test in the PLA and lactate conditions compared with control (P < .05). The lactate condition worsened performance during running anaerobic sprint test for peak power, mean power, and fatigue index compared with control and PLA (P < .05). CONCLUSIONS: Calcium lactate supplementation worsened repetitive running sprint ability and 20-m sprint performance. However, lactate supplementation does not affect jump or agility capacity. Therefore, calcium lactate supplementation seems to be an ineffective strategy to improve anaerobic and neuromuscular performance in soccer players 15 years of age or less.

IL-33 in Ischemic Stroke: Brain vs. Periphery.

Cerebrovascular disease is the second-leading cause of death and disability worldwide, with stroke being the most common cause. In ischemic stroke, several processes combine to produce immunosuppression, leaving the post-stroke body susceptible to infection, which in turn affects neuroinflammation. Interleukin-33 (IL-33), a member of the interleukin-1 family (IL-1), functions as a modulator of immune responses and inflammation, playing a crucial role in the establishment of immunologic responses. IL-33 has been shown to have a protective effect on brain injury and represents a potential target by modulating inflammatory cytokines and stimulating immune regulatory cells. With an emphasis on preclinical and clinical studies, this review covers the impact of IL-33 on immune system mechanisms following ischemic stroke.

Second Primary Malignancies after CAR T-Cell Therapy: A Systematic Review and Meta-analysis of 5,517 Lymphoma and Myeloma Patients.

PURPOSE: Chimeric antigen receptor (CAR) T-cell therapy is a potent immunotherapy for hematologic malignancies, but patients can develop long-term adverse events, including second primary malignancies (SPM) that impact morbidity and mortality. To delineate the frequency and subtypes of SPMs following CAR-T in lymphoma and myeloma, we performed a systematic review and meta-analysis. EXPERIMENTAL DESIGN: A literature search was conducted in the MEDLINE, Embase, and Cochrane CENTRAL databases. Following the extraction of SPM cases and assignment of malignant origin, we analyzed SPM point estimates using random effects models. RESULTS: We identified 326 SPMs across 5,517 patients from 18 clinical trials and 7 real-world studies. With a median follow-up of 21.7 months, the overall SPM point estimate was 6.0% (95% confidence interval, 4.8%-7.4%). SPM estimates were associated with treatment setting (clinical trials > real-world studies), duration of follow-up, and number of prior treatment lines, which were each confirmed as independent study-level risk factors of SPM in a meta-regression model. A subgroup meta-analysis of the four trials that randomized CAR-T versus standard-of-care revealed a similar risk of SPM with either treatment strategy (P = 0.92). In a distribution analysis of SPM subtypes, hematologic malignancies were the most common entity (37%), followed by solid tumors (27%) and non-melanoma skin cancers (16%). T-cell malignancies represented a small minority of events (1.5%). We noted disease- and product-specific variations in SPM distribution. CONCLUSIONS: These data raise awareness of SPM as a clinically relevant long-term adverse event in patients receiving CAR T-cell therapy. However, our findings do not indicate that SPM frequency is higher with CAR-T versus previous standard-of-care strategies.

Short-chain fatty acid on blood-brain barrier and glial function in ischemic stroke.

Stroke is the second most common cause of death and one of the most common causes of disability worldwide. The intestine is home to several microorganisms that fulfill essential functions for the natural and physiological functioning of the human body. There is an interaction between the central nervous system (CNS) and the gastrointestinal system that enables bidirectional communication between them, the so-called gut-brain axis. Based on the gut-brain axis, there is evidence of a link between the gut microbiota and the regulation of microglial functions through glial activation. This interaction is partly due to the immunological properties of the microbiota and its connection with the CNS, such that metabolites produced by the microbiota can cross the gut barrier, enter the bloodstream and reach the CNS and significantly affect microglia, astrocytes and other cells of the immune system. Studies addressing the effects of short-chain fatty acids (SCFAs) on glial function and the BBB in ischemic stroke are still scarce. Therefore, this review aims to stimulate the investigation of these associations, as well as to generate new studies on this topic that can clarify the role of SCFAs after stroke in a more robust manner.

The monotopic quinone reductases from Staphylococcus aureus.

Staphylococcus aureus, a Gram-positive bacterium, is an opportunistic pathogen and one of the most frequent causes for community acquired and nosocomial infections that has become a major public health threat due to the increased incidence of its drug resistance. Although being a prominent pathogen, its energetic metabolism is still underexplored, and its respiratory enzymes have been escaping attention. S. aureus can adapt to different environmental conditions by performing both aerobic and anaerobic respirations, which is particularly important as it frequently colonizes niches with different oxygen concentrations. This adaptability is derived from the composition of its respiratory chain, specifically from the presence of terminal electron acceptor reductases. The plasticity of S. aureus energy metabolism is enlarged by the ten quinone reductases encoded in its genome, eight of them being monotopic proteins. The role of these proteins is critical as they connect the different catabolic pathways to the respiratory chain. In this work, we identify, describe, and revise the monotopic quinone reductases present in S. aureus, providing an integrated view of its respiratory chain.

Certainty in holistic thinking and responses to contradiction: Dialectical proverbs, counter-attitudinal change and ambivalence.

The present research examined whether consideration of individuals' certainty in their holism can enhance the ability of this individual difference to predict how they respond to contradiction-relevant outcomes. Across four studies, participants first completed a standardized measure of holistic-analytic thinking. Then, they rated how certain they were in their responses to the holism scale or were experimentally induced to feel high or low certainty. Next, participants were exposed to dialectical proverbs (Study 1a and 1b), to a counter-attitudinal change induction (Study 2), or to a paradigm of attitudinal ambivalence (Study 3). Results revealed that participants with higher certainty in their holistic thinking exhibited higher preference for dialectical proverbs (Study 1a and 1b), changed their attitude less following a counter-attitudinal task (Study 2) and showed weaker correspondence between objective and subjective ambivalence (Study 3). Beyond examining new domains and discovering novel findings, the present work was designed to be the first to show moderation of previously identified effects in the domain of holistic thinking and responses to contradiction.

Performance Assessment of Object Detection Models Trained with Synthetic Data: A Case Study on Electrical Equipment Detection.

This paper explores a data augmentation approach for images of rigid bodies, particularly focusing on electrical equipment and analogous industrial objects. By leveraging manufacturer-provided datasheets containing precise equipment dimensions, we employed straightforward algorithms to generate synthetic images, permitting the expansion of the training dataset from a potentially unlimited viewpoint. In scenarios lacking genuine target images, we conducted a case study using two well-known detectors, representing two machine-learning paradigms: the Viola-Jones (VJ) and You Only Look Once (YOLO) detectors, trained exclusively on datasets featuring synthetic images as the positive examples of the target equipment, namely lightning rods and potential transformers. Performances of both detectors were assessed using real images in both visible and infrared spectra. YOLO consistently demonstrates F1 scores below 26% in both spectra, while VJ's scores lie in the interval from 38% to 61%. This performance discrepancy is discussed in view of paradigms' strengths and weaknesses, whereas the relatively high scores of at least one detector are taken as empirical evidence in favor of the proposed data augmentation approach.

A systematic review and meta-analysis of nonrelapse mortality after CAR T cell therapy.

Although chimeric antigen receptor (CAR) T cell therapy represents a transformative immunotherapy, it is also associated with distinct toxicities that contribute to morbidity and mortality. In this systematic review and meta-analysis, we searched MEDLINE, Embase and CINAHL (Cochrane) for reports of nonrelapse mortality (NRM) after CAR T cell therapy in lymphoma and multiple myeloma up to March 2024. After extraction of causes and numbers of death, we analyzed NRM point estimates using random-effect models. We identified 7,604 patients across 18 clinical trials and 28 real-world studies. NRM point estimates varied across disease entities and were highest in patients with mantle-cell lymphoma (10.6%), followed by multiple myeloma (8.0%), large B cell lymphoma (6.1%) and indolent lymphoma (5.7%). Entity-specific meta-regression models for large B cell lymphoma and multiple myeloma revealed that axicabtagene ciloleucel and ciltacabtagene autoleucel were independently associated with increased NRM point estimates, respectively. Of 574 reported nonrelapse deaths, over half were attributed to infections (50.9%), followed by other malignancies (7.8%) and cardiovascular/respiratory events (7.3%). Conversely, the CAR T cell-specific side effects, immune effector cell-associated neurotoxicity syndrome/neurotoxicity, cytokine release syndrome and hemophagocytic lymphohistiocytosis, represented only a minority of nonrelapse deaths (cumulatively 11.5%). Our findings underline the critical importance of infectious complications after CAR T cell therapy and support the comprehensive reporting of NRM, including specific causes and long-term outcomes.

Sepsis after middle cerebral artery occlusion exacerbates peripheral oxidative stress in a sex-specific manner.

Ischemic stroke occurs due a blockage in the blood flow to the brain, leading to damage to the nervous system. The prevalent morbidities resulting from stroke include post-stroke infection, as sepsis. Additionally, oxidative stress is recognized for inducing functional deficits in peripheral organs during sepsis. Therefore, sex differences in stroke exist and we aimed to investigate the peripheral oxidative stress caused by sepsis after stroke in male and female rats. Wistar rats (male and female) were divided into sham+sham, middle cerebral artery occlusion (MCAO) + sham, sham+ cecal ligation and perforation (CLP) and MCAO+CLP groups to males and female rats. Animals were subjected to MCAO or sham and after 7 days, were subjected to sepsis by CLP or sham. After 24 h, serum, total brain, lung, liver, heart, and spleen were collected. Brain edema, myeloperoxidase (MPO) activity, nitrite/nitrate (N/N) concentration, oxidative damage to lipids and proteins, and catalase activity were evaluated. Brain edema was observed only in male rats in MCAO+CLP group compared to MCAO+sham. Regarding MPO activity, an increase was verified in male in different organs and serum in MCAO+CLP group. For N/N levels, the increase was more pronounced in females submitted to MCAO+CLP. In general, to oxidative stress, an increase was only observed in animals exposed to MCAO+CLP, or with a greater increase in this group compared to the others. The findings provided the first indication that animals exposed to MCAO exhibit a heightened vulnerability to the harmful impacts of sepsis, as evidenced by brain edema and peripheral oxidative stress, and this susceptibility is dependent of sex.

Biodegradable starch foams reinforced by food-chain side streams.

Biodegradable starch foam trays offer an eco-friendly substitute for petroleum-based single-use packaging, notably polystyrene foams. However, they lack flexibility, tensile strength, and water-sensitivity, addressable through lignocellulosic reinforcement. This study aimed to develop biodegradable starch foam trays filled with different food-chain side streams for sustainable alternative packaging. Corncob, soybean straw, cassava peel, araucaria seed hull, yerba mate stalks and yerba mate leaves petiole were collected, dried and ground to <250 µm. The trays were filled with 13 % (w/w) of each food-chain side streams and produced by hot molding. The trays morphology, moisture, water activity (aw), thickness, bulk density, tensile strength, elongation at break, Young's modulus, bending strength, maximum deflection, and sorption isotherms were investigated. Reinforcements slightly increased the foams bulk density, reduced the tensile strength and maximum deflection and while bending strength increased from 0.20 MPa to 1.17-1.80 MPa. The elasticity modulus decreased by adding any filling, that resulted in ductility improvement; however, these packaging have moisture-sensitive material especially for aw higher than 0.52, which drives the use recommendation for dry products storage or shipping/transport. The biodegradable starch foam trays filled with side streams were successfully produced and offer excellent alternative to petroleum-based packaging low-density material with bending strength improved.

Efficient Anthocyanin Recovery from Black Bean Hulls Using Eutectic Mixtures: A Sustainable Approach for Natural Dye Development.

There is a growing interest in exploring new natural sources of colorants. This study aimed to extract anthocyanins from broken black bean hulls (Phaseolus vulgaris L.) by modifying water with a eutectic mixture (choline chloride:citric acid (ChCl:Ca)). Ultrasound-assisted extraction (UAE) was employed and optimized in terms of temperature (30-70 °C), ultrasound power (150-450 W), and eutectic mixture concentration in water (1-9% (w/v)), resulting in an optimal condition of 66 °C, 420 W, and 8.2% (w/v), respectively. The main quantified anthocyanins were delphinidin-3-O-glycoside, petunidin-3-O-glycoside, and malvidin-3-O-glycoside. The half-life of the anthocyanins at 60 °C increased twelvefold in the eutectic mixture extract compared to the control, and when exposed to light, the half-life was 10 times longer, indicating greater resistance of anthocyanins in the extracted eutectic mixture. Additionally, the extracts were concentrated through centrifuge-assisted cryoconcentration, with the initial cycle almost double the extract value, making this result more favorable regarding green metrics. The first concentration cycle, which showed vibrant colors of anthocyanins, was selected to analyze the color change at different pH levels. In general, the technology that uses eutectic mixtures as water modifiers followed by cryoconcentration proved to be efficient for use as indicators in packaging, both in quantity and quality of anthocyanins.

Comparative performance of scFv-based anti-BCMA CAR formats for improved T cell therapy in multiple myeloma.

In multiple myeloma (MM), B cell maturation antigen (BCMA)-directed CAR T cells have emerged as a novel therapy with potential for long-term disease control. Anti-BCMA CAR T cells with a CD8-based transmembrane (TM) and CD137 (41BB) as intracellular costimulatory domain are in routine clinical use. As the CAR construct architecture can differentially impact performance and efficacy, the optimal construction of a BCMA-targeting CAR remains to be elucidated. Here, we hypothesized that varying the constituents of the CAR structure known to impact performance could shed light on how to improve established anti-BCMA CAR constructs. CD8TM.41BBIC-based anti-BCMA CAR vectors with either a long linker or a short linker between the light and heavy scFv chain, CD28TM.41BBIC-based and CD28TM.CD28IC-based anti-BCMA CAR vector systems were used in primary human T cells. MM cell lines were used as target cells. The short linker anti-BCMA CAR demonstrated higher cytokine production, whereas in vitro cytotoxicity, T cell differentiation upon activation and proliferation were superior for the CD28TM.CD28IC-based CAR. While CD28TM.CD28IC-based CAR T cells killed MM cells faster, the persistence of 41BBIC-based constructs was superior in vivo. While CD28 and 41BB costimulation come with different in vitro and in vivo advantages, this did not translate into a superior outcome for either tested model. In conclusion, this study showcases the need to study the influence of different CAR architectures based on an identical scFv individually. It indicates that current scFv-based anti-BCMA CAR with clinical utility may already be at their functional optimum regarding the known structural variations of the scFv linker.

Meaning in life during the COVID-19 pandemic in Brazil: Impact of quality of life and sociodemographic factors.

Research on meaning in life typically emphasizes the psychological aspects of quality of life, neglecting broader dimensions. Additionally, its relevance to the COVID-19 context remains limited. This study investigated the relationship of meaning in life with quality of life and sociodemographic factors related to COVID-19 pandemic in Brazil. A total of 4133 Brazilian adults completed Meaning in Life Questionnaire (MLQ), WHOQOL-BREF, WHOQOL-SRPB BREF, and sociodemographic information. Our results indicated a positive correlation between the presence of meaning and quality of life dimensions, with psychological health exhibiting the strongest relationship. We found a lower presence of meaning among individuals experiencing heightened social isolation, while vaccinated individuals exhibited a greater presence of meaning. Additionally, non-working participants reported lower presence and higher search for meaning than employed individuals, with frontline workers showing the highest search for meaning. Theoretical and practical implications of these findings are discussed.

A robust and flexible baculovirus-insect cell system for AAV vector production with improved yield, capsid ratios and potency.

Manufacturing of adeno-associated viruses (AAV) for gene and cell therapy applications has increased significantly and spurred development of improved mammalian and insect cell-based production systems. We developed a baculovirus-based insect cell production system-the SGMO Helper-with a novel gene architecture and greater flexibility to modulate the expression level and content of individual Rep and Cap proteins. In addition, we incorporated modifications to the AAV6 capsid sequence that improves yield, capsid integrity, and potency. Production of recombinant AAV 6 (rAAV6) using the SGMO Helper had improved yields compared to the Bac-RepCap helper from the Kotin lab. SGMO Helper-derived rAAV6 is resistant to a previously described proteolytic cleavage unique to baculovirus-insect cell production systems and has improved capsid ratios and potency, in vitro and in vivo, compared with rAAV6 produced using Bac-RepCap. Next-generation sequencing sequence analysis demonstrated that the SGMO Helper is stable over six serial passages and rAAV6 capsids contain comparable amounts of non-vector genome DNA as rAAV6 produced using Bac-RepCap. AAV production using the SGMO Helper is scalable using bioreactors and has improved yield, capsid ratio, and in vitro potency. Our studies demonstrate that the SGMO Helper is an improved platform for AAV manufacturing to enable delivery of cutting-edge gene and cell therapies.

Cannabidiol effect on long-term brain alterations in septic rats: Involvement of PPARγ activation.

Sepsis is a life-threatening condition induced by a deregulated host response to infection. Post-sepsis injury includes long-term cognitive impairment, whose neurobiological mechanisms and effective treatment remain unknown. The present study was designed to determine the potential effects of cannabidiol (CBD) in a sepsis-associated encephalopathy (SAE) model and explore if peroxisome proliferator activated receptor gamma (PPARγ) is the putative mechanism underpinning the beneficial effects. SAE was induced in Wistar rats by cecal ligation and puncture (CLP) or sham (control). CLP rats received vehicle, CBD (10 mg/kg), PPARγ inhibitor (GW9662 - 1 mg/kg), or GW9662 (1 mg/kg) + CBD (10 mg/kg) intraperitoneally for ten days. During this period, the survival rate was recorded, and at the end of 10 days, a memory test was performed, and the prefrontal cortex and hippocampus were removed to verify brain-derived neurotrophic factor (BDNF), cytokines (IL-1ß, IL-6 and IL-10), myeloperoxidase activity, nitrite nitrate concentration, and lipid and protein carbonylation and catalase activity. Septic rats presented cognitive decline and an increase in mortality following CLP. Only CBD alone improved the cognitive impairment, which was accompanied by restoration of BDNF, reduced neuroinflammation, and oxidative stress, mainly in the hippocampus. This study shows that CLP induces an increase in brain damage and CBD has neuroprotective effects on memory impairment and neurotrophins, as well as against neuroinflammation and oxidative stress, and is mediated by PPARγ activation.

Changing Attitudes About a Pro-Environmental Proposal Concerning Solar Power: The Self-Validating Role of Ingroup Versus Outgroup Sources.

BACKGROUND: In this study, we examined whether a persuasive message in favor of a pro-environmental proposal could influence attitude change through a self-validation process when individuals were told that the source of the proposal belonged to their ingroup (vs. their outgroup). METHOD: Participants read a message that advocated for the use of solar power. Immediately following the message, participants were asked to list their thoughts regarding the persuasive proposal. A thought favorability index was created for each participant. Following the thought-listing task, participants received the experimental manipulation (i.e., ingroup vs. outgroup source) based on the minimal group paradigm, after which they reported their attitudes towards the proposal. RESULTS: A regression analysis showed the predicted interaction between thought favorability and type of source (i.e., ingroup vs. outgroup) on attitudes towards the solar power proposal. According to our expectations, thought favorability was a better predictor of attitudes for participants in the ingroup (vs. outgroup) source condition. CONCLUSIONS: Attitudes can be polarized as a function of ingroup versus outgroup differentiation through a self-validation process.

Blood-brain barrier permeability in the ischemic stroke: An update.

Stroke is the second leading cause of death globally and the major cause of long-term disability. Among the types of strokes, ischemic stroke, which occurs due to obstruction of blood vessels responsible for cerebral irrigation, is considered the most prevalent, accounting for approximately 86 % of all stroke cases. This interruption of blood supply leads to a critical pathophysiological mechanism, including oxidative stress and neuroinflammation which are responsible for structural alterations of the blood-brain barrier (BBB). The increased BBB permeability associated with cerebral ischemia-reperfusion may contribute to a worse outcome after stroke. Thus, this narrative review aims to update the pathophysiological mechanisms involved in the increase in BBB permeability and to list the possible therapeutic strategies.

Population-Based Evidence of Climate Change Adaptation in an Endangered Plant Endemic to a Biodiversity Hotspot.

Climate change is expected to impact both the population structure and geographic distribution of plants. Species distribution models are widely used to assess range shifts and the vulnerability of plants to climate change. Despite the abundance of modeling studies, little is known about how existing populations respond to climate change. We investigated the demographic structure and vulnerability to climate change in Anemone moorei, a sub-shrub with a highly restricted distribution in a biodiversity hotspot. We improved the distribution knowledge through intensive field work. We conducted a census of stem length as a proxy for age for all known populations. We used ensemble forecasting to project distributions considering 10 future climate scenarios and developed a novel climate change vulnerability index for the species' distribution. We found that the mean stem length decreases and the proportion of young plants increases, while the size of fruiting plants decreases as A. moorei faces greater climate change vulnerability. We interpret these results as evidence for the onset of recent adaptation to climate change, consisting of reduced adult longevity and an earlier onset of reproduction. As a result of these changes, the proportion of juveniles in the population increases.