Tumor-targeted delivery of hyaluronic acid/polydopamine-coated Fe2+-doped nano-scaled metal-organic frameworks with doxorubicin payload for glutathione depletion-amplified chemodynamic-chemo cancer therapy.

Chemodynamic therapy (CDT), an emerging cancer treatment modality, uses multivalent metal elements to convert endogenous hydrogen peroxide (H2O2) to toxic hydroxyl radicals (•OH) via a Fenton or Fenton-like reaction, thus eliciting oxidative damage of cancer cells. However, the antitumor potency of CDT is largely limited by the high glutathione (GSH) concentration and low catalytic efficiency in the tumor sites. The combination of CDT with chemotherapy provides a promising strategy to overcome these limitations. In this work, to enhance antitumor potency by tumor-targeted and GSH depletion-amplified chemodynamic-chemo therapy, the hyaluronic acid (HA)/polydopamine (PDA)-decorated Fe2+-doped ZIF-8 nano-scaled metal-organic frameworks (FZ NMs) were fabricated and utilized to load doxorubicin (DOX), a chemotherapy drug, via hydrophobic, π-π stacking and charge interactions. The attained HA/PDA-covered DOX-carrying FZ NMs (HPDFZ NMs) promoted DOX and Fe2+ release in weakly acidic and GSH-rich milieu and exhibited acidity-activated •OH generation. Through efficient CD44-mediated endocytosis, the HPDFZ NMs internalized by CT26 cells not only prominently enhanced •OH accumulation by consuming GSH via PDA-mediated Michael addition combined with Fe2+/Fe3+ redox couple to cause mitochondria damage and lipid peroxidation, but also achieved intracellular DOX release, thus eliciting apoptosis and ferroptosis. Importantly, the HPDFZ NMs potently inhibited CT26 tumor growth in vivo at a low DOX dose and had good biosafety, thereby showing promising potential in tumor-specific treatment.

Naked mesoporous rhodium nanospheres with glutathione depletion and photothermal capabilities for tumor therapy.

Pancreatic and colon cancer are malignant tumors of the digestive system that currently lack effective treatments. In cancer cells, a high level of glutathione (GSH) is indispensable to scavenge excessive reactive oxygen species (ROS) and detoxify xenobiotics, which make it a potential target for cancer therapy. GSH depletion has been proved to improve the therapeutic efficacy of photodynamic therapy. Here, we reported that naked mesoporous rhodium nanospheres (Rh MNs), prepared by soft template redox method, can act as GSH depletion agent and photothermal conversion agent to achieve synergistic therapy respectively. Different from conventional nanoagents, Rh MNs with the characteristics of easy synthesis, simple structure and multiple functions can decrease the GSH level in tumor and depict excellent photothermal ability with a high photothermal conversion efficiency (PTCE) up to 39%. Notably, multiple anti-tumor mechanisms in CT26 and BxPC-3 tumor models, include inhibited anti-apoptosis, DNA replication repair, and GSH synthesis are revealed, and the pancreatic tumor cure rate of the cooperative treatment group is 80%. Collectively, we developed Rh MNs to combine GSH depletion with photothermal therapy for cancer treatment.

Polypeptide-Based Copper Ionophore for In Situ Glutathione-Triggered Chemodynamic and Chemotherapy.

Intracellular copper ion homeostasis has become an attractive target for cancer therapy. Herein, we report a 2,2'-dipicolylamine (DPA) functionalized polyglutamate derivative (PDHB) which is capable of rapidly forming PDHB-copper complex (PDHB@Cu) due to the strong coordination ability of pendant DPA with Cu2+. High drug loading content of doxorubicin (DOX) (>30 wt %) is realized due to the strong affinity of Cu2+ to DOX, while that is about 10 wt % for PDHB without Cu2+. The obtained PDHB@Cu-DOX can respond to specific endogenous stimuli (pH and glutathione (GSH)), releasing Cu2+ and DOX. The released DOX directly damages the DNA of tumor cells to cause apoptosis, while Cu2+ depletes intracellular GSH and is reduced to Cu+ simultaneously, which reacts with local H2O2 to produce highly toxic ·OH via a Fenton-like reaction, thus realizing synergistic chemodynamics and chemotherapy. This report provides an interesting polymeric ionophore strategy to deliver enough copper ions into cancer cells, which can also easily extend to other metal ions by replacing the ionophore components, thus having a wide application in nanomedicine.

An in-silico study of conventional and FLASH radiotherapy iso-effectiveness: potential impact of radiolytic oxygen depletion on tumor growth curves and tumor control probability.

Objective: This work aims to investigate the iso-effectiveness of conventional and FLASH radiotherapy on tumors through in-silico mathematical models. We focused on the role of radiolytic oxygen depletion (ROD), which has been argued as a possible factor to explain the FLASH effect. Approach: We used a spatiotemporal reaction-diffusion model, including ROD, to simulate tumor oxygenation and response. From those oxygen distributions we obtained surviving fractions (SFs) using the linear-quadratic (LQ) model with the oxygen enhancement ratios (OER). We then employed the calculated SFs to describe the evolution of preclinical tumor volumes through a mathematical model of tumor response, and we also extrapolated those results to calculate tumor control probabilities (TCPs) using the Poisson-LQ approach. Main results: Our study suggests that the ROD effect may cause differences in SF between FLASH and conventional radiotherapy, especially in low α/ß and poorly oxygenated cells. However, a statistical analysis showed that these changes in SF generally do not result in significant differences in the evolution of preclinical tumor growth curves when the sample size is small, because such differences in SF may not be noticeable in the heterogeneity of the population of animals}. Nonetheless, when extrapolating this effect to TCP curves, we observed important differences between both techniques (TCP is lower in FLASH radiotherapy). When analyzing the response of tumors with heterogeneous oxygenations, differences in TCP are more important for well oxygenated tumors. This apparent contradiction with the results obtained for homogeneously oxygenated cells is explained by the complex interplay between the heterogeneity of tumor oxygenation, the OER effect, and the ROD effect. Significance: This study supports the experimentally observed iso-effectiveness of FLASH and conventional radiotherapy when analyzing the volume evolution of preclinical tumors (that are far from control). However, this study also hints that tumor growth curves may be less sensitive to small variations in SF than tumor control probability: ROD may lead to increased SF in FLASH radiotherapy, which while not large enough to cause significant differences in tumor growth curves, could lead to important differences in clinical TCPs. Nonetheless, it cannot be discarded that other effects not modeled in this work, like radiation-induced immune effects, can contribute to tumor control and maintain the iso-effectiveness of FLASH radiotherapy. The study of tumor growth curves may not be the ideal experiment to test the iso-effectiveness of FLASH, and experiments reporting TCP or D50 may be preferred.

Reprogramming the Tumor Immune Microenvironment Through Activatable Photothermal Therapy and GSH depletion Using Liposomal Gold Nanocages to Potentiate Anti-Metastatic Immunotherapy.

Cancer immunotherapy offers significant clinical benefits for patients with advanced or metastatic tumors. However, immunotherapeutic efficacy is often hindered by the tumor microenvironment's high redox levels, leading to variable patient outcomes. Herein, a therapeutic liposomal gold nanocage (MGL) is innovatively developed based on photo-triggered hyperthermia and a releasable strategy by combining a glutathione (GSH) depletion to remodel the tumor immune microenvironment, fostering a more robust anti-tumor immune response. MGL comprises a thermosensitive liposome shell and a gold nanocage core loaded with maleimide. The flexible shell promotes efficient uptake by cancer cells, enabling targeted destruction through photothermal therapy while triggering immunogenic cell death and the maturation of antigen-presenting cells. The photoactivated release of maleimide depletes intracellular GSH, increasing tumor cell sensitivity to oxidative stress and thermal damage. Conversely, GSH reduction also diminishes immunosuppressive cell activity, enhances antigen presentation, and activates T cells. Moreover, photothermal immunotherapy decreases elevated levels of heat shock proteins in tumor cells, further increasing their sensitivity to hyperthermia. In summary, MGL elicited a robust systemic antitumor immune response through GSH depletion, facilitating an effective photothermal immunotherapeutic strategy that reprograms the tumor microenvironment and significantly inhibits primary and metastatic tumors. This approach demonstrates considerable translational potential and clinical applicability.

Relevance of charged and polar amino acids for functionality of membrane toxin TisB.

Bacterial dormancy is marked by reduced cellular activity and the suspension of growth. It represents a valuable strategy to survive stressful conditions, as exemplified by the long-term tolerance towards antibiotics that is attributable to a fraction of dormant cells, so-called persisters. Here, we investigate the membrane toxin TisB (29 amino acids) from the chromosomal toxin-antitoxin system tisB/istR-1 in Escherichia coli. TisB depolarizes the inner membrane in response to DNA damage, which eventually promotes a stress-tolerant state of dormancy within a small fraction of the population. Using a plasmid-based system for moderate tisB expression and single amino acid substitutions, we dissect the importance of charged and polar amino acids. We observe that the central amino acids lysine 12 and glutamine 19 are of major importance for TisB functionality, which is further validated for lysine 12 in the native context upon treatment with the DNA-damaging antibiotic ciprofloxacin. Finally, we apply a library-based approach to test additional TisB variants in higher throughput, revealing that at least one positive charge at the C-terminus (either lysine 26 or 29) is mandatory for TisB-mediated dormancy. Our study provides insights into the molecular basis for TisB functionality and extends our understanding of bacterial membrane toxins.

Prospective study of risk factors for community-acquired acute kidney injury.

BACKGROUND AND HYPOTHESIS: Causes and risk factors for community-acquired acute kidney injury (CA-AKI) have not been thoroughly studied. The aim of this study was to examine the risk factors for CA-AKI. METHODS: In this prospective study, we examined serum creatinine from all individuals visiting a university hospital's emergency department (ED) over an 11-month period for the presence of AKI defined according to the KDIGO criteria. Patients with AKI were invited to participate. Randomly selected controls (1:2) were paired according to age, sex, and date of admission. Participants answered questions about their medical history and medication use, including over-the-counter (OTC) drugs. Conditional logistic regression was used to identify factors associated with AKI. RESULTS: Of 602 AKI cases identified, 512 participated in the study. AKI cases were significantly more likely than controls to have used nonsteroidal anti-inflammatory drugs (NSAIDs) (26.0 % vs 18.0 %, p = 0,001) in the week preceding the ED visit, particularly OTC NSAIDs (23.3 % vs 15.9 %, p < 0.001). AKI was associated with a recent history of vomiting (OR 2.52 [95 %CI 1.87-3.39]), diarrhea (1.30 [1.00-1.70]) and urinary retention (1.92 [1.36-2.72]), use of non-selective NSAIDs (1.84, [1.37-2.48]), RAAS blockers (1.63 [1.21-2.19]), and diuretics (1.53 [1.13-2.08]), and a history of diabetes (1.42 [1.04-1.94]), CKD (1.36 [1.01-1.83]) and smoking (1.72 [1.24-2.37]). CONCLUSIONS: Events in the setting of acute illness and medication use, including OTC NSAIDs, may play a greater role in the development of CA-AKI than comorbid conditions. Frequent use of OTC NSAIDs is a concern and should be addressed in view of serious adverse effects.

Macrophage-derived amphiregulin promoted the osteogenic differentiation of chondrocytes through EGFR/Yap axis and TGF-ehß activation.

Endochondral ossification represents a crucial biological process in skeletal development and bone defect repair. Macrophages, recognized as key players in the immune system, are now acknowledged for their substantial role in promoting endochondral ossification within cartilage. Concurrently, the epidermal growth factor receptor (EGFR) ligand amphiregulin (Areg) has been documented for its contributory role in restoring bone tissue homeostasis post-injury. However, the mechanism by which macrophage-secreted Areg facilitates bone repair remains elusive. In this study, the induction of macrophage depletion through in vivo administration of clodronate liposomes was employed in a standard open tibial fracture mouse model to assess bone healing using micro-computed tomography (micro-CT) analysis, histomorphology, and ELISA serum evaluations. The investigation revealed sustained expression of Areg during the fracture healing period in wild-type mice. Macrophage depletion significantly reduced the number of macrophages on the local bone surface and vital organs. This reduction led to diminished Areg secretion, decreased collagen production, and delayed fracture healing. However, histological and micro-CT assessments at 7 and 21 days post-local Areg treatment exhibited a marked improvement of bone healing compared to the vehicle control. In vitro studies demonstrated an increase of Areg secretion by the Raw264.7 cells upon ATP stimulation. Indirect co-culture of Raw264.7 and ATDC5 cells indicated that Areg overexpression enhanced the osteogenic potential of chondrocytes, and vice versa. This osteogenic promotion was attributed to Areg's activation of the membrane receptor EGFR in the ATDC5 cell line, the enhanced phosphorylation of transcription factor Yap, and the facilitation of the expression of bioactive TGF-ß by chondrocytes. Collectively, this research elucidates the direct mechanistic effects of macrophage-secreted Areg in promoting bone homeostasis following bone injury.

Assessing the persistence of a contaminant plume generated by linear aquifer source depletion and back diffusion from an aquitard.

This study presents analytical solutions for describing contaminant storage and release from an aquitard with linear source depletion (LSD) boundary conditions. We investigated three scenarios for trichloroethylene (TCE) mass exchange before and after the LSD period in an aquifer bounded by an adjacent aquitard based on the LSD dynamics, a resistance coefficient, and the aquitard thickness. The developed analytical solutions showed good agreement with measured profiles and breakthrough curves from a previous study. In three scenarios, the factors delaying the onset of TCE release into the aquifer were a decrease in the resistance coefficient, an increase in LSD period and aquitard thickness. The changes in the duration, mass, and rate of TCE storage in the aquitard during LSD loading process affected the equilibrium of the aquifer-aquitard concentration gradient. After TCE loading, the period maintained above the maximum contaminant level was directly related to the three variables; the longest plume persistence occurred when TCE penetration distance at transition point from storage to release coincided with the aquitard thickness. Overall, the developed analytical solution aids in evaluating the risk of plume persistence, enhancing site management efficiency, and reducing remediation costs.

Too much information! When job resources become job demands, producing a curvilinear relationship between informational social support and creativity.

OBJECTIVE: Informational social support can have both positive and negative effects on employees. This research aims to examine the curvilinear relationship between informational social support and employees' cognitive processes, specifically cognitive depletion and creativity. Additionally, we investigate the moderating role of emotional stability on this curvilinear relationship, particularly regarding cognitive depletion. METHODS: A total of 108 male employees in South Korea participated in the study, completing 864 two-wave, time-lagged daily diary questionnaires. The surveys measured informational social support, cognitive depletion, creativity, and emotional stability. RESULTS: The findings reveal that informational social support enhances employees' cognitive processes up to a certain threshold, after which its effects become detrimental, demonstrating a curvilinear pattern. Furthermore, emotional stability moderates this relationship: emotionally stable employees show a linear relationship between informational social support and cognitive depletion, while emotionally unstable employees exhibit a curvilinear relationship. CONCLUSION: Our results suggest that excessive informational social support may harm employees' cognitive processes, indicating that there is an optimal level of support, beyond which the effects become counterproductive.

Residue Depletion of Nitrofurazone Metabolites, Semicarbazide and 5-Nitro-2-Furaldehyde, in Broiler Chickens After Oral Administration.

Nitrofurazone (NFZ) antibiotic is banned in food-producing animals, and its metabolite, semicarbazide (SEM), is used as a marker residue for nitrofurazone abuse. However, SEM can also be generated during food processing without veterinary treatment. Therefore, SEM cannot be considered an unequivocal marker of NFZ. This study investigates the use of 5-nitro-2-furaldehyde (5-NF) as an additional marker for nitrofurazone in broiler chickens. After oral administration of NFZ and 5-NF at 25 mg·kg-1 BW for 10 days, tissues (muscle and liver) and plasma samples were analyzed by liquid chromatography-tandem mass spectrometry. In NFZ-treated chickens, 5-NF was detected within 1 h in plasma at a peak concentration of 1.4 ± 0.25 µg·kg-1, while in 5-NF-treated ones, the maximum concentration was 0.85 ± 0.06 µg·kg-1 after 2 h. 5-NF was not detected in muscle and liver for both treated groups from 0 to 21 days. However, SEM persisted for up to 3 weeks in muscle (0.3 ± 0.018 µg·kg-1), 2 weeks in liver (0.16 ± 0.008 µg·kg-1), and 1 week in plasma (0.4 ± 0.05 µg·kg-1) with a faster elimination rate in liver tissues (half-life of 4.6 days) compared to muscle tissues (half-life of 6.5 days). These findings suggest that SEM remains a better marker for detecting nitrofurazone abuse in chickens compared to 5-NF.

Biomimetic Single-Atom Nanozyme for Dual Starvation-Enhanced Breast Cancer Immunotherapy.

Cold exposure (CE) therapy is an innovative and cost-efficient cancer treatment that activates brown adipose tissue to compete for glucose uptake, leading to metabolic starvation in tumors. Exploring the combined antitumor mechanisms of CE and traditional therapies (such as nanocatalysis) is exciting and promising. In this study, a platelet membrane biomimetic single-atom nanozyme (SAEs) nanodrug (PFB) carrying bis-2-(5-phenylacetamido-1, 2, 4-thiadiazol-2-yl) ethyl sulfide (BPTES) is developed for use in cancer CE therapy. Owing to the platelet membrane modification, PFB can effectively target tumors. Upon entering cancer cells, the dual starvation effect induced by CE treatment and BPTES can significantly diminish intracellular glucose and ATP levels, resulting in a substantial reduction in cellular (glutathione) GSH, which can enhance the cytotoxic efficacy of reactive oxygen species generated by SAEs. This strategy not only boosts ROS production in tumors, but also strengthens immune responses, particularly by increasing memory T-cell abundance and suppressing distant tumor growth and tumor metastasis. Compared with SAEs therapy alone, this combined approach offers superior benefits for tumor immunotherapy. This study achieves a combination of CE and nanomedicines for the first time, providing new ideas for future nanomedicine combination therapy modalities.

Simple ROS-responsive micelles loaded Shikonin for efficient ovarian cancer targeting therapy by disrupting intracellular redox homeostasis.

Ovarian cancer is the most common malignant tumor in women. Shikonin (SHK), an herbal extract from Chinese medicine, shows promise in treating ovarian cancer by inducing reactive oxygen species (ROS). However, its clinical use is limited by poor tumor targeting and low bioavailability, and its therapeutic potential is further compromised by the elevated levels of antioxidants such as glutathione (GSH) within tumor cells. In this study, a novel formulation of ROS-responsive micelles loaded with SHK was developed using hyaluronic acid-phenylboronic acid pinacol ester conjugation (HA-PBAP) for targeted therapy of ovarian cancer through disruption of intracellular redox homeostasis. The SHK@HA-PBAP exhibits targeted delivery to ovarian cancer cells through the interaction between HA and CD44 receptors. Upon internalization by cancer cells, the high levels of intracellular ROS triggered the degradation of SHK@HA-PBAP and simultaneously released SHK and generated GSH scavenger quinone methide (QM). The SHK and QM released from the SHK@HA-PBAP effectively induce the production of ROS and deplete intracellular GSH, leading to the disruption of intracellular redox homeostasis and subsequent induction of cell death. These characteristics collectively inhibit the growth of ovarian cancer. In vitro and in vivo studies have demonstrated that SHK@HA-PBAP micelles exhibit superior antitumor efficacy compared to free SHK in both A2780 cells and A2780 tumor-bearing mice. The ROS-responsive SHK@HA-PBA presents a promising therapeutic approach for the treatment of ovarian cancer.

The combined effects of polystyrene nanoplastics and dissolved organic matter on the environmental bioavailability of carbamazepine.

The bioavailability of active pharmaceutical ingredients (APIs) plays a crucial role in determining the toxicity and risk of contaminants in the environment. However, the bioavailability of APIs in complex environmental matrices is still unclear. In this study, the combined effects of polystyrene nanoplastics (PS NPs) with various particle sizes (50, 100, and 1000 nm) and fulvic acid (FA) on the bioavailability of carbamazepine (CBZ) were investigated via negligible depletion solid-phase microextraction (nd-SPME) and Daphnia magna (D. magna) accumulation. The uptake kinetic study revealed that both PS NPs and FA reduced the elimination rate (k2) in most cases. The availability of CBZ to nd-SPME was determined by the hydrodynamic particle size of PS NPs, whereas the bioavailability to D. magna depended on the intrinsic particle size. The CBZ bioavailability was greater in co-exposed matrices due to the attenuated sorption of PS NPs to CBZ by FA modification. Notably, co-exposure of PS NPs and FA resulted in a higher bioaccumulation factor (BAF) of CBZ, probably due to the desorption and reabsorption of particle-associated CBZ. This study demonstrated that both PS NP particle size and FA binding affect the bioavailability of CBZ, and nd-SPME can mimic only the bioaccumulation of CBZ via diffusion.

Assessment of skeletal muscle dynamics and milk production across a 300-day lactation in multiparous dairy cattle.

The objective of this study was to evaluate changes in longissimus dorsi muscle depth (LDD) across lactation (0 to 300 DIM) and identify the impact of low versus high muscle reserves immediately after parturition on body weight and body reserve changes as well as production variables across a 300-d lactation. Forty multiparous cows were classified as high muscle (HM; LDD > 5.0 cm; n = 18) or low muscle (LM; LDD ≤ 5.0 cm; n = 22) based on LDD measurements collected within 24 h of parturition. Body weights (BW) and ultrasound scans to assess LDD and back fat depth (BFD) were collected monthly from parturition until 300 DIM. Ultrasound scans captured and measured using available software. Blood samples were taken at 7, 150 and 300 DIM, and plasma was analyzed for markers of metabolic status by measuring insulin, nonesterified fatty acids (NEFA), creatinine, and 3-methylhistidine (3-MH). Milk yield was recorded daily and milk components were analyzed monthly. Data analysis was performed and the statistical models included the fixed effect of muscle group, time, their interaction, and the random effect of cow nested within muscle group with repeated measures using a first-order autoregressive covariance structure. Muscle group was not related with BW or BFD for any of the time points measured. Cows lost BW from 0 to 60 DIM and gained weight from 60 to 300 DIM. Similarly, BFD decreased between 0 to 90 DIM and increased BFD after 90 DIM until 300 DIM. A muscle group by time interaction was observed for LDD. The HM cows had more muscle at 0 DIM, indicative of treatment assignment (1.34 cm more), and 300 DIM (0.78 cm more) and tended to have more muscle at 60 DIM (0.66 cm more) compared with LM. After 240 DIM, both muscle groups began net accretion of muscle reserves until 300 DIM. No differences were observed for blood metabolites measured based on muscle group. However, there were significant time effects for creatinine, 3-MH, and NEFA concentrations, which reflected the observed changes in BFD and LDD measured in ultrasound scans. For statistical analysis of daily milk production, observations were grouped into 3 stages of lactation, early (0-60 DIM), mid (60-240 DIM), and late lactation (240-300 DIM). There was a muscle group by stage of lactation interaction, where in early and mid-lactation, HM cows produced, on average, 1.9 kg more milk/d; however, in late lactation, LM cows produced 1.8 kg more milk/d. Our results indicate that muscle reserves are depleted in early lactation, and accreted in late lactation, whereas BW and BFD started to increase by 90 DIM. Data also supports that cows with more extensive muscle depletion in early lactation had greater milk production, however, substantial muscle accretion in late lactation may result in reduced milk production.

A Loss Cycle of Burnout Symptoms and Reduced Coping Self-Efficacy: A Latent Change Score Modelling Approach.

Police officers are frequently faced with chronic and acute stressors, such as excessive workload, organizational stressors and emotionally charged reports. This study aims to examine the relationship between a form of chronic strain (ie, burnout symptoms) and a resource (ie, coping self-efficacy) in a sample of Dutch police officers. Specifically, we aim to investigate the existence of a loss cycle of resources. We use Latent Change Score modeling to investigate the potential depletion or loss cycle of coping self-efficacy as a result of burnout symptoms in a sample of 95 police officers who completed a survey on three consecutive timepoints. The lag between the measurements was approximately one year. We found that, during both one-year intervals, within-person increases in burnout symptoms were related to within-person decreases in coping self-efficacy. Also, the results emphasize the buffering role of coping self-efficacy for burnout symptoms, as within-person decreases in coping self-efficacy during the first year were associated with within-person increases in burnout symptoms during the following year. Together, the results imply that a loss cycle of coping self-efficacy and burnout symptoms may occur. For this we used Latent Change Score modeling, which is a relatively new approach which provides researchers with the opportunity to analyse multi-wave longitudinal data while focusing on within-person changes over time. Practically, police organizations are advised to monitor personnel wellbeing and resources, to maintain and promote sustainable employability of police officers and to be able to timely provide individuals with interventions. Limitations discussed are the use of self-report measures and large intervals between the measurements. Finally, future directions of research are discussed that would circumvent the reported limitations, such as multiple wave with shorter lags and incorporating confounding factors that could affect coping self-efficacy.

[Corona vaccination under immunosuppression]. / Coronaimpfung unter Immunsuppression.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to play a major role as a severe and potentially fatal airway infection, especially in vulnerable patient groups. In view of the thin data situation on the influence of treatment and response to vaccination, at the beginning of the corona pandemic it was a major challenge to predict the tolerability and effectiveness in patients with inflammatory rheumatic diseases under immunomodulation or immunosuppression. In the meantime, numerous studies have addressed the questions of response and tolerability, at least for the COVID-19 vaccination. Even in the first months of the vaccination campaign, a small study on a single center cohort could show that apart from patients with B­cell depletion, all included patients showed a seroconversion after the first two vaccinations. This resulted in neither an increased occurrence of exacerbations of the underlying disease nor new autoimmune phenomena. Various studies have since then confirmed these data.

'The phenotypic conundrum of Trp748Ser variant in POLG gene: a report of two patients'.

We present two cases of a 23-years and 32-years old female respectively, who presented with recurrent seizures, ataxia, dysarthria, psychomotor slowing. Magnetic resonance imaging (MRI) of the brain in the first patient revealed T2/FLAIR hyperintensity in the bilateral thalamus and cerebellar white matter with diffusion restriction, with no contrast enhancement. In the second patient, magnetic resonance imaging of brain showed FLAIR hyperintensity in precuneus while CSF showed raised HSV IgG titre on first presentation leading to suspicion of infective etiology. The initial differential diagnosis included autoimmune, metabolic and demyelinating causes. However, routine laboratory investigations, cerebrospinal fluid analysis, and autoimmune panel and demyelination workup were inconclusive. Considering the possibility of a genetic-mediated metabolic disorder, genetic testing was carried out leading to the identification of the Trp748Ser variation in POLG gene associated with mitochondrial DNA depletion syndrome. These cases highlight the diagnostic challenges and complexities in identifying rare metabolic encephalopathy, emphasizing the importance of a multidisciplinary approach in such cases.

Redox-manipulating nanocarriers for anticancer drug delivery: a systematic review.

Spatiotemporally controlled cargo release is a key advantage of nanocarriers in anti-tumor therapy. Various external or internal stimuli-responsive nanomedicines have been reported for their ability to increase drug levels at the diseased site and enhance therapeutic efficacy through a triggered release mechanism. Redox-manipulating nanocarriers, by exploiting the redox imbalances in tumor tissues, can achieve precise drug release, enhancing therapeutic efficacy while minimizing damage to healthy cells. As a typical redox-sensitive bond, the disulfide bond is considered a promising tool for designing tumor-specific, stimulus-responsive drug delivery systems (DDS). The intracellular redox imbalance caused by tumor microenvironment (TME) regulation has emerged as an appealing therapeutic target for cancer treatment. Sustained glutathione (GSH) depletion in the TME by redox-manipulating nanocarriers can exacerbate oxidative stress through the exchange of disulfide-thiol bonds, thereby enhancing the efficacy of ROS-based cancer therapy. Intriguingly, GSH depletion is simultaneously associated with glutathione peroxidase 4 (GPX4) inhibition and dihydrolipoamide S-acetyltransferase (DLAT) oligomerization, triggering mechanisms such as ferroptosis and cuproptosis, which increase the sensitivity of tumor cells. Hence, in this review, we present a comprehensive summary of the advances in disulfide based redox-manipulating nanocarriers for anticancer drug delivery and provide an overview of some representative achievements for combinational therapy and theragnostic. The high concentration of GSH in the TME enables the engineering of redox-responsive nanocarriers for GSH-triggered on-demand drug delivery, which relies on the thiol-disulfide exchange reaction between GSH and disulfide-containing vehicles. Conversely, redox-manipulating nanocarriers can deplete GSH, thereby enhancing the efficacy of ROS-based treatment nanoplatforms. In brief, we summarize the up-to-date developments of the redox-manipulating nanocarriers for cancer therapy based on DDS and provide viewpoints for the establishment of more stringent anti-tumor nanoplatform.

Confined copper depletion via a hydrogel platform for reversing dabrafenib/cetuximab resistance in BRAFV600E-mutant colorectal cancer.

BRAFV600E-mutant colorectal cancer (CRC) is resistant to most first-line therapeutics, including the BRAF inhibitor dabrafenib and epidermal growth factor receptor (EGFR) inhibitor cetuximab. Although copper depletion shows promise in reversing dabrafenib/cetuximab resistance in BRAFV600E-mutant CRC, its application is limited by the potential for excessive copper depletion in non-tumor objects. In this study, we have developed a hydrogel platform for confined copper depletion in BRAFV600E-mutant CRC cells, which effectively reverses dabrafenib/cetuximab resistance and enhancing therapeutic efficiency. The hydrogel platform enables precise intracellular copper depletion through localized administration, acidity-triggered drug release, and oxidized activation of a copper prochelator. The dosage of this prochelator is 37.5 µg/kg in mouse models, which is significantly lower than the commonly used tetrathiomolybdate. Furthermore, both dabrafenib and the prochelator are preloaded into acid-responsive nanoparticles before being embedded in the hydrogel matrix to facilitate efficient endocytosis and acid-activatable drug release. Confined copper depletion inhibits MEK1 signaling and suppresses the MAPK signaling pathway when combined with BRAF and EGFR inhibitors. Moreover, the hydrogel platform inhibits tumor growth and prolongs survival in subcutaneous and postsurgical models of BRAFV600E-mutant CRC. This study provides an innovative strategy for overcoming dabrafenib/cetuximab resistance in BRAFV600E-mutant CRC through precise intracellular copper depletion.