RNA aggregates harness the danger response for potent cancer immunotherapy.

Cancer immunotherapy remains limited by poor antigenicity and a regulatory tumor microenvironment (TME). Here, we create "onion-like" multi-lamellar RNA lipid particle aggregates (LPAs) to substantially enhance the payload packaging and immunogenicity of tumor mRNA antigens. Unlike current mRNA vaccine designs that rely on payload packaging into nanoparticle cores for Toll-like receptor engagement in immune cells, systemically administered RNA-LPAs activate RIG-I in stromal cells, eliciting massive cytokine/chemokine response and dendritic cell/lymphocyte trafficking that provokes cancer immunogenicity and mediates rejection of both early- and late-stage murine tumor models. In client-owned canines with terminal gliomas, RNA-LPAs improved survivorship and reprogrammed the TME, which became "hot" within days of a single infusion. In a first-in-human trial, RNA-LPAs elicited rapid cytokine/chemokine release, immune activation/trafficking, tissue-confirmed pseudoprogression, and glioma-specific immune responses in glioblastoma patients. These data support RNA-LPAs as a new technology that simultaneously reprograms the TME while eliciting rapid and enduring cancer immunotherapy.

Edoxaban Antithrombotic Therapy for Atrial Fibrillation and Stable Coronary Artery Disease.

BACKGROUND: Despite consistent recommendations from clinical guidelines, data from randomized trials on a long-term antithrombotic treatment strategy for patients with atrial fibrillation and stable coronary artery disease are still lacking. METHODS: We conducted a multicenter, open-label, adjudicator-masked, randomized trial comparing edoxaban monotherapy with dual antithrombotic therapy (edoxaban plus a single antiplatelet agent) in patients with atrial fibrillation and stable coronary artery disease (defined as coronary artery disease previously treated with revascularization or managed medically). The risk of stroke was assessed on the basis of the CHA2DS2-VASc score (scores range from 0 to 9, with higher scores indicating a greater risk of stroke). The primary outcome was a composite of death from any cause, myocardial infarction, stroke, systemic embolism, unplanned urgent revascularization, and major bleeding or clinically relevant nonmajor bleeding at 12 months. Secondary outcomes included a composite of major ischemic events and the safety outcome of major bleeding or clinically relevant nonmajor bleeding. RESULTS: We assigned 524 patients to the edoxaban monotherapy group and 516 patients to the dual antithrombotic therapy group at 18 sites in South Korea. The mean age of the patients was 72.1 years, 22.9% were women, and the mean CHA2DS2-VASc score was 4.3. At 12 months, a primary-outcome event had occurred in 34 patients (Kaplan-Meier estimate, 6.8%) assigned to edoxaban monotherapy and in 79 patients (16.2%) assigned to dual antithrombotic therapy (hazard ratio, 0.44; 95% confidence interval [CI], 0.30 to 0.65; P<0.001). The cumulative incidence of major ischemic events at 12 months appeared to be similar in the trial groups. Major bleeding or clinically relevant nonmajor bleeding occurred in 23 patients (Kaplan-Meier estimate, 4.7%) in the edoxaban monotherapy group and in 70 patients (14.2%) in the dual antithrombotic therapy group (hazard ratio, 0.34; 95% CI, 0.22 to 0.53). CONCLUSIONS: In patients with atrial fibrillation and stable coronary artery disease, edoxaban monotherapy led to a lower risk of a composite of death from any cause, myocardial infarction, stroke, systemic embolism, unplanned urgent revascularization, or major bleeding or clinically relevant nonmajor bleeding at 12 months than dual antithrombotic therapy. (Funded by the CardioVascular Research Foundation and others; EPIC-CAD ClinicalTrials.gov number, NCT03718559.).

Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries.

Balanced chromosomal abnormalities (BCAs) represent a relatively untapped reservoir of single-gene disruptions in neurodevelopmental disorders (NDDs). We sequenced BCAs in patients with autism or related NDDs, revealing disruption of 33 loci in four general categories: (1) genes previously associated with abnormal neurodevelopment (e.g., AUTS2, FOXP1, and CDKL5), (2) single-gene contributors to microdeletion syndromes (MBD5, SATB2, EHMT1, and SNURF-SNRPN), (3) novel risk loci (e.g., CHD8, KIRREL3, and ZNF507), and (4) genes associated with later-onset psychiatric disorders (e.g., TCF4, ZNF804A, PDE10A, GRIN2B, and ANK3). We also discovered among neurodevelopmental cases a profoundly increased burden of copy-number variants from these 33 loci and a significant enrichment of polygenic risk alleles from genome-wide association studies of autism and schizophrenia. Our findings suggest a polygenic risk model of autism and reveal that some neurodevelopmental genes are sensitive to perturbation by multiple mutational mechanisms, leading to variable phenotypic outcomes that manifest at different life stages.

Potential circadian effects on translational failure for neuroprotection.

Neuroprotectant strategies that have worked in rodent models of stroke have failed to provide protection in clinical trials. Here we show that the opposite circadian cycles in nocturnal rodents versus diurnal humans1,2 may contribute to this failure in translation. We tested three independent neuroprotective approaches-normobaric hyperoxia, the free radical scavenger α-phenyl-butyl-tert-nitrone (αPBN), and the N-methyl-D-aspartic acid (NMDA) antagonist MK801-in mouse and rat models of focal cerebral ischaemia. All three treatments reduced infarction in day-time (inactive phase) rodent models of stroke, but not in night-time (active phase) rodent models of stroke, which match the phase (active, day-time) during which most strokes occur in clinical trials. Laser-speckle imaging showed that the penumbra of cerebral ischaemia was narrower in the active-phase mouse model than in the inactive-phase model. The smaller penumbra was associated with a lower density of terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL)-positive dying cells and reduced infarct growth from 12 to 72 h. When we induced circadian-like cycles in primary mouse neurons, deprivation of oxygen and glucose triggered a smaller release of glutamate and reactive oxygen species, as well as lower activation of apoptotic and necroptotic mediators, in 'active-phase' than in 'inactive-phase' rodent neurons. αPBN and MK801 reduced neuronal death only in 'inactive-phase' neurons. These findings suggest that the influence of circadian rhythm on neuroprotection must be considered for translational studies in stroke and central nervous system diseases.

Author Correction: Potential circadian effects on translational failure for neuroprotection.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Diurnal Rhythms in the Red Seaweed Gracilariopsis chorda are Characterized by Unique Regulatory Networks of Carbon Metabolism.

Cellular and physiological cycles are driven by endogenous pacemakers, the diurnal and circadian rhythms. Key functions such as cell cycle progression and cellular metabolism are under rhythmic regulation, thereby maintaining physiological homeostasis. The photoreceptors phytochrome and cryptochrome, in response to light cues, are central input pathways for physiological cycles in most photosynthetic organisms. However, among Archaeplastida, red algae are the only taxa that lack phytochromes. Current knowledge about oscillatory rhythms is primarily derived from model species such as Arabidopsis thaliana and Chlamydomonas reinhardtii in the Viridiplantae, whereas little is known about these processes in other clades of the Archaeplastida, such as the red algae (Rhodophyta). We used genome-wide expression profiling of the red seaweed Gracilariopsis chorda and identified 3,098 rhythmic genes. Here, we characterized possible cryptochrome-based regulation and photosynthetic/cytosolic carbon metabolism in this species. We found a large family of cryptochrome genes in G. chorda that display rhythmic expression over the diurnal cycle and may compensate for the lack of phytochromes in this species. The input pathway gates regulatory networks of carbon metabolism which results in a compact and efficient energy metabolism during daylight hours. The system in G. chorda is distinct from energy metabolism in most plants, which activates in the dark. The green lineage, in particular, land plants, balance water loss and CO2 capture in terrestrial environments. In contrast, red seaweeds maintain a reduced set of photoreceptors and a compact cytosolic carbon metabolism to thrive in the harsh abiotic conditions typical of intertidal zones.

PRMT5 supports multiple oncogenic pathways in mantle cell lymphoma.

Mantle cell lymphoma (MCL) is an incurable B-cell malignancy with an overall poor prognosis, particularly for patients that progress on targeted therapies. Novel, more durable treatment options are needed for patients with MCL. Protein arginine methyltransferase 5 (PRMT5) is overexpressed in MCL and plays an important oncogenic role in this disease via epigenetic and posttranslational modification of cell cycle regulators, DNA repair genes, components of prosurvival pathways, and RNA splicing regulators. The mechanism of targeting PRMT5 in MCL remains incompletely characterized. Here, we report on the antitumor activity of PRMT5 inhibition in MCL using integrated transcriptomics of in vitro and in vivo models of MCL. Treatment with a selective small-molecule inhibitor of PRMT5, PRT-382, led to growth arrest and cell death and provided a therapeutic benefit in xenografts derived from patients with MCL. Transcriptional reprograming upon PRMT5 inhibition led to restored regulatory activity of the cell cycle (p-RB/E2F), apoptotic cell death (p53-dependent/p53-independent), and activation of negative regulators of B-cell receptor-PI3K/AKT signaling (PHLDA3, PTPROt, and PIK3IP1). We propose pharmacologic inhibition of PRMT5 for patients with relapsed/refractory MCL and identify MTAP/CDKN2A deletion and wild-type TP53 as biomarkers that predict a favorable response. Selective targeting of PRMT5 has significant activity in preclinical models of MCL and warrants further investigation in clinical trials.

Non-line-of-sight imaging using phasor-field virtual wave optics.

Non-line-of-sight imaging allows objects to be observed when partially or fully occluded from direct view, by analysing indirect diffuse reflections off a secondary relay surface. Despite many potential applications1-9, existing methods lack practical usability because of limitations including the assumption of single scattering only, ideal diffuse reflectance and lack of occlusions within the hidden scene. By contrast, line-of-sight imaging systems do not impose any assumptions about the imaged scene, despite relying on the mathematically simple processes of linear diffractive wave propagation. Here we show that the problem of non-line-of-sight imaging can also be formulated as one of diffractive wave propagation, by introducing a virtual wave field that we term the phasor field. Non-line-of-sight scenes can be imaged from raw time-of-flight data by applying the mathematical operators that model wave propagation in a conventional line-of-sight imaging system. Our method yields a new class of imaging algorithms that mimic the capabilities of line-of-sight cameras. To demonstrate our technique, we derive three imaging algorithms, modelled after three different line-of-sight systems. These algorithms rely on solving a wave diffraction integral, namely the Rayleigh-Sommerfeld diffraction integral. Fast solutions to Rayleigh-Sommerfeld diffraction and its approximations are readily available, benefiting our method. We demonstrate non-line-of-sight imaging of complex scenes with strong multiple scattering and ambient light, arbitrary materials, large depth range and occlusions. Our method handles these challenging cases without explicitly inverting a light-transport model. We believe that our approach will help to unlock the potential of non-line-of-sight imaging and promote the development of relevant applications not restricted to laboratory conditions.

PET imaging of TSPO expression in immune cells can assess organ-level pathophysiology in high-consequence viral infections.

Ebola virus (EBOV) disease is characterized by lymphopenia, breach in vascular integrity, cytokine storm, and multiorgan failure. The pathophysiology of organ involvement, however, is incompletely understood. Using [18F]-DPA-714 positron emission tomography (PET) imaging targeting the translocator protein (TSPO), an immune cell marker, we sought to characterize the progression of EBOV-associated organ-level pathophysiology in the EBOV Rhesus macaque model. Dynamic [18F]-DPA-714 PET/computed tomography imaging was performed longitudinally at baseline and at multiple time points after EBOV inoculation, and distribution volumes (Vt) were calculated as a measure of peripheral TSPO binding. Using a mixed-effect linear regression model, spleen and lung Vt decreased, while the bone marrow Vt increased over time after infection. No clear trend was found for liver Vt. Multiple plasma cytokines correlated negatively with lung/spleen Vt and positively with bone marrow Vt. Multiplex immunofluorescence staining in spleen and lung sections confirmed organ-level lymphoid and monocytic loss/apoptosis, thus validating the imaging results. Our findings are consistent with EBOV-induced progressive monocytic and lymphocytic depletion in the spleen, rather than immune activation, as well as depletion of alveolar macrophages in the lungs, with inefficient reactive neutrophilic activation. Increased bone marrow Vt, on the other hand, suggests hematopoietic activation in response to systemic immune cell depletion and leukocytosis and could have prognostic relevance. In vivo PET imaging provided better understanding of organ-level pathophysiology during EBOV infection. A similar approach can be used to delineate the pathophysiology of other systemic infections and to evaluate the effectiveness of newly developed treatment and vaccine strategies.

Artificial Synapse Based on a δ-FAPbI3/Atomic-Layer-Deposited SnO2 Bilayer Memristor.

Halide perovskite-based resistive switching memory (memristor) has potential in an artificial synapse. However, an abrupt switch behavior observed for a formamidinium lead triiodide (FAPbI3)-based memristor is undesirable for an artificial synapse. Here, we report on the δ-FAPbI3/atomic-layer-deposited (ALD)-SnO2 bilayer memristor for gradual analogue resistive switching. In comparison to a single-layer δ-FAPbI3 memristor, the heterojunction δ-FAPbI3/ALD-SnO2 bilayer effectively reduces the current level in the high-resistance state. The analog resistive switching characteristics of δ-FAPbI3/ALD-SnO2 demonstrate exceptional linearity and potentiation/depression performance, resembling an artificial synapse for neuromorphic computing. The nonlinearity of long-term potentiation and long-term depression is notably decreased from 12.26 to 0.60 and from -8.79 to -3.47, respectively. Moreover, the δ-FAPbI3/ALD-SnO2 bilayer achieves a recognition rate of ≤94.04% based on the modified National Institute of Standards and Technology database (MNIST), establishing its potential in an efficient artificial synapse.

Interaction between p21-activated kinase 4 and ß-catenin as a novel pathway for PTH-dependent osteoblast activation.

Parathyroid hormone (PTH) serves dual roles in bone metabolism, exhibiting both anabolic and catabolic effects. The anabolic properties of PTH have been utilized in the treatment of osteoporosis with proven efficacy in preventing fractures. Despite these benefits, PTH can be administered therapeutically for up to 2 years, and its use in patients with underlying malignancies remains a subject of ongoing debate. These considerations underscore the need for a more comprehensive understanding of the underlying mechanisms. p21-activated kinase 4 (PAK4) is involved in bone resorption and cancer-associated osteolysis; however, its role in osteoblast function and PTH action remains unknown. Therefore, in this study, we aimed to clarify the role of PAK4 in osteoblast function and its effects on PTH-induced anabolic activity. PAK4 enhanced MC3T3-E1 osteoblast viability and proliferation and upregulated cyclin D1 expression. PAK4 also augmented osteoblast differentiation, as indicated by increased mineralization found by alkaline phosphatase and Alizarin Red staining. Treatment with PTH (1-34), an active PTH fragment, stimulated PAK4 expression and phosphorylation in a protein kinase A-dependent manner. In addition, bone morphogenetic protein-2 (which is known to promote bone formation) increased phosphorylated PAK4 (p-PAK4) and PAK4 levels. PAK4 regulated the expression of both phosphorylated and total ß-catenin, which are critical for osteoblast proliferation and differentiation. Moreover, p-PAK4 directly interacted with ß-catenin, and disruption of ß-catenin's binding to T-cell factor impaired PAK4- and PTH-induced osteoblast differentiation. Our findings elucidate the effect of PAK4 on enhancing bone formation in osteoblasts and its pivotal role in the anabolic activity of PTH mediated through its interaction with ß-catenin. These insights improve the understanding of the mechanisms underlying PTH activity and should inform the development of more effective and safer osteoporosis treatments.

ATF5-Mediated Mitochondrial Unfolded Protein Response (UPRmt) Protects Neurons Against Oxygen-Glucose Deprivation and Cerebral Ischemia.

BACKGROUND: The mitochondrial unfolded protein response (UPRmt) is an evolutionarily conserved mitochondrial response that is critical for maintaining mitochondrial and energetic homeostasis under cellular stress after tissue injury and disease. Here, we ask whether UPRmt may be a potential therapeutic target for ischemic stroke. METHODS: We performed the middle cerebral artery occlusion and oxygen-glucose deprivation models to mimic ischemic stroke in vivo and in vitro, respectively. Oligomycin and meclizine were used to trigger the UPRmt. We used 2,3,5-triphenyltetrazolium chloride staining, behavioral tests, and Nissl staining to evaluate cerebral injury in vivo. The Cell Counting Kit-8 assay and the Calcein AM Assay Kit were conducted to test cerebral injury in vitro. RESULTS: Inducing UPRmt with oligomycin protected neuronal cultures against oxygen-glucose deprivation. UPRmt could also be triggered with meclizine, and this Food and Drug Administration-approved drug also protected neurons against oxygen-glucose deprivation. Blocking UPRmt with siRNA against activating transcription factor 5 eliminated the neuroprotective effects of meclizine. In a mouse model of focal cerebral ischemia, pretreatment with meclizine was able to induce UPRmt in vivo, which reduced infarction and improved neurological outcomes. CONCLUSIONS: These findings suggest that the UPRmt is important in maintaining the survival of neurons facing ischemic/hypoxic stress. The UPRmt mechanism may provide a new therapeutic avenue for ischemic stroke.

Water Hydrogen-Bond Mediated Layer by Layer Alignment of Lipid Rafts as a Precursor of Intermembrane Processes.

Lipid rafts, which are dynamic nanodomains in the plasma membrane, play a crucial role in intermembrane processes by clustering together and growing in size within the plane of the membrane while also aligning with each other across different membranes. However, the physical origin of layer by layer alignment of lipid rafts remains to be elucidated. Here, by using fluorescence imaging and synchrotron X-ray reflectivity in a phase-separated multilayer system, we find that the alignment of raft-mimicking Lo domains is regulated by the distance between bilayers. Molecular dynamics simulations reveal that the aligned state is energetically preferred when the intermembrane distance is small due to its ability to minimize the volume of surface water, which has fewer water hydrogen bonds (HBs) compared to bulk water. Our results suggest that water HB-driven alignment of lipid rafts plays a role as a precursor of intermembrane processes such as cell-cell fusion, virus entry, and signaling.

Adipose Tissue Macrophage Polarization Is Altered during Recovery after Exercise: A Large-Scale Flow Cytometric Study.

We performed a large-scale flow cytometric analysis to determine whether M1 macrophage (M1Ø) and M2 macrophage (M2Ø) polarization in white adipose tissue (WAT) was altered immediately after exercise. Additionally, we comprehensively investigated the effects of obesity, exercise intensity, and recovery time on macrophage polarization in WAT. A single exercise bout of various intensities (ND, non-exercise control; -LIE, low-intensity exercise; -MIE, mid-intensity exercise; -HIE, high-intensity exercise) was performed by normal mice (ND) and obese mice (HFD). To confirm differences in M1Ø/M2Ø polarization in WAT based on the recovery time after a single exercise bout, WAT was acquired at 2 h, 24 h, and 48 h after exercise (total n = 168, 7 mice × 4 groups × 2 diets × 3 recovery time). The harvested WAT was immediately analyzed by flow cytometry, and macrophages were fluorescently labeled using F4/80, as well as M1Ø with CD11c and M2Øs with CD206. After a single bout of exercise, the M2Ø/M1Ø polarization ratio of WAT increases in both normal and obese mice, but differences vary depending on recovery time and intensity. Regardless of obesity, our findings showed that there could be a transient increase in M1Ø in WAT over a short recovery time (24 h) post-exercise (in ND-MIE, ND-HIE, and HFD-HIE). Furthermore, it was observed that the greater the exercise intensity in obese mice, the more effective the induction of M2Ø polarization immediately after exercise, as well as the maintenance of high M2Ø polarization, even after a prolonged recovery time.

Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Transcription Regulation of AgRP and POMC Genes.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors regulate plasma glucose levels in patients with type 2 diabetes mellitus (T2DM) by inhibiting renal glucose reabsorption. This study investigated the impact of empagliflozin (EMPA), an SGLT2 inhibitor, on hypothalamic energy regulation. To directly investigate the role of SGLT2 inhibitors in the hypothalamus, we administered EMPA through intracerebroventricular (i.c.v.) injections into the murine ventricles. After dental cementing the i.c.v. cannula onto the skull, the mice were given 5 days to recover before receiving vehicle or EMPA (50 nM/2 µL) injections. In a high-fat diet (HFD)-induced obesity model, we determined the gene expression levels of agouti-related peptide (AgRP) and pro-opiomelanocortin (POMC) in the hypothalamus. Additionally, we assessed FoxO1 expression, which regulates AgRP and POMC gene transcription in hypothalamic cell lines. We found that EMPA directly influenced the expression of endogenous mRNA of POMC and AgRP, which are critical for energy homeostasis, and modulated their transcription in high-fat diet-induced obese mice. Additionally, EMPA affected the expression of FoxO1, a key transcriptional regulator of glucose homeostasis, thereby regulating the transcriptional activity of POMC and AgRP. These results indicate that EMPA significantly influences hypothalamic energy homeostasis, highlighting its potential as a regulator in obesity and T2DM management.

A nationwide study of breast reconstruction after mastectomy in patients with breast cancer receiving postmastectomy radiotherapy: comparison of complications according to radiotherapy fractionation and reconstruction procedures.

BACKGROUND: We examined the patterns of breast reconstruction postmastectomy in breast cancer patients undergoing postmastectomy radiotherapy (PMRT) and compared complications based on radiotherapy fractionation and reconstruction procedures. METHODS: Using National Health Insurance Service (NHIS) data (2015-2020), we analysed 4669 breast cancer patients with PMRT and reconstruction. Using propensity matching, cohorts for hypofractionated fractionation (HF) and conventional fractionation (CF) were created, adjusting for relevant factors and identifying grade ≥3 complications. RESULT: Of 4,669 patients, 30.6% underwent HF and 69.4% CF. The use of HF has increased from 19.4% in 2015 to 41.0% in 2020. Immediate autologous (32.9%) and delayed two-stage implant reconstruction (33.9%) were common. Complication rates for immediate (N = 1286) and delayed two-stage (N = 784) reconstruction were similar between HF and CF groups (5.1% vs. 5.4%, P = 0.803, and 10.5% vs. 10.7%, P = 0.856, respectively) with median follow-ups of 2.5 and 2.6 years. HF showed no increased risk of complications across reconstruction methods. CONCLUSION: A nationwide cohort study revealed no significant difference in complication rates between the HF and CF groups, indicating HF for reconstructed breasts is comparable to CF. However, consultation regarding the fractionation for reconstructed breast cancer patients may still be necessary.

Combination of rituximab and methotrexate followed by rituximab and cytarabine in elderly patients with primary central nervous system lymphoma.

The optimal treatment strategy for newly diagnosed primary central nervous system lymphoma (PCNSL) has yet to be established, especially in the elderly. In the current study, we conducted a phase II study to evaluate the efficacy and safety of rituximab plus high-dose MTX followed by rituximab plus cytarabine in patients aged ≥60 years newly diagnosed with PCNSL. Patients received an induction treatment of high-dose methotrexate plus rituximab followed by two cycles of a consolidation treatment of cytarabine plus rituximab. The primary end-point was a 2-year progression-free survival (PFS) rate. A total of 35 patients were recruited, and their median age was 73 (range: 60-81). After induction treatment, the complete and partial responses (PRs) were 56% and 20% respectively. Twenty-six patients proceeded to the consolidation treatment; the complete and PRs were 59% and 9% respectively. After a median follow-up duration of 36.0 months, the 2-year PFS rate was 58.7%. Treatment was generally well-tolerated as only three patients were withdrawn from the study due to toxicity, and no treatment-related mortality was reported. The 2-year overall survival rate was 77.9%. The current study may suggest the feasibility of administering high-dose MTX plus cytarabine in PCNSL patients aged ≥60 years and the potential role of additive rituximab.

Morphology Control of Mixed Metallic Organic Framework for High-Performance Hybrid Supercapacitors.

The study presents the binder-free synthesis of mixed metallic organic frameworks (MMOFs) supported on a ternary metal oxide (TMO) core as an innovative three-dimensional (3D) approach to enhance electron transport and mass transfer during the electrochemical charge-discharge process, resulting in high-performance hybrid supercapacitors. The research demonstrates that the choice of organic linkers can be used to tailor the morphology of these MMOFs, thus optimizing their electrochemical efficiency. Specifically, a NiCo-MOF@NiCoO2@Ni electrode, based on terephthalic linkers, exhibits highly ordered porosity and a vast internal surface area, achieving a maximum specific capacity of 2320 mC cm-2, while maintaining excellent rate capability and cycle stability. With these performances, the hybrid supercapacitor (HSC) achieves a maximum specific capacitance of 424.6 mF cm-2 (specific capacity 653.8 mC cm-2) and 30.7 F cm-3 with energy density values of 10.1 mWh cm-3 at 167.4 mW cm-3 (139.8 µWh cm-2 at 2310 µW cm-2), which are higher than those of previously reported MMOFs based electrodes. This research introduces a novel approach for metal organic framework based HSC electrodes, diverging from the traditional emphasis on metal ions, in order to achieve the desired electrochemical performance.

A point-of-care pilot randomized intervention to connect patients with cancer-induced financial toxicity to telehealth financial counseling.

PURPOSE: Elevated costs of cancer treatment can result in economic and psychological "financial toxicity" distress. This pilot study assessed the feasibility of a point-of-care intervention to connect adult patients with cancer-induced financial toxicity to telehealth-delivered financial counseling. METHODS: We conducted a three-armed parallel randomized pilot study, allocating newly referred patients with cancer and financial toxicity to individual, group accredited telehealth financial counseling, or usual care with educational material (1:1:1). We assessed the feasibility of recruitment, randomization, retention, baseline and post-intervention COmprehensive Score for Financial Toxicity (COST), and Telehealth Usability Questionnaire (TUQ) scores. RESULTS: Of 382 patients screened, 121 were eligible and enrolled. 58 (48%) completed the intervention (9 individual, 9 group counseling, 40 educational booklet). 29 completed follow-up surveys: 45% female, 17% African American, 79% white, 7% Hispanic, 55% 45-64 years old, 31% over 64, 34% lived in rural areas, 24% had cancer stage I, 21% II, 7% III, 31% IV. Baseline characteristics were balanced across arms, retention status, surveys completion. Mean (SD) COST was 12.4 (6.1) at baseline and 16.0 (8.4) post-intervention. Mean (SD) COST score differences were 6.3 (11.6) after individual counseling, 5.8 (8.5) after group counseling, and 2.5 (6.4) after usual care. Mean TUQ score among nine counseling participants was 5.5 (0.9) over 7.0. Non-parametric comparisons were not statistically meaningful. CONCLUSION: Recruitment and randomization were feasible, while study retention presented challenges. Nine participants reported good usability and satisfaction with telehealth counseling. Larger-scale trials focused on improving participation, retention, and impact of financial counseling among patients with cancer are justified.

Empowering SARS-CoV-2 variant neutralization with a bifunctional antibody engineered with tandem heptad repeat 2 peptides.

With the global pandemic and the continuous mutations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the need for effective and broadly neutralizing treatments has become increasingly urgent. This study introduces a novel strategy that targets two aspects simultaneously, using bifunctional antibodies to inhibit both the attachment of SARS-CoV-2 to host cell membranes and viral fusion. We developed pioneering IgG4-(HR2)4 bifunctional antibodies by creating immunoglobulin G4-based and phage display-derived human monoclonal antibodies (mAbs) that specifically bind to the SARS-CoV-2 receptor-binding domain, engineered with four heptad repeat 2 (HR2) peptides. Our in vitro experiments demonstrate the superior neutralization efficacy of these engineered antibodies against various SARS-CoV-2 variants, ranging from original SARS-CoV-2 strain to the recently emerged Omicron variants, as well as SARS-CoV, outperforming the parental mAb. Notably, intravenous monotherapy with the bifunctional antibody neutralizes a SARS-CoV-2 variant in a murine model without causing significant toxicity. In summary, this study unveils the significant potential of HR2 peptide-driven bifunctional antibodies as a potent and versatile strategy for mitigating SARS-CoV-2 infections. This approach offers a promising avenue for rapid development and management in the face of the continuously evolving SARS-CoV-2 variants, holding substantial promise for pandemic control.