Immune Checkpoint Inhibition-related Neuroinflammation Disrupts Cognitive Function.

Combinatorial blockade of Cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and Programmed Cell Death Protein 1 (PD-1) significantly improve the progression-free survival of individuals with metastatic cancers, including melanoma. In addition to unleashing anti-tumor immunity, combination immune checkpoint inhibition (ICI) disrupts immune-regulatory networks critical for maintaining homeostasis in various tissues, including the central nervous system (CNS). Although ICI- and cancer-related cognitive impairments (CRCI) in survivors are increasingly becoming evident, our understanding of ICI-induced immune-related adverse effects (IREA) in the CNS remains incomplete. Here, our murine melanoma model reveals that combination ICI impairs hippocampal-dependent learning and memory, as well as memory consolidation processes. Mechanistically, combination ICI disrupted synaptic integrity, and neuronal plasticity, reduced myelin, and further predisposed CNS for exaggerated experimental autoimmune encephalomyelitis. Combination ICI substantially altered both lymphoid and myeloid cells in the CNS. Neurogenesis was unaffected, however, microglial activation persisted for two-months post- ICI, concurrently with cognitive deficits, which parallels clinical observations in survivors. Overall, our results demonstrate that blockade of CTLA-4 and PD-1 alters neuro-immune homeostasis and activates microglia, promoting long-term neurodegeneration and driving cognitive impairments. Therefore, limiting microglial activation is a potential avenue to mitigate CNS IRAE while maintaining the therapeutic benefits of rapidly evolving ICIs and their combinations. SIGNIFICANCE: Despite the superior therapeutic efficacy of immune checkpoint inhibition (ICI) for cancers, its undesired effects on brain function are not fully understood. Here, we demonstrate that combination ICI elevates neuroinflammation, activates microglia, leading to detrimental neurodegenerative and neurocognitive sequelae.

Short-Term Readmission Following Community-Acquired Pneumonia: A Cross-Sectional Study.

Background:Community-acquired pneumonia continues to be a major cause of morbidity and mortality. Hospital readmissions following community-acquired pneumonia are linked to significant cost of care and medical burdens. This study aimed to determine the incidence and reasons for readmission as well as to assess factors associated with short-term hospital readmission among community-acquired pneumonia patients. Methods:A retrospective, cross-sectional study was conducted on 582 medical records of community-acquired pneumonia inpatients from December 2018 to December 2019 at an 800-bed tertiary hospital in Ho Chi Minh City, Vietnam. We collected data on patient characteristics, pneumonia severity at hospital admission, microbiology and antibiotic resistance, appropriateness of empiric antibiotic therapies, and the readmissions information. Multivariable logistic regression analyses were performed to identify factors associated with 30-day hospital readmission. Results: Of the 582 hospitalized community-acquired pneumonia patients, 11.9% were readmitted to the hospital within 30 days. About half of the cases (43.5%) were due to pneumonia. Multidrug-resistant bacteria accounted for 43.2% of the pathogen isolates. A high Charlson comorbidity index (aOR, 1.40; CI 95%, 1.08-1.82) and multidrug-resistant infection (aOR, 2.63; CI 95%, 1.05-6.56) were associated with higher odds of all-cause readmission. Conclusions:Hospital readmissions within 30 days occurred frequently among community-acquired pneumonia inpatients, and the most common reason for readmission recorded was pneumonia-related. Monitoring closely patients with multimorbidity or multidrug-resistant infections may improve treatment outcomes.

C2 IgM Natural Antibody Enhances Inflammation and Its Use in the Recombinant Single Chain Antibody-Fused Complement Inhibitor C2-Crry to Target Therapeutics to Joints Attenuates Arthritis in Mice.

Natural IgM antibodies (NAbs) have been shown to recognize injury-associated neoepitopes and to initiate pathogenic complement activation. The NAb termed C2 binds to a subset of phospholipids displayed on injured cells, and its role(s) in arthritis, as well as the potential therapeutic benefit of a C2 NAb-derived ScFv-containing protein fused to a complement inhibitor, complement receptor-related y (Crry), on joint inflammation are unknown. Our first objective was to functionally test mAb C2 binding to apoptotic cells from the joint and also evaluate its inflammation enhancing capacity in collagen antibody-induced arthritis (CAIA). The second objective was to generate and test the complement inhibitory capacity of C2-Crry fusion protein in the collagen-induced arthritis (CIA) model. The third objective was to demonstrate in vivo targeting of C2-Crry to damaged joints in mice with arthritis. The effect of C2-NAb on CAIA in C57BL/6 mice was examined by inducing a suboptimal disease. The inhibitory effect of C2-Crry in DBA/1J mice with CIA was determined by injecting 2x per week with a single dose of 0.250 mg/mouse. Clinical disease activity (CDA) was examined, and knee joints were fixed for analysis of histopathology, C3 deposition, and macrophage infiltration. In mice with suboptimal CAIA, at day 10 there was a significant (p < 0.017) 74% increase in the CDA in mice treated with C2 NAb, compared to mice treated with F632 control NAb. In mice with CIA, at day 35 there was a significant 39% (p < 0.042) decrease in the CDA in mice treated with C2-Crry. Total scores for histopathology were also 50% decreased (p < 0.0005) in CIA mice treated with C2-Crry. C3 deposition was significantly decreased in the synovium (44%; p < 0.026) and on the surface of cartilage (42%; p < 0.008) in mice treated with C2-Crry compared with PBS treated CIA mice. Furthermore, C2-Crry specifically bound to apoptotic fibroblast-like synoviocytes in vitro, and also localized in the knee joints of arthritic mice as analyzed by in vivo imaging. In summary, NAb C2 enhanced arthritis-related injury, and targeted delivery of C2-Crry to inflamed joints demonstrated disease modifying activity in a mouse model of human inflammatory arthritis.

Feasibility of identifying reflection artifacts in photoacoustic imaging using two-wavelength excitation.

One of the remaining challenges of bringing photoacoustic imaging to clinics is the occurrence of reflection artifacts. Previously, we proposed a method using multi-wavelength excitation to identify and remove the RAs. However, this method requires at least 3 wavelengths. Here we improve the method further by reducing the required number of wavelengths to 2. We experimentally demonstrate this new method and compare it with the previous one. Results show that this new method holds great feasibility for identifying reflection artifacts in addition to preserving all advantages of the previous method.

Three-dimensional view of out-of-plane artifacts in photoacoustic imaging using a laser-integrated linear-transducer-array probe.

Research on photoacoustic imaging (PAI) using a handheld integrated photoacoustic probe has been a recent focus of clinical translation of this imaging technique. One of the remaining challenges is the occurrence of out-of-plane artifacts (OPAs) in such a probe. Previously, we proposed a method to identify and remove OPAs by axially displacing the transducer array. Here we show that besides the benefit of removing OPAs from the imaging plane, the proposed method can provide a three-dimensional (3D) view of the OPAs. In this work, we present a 3D reconstruction method using axial transducer array displacement. By axially displacing the transducer array, out-of-plane absorbers can be three-dimensionally visualized at an elevation distance of up to the acquired imaging depth. Additionally, OPAs in the in-plane image are significantly reduced. We experimentally demonstrate the method with phantom and in vivo experiments using an integrated PAI probe. We also compare the method with elevational transducer array displacement and take into account the sensitivity of the transducer array in the 3D reconstruction.

Key Components of the Complement Lectin Pathway Are Not Only Required for the Development of Inflammatory Arthritis but Also Regulate the Transcription of Factor D.

The complement system plays an important role in the pathogenesis of rheumatoid arthritis (RA). Besides driving lectin pathway (LP) activation, the mannan-binding lectin (MBL)-associated serine proteases (MASPs) also play a key role in regulating the alternative pathway (AP). We evaluated the effects of N-acetylgalactosamine (GalNAc)-conjugated MASP-1 and MASP-2 duplexes in vitro and in mice with and without arthritis to examine whether knockdown of MASP-1 and MASP-2 expression affects the development of arthritis. GalNAc-siRNAs for MASP-1 and MASP-2 demonstrated robust silencing of MASP-1 or MASP-2 at pM concentrations in vitro. To evaluate the impact of silencing in arthritic mice, we used the collagen antibody-induced arthritis (CAIA) mouse model of RA. Mice were injected a 10 mg/kg dose of GalNAc-siRNAs 3x s.q. prior to the induction of CAIA. Liver gene expression was examined using qRT-PCR, and protein levels were confirmed in the circulation by sandwich immunoassays and Western blot. At day 10, CAIA mice separately treated with MASP-1 and MASP-2 duplexes had a specific reduction in expression of liver MASP-1 (70-95%, p < 0.05) and MASP-2 (90%, p < 0.05) mRNA, respectively. MASP-1-siRNA treatment resulted in a 95% reduction in levels of MASP-1 protein in circulation with no effect on MASP-2 levels and clinical disease activity (CDA). In mice injected with MASP-2 duplex, there was a significant (p < 0.05) 90% decrease in ex vivo C4b deposition on mannan, with nearly complete elimination of MASP-2 in the circulation. MASP-2 silencing initially significantly decreased CDA by 60% but subsequently changed to a 40% decrease vs. control. Unexpectedly, GalNAc-siRNA-mediated knockdown of MASP-1 and MASP-2 revealed a marked effect of these proteins on the transcription of FD under normal physiological conditions, whereas LPS-induced inflammatory conditions reversed this effect on FD levels. LPS is recognized by Toll-like receptor 4 (TLR4), we found MBL not only binds to TLR4 an interaction with a Kd of 907 nM but also upregulated FD expression in differentiated adipocytes. We show that MASP-2 knockdown impairs the development of RA and that the interrelationship between proteins of the LP and the AP may extend to the transcriptional modulation of the FD gene.

Reducing artifacts in photoacoustic imaging by using multi-wavelength excitation and transducer displacement.

The occurrence of artifacts is a major challenge in photoacoustic imaging. The artifacts negatively affect the quality and reliability of the images. An approach using multi-wavelength excitation has previously been reported for in-plane artifact identification. Yet, out-of-plane artifacts cannot be tackled with this method. Here we propose a new method using ultrasound transducer array displacement. By displacing the ultrasound transducer array axially, we can de-correlate out-of-plane artifacts with in-plane image features and thus remove them. Combining this new method with the previous one allows us to remove potentially completely both in-plane and out-of-plane artifacts in photoacoustic imaging. We experimentally demonstrate this with experiments in phantoms as well as in vivo.

Reflection artifact identification in photoacoustic imaging using multi-wavelength excitation.

Photoacoustic imaging has been a focus of research for clinical applications owing to its ability for deep visualization with optical absorption contrast. However, there are various technical challenges remaining for this technique to find its place in clinics. One of the challenges is the occurrence of reflection artifacts. The reflection artifacts may lead to image misinterpretation. Here we propose a new method using multiple wavelengths for identifying and removing the reflection artifacts. By imaging the sample with multiple wavelengths, the spectral response of the features in the photoacoustic image is obtained. We assume that the spectral response of the reflection artifact is better correlated with the proper image feature of its corresponding absorber than with other features in the image. Based on this, the reflection artifacts can be identified and removed. Here, we experimentally demonstrated the potential of this method for real-time identification and correction of reflection artifacts in photoacoustic images in phantoms as well as in vivo using a handheld photoacoustic imaging probe.

Recent Development of Technology and Application of Photoacoustic Molecular Imaging Toward Clinical Translation.

The deep imaging capability and optical absorption contrast offered by photoacoustic imaging promote the use of this technology in clinical applications. By exploiting the optical absorption properties of endogenous chromophores such as hemoglobin and lipid, molecular information at a depth of a few centimeters can be unveiled. This information shows promise to reveal lesions indicating early stage of various human diseases, such as cancer and atherosclerosis. In addition, the use of exogenous contrast agents can further extend the capability of photoacoustic imaging in clinical diagnosis and treatment. In this review, the current state of the art and applications of photoacoustic molecular probes will be critically reviewed, as well as some spearheading translational efforts that have taken place over the past 5 years. Some of the most critical barriers to clinical translation of this novel technology will be discussed, and some thoughts will be given on future endeavors and pathways.

Enhancement of recombination process using silver and graphene quantum dot embedded intermediate layer for efficient organic tandem cells.

High performance of organic tandem solar cell is largely dependent on transparent and conductive intermediate layer (IML). The current work reports the design and fabrication of an IML using a simple solution process. The efficiency of a homo-tandem device with poly(3-hexylthiophene):phenyl-C61-butyric acid methyl ester as an active layer and poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate)/poly(ethylenimine) as an IML was initially found to be 3.40%. Further enhancement of the cell efficiency was achieved using silver nanoparticles (Ag-NPs) of different sizes and graphene quantum dot embedded IML. A maximum efficiency of 4.03% was achieved using 7 nm Ag-NPs that contribute to a better recombination process. Also, the performance of the tandem cell was solely based on the electrical improvements indicated by the current - voltage measurements, external quantum efficiency and impedance analysis. The use of Ag-NPs in the IML has been shown to lengthen the life time of electron-hole pairs in the device. This study thus paves way to develop such efficient IMLs for more efficient tandem solar cells.

Tubedown regulation of retinal endothelial permeability signaling pathways.

Tubedown (Tbdn; Naa15), a subunit of the N-terminal acetyltransferase NatA, complexes with the c-Src substrate Cortactin and supports adult retinal homeostasis through regulation of vascular permeability. Here we investigate the role of Tbdn expression on signaling components of retinal endothelial permeability to understand how Tbdn regulates the vasculature and supports retinal homeostasis. Tbdn knockdown-induced hyperpermeability to Albumin in retinal endothelial cells was associated with an increase in the levels of activation of the Src family kinases (SFK) c-Src, Fyn and Lyn and phospho-Cortactin (Tyr421). The knockdown of Cortactin expression reduced Tbdn knockdown-induced permeability to Albumin and the levels of activated SFK. Inhibition of SFK in retinal endothelial cells decreased Tbdn knockdown-induced permeability to Albumin and phospho-Cortactin (Tyr421) levels. Retinal lesions of endothelial-specific Tbdn knockdown mice, with tissue thickening, fibrovascular growth, and hyperpermeable vessels displayed an increase in the levels of activated c-Src. Moreover, the retinal lesions of patients with proliferative diabetic retinopathy (PDR) associated with a loss of Tbdn expression and hyperpermeability to Albumin displayed increased levels of activated SFK in retinal blood vessels. Taken together, these results implicate Tbdn as an important regulator of retinal endothelial permeability and homeostasis by modulating a signaling pathway involving c-Src and Cortactin.

Sex pheromones of three citrus leafrollers, Archips atrolucens, Adoxophyes privatana, and Homona sp., inhabiting the Mekong Delta of Vietnam.

Archips atrolucens, Adoxophyes privatana, and Homona sp. are serious defoliators of citrus trees in the Mekong Delta of Vietnam. In order to establish a sustainable pest-management program for the three species, their female-produced sex pheromones were investigated by GC-EAD and GC-MS analyses, and the following multi-component pheromones were identified: (Z)-11-tetradecenyl acetate (Z11-14:OAc), (E)-11-tetradecenyl acetate (E11-14:OAc), and tetradecyl acetate (14:OAc) in a ratio of 64:32:4 for A. atrolucens; Z11-14:OAc and (Z)-9-tetradecenyl acetate (Z9-14:OAc) in a ratio of 92:8 for A. privatana; and Z11-14:OAc and (Z)-9-dodecenyl acetate (Z9-12:OAc) in a ratio of 96:4 for Homona sp. Each lure baited with synthetic components as a mimic of the natural pheromone attracted males of the target species specifically, indicating that each monounsaturated minor component plays a significant role for mating communication and reproductive isolation of the three species inhabiting the same citrus orchards. In an extract of the pheromone glands of A. atrolucens females, the content of 14:OAc was very low, but a synergistic effect was observed clearly when the saturated compound was mixed at the same level as the E11-14:OAc. The synthetic lures will provide useful tools for monitoring flights of adults of the three species.

Controlled cell proliferation on an electrochemically engineered collagen scaffold.

Therapies for corneal disease and injury often rely on artificial implants, but integrating cells into synthetic corneal materials remains a significant challenge. The electrochemically formed collagen-based matrix presented here is non-toxic to cells and controls the proliferation in the corneal fibroblasts seeded onto it. Histology and biomolecular studies show a behavior similar to corneal stromal cells in a native corneal environment. Not only is this result an important first step toward developing a more realistic, multi-component artificial cornea, but it also opens possibilities for using this matrix to control and contain the growth of cells in engineered tissues.