ABSTRACT
Animal fertilization relies on hundreds of sperm racing toward the egg, whereas, in angiosperms, only two sperm cells are delivered by a pollen tube to the female gametes (egg cell and central cell) for double fertilization. However, unsuccessful fertilization under this one-pollen-tube design can be detrimental to seed production and plant survival. To mitigate this risk, unfertilized-gamete-controlled extra pollen tube entry has been evolved to bring more sperm cells and salvage fertilization. Despite its importance, the underlying molecular mechanism of this phenomenon remains unclear. In this study, we report that, in Arabidopsis, the central cell secretes peptides SALVAGER1 and SALVAGER2 in a directional manner to attract pollen tubes when the synergid-dependent attraction fails or is terminated by pollen tubes carrying infertile sperm cells. Moreover, loss of SALs impairs the fertilization recovery capacity of the ovules. Therefore, this research uncovers a female gamete-attraction system that salvages seed production for reproductive assurance.
Subject(s)
Arabidopsis Proteins , Arabidopsis , Animals , Arabidopsis/physiology , Fertilization , Pollen Tube , Seeds , Germ Cells, PlantABSTRACT
Photonic computing enables faster and more energy-efficient processing of vision data1-5. However, experimental superiority of deployable systems remains a challenge because of complicated optical nonlinearities, considerable power consumption of analog-to-digital converters (ADCs) for downstream digital processing and vulnerability to noises and system errors1,6-8. Here we propose an all-analog chip combining electronic and light computing (ACCEL). It has a systemic energy efficiency of 74.8 peta-operations per second per watt and a computing speed of 4.6 peta-operations per second (more than 99% implemented by optics), corresponding to more than three and one order of magnitude higher than state-of-the-art computing processors, respectively. After applying diffractive optical computing as an optical encoder for feature extraction, the light-induced photocurrents are directly used for further calculation in an integrated analog computing chip without the requirement of analog-to-digital converters, leading to a low computing latency of 72 ns for each frame. With joint optimizations of optoelectronic computing and adaptive training, ACCEL achieves competitive classification accuracies of 85.5%, 82.0% and 92.6%, respectively, for Fashion-MNIST, 3-class ImageNet classification and time-lapse video recognition task experimentally, while showing superior system robustness in low-light conditions (0.14 fJ µm-2 each frame). ACCEL can be used across a broad range of applications such as wearable devices, autonomous driving and industrial inspections.
ABSTRACT
The differential performance of polygenic risk scores (PRSs) by group is one of the major ethical barriers to their clinical use. It is also one of the main practical challenges for any implementation effort. The social repercussions of how people are grouped in PRS research must be considered in communications with research participants, including return of results. Here, we outline the decisions faced and choices made by a large multi-site clinical implementation study returning PRSs to diverse participants in handling this issue of differential performance. Our approach to managing the complexities associated with the differential performance of PRSs serves as a case study that can help future implementers of PRSs to plot an anticipatory course in response to this issue.
Subject(s)
Genetic Predisposition to Disease , Multifactorial Inheritance , Humans , Multifactorial Inheritance/genetics , Risk Factors , Genome-Wide Association Study , Risk Assessment , Genetic Testing/methods , Genetic Risk ScoreABSTRACT
As large-scale genomic screening becomes increasingly prevalent, understanding the influence of actionable results on healthcare utilization is key to estimating the potential long-term clinical impact. The eMERGE network sequenced individuals for actionable genes in multiple genetic conditions and returned results to individuals, providers, and the electronic health record. Differences in recommended health services (laboratory, imaging, and procedural testing) delivered within 12 months of return were compared among individuals with pathogenic or likely pathogenic (P/LP) findings to matched individuals with negative findings before and after return of results. Of 16,218 adults, 477 unselected individuals were found to have a monogenic risk for arrhythmia (n = 95), breast cancer (n = 96), cardiomyopathy (n = 95), colorectal cancer (n = 105), or familial hypercholesterolemia (n = 86). Individuals with P/LP results more frequently received services after return (43.8%) compared to before return (25.6%) of results and compared to individuals with negative findings (24.9%; p < 0.0001). The annual cost of qualifying healthcare services increased from an average of $162 before return to $343 after return of results among the P/LP group (p < 0.0001); differences in the negative group were non-significant. The mean difference-in-differences was $149 (p < 0.0001), which describes the increased cost within the P/LP group corrected for cost changes in the negative group. When stratified by individual conditions, significant cost differences were observed for arrhythmia, breast cancer, and cardiomyopathy. In conclusion, less than half of individuals received billed health services after monogenic return, which modestly increased healthcare costs for payors in the year following return.
Subject(s)
Breast Neoplasms , Cardiomyopathies , Adult , Humans , Female , Prospective Studies , Patient Acceptance of Health Care , Arrhythmias, Cardiac , Breast Neoplasms/genetics , Cardiomyopathies/geneticsABSTRACT
Mitochondrial homeostasis is essential for providing cellular energy, particularly in resource-demanding neurons, defects in which cause neurodegeneration, but the function of interferons (IFNs) in regulating neuronal mitochondrial homeostasis is unknown. We found that neuronal IFN-ß is indispensable for mitochondrial homeostasis and metabolism, sustaining ATP levels and preventing excessive ROS by controlling mitochondrial fission. IFN-ß induces events that are required for mitochondrial fission, phosphorylating STAT5 and upregulating PGAM5, which phosphorylates serine 622 of Drp1. IFN-ß signaling then recruits Drp1 to mitochondria, oligomerizes it, and engages INF2 to stabilize mitochondria-endoplasmic reticulum (ER) platforms. This process tethers damaged mitochondria to the ER to separate them via fission. Lack of neuronal IFN-ß in the Ifnb-/- model of Parkinson disease (PD) disrupts STAT5-PGAM5-Drp1 signaling, impairing fission and causing large multibranched, damaged mitochondria with insufficient ATP production and excessive oxidative stress to accumulate. In other PD models, IFN-ß rescues dopaminergic neuronal cell death and pathology, associated with preserved mitochondrial homeostasis. Thus, IFN-ß activates mitochondrial fission in neurons through the pSTAT5/PGAM5/S622 Drp1 pathway to stabilize mitochondria/ER platforms, constituting an essential neuroprotective mechanism.
Subject(s)
Interferon-beta/metabolism , Mitochondrial Dynamics , Parkinson Disease/metabolism , Animals , Cell Line , Cell Line, Tumor , Dynamins/metabolism , Formins/metabolism , Interferon-beta/genetics , Mice , Mitochondria/metabolism , Neurons/metabolism , Phosphoprotein Phosphatases/metabolism , STAT5 Transcription Factor/metabolismABSTRACT
Adenosine-to-inosine (A-to-I) RNA editing is a post-transcriptional processing event involved in diversifying the transcriptome and is responsible for various biological processes. In this context, we developed a new method based on the highly selective cleavage activity of Endonuclease V against Inosine and the universal activity of sodium periodate against all RNAs to enrich the inosine-containing RNA and accurately identify the editing sites. We validated the reliability of our method in human brain in both Alu and non-Alu elements. The conserved sites of A-to-I editing in human cells (HEK293T, HeLa, HepG2, K562 and MCF-7) primarily occurs in the 3'UTR of the RNA, which are highly correlated with RNA binding and protein binding. Analysis of the editing sites between the human brain and mouse brain revealed that the editing of exons is more conserved than that in other regions. This method was applied to three neurological diseases (Alzheimer's, epilepsy and ageing) of mouse brain, reflecting that A-to-I editing sites significantly decreased in neuronal activity genes.
Subject(s)
RNA Editing , Transcriptome , Animals , Humans , Mice , Inosine/genetics , Inosine/metabolism , Reproducibility of Results , RNA Editing/genetics , Transcriptome/genetics , Exons , Cell LineABSTRACT
The cGAS-STING pathway is essential for immune defense against microbial pathogens and malignant cells; as such, STING is an attractive target for cancer immunotherapy. However, systemic administration of STING agonists poses safety issues while intratumoral injection is limited by tumor accessibility. Here, we generated antibody-drug conjugates (ADCs) by conjugating a STING agonist through a cleavable linker to antibodies targeting tumor cells. Systemic administration of these ADCs was well tolerated and exhibited potent antitumor efficacy in syngeneic mouse tumor models. The STING ADC further synergized with an anti-PD-L1 antibody to achieve superior antitumor efficacy. The STING ADC promoted multiple aspects of innate and adaptive antitumor immune responses, including activation of dendritic cells, T cells, natural killer cells and natural killer T cells, as well as promotion of M2 to M1 polarization of tumor-associated macrophages. These results provided the proof of concept for clinical development of the STING ADCs.
Subject(s)
Immunoconjugates , Neoplasms , Animals , Mice , Immunotherapy , Immunologic Factors , Neoplasms/therapy , Tumor-Associated MacrophagesABSTRACT
Alzheimer's disease (AD) is characterized by the accumulation of amyloid-ß plaques and Tau tangles in brain tissues. Recent studies indicate that aberrant splicing and increased level of intron retention is linked to AD pathogenesis. Bioinformatic analysis revealed increased retention of intron 11 at the Tau gene in AD female dorsal lateral prefrontal cortex as compared to healthy controls, an observation validated by quantitative polymerase chain reaction using different brain tissues. Retention of intron 11 introduces a premature stop codon, resulting in the production of truncated Tau11i protein. Probing with customized antibodies designed against amino acids encoded by intron 11 showed that Tau11i protein is more enriched in AD hippocampus, amygdala, parietal, temporal, and frontal lobe than in healthy controls. This indicates that Tau messenger RNA with the retained intron is translated in vivo instead of being subjected to nonsense-mediated decay. Compared to full-length Tau441 isoform, ectopically expressed Tau11i forms higher molecular weight species, is enriched in Sarkosyl-insoluble fraction, and exhibits greater protein stability in cycloheximide assay. Stably expressed Tau11i also shows weaker colocalization with α-tubulin of microtubule network in human mature cortical neurons as compared to Tau441. Endogenous Tau11i is enriched in Sarkosyl-insoluble fraction in AD hippocampus and forms aggregates that colocalize weakly with Tau4R fibril-like structure in AD temporal lobe. The elevated level of Tau11i protein in AD brain tissues tested, coupled with biochemical properties resembling pathological Tau species suggest that retention of intron 11 of Tau gene might be an early biomarker of AD pathology.
Subject(s)
Alzheimer Disease , tau Proteins , Alzheimer Disease/diagnosis , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Biomarkers/analysis , Biomarkers/metabolism , Brain/metabolism , Early Diagnosis , Female , Humans , Introns/genetics , Plaque, Amyloid/metabolism , tau Proteins/analysis , tau Proteins/genetics , tau Proteins/metabolismABSTRACT
Hypertriglyceridemia (HTG) is a common cardiovascular risk factor characterized by elevated triglyceride (TG) levels. Researchers have assessed the genetic factors that influence HTG in studies focused predominantly on individuals of European ancestry. However, relatively little is known about the contribution of genetic variation of HTG in people of African ancestry (AA), potentially constraining research and treatment opportunities. Our objective was to characterize genetic profiles among individuals of AA with mild-to-moderate HTG and severe HTG versus those with normal TGs by leveraging whole-genome sequencing data and longitudinal electronic health records available in the All of Us program. We compared the enrichment of functional variants within five canonical TG metabolism genes, an AA-specific polygenic risk score for TGs, and frequencies of 145 known potentially causal TG variants between HTG patients and normal TG among a cohort of AA patients (N = 15,373). Those with mild-to-moderate HTG (N = 342) and severe HTG (N ≤ 20) were more likely to carry APOA5 p.S19W (odds ratio = 1.94, 95% confidence interval = [1.48-2.54], P = 1.63 × 10-6 and OR = 3.65, 95% confidence interval: [1.22-10.93], P = 0.02, respectively) than those with normal TG. They were also more likely to have an elevated (top 10%) polygenic risk score, elevated carriage of potentially causal variant alleles, and carry any genetic risk factor. Alternative definitions of HTG yielded comparable results. In conclusion, individuals of AA with HTG were enriched for genetic risk factors compared to individuals with normal TGs.
Subject(s)
Hypertriglyceridemia , Triglycerides , Humans , Triglycerides/blood , Male , Female , Hypertriglyceridemia/genetics , Middle Aged , United States/epidemiology , Apolipoprotein A-V/genetics , Black People/genetics , Adult , Black or African American/geneticsABSTRACT
Here we report the first and concise total synthesis of a complex ophiobolin-derived sesterterpene, bipolarolide D, which hinges on two strategic applications of pentafulvene: (1) enantioselective pentafulvene-involved [6+2] cycloaddition; (2) regioselective and diastereoselective pentafulvene-involved Heck cyclization. Late-stage selective allylic addition to the ketone moiety facilitates the successful installation of the side chain. This strategy enabled the accomplishment of its first enantioselective total synthesis through a modular approach. This synthesis will facilitate the investigation of relevant biological activities and provide a synthetic blueprint for utilizing fulvenes as versatile synthons in other complex natural product synthesis.
ABSTRACT
Gene targeting (GT) allows precise manipulation of genome sequences, such as knock-ins and sequence substitutions, but GT in seed plants remains a challenging task. Engineered sequence-specific nucleases (SSNs) are known to facilitate GT via homology-directed repair (HDR) in organisms. Here, we demonstrate that Cas12a and a temperature-tolerant Cas12a variant (ttCas12a) can efficiently establish precise and heritable GT at two loci in Arabidopsis thaliana (Arabidopsis) through a sequential transformation strategy. As a result, ttCas12a showed higher GT efficiency than unmodified Cas12a. In addition, the efficiency of transcriptional and translational enhancers for GT via sequential transformation strategy was also investigated. These enhancers and their combinations were expected to show an increase in GT efficiency in the sequential transformation strategy, similar to previous reports of all-in-one strategies, but only a maximum twofold increase was observed. These results indicate that the frequency of double strand breaks (DSBs) at the target site is one of the most important factors determining the efficiency of genetic GT in plants. On the other hand, a higher frequency of DSBs does not always lead to higher efficiency of GT, suggesting that some additional factors are required for GT via HDR. Therefore, the increase in DSB can no longer be expected to improve GT efficiency, and a new strategy needs to be established in the future. This research opens up a wide range of applications for precise and heritable GT technology in plants.
Subject(s)
Arabidopsis , Gene Targeting , Arabidopsis/genetics , Gene Targeting/methods , Transformation, Genetic , CRISPR-Associated Proteins/genetics , CRISPR-Associated Proteins/metabolism , CRISPR-Cas Systems , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Endodeoxyribonucleases/genetics , Endodeoxyribonucleases/metabolism , Plants, Genetically Modified/geneticsABSTRACT
Lead-free halide perovskites as a new kind of potential candidate for photocatalytic organic synthesis have attracted much attention recently. The rational heterojunction construction is regarded as an efficient strategy to delicately regulate their catalytic performances. Herein, a semi-conductive covalent organic framework (COF) nanosheet, C4N, is employed as the functional component to construct Cs2AgBiCl6/C4N (CABC/C4N) heterojunction. It is found that the C4N nanosheets with rich surface functional groups can serve as heterogeneous nucleation sites to manipulate the growth of CABC nanocrystals and afford close contact between each other, therefore facilitate the transfer and spatial separation of photogenerated charge carriers, as verified by in situ X-ray photoelectronic spectroscopy and Kelvin probe force microscopy. Moreover, the oxygen affinity of C4N endows the heterojunctions with outstanding aerobic reactivity, thus improving the photocatalytic performance largely. The optimal CABC/C4N heterojunction delivers a thioanisole conversion efficiency of 100% after 6 h, which is 2.2 and 7.7-fold of that of CABC and C4N. This work provides a new ideal for the design and application of lead-free perovskite heterojunction photocatalysts for organic reactions.
ABSTRACT
The development of ultraviolet circularly polarized light (UVCPL) sources has the potential to benefit plenty of practical applications but remains a challenge due to limitations in available material systems and a limited understanding of the excited state chirality transfer. Herein, by constructing hybrid structures of the chiral perovskite CsPbBr3 nanoplatelets and organic molecules, excited state chirality transfer is achieved, either via direct binding or triplet energy transfer, leading to efficient UVCPL emission. The underlying photophysical mechanisms of these two scenarios are clarified by comprehensive optical studies. Intriguingly, UVCPL realized via the triple energy transfer, followed by the triplet-triplet annihilation upconversion processes, demonstrates a 50-fold enhanced dissymmetry factor glum. Furthermore, stereoselective photopolymerization of diacetylene monomer is demonstrated by using such efficient UVCPL. This study provides both novel insights and a practical approach for realizing UVCPL, which can also be extended to other material systems and spectral regions, such as visible and near-infrared.
ABSTRACT
Organic-inorganic hybrid linear and nonlinear optical (NLO) materials have received increasingly wide spread attention in recent years. Herein, the first hybrid noncentrosymmetric (NCS) borophosphate, (C5H6N)2B2O(HPO4)2 (4PBP), is rationally designed and synthesized by a covalent-linkage strategy. 4-pyridyl-boronic acid (4 PB) is considered as a bifunctional unit, which may effectively improve the optical properties and stability of the resultant material. On the one hand, 4 PB units are covalently linked with PO3(OH) groups via strong B-O-P connections, which significantly enhances the thermal stability of 4PBP (decomposition at 321, vs lower 200 °C of most of hybrid materials). On the other hand, the planar π-conjugated C5H6N units and their uniform layered arrangements represent large structural anisotropy and hyperpolarizability, achieving the largest birefringence (0.156 @ 546 nm) in the reported borophosphates and a second-harmonic generation response (0.7 × KDP). 4PBP also exhibits a wide transparency range (0.27-1.50 µm). This work not only provides a promising birefringent material, but also offers a practical covalent-attachment strategy for the rational design of new high-performance optical materials.
ABSTRACT
BACKGROUND: The obesity paradox has been reported among older adults. However, whether the favorable effect of obesity is dependent on metabolic status remains largely unknown. We aimed to explore the association of metabolic obesity phenotypes and their changes with all-cause mortality among the Chinese oldest-old population. METHODS: This prospective cohort study included 1207 Chinese oldest old (mean age: 91.8 years). Metabolic obesity phenotypes were determined by central obesity and metabolic status, and participants were classified into metabolically healthy obesity (MHO), metabolically unhealthy obesity (MUO), metabolically healthy non-obesity (MHN), and metabolically unhealthy non-obesity (MUN). The hazard ratios (HRs) and 95% confidence intervals (95% CIs) were estimated by Cox regression models. RESULTS: During 5.3 years of follow-up, 640 deaths were documented. Compared with non-obesity, obesity was associated with a decreased mortality risk among participants with metabolically healthy (HR, 0.75; 95% CI, 0.63-0.91) while this association was insignificant among metabolically unhealthy. Compared to MHO, MHN (HR, 1.27; 95% CI, 1.06-1.53) and MUN (HR, 1.49; 95% CI, 1.10-2.02) were significantly associated with an increased mortality risk. Compared to those with stable MHO, those transited from MHO to MUO demonstrated a higher mortality risk (HR, 1.81; 95% CI, 1.06-3.11). CONCLUSIONS: MHO predicts better survival among the Chinese oldest-old population. These findings suggest that ensuring optimal management of metabolic health is beneficial and taking caution in weight loss based on the individual body weight for the metabolically healthy oldest-old adults.
ABSTRACT
Peripheral T-cell lymphomas (PTCLs) are heterogenous T-cell neoplasms often associated with epigenetic dysregulation. We investigated de novo DNA methyltransferase 3A (DNMT3A) mutations in common PTCL entities, including angioimmunoblastic T-cell lymphoma and novel molecular subtypes identified within PTCL-not otherwise specified (PTCL-NOS) designated as PTCL-GATA3 and PTCL-TBX21. DNMT3A-mutated PTCL-TBX21 cases showed inferior overall survival (OS), with DNMT3A-mutated residues skewed toward the methyltransferase domain and dimerization motif (S881-R887). Transcriptional profiling demonstrated significant enrichment of activated CD8+ T-cell cytotoxic gene signatures in the DNMT3A-mutant PTCL-TBX21 cases, which was further validated using immunohistochemistry. Genomewide methylation analysis of DNMT3A-mutant vs wild-type (WT) PTCL-TBX21 cases demonstrated hypomethylation in target genes regulating interferon-γ (IFN-γ), T-cell receptor signaling, and EOMES (eomesodermin), a master transcriptional regulator of cytotoxic effector cells. Similar findings were observed in a murine model of PTCL with Dnmt3a loss (in vivo) and further validated in vitro by ectopic expression of DNMT3A mutants (DNMT3A-R882, -Q886, and -V716, vs WT) in CD8+ T-cell line, resulting in T-cell activation and EOMES upregulation. Furthermore, stable, ectopic expression of the DNMT3A mutants in primary CD3+ T-cell cultures resulted in the preferential outgrowth of CD8+ T cells with DNMT3AR882H mutation. Single-cell RNA sequencing(RNA-seq) analysis of CD3+ T cells revealed differential CD8+ T-cell subset polarization, mirroring findings in DNMT3A-mutated PTCL-TBX21 and validating the cytotoxic and T-cell memory transcriptional programs associated with the DNMT3AR882H mutation. Our findings indicate that DNMT3A mutations define a cytotoxic subset in PTCL-TBX21 with prognostic significance and thus may further refine pathological heterogeneity in PTCL-NOS and suggest alternative treatment strategies for this subset.
Subject(s)
Interferon-gamma , Lymphoma, T-Cell, Peripheral , Animals , Interferon-gamma/genetics , Lymphoma, T-Cell, Peripheral/pathology , Methyltransferases/genetics , Mice , Mutation , Prognosis , Receptors, Antigen, T-Cell/geneticsABSTRACT
BACKGROUND: Atherogenic index of plasma (AIP), a marker of atherosclerosis and cardiovascular disease (CVD). However, few studies have investigated association between AIP and all-cause mortality and specific-mortality in the general population. METHODS: This study included data from 14,063 American adults. The exposure variable was the AIP, which was defined as log10 (triglycerides/high-density lipoprotein cholesterol). The outcome variables included all-cause mortality and specific-mortality. Survey-weighted cox regressions were performed to evaluate the relation between AIP and all-cause mortality and specific-mortality. Weighted restricted cubic spline was conducted to examin the non-linear relationship. RESULTS: During 10 years of follow-up, we documented 2,077, 262, 854, and 476 cases of all-cause mortality, diabetes mortality, CVD mortality and cancer mortality, respectively. After adjustment for potential confounders, we found that atherogenic index of plasma (AIP) was significantly associated with an increased risk of diabetes mortality when comparing the highest to the lowest quantile of AIP in female (p for trend = 0.001) or participants older than 65 years (p for trend = 0.002). AIP was not significantly associated with all-cause mortality, CVD mortality and cancer mortality (p > 0.05). Moreover, a non-linear association was observed between AIP and all-cause mortality in a U-shape (p for non-linear = 0.0011), while a linear relationship was observed with diabetes mortality and non-diabetes mortality (p for linear < 0.0001). CONCLUSIONS: In this study, there is a no significant association between high AIP levels and a high risk of all-cause and cardiovascular mortality. Besides, a higher AIP was significantly associated with an increased risk of diabetes mortality, which only found in women older than 65 years. AIP was associated with all-cause mortality in a U-shape. This association could be explained by the finding that higher AIP predicted a higher risk of death from diabetes, and that lower AIP predicted a higher risk of death from non-diabetes causes.
We used a large national database and a prospective cohort study with a long follow-up period. Higher AIP was significantly associated with an increased risk of diabetes mortality, only in women older than 65 years. There is a no significant association between high AIP levels and a high risk of all-cause and cardiovascular mortality. AIP was associated with all-cause mortality in a U-shape. This finding suggest that controlling AIP levels may have a positive effect on reducing diabetes mortality.
Subject(s)
Atherosclerosis , Biomarkers , Cause of Death , Cholesterol, HDL , Diabetes Mellitus , Triglycerides , Humans , Female , Male , Middle Aged , Aged , Risk Assessment , Biomarkers/blood , Atherosclerosis/mortality , Atherosclerosis/blood , Atherosclerosis/diagnosis , Risk Factors , Time Factors , Adult , Diabetes Mellitus/mortality , Diabetes Mellitus/blood , Diabetes Mellitus/diagnosis , Diabetes Mellitus/epidemiology , Cholesterol, HDL/blood , United States/epidemiology , Triglycerides/blood , Prognosis , Neoplasms/mortality , Neoplasms/blood , Neoplasms/diagnosis , Cardiovascular Diseases/mortality , Cardiovascular Diseases/blood , Cardiovascular Diseases/diagnosisABSTRACT
BACKGROUND: Immune checkpoint inhibitors (ICI) combined with chemotherapy are efficacious for treating advanced non-small cell lung cancer (NSCLC); however, the effectiveness of this approach in the malignant pleural effusion (MPE) population is unclear. This study evaluated ICI plus chemotherapy in NSCLC patients with MPE. METHODS: Patients from 3 centers in China with NSCLC and MPE who received ICI plus chemotherapy (ICI Plus Chemo) or chemotherapy alone (Chemo) between December 2014 and June 2023 were enrolled. Clinical outcomes and adverse events (AEs) were compared. RESULTS: Of 155 eligible patients, the median age was 61.0 years old. Males and never-smokers accounted for 73.5% and 39.4%, respectively. Fifty-seven and 98 patients received ICI Plus Chemo or Chemo, respectively. With a median study follow-up of 10.8 months, progression-free survival (PFS) was significantly longer with ICI Plus Chemo than with Chemo (median PFS: 7.4 versus 5.7 months; HR = 0.594 [95% CI: 0.403-0.874], P = 0.008). Median overall survival (OS) did not differ between groups (ICI Plus Chemo: 34.2 versus Chemo: 28.3 months; HR = 0.746 [95% CI: 0.420-1.325], P = 0.317). The most common grade 3 or worse AEs included decreased neutrophil count (3 [5.3%] patients in the ICI Plus Chemo group vs. 5 [5.1%] patients in the Chemo group) and decreased hemoglobin (3 [5.3%] versus 10 [10.2%]). CONCLUSIONS: In patients with untreated NSCLC with MPE, ICI plus chemotherapy resulted in significantly longer PFS than chemotherapy and had a manageable tolerability profile, but the effect on OS may be limited.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Pleural Effusion, Malignant , Humans , Male , Middle Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Non-Small-Cell Lung/complications , Carcinoma, Non-Small-Cell Lung/drug therapy , Immune Checkpoint Inhibitors/adverse effects , Lung Neoplasms/complications , Lung Neoplasms/drug therapy , Pleural Effusion, Malignant/drug therapy , Pleural Effusion, Malignant/pathology , Retrospective Studies , FemaleABSTRACT
In this paper, we introduced a novel phase-transfer strategy tailored for the efficient batch detection of ascorbic acid in vitamin C tablets. This method entailed the reaction between ascorbic acid and an excess of potassium permanganate. Subsequent reaction of the residual potassium permanganate with sodium oxalate in an acidic medium led to the generation of carbon dioxide. The quantification of the produced carbon dioxide was achieved using headspace GC, enabling the indirect measurement of ascorbic acid. The obtained findings revealed that the headspace method exhibited satisfied precision with a relative standard deviation of less than 2.11% and high sensitivity with a limit of quantitation of 0.27 µmol. These results firmly establish the reliability of this innovative approach for determining ascorbic acid. In addition, the highly automated feature of headspace method significantly enhances the efficiency of batch sample detection and reduces the errors caused by human operation. Thus, the adoption of the transformed phase strategy has demonstrated its effectiveness in assessing ascorbic acid, especially for large-scale sample analysis in industrial applications, owing to its efficiency, precision, and sensitivity.
ABSTRACT
In the field of neurodegenerative diseases, especially sporadic Parkinson's disease (sPD) with dementia (sPDD), the question of how the disease starts and spreads in the brain remains central. While prion-like proteins have been designated as a culprit, recent studies suggest the involvement of additional factors. We found that oxidative stress, damaged DNA binding, cytosolic DNA sensing, and Toll-Like Receptor (TLR)4/9 activation pathways are strongly associated with the sPDD transcriptome, which has dysregulated type I Interferon (IFN) signaling. In sPD patients, we confirmed deletions of mitochondrial (mt)DNA in the medial frontal gyrus, suggesting a potential role of damaged mtDNA in the disease pathophysiology. To explore its contribution to pathology, we used spontaneous models of sPDD caused by deletion of type I IFN signaling (Ifnb-/-/Ifnar-/- mice). We found that the lack of neuronal IFNß/IFNAR leads to oxidization, mutation, and deletion in mtDNA, which is subsequently released outside the neurons. Injecting damaged mtDNA into mouse brain induced PDD-like behavioral symptoms, including neuropsychiatric, motor, and cognitive impairments. Furthermore, it caused neurodegeneration in brain regions distant from the injection site, suggesting that damaged mtDNA triggers spread of PDD characteristics in an "infectious-like" manner. We also discovered that the mechanism through which damaged mtDNA causes pathology in healthy neurons is independent of Cyclic GMP-AMP synthase and IFNß/IFNAR, but rather involves the dual activation of TLR9/4 pathways, resulting in increased oxidative stress and neuronal cell death, respectively. Our proteomic analysis of extracellular vesicles containing damaged mtDNA identified the TLR4 activator, Ribosomal Protein S3 as a key protein involved in recognizing and extruding damaged mtDNA. These findings might shed light on new molecular pathways through which damaged mtDNA initiates and spreads PD-like disease, potentially opening new avenues for therapeutic interventions or disease monitoring.