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BACKGROUND: An increasing number of clinical studies have begun to explore combination strategies with immune checkpoint inhibitors, aiming to present new opportunities for overcoming anti-PD-1 treatment resistance in gastric cancer. Unfortunately, the exploration of certain immune checkpoint inhibitor combination strategies has yielded suboptimal results. Therefore, it is necessary to comprehensively analyze the expression patterns of immune checkpoints and identify optimal combination regimens of anti-PD-1 inhibitors with other immune checkpoint inhibitors. METHODS: Leveraging single-cell RNA sequencing (scRNA-seq) and multivariate linear regression interaction models, we dissected the immune checkpoint expression characteristics of CD8+ T cells in gastric cancer and the immune checkpoint expression pattern (ICEP) mediating anti-PD-1 treatment resistance. Furthermore, we employed transcription factor analysis and CellOracle to explore the transcriptional regulatory mechanisms governing CD8+ T cell differentiation fates. Finally, we utilized Nichenet and spatial transcriptomic analysis to investigate the spatial expression patterns of immune checkpoints. RESULTS: Interaction analysis indicated that, among the known immune checkpoints, co-expression of NKG2A and PD-1 might exert a more profound inhibitory effect on the proliferative capacity of CD8+ T cells. The co-expression analysis revealed differential co-expression pattern of PD-1 and NKG2A, defined as ICEP1 (CD8+ T cells co-expressing PD-1, CTLA-4, TIGIT, LAG-3 or CD38) and ICEP2 (CD8+ T cells solely expressing NKG2A or co-expressing with other immune checkpoints), reflecting the co-occurrence pattern of PD-1 and the mutual exclusivity of NKG2A. Further, these two ICEP CD8+ T cell subsets represented distinct CD8+ T cell differentiation fates governed by MSC and RUNX3. Notably, ICEP2 CD8+ T cells were associated with anti-PD-1 therapy resistance in gastric cancer. This phenomenon may be attributed to the recruitment of LGMN+ macrophages mediated by the CXCL16-CXCR6 signaling pathway. CONCLUSION: This study unveiled two distinct ICEPs and the mutually exclusivity and co-occurrence characteristics of CD8+ T cells in gastric cancer. The ICEP2 CD8+ T cell subset, highly expressed in gastric cancer patients resistant to anti-PD-1 therapy, may be recruited by LGMN+ macrophages through CXCL16-CXCR6 axis. These findings provide evidence for NKG2A as a novel immunotherapeutic target in gastric cancer and offer new insights into combination strategies for immune checkpoint inhibitors in gastric cancer.
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Linfocitos T CD8-positivos , Resistencia a Antineoplásicos , Inhibidores de Puntos de Control Inmunológico , Subfamília C de Receptores Similares a Lectina de Células NK , Receptor de Muerte Celular Programada 1 , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Resistencia a Antineoplásicos/genética , Linfocitos T CD8-positivos/inmunología , Subfamília C de Receptores Similares a Lectina de Células NK/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Regulación Neoplásica de la Expresión Génica , Proteínas de Punto de Control Inmunitario/metabolismo , Proteínas de Punto de Control Inmunitario/genética , Diferenciación CelularRESUMEN
The mechanisms of chemical reactions, including the transformation pathways of the electronic and geometric structures of molecules, are crucial for comprehending the essence and developing new chemistry. However, it is extremely difficult to realize at the single-molecule level. Here, we report a single-molecule approach capable of electrically probing stochastic fluctuations under equilibrium conditions and elucidating time trajectories of single species in non-equilibrated systems. Through molecular engineering, a single molecular wire containing a functional center of 9-phenyl-9-fluorenol was covalently wired into nanogapped graphene electrodes to form stable single-molecule junctions. Both experimental and theoretical studies consistently demonstrate and interpret the direct measurement of the formation dynamics of individual carbocation intermediates with a strong solvent dependence in a nucleophilic-substitution reaction. We also show the kinetic process of competitive transitions between acetate and bromide species, which is inevitable through a carbocation intermediate, confirming the classical mechanism. This unique method creates plenty of opportunities for carrying out single-molecule dynamics or biophysics investigations in broad fields beyond reaction chemistry through molecular design and engineering.
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A heterostructure photovoltaic diode featuring an all-solid-state TiO2/graphene/dye ternary interface with high-efficiency photogenerated charge separation/transport is described here. Light absorption is accomplished by dye molecules deposited on the outside surface of graphene as photoreceptors to produce photoexcited electron-hole pairs. Unlike conventional photovoltaic conversion, in this heterostructure both photoexcited electrons and holes tunnel along the same direction into graphene, but only electrons display efficient ballistic transport toward the TiO2 transport layer, thus leading to effective photon-to-electricity conversion. On the basis of this ipsilateral selective electron tunnelling (ISET) mechanism, a model monolayer photovoltaic device (PVD) possessing a TiO2/graphene/acridine orange ternary interface showed â¼86.8% interfacial separation/collection efficiency, which guaranteed an ultrahigh absorbed photon-to-current efficiency (APCE, â¼80%). Such an ISET-based PVD may become a fundamental device architecture for photovoltaic solar cells, photoelectric detectors, and other novel optoelectronic applications with obvious advantages, such as high efficiency, easy fabrication, scalability, and universal availability of cost-effective materials.
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OBJECTIVE: To explore the application of the gray series model GM (1, 1) in predicting trends in the incidence of pneumoconiosis and evaluate its degree of predicted precision. METHODS: Analyzing the incidence of pneumoconiosis in this region from 2009 to 2013, and predicting the incidence of pneumoconiosis of the area in 2014-2016 by establishing GM (1, 1) according to the gray system theory. RESULTS: Using occupational pneumoconiosis population data from 2009 to 2013, to establish GM (1, 1) model: yt = 1396.89e(0.12(t-1)), α = -0.12, µ = 147.2. The pneumoconiosis in 2014, 2015, 2016 were predicted respectively 51, 47, 43 cases based on the GM (1, 1) model, and C value of model is 0.15, P value is 1, all of them meet the requirements of model predictions. It shows the cases of pneumoconiosis are rising significantly. CONCLUSION: GM (1, 1) model can be used to predict the recent trend in the incidence of pneumoconiosis.
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Predicción/métodos , Modelos Teóricos , Neumoconiosis/epidemiología , Humanos , IncidenciaRESUMEN
Recurrent spontaneous abortion (RSA) has various complicated causes, and more and more researches are focused on its etiology. Genetic factors are the most common risk factors of RSA; immune factors, infection factors, male factors and female factors play an important role; environmental pollution and some other unknown factors may also be conspirators. This article presents an overview on the possible risk factors of RSA.
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Aborto Habitual/etiología , Femenino , Humanos , Masculino , Embarazo , Factores de RiesgoRESUMEN
Progesterone, as a female hormone, plays an important role in the physiological function and pregnancy maintenance in women. Recent studies show that progesterone and its receptor are also involved in male reproduction, and its receptor mRNA exists in male sexual glands. It is believed that progesterone, binding to its receptor, can regulate spermatogenesis and improve the fertilization of sperm, while the sperm from those with oligospermia, asthenozoospermia, teratospermia or unexplained infertility exhibit a low fertility due to the deficient expression of the progesterone receptor and insensitive reaction to progesterone. This review focuses on the progress in the studies of progesterone and its receptor in male reproduction.
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Progesterona/fisiología , Receptores de Progesterona/fisiología , Espermatozoides/fisiología , Fertilidad , Humanos , Masculino , Espermatogénesis , Testículo/metabolismoRESUMEN
PURPOSE: Patients with cancer often have compromised immune system which can lead to worse COVID-19 outcomes. The purpose of this study is to assess the association between COVID-19 outcomes and existing cancer-specific characteristics. PATIENTS AND METHODS: Patients aged 18 or older with laboratory-confirmed COVID-19 between June 1, 2020, and December 31, 2020, were identified (n = 314 004) from the Optum® de-identified COVID-19 Electronic Health Record (EHR) derived from more than 700 hospitals and 7000 clinics in the United States. To allow sufficient observational time, patients with less than one year of medical history in the EHR dataset before their COVID-19 tests were excluded (n = 42 365). Assessed COVID-19 outcomes including all-cause 30-day mortality, hospitalization, ICU admission, and ventilator use, which were compared using relative risks (RRs) according to cancer status and treatments. RESULTS: Among 271 639 patients with COVID-19, 18 460 had at least one cancer diagnosis: 8034 with a history of cancer and 10 426 with newly diagnosed cancer within one year of COVID-19 infection. Patients with a cancer diagnosis were older and more likely to be male, white, Medicare beneficiaries, and have higher prevalences of chronic conditions. Cancer patients had higher risks for 30-day mortality (RR 1.07, 95% CI 1.01-1.14, P = 0.028) and hospitalization (RR 1.04, 95% CI 1.01-1.07, P = 0.006) but without significant differences in ICU admission and ventilator use compared to non-cancer patients. Recent cancer diagnoses were associated with higher risks for worse COVID-19 outcomes (RR for mortality 1.17, 95% CI 1.08-1.25, P<0.001 and RR for hospitalization 1.10, 95% CI 1.06-1.14, P<0.001), particularly among recent metastatic (stage IV), hematological, liver and lung cancers compared with the non-cancer group. Among COVID-19 patients with recent cancer diagnosis, mortality was associated with chemotherapy or radiation treatments within 3 months before COVID-19. Age, black patients, Medicare recipients, South geographic region, cardiovascular, diabetes, liver, and renal diseases were also associated with increased mortality. CONCLUSIONS AND RELEVANCE: Individuals with cancer had higher risks for 30-day mortality and hospitalization after SARS-CoV-2 infection compared to patients without cancer. More specifically, patients with a cancer diagnosis within 1 year and those receiving active treatment were more vulnerable to worse COVID-19 outcomes.
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COVID-19 , Neoplasias Pulmonares , Anciano , COVID-19/epidemiología , COVID-19/terapia , Registros Electrónicos de Salud , Femenino , Hospitalización , Humanos , Masculino , Medicare , SARS-CoV-2 , Estados Unidos/epidemiologíaRESUMEN
OBJECTIVE: To study the effect of SOD2 and its C47T mutation on oxidative injury in cochlea hair cells. METHODS: HEI-OC1 cells were transfected with the SOD2 of Ala16 and Vla16. Cells' proliferation ability was determined by MTT assay. The intracellular SOD2 activities were detected by xanthine oxidase method. Intracellular ROS were determined by DCFH-DA after exposure to 100 µmol/L t-BHP and the early apoptotic and necrotic rate or late apoptotic rate were quantified by flow cytometry (FCM) using Annexin V/PI double staining. RESULTS: MTT method showed the transfection of SOD2 gene and empty plasmid did not affect the proliferation capacity. SOD2 vitality in Ala(16) and Val(16) SOD2 transfected cells increased 2.51 and 2.71 times respectively (P < 0.01), but the difference between the two transfection groups was not statistically significant (P > 0.05). After exposed to t-BHP, the majority of the untransfected and empty plasmid transfected cells sent '++' class bright fluorescence, while in Ala(16) and Val(16) SOD2 transfected groups, only about half cells sent '±' â¼ '+' level fuzzy fluorescence. determination of FCM suggested the early apoptotic and necrotic rate or late apoptotic rate decreased after SOD2 transfection (P < 0.01), but the difference between the two genotypes of SOD2 was not statistically significant (P > 0.05). CONCLUSION: High expression of SOD2 below 3.71 times can reduce intracellular ROS level in HEI-OC1 cells, while SOD2 C47T mutation had no effect on them. SOD2 can be considered as NIHL susceptibility gene and its rs4880 SNP may be not directly related to NIHL genetic susceptibility.
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Células Ciliadas Auditivas/metabolismo , Mutación , Estrés Oxidativo , Superóxido Dismutasa/genética , Línea Celular , Cóclea/metabolismo , Humanos , Polimorfismo de Nucleótido Simple , Especies Reactivas de Oxígeno/metabolismoRESUMEN
OBJECTIVE: To explore the effects of phosphatidylinositol 3-kinase/Serine-threonine kinase (PI3K/Akt) signal pathway on the proliferation of HL-60 cells exposed to benzoquinone (BQ). METHODS: HL60 cells were divided into 3 groups: control group (treated with PBS), BQ group (treated with 3 micromol/L BQ) and LY294002 plus BQ group (treated with 20 micromol/L LY294002 plus 3 micromol/L BQ). The cell proliferation was measured with alamar blue dye assay. Western blot assay was used to detect the expression of p-Akt and Akt proteins and flow cytometer was used to observe the cell cycle. RESULTS: The cell proliferation rate and the cell proportion in the S, G2 phase of BQ group were 185.00% +/- 30.00%, 48.23% +/- 1.37% and 15.40% +/- 1.21%, respectively, which were significantly higher than those (100.00% +/- 0.00%, 42.47% +/- 0.45% and 5.40% +/- 0.40%) of control group (P<0.05). But the cell proportion rate (36.37% +/- 0.40%) in the G1 phase in BQ group was significantly lower than that (52.13 +/- 0.75%) in control group (P<0.05). The expression level of p-Akt protein in BQ group was significantly higher than that in control group (P<0.05). The cell proliferation rate and the cell proportion in the S, G2 phase of LY294002 plus BQ group were 82.59% +/- 15.00%, 42.03% +/- 0.50% and 3.87% +/- 0.47%, respectively, which were significantly lower than those of BQ group (P<0.05). But the cell proportion rate (54.43% +/- 0.40%) in the G1 phase in LY294002 plus BQ group was significantly higher than that in BQ group (P<0.05). CONCLUSION: The PI3K/Akt signal pathway may play an important role in the proliferation of HL-60 cells exposed to BQ.
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Benzoquinonas/toxicidad , Proliferación Celular/efectos de los fármacos , Fosfatidilinositol 3-Quinasa/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal , Células HL-60 , HumanosRESUMEN
PURPOSE: We evaluated a previously published risk model (Novant model) to identify patients at risk for healthcare facility-onset Clostridioides difficile infection (HCFO-CDI) at 2 hospitals within a large health system and compared its predictive value to that of a new model developed based on local findings. METHODS: We conducted a retrospective case-control study including adult patients admitted from July 1, 2016, to July 1, 2018. Patients with HCFO-CDI who received systemic antibiotics were included as cases and were matched 1 to 1 with controls (who received systemic antibiotics without developing HCFO-CDI). We extracted chart data on patient risk factors for CDI, including those identified in prior studies and those included in the Novant model. We applied the Novant model to our patient population to assess the model's utility and generated a local model using logistic regression-based prediction scores. A receiver operating characteristic area under the curve (ROC-AUC) score was determined for each model. RESULTS: We included 362 patients, with 161 controls and 161 cases. The Novant model had a ROC-AUC of 0.62 in our population. Our local model using risk factors identifiable at hospital admission included hospitalization within 90 days of admission (adjusted odds ratio [OR], 3.52; 95% confidence interval [CI], 2.06-6.04), hematologic malignancy (adjusted OR, 12.87; 95% CI, 3.70-44.80), and solid tumor malignancy (adjusted OR, 4.76; 95% CI, 1.27-17.80) as HCFO-CDI predictors and had a ROC-AUC score of 0.74. CONCLUSION: The Novant model evaluating risk factors identifiable at admission poorly predicted HCFO-CDI in our population, while our local model was a fair predictor. These findings highlight the need for institutions to review local risk factors to adjust modeling for their patient population.
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Clostridioides difficile , Infecciones por Clostridium , Infección Hospitalaria , Adulto , Estudios de Casos y Controles , Clostridioides , Infecciones por Clostridium/diagnóstico , Infecciones por Clostridium/epidemiología , Infección Hospitalaria/diagnóstico , Infección Hospitalaria/epidemiología , Atención a la Salud , Humanos , Estudios Retrospectivos , Medición de RiesgoRESUMEN
Neutrophils are often considered terminally differentiated and poised for bacterial killing. In chronic diseases such as cystic fibrosis (CF), an unexplained paradox pits massive neutrophil presence against prolonged bacterial infections. Here, we show that neutrophils recruited to CF airways in vivo and in an in vitro transmigration model display rapid and broad transcriptional firing, leading to an upregulation of anabolic genes and a downregulation of antimicrobial genes. Newly transcribed RNAs are mirrored by the appearance of corresponding proteins, confirming active translation in these cells. Treatment by the RNA polymerase II and III inhibitor α-amanitin restores the expression of key antimicrobial genes and increases the bactericidal capacity of CF airway neutrophils in vitro and in short-term sputum cultures ex vivo. Broadly, our findings show that neutrophil plasticity is regulated at the site of inflammation via RNA and protein synthesis, leading to adaptations that affect their canonical functions (i.e., bacterial clearance).
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Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Fibrosis Quística/metabolismo , Neutrófilos/metabolismo , Sistema Respiratorio/microbiología , Fibrosis Quística/genética , Fibrosis Quística/microbiología , Trampas Extracelulares/microbiología , Humanos , Neutrófilos/microbiología , Pseudomonas aeruginosa/patogenicidad , Esputo/metabolismo , Esputo/microbiologíaRESUMEN
Molecular self-assembly into crystallised films or wires on surfaces produces a big family of motifs exhibiting unique optoelectronic properties. However, little attention has been paid to the fundamental mechanism of molecular crystallisation. Here we report a biomimetic design of phosphonate engineered, amphiphilic organic semiconductors capable of self-assembly, which enables us to use real-time in-situ scanning probe microscopy to monitor the growth trajectories of such organic semiconducting films as they nucleate and crystallise from amorphous solid states. The single-crystal film grows through an evolutionary selection approach in a two-dimensional geometry, with five distinct steps: droplet flattening, film coalescence, spinodal decomposition, Ostwald ripening, and self-reorganised layer growth. These sophisticated processes afford ultralong high-density microwire arrays with high mobilities, thus promoting deep understanding of the mechanism as well as offering important insights into the design and development of functional high-performance organic optoelectronic materials and devices through molecular and crystal engineering.
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Carbon nanoelectrodes with nanogap are reliable platforms for achieving ultra-small electronic devices. One of the main challenges in fabricating nanogapped carbon electrodes is precise control of the gap size. Herein, we put forward an electroburning approach for controllable fabrication of graphene nanoelectrodes from preprocessed nanoconstriction arrays. The electroburning behavior was investigated in detail, which revealed a dependence on the size of nanoconstriction units. The electroburnt nanoscale electrodes showed the capacity to build molecular devices. The methodology and mechanism presented in this study provide significant guidance for the fabrication of proper graphene and other carbon nanoelectrodes.
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The measurements of molecular electronic devices usually suffer from serious noise. Although noise hampers the operation of electric circuits in most cases, current fluctuations in single-molecule junctions are essentially related to their intrinsic quantum effects in the process of electron transport. Noise analysis can reveal and understand these processes from the behavior of current fluctuations. Here, in this study we observe and analyze the faint asymmetric current distribution in single-molecule junctions, in which the asymmetric intensity is highly related to the applied biases. The exploration of high-order moments within bias and temperature dependent measurements, in combination with model Hamiltonian calculations, statistically prove that the asymmetric current distribution originates from the inelastic electron tunneling process. Such results demonstrate a potential noise analysis method based on the fine structures of the current distribution rather than the noise power, which has obvious advantages in the investigation of the inelastic electron tunneling process in single-molecule junctions.
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Single-molecule detection can reveal time trajectories and reaction pathways of individual intermediates/transition states in chemical reactions and biological processes, which is of fundamental importance to elucidate their intrinsic mechanisms. We present a reliable, label-free single-molecule approach that allows us to directly explore the dynamic process of basic chemical reactions at the single-event level by using stable graphene-molecule single-molecule junctions. These junctions are constructed by covalently connecting a single molecule with a 9-fluorenone center to nanogapped graphene electrodes. For the first time, real-time single-molecule electrical measurements unambiguously show reproducible large-amplitude two-level fluctuations that are highly dependent on solvent environments in a nucleophilic addition reaction of hydroxylamine to a carbonyl group. Both theoretical simulations and ensemble experiments prove that this observation originates from the reversible transition between the reactant and a new intermediate state within a time scale of a few microseconds. These investigations open up a new route that is able to be immediately applied to probe fast single-molecule physics or biophysics with high time resolution, making an important contribution to broad fields beyond reaction chemistry.
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The hydrogen bond represents a fundamental interaction widely existing in nature, which plays a key role in chemical, physical and biochemical processes. However, hydrogen bond dynamics at the molecular level are extremely difficult to directly investigate. Here, in this work we address direct electrical measurements of hydrogen bond dynamics at the single-molecule and single-event level on the basis of the platform of molecular nanocircuits, where a quadrupolar hydrogen bonding system is covalently incorporated into graphene point contacts to build stable supramolecule-assembled single-molecule junctions. The dynamics of individual hydrogen bonds in different solvents at different temperatures are studied in combination with density functional theory. Both experimental and theoretical results consistently show a multimodal distribution, stemming from the stochastic rearrangement of the hydrogen bond structure mainly through intermolecular proton transfer and lactam-lactim tautomerism. This work demonstrates an approach of probing hydrogen bond dynamics with single-bond resolution, making an important contribution to broad fields beyond supramolecular chemistry.
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Ultrasonic degradation of halomethane mixtures, with very low initial concentration in chlorinated drinking water was investigated. It was observed that the removal efficiencies of four halomethanes after 1 h ultrasonic irradiation followed the increasing order: CHCl(3) < CHBr(2)Cl < CHBrCl(2) < CCl(4) and the degradation reactions of the halomethanes were well described by the pseudo-first-order kinetics model. Molecular polarity was found to be an important factor controlling the sonodegradation of halomethane mixtures. Increasing acoustic intensity enhanced the removal of halomethanes in chlorinated drinking water. In addition, ultrasonic irradiation led to a slightly decrease of pH and TOC of chlorinated drinking water.