Emergence and rapid transmission of SARS-CoV-2 B.1.1.7 in the United States.

The highly transmissible B.1.1.7 variant of SARS-CoV-2, first identified in the United Kingdom, has gained a foothold across the world. Using S gene target failure (SGTF) and SARS-CoV-2 genomic sequencing, we investigated the prevalence and dynamics of this variant in the United States (US), tracking it back to its early emergence. We found that, while the fraction of B.1.1.7 varied by state, the variant increased at a logistic rate with a roughly weekly doubling rate and an increased transmission of 40%-50%. We revealed several independent introductions of B.1.1.7 into the US as early as late November 2020, with community transmission spreading it to most states within months. We show that the US is on a similar trajectory as other countries where B.1.1.7 became dominant, requiring immediate and decisive action to minimize COVID-19 morbidity and mortality.

Amygdala Metabotropic Glutamate Receptor 1 Influences Synaptic Transmission to Participate in Fentanyl-Induced Hyperalgesia in Rats.

The underlying mechanisms of opioid-induced hyperalgesia (OIH) remain unclear. Herein, we found that the protein expression of metabotropic glutamate receptor 1 (mGluR1) was significantly increased in the right but not in the left laterocapsular division of central nucleus of the amygdala (CeLC) in OIH rats. In CeLC neurons, the frequency and the amplitude of mini-excitatory postsynaptic currents (mEPSCs) were significantly increased in fentanyl group which were decreased by acute application of a mGluR1 antagonist, A841720. Finally, the behavioral hypersensitivity could be reversed by A841720 microinjection into the right CeLC. These results show that the right CeLC mGluR1 is an important factor associated with OIH that enhances synaptic transmission and could be a potential drug target to alleviate fentanyl-induced hyperalgesia.

Quantitative identification of groundwater contamination sources by combining isotope tracer technique with PMF model in an arid area of northwestern China.

Nowadays, groundwater quality has deteriorated because of intensive human activities. It is important to accurately identify the pollution source for controlling the deterioration of groundwater quality. However, the accuracy of the current source analysis method needs to be improved. In this study, we combined hydrochemical method, isotope tracing technique and PMF model, for the first time, to trace the source of groundwater pollution in Beichuan River basin, Qinghai Province, China. According to the results, there were 35.8% of Fe, 34.1% of total hardness, 24.3% of SO42- and 8.09% of NO3- samples exceeded the Grade III standards for Groundwater quality in China, which indicated that the groundwater in the study area has been significantly affected by human activities. Hydrochemical method suggested that the chemical component originated from rock weathering, cation exchange and mineral dissolution. Based on isotope tracing technique (δ15N-NO3-, δ18O-NO3-, δ34S-SO42- and δ18O-SO42-), the primary sources of nitrate and sulfate in groundwater were soil nitrogen and oxidation of sulfide minerals in the forest area, domestic sewage and oxidation of sulfide minerals in the urban and industrial area, and mixed sources in the village and agricultural area. Finally, the pollution source of groundwater was distinguished by combining the PMF model, isotope tracing technique and hydrochemical method. Results showed that the main pollutant of groundwater is domestic sewage in the urban, village and industrial area. The contribution rates to groundwater pollution were 60.7%, 60.8% and 57.8%, respectively. However, in the forest and agricultural area, the main source changed to water-rock interaction and chemical fertilizer, and the contribution rates to groundwater quality were 53.5% and 61.0%, respectively. Our results suggested that the coupling tracing methodology can improve the accuracy of source resolution in the water environment and it can be applied to other areas of the world.

Derivation and Validation of an Ensemble Model for the Prediction of Agitation in Mechanically Ventilated Patients Maintained Under Light Sedation.

OBJECTIVES: Light sedation is recommended over deep sedation for invasive mechanical ventilation to improve clinical outcome but may increase the risk of agitation. This study aimed to develop and prospectively validate an ensemble machine learning model for the prediction of agitation on a daily basis. DESIGN: Variables collected in the early morning were used to develop an ensemble model by aggregating four machine learning algorithms including support vector machines, C5.0, adaptive boosting with classification trees, and extreme gradient boosting with classification trees, to predict the occurrence of agitation in the subsequent 24 hours. SETTING: The training dataset was prospectively collected in 95 ICUs from 80 Chinese hospitals on May 11, 2016, and the validation dataset was collected in 20 out of these 95 ICUs on December 16, 2019. PATIENTS: Invasive mechanical ventilation patients who were maintained under light sedation for 24 hours prior to the study day and who were to be maintained at the same sedation level for the next 24 hours. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 578 invasive mechanical ventilation patients from 95 ICUs in 80 Chinese hospitals, including 459 in the training dataset and 119 in the validation dataset, were enrolled. Agitation was observed in 36% (270/578) of the invasive mechanical ventilation patients. The stepwise regression model showed that higher body temperature (odds ratio for 1°C increase: 5.29; 95% CI, 3.70-7.84; p < 0.001), greater minute ventilation (odds ratio for 1 L/min increase: 1.15; 95% CI, 1.02-1.30; p = 0.019), higher Richmond Agitation-Sedation Scale (odds ratio for 1-point increase: 2.43; 95% CI, 1.92-3.16; p < 0.001), and days on invasive mechanical ventilation (odds ratio for 1-d increase: 0.95; 95% CI, 0.93-0.98; p = 0.001) were independently associated with agitation in the subsequent 24 hours. In the validation dataset, the ensemble model showed good discrimination (area under the receiver operating characteristic curve, 0.918; 95% CI, 0.866-0.969) and calibration (Hosmer-Lemeshow test p = 0.459) in predicting the occurrence of agitation within 24 hours. CONCLUSIONS: This study developed an ensemble model for the prediction of agitation in invasive mechanical ventilation patients under light sedation. The model showed good calibration and discrimination in an independent dataset.

Abnormal temperature-dependent photoluminescence characteristics of ReS2nanowalls.

Two samples with [001] orientated rhenium disulfide (ReS2) nanowalls (NWs) grown above and in front of precursor (NH4ReO4) by chemical vapor deposition were investigated. The temperature-dependent photoluminescence (PL) indicated that the PL peak exhibited linear blue-shift at a rate of ∼0.24 meV K-1with increasing the temperature from 10 to 300 K, while the linewidth monotonically increased due to the exciton-phonon interaction. This abnormal blue-shift of PL emission energy, which is explained by a competition between the band gap shrinkage and the energy level degeneracy with respect to the increase of temperature and lattice constant, enables ReS2NWs to possess great potential for development of thermal sensors. In addition, exciton localization effect in the ReS2NWs from abundant edges and weak interlayer interaction was also observed to be related to the height and density of ReS2NWs. These results not only enrich the understanding for exciton dynamics in ReS2NWs, but also help to exploit ReS2NWs for device applications.

Individualized resuscitation strategy for septic shock formalized by finite mixture modeling and dynamic treatment regimen.

BACKGROUND: Septic shock comprises a heterogeneous population, and individualized resuscitation strategy is of vital importance. The study aimed to identify subclasses of septic shock with non-supervised learning algorithms, so as to tailor resuscitation strategy for each class. METHODS: Patients with septic shock in 25 tertiary care teaching hospitals in China from January 2016 to December 2017 were enrolled in the study. Clinical and laboratory variables were collected on days 0, 1, 2, 3 and 7 after ICU admission. Subclasses of septic shock were identified by both finite mixture modeling and K-means clustering. Individualized fluid volume and norepinephrine dose were estimated using dynamic treatment regime (DTR) model to optimize the final mortality outcome. DTR models were validated in the eICU Collaborative Research Database (eICU-CRD) dataset. RESULTS: A total of 1437 patients with a mortality rate of 29% were included for analysis. The finite mixture modeling and K-means clustering robustly identified five classes of septic shock. Class 1 (baseline class) accounted for the majority of patients over all days; class 2 (critical class) had the highest severity of illness; class 3 (renal dysfunction) was characterized by renal dysfunction; class 4 (respiratory failure class) was characterized by respiratory failure; and class 5 (mild class) was characterized by the lowest mortality rate (21%). The optimal fluid infusion followed the resuscitation/de-resuscitation phases with initial large volume infusion and late restricted volume infusion. While class 1 transitioned to de-resuscitation phase on day 3, class 3 transitioned on day 1. Classes 1 and 3 might benefit from early use of norepinephrine, and class 2 can benefit from delayed use of norepinephrine while waiting for adequate fluid infusion. CONCLUSIONS: Septic shock comprises a heterogeneous population that can be robustly classified into five phenotypes. These classes can be easily identified with routine clinical variables and can help to tailor resuscitation strategy in the context of precise medicine.

Hydrogeochemistry and health hazards of fluoride-enriched groundwater in the Tarim Basin, China.

Fluoride (F-) enrichment reduces the availability of groundwater resources in the arid region, and it is thus important to investigate the hydrogeochemistry and health hazards of fluoride-enriched groundwater. Seventy-two groundwater samples (20 unconfined samples from the piedmont plain, 22 unconfined samples and 30 shallow confined samples from the alluvial plain) were collected in the Tarim Basin of China to illustrate the geochemical processes driving the F- enrichment and the incidence of dental fluorosis. The patterns of average ions contents in groundwater are Na+ > Ca2+ > Mg2+ > K+ and SO42- > Cl- > HCO3- > NO3- > F-. The highest F- concentration (average 2.16 mg/L) is observed in unconfined groundwater in the alluvial plain, while the lowest (average 0.63 mg/L) is recorded in unconfined groundwater in the piedmont plain. Approximately 5.0% of unconfined groundwater in the piedmont plain, 90.9% of unconfined groundwater and 33.3% of shallow confined groundwater in the alluvial plain contain F- concentrations exceeding 1.0 mg/L (Chinese drinking water standard). Mineral dissolution, cation exchange, and evaporation play a significant role in the formation of solutes in groundwater. High-F- groundwater is mostly associated with SO4·Cl-Na·Ca, SO4·Cl-Na·Mg, and SO4·Cl-Na types water. Thermodynamic simulations reveal that the dissolution of F-bearing minerals (e.g., fluorite) significantly controls the F- contents in groundwater. High concentrations of F- are closely related to high HCO3-, high Na+, high salinity, cation exchange, and evaporation. This demonstrates that high F- concentrations are caused by the increase in fluorite solubility due to high ionic strength, Ca2+ consumption and the desorption of F- from solid surfaces under alkaline conditions. Mixing with the upper unconfined groundwater plays a vital role in the enrichment of F- in shallow confined groundwater in the alluvial plain. The health risk assessment based on Dean's classification indicates that the percentage prevalence of fluorosis for boys aged 6 to 18 is 15.5% for Yecheng (YC), 18.4% for Zepu (ZP), 33.3% for Shache (SC), 29.8% for Maigaiti (MG), and 44.9% for Bachu (BC), while that for girls of the same age is 14.3% for YC, 24.3% for ZP, 42.2% for SC, 41.4% for MG, and 45.3% for BC. For male and female adults aged between 19 and 68, the percentage prevalence of fluorosis is: YC (11.5%, 12.0%), ZP (18.3%, 20.0%), SC (35.4%, 35.0%), MG (32.5%, 39.7%), and BC (42.4%, 44.3%). It is obvious that younger generation, especially girls, suffers from more severe dental fluorosis. This study has implications for the effective management of high-F- groundwater in arid regions.

Infrared Small Target Detection Method with Trajectory Correction Fuze Based on Infrared Image Sensor.

Due to the complexity of background and diversity of small targets, robust detection of infrared small targets for the trajectory correction fuze has become a challenge. To solve this problem, different from the traditional method, a state-of-the-art detection method based on density-distance space is proposed to apply to the trajectory correction fuze. First, parameters of the infrared image sensor on the fuze are calculated to set the boundary limitations for the target detection method. Second, the density-distance space method is proposed to detect the candidate targets. Finally, the adaptive pixel growth (APG) algorithm is used to suppress the clutter so as to detect the real targets. Three experiments, including equivalent detection, simulation and hardware-in-loop, were implemented to verify the effectiveness of this method. Results illustrated that the infrared image sensor on the fuze has a stable field of view under rotation of the projectile, and could clearly observe the infrared small target. The proposed method has superior anti-noise, different size target detection, multi-target detection and various clutter suppression capability. Compared with six novel algorithms, our algorithm shows a perfect detection performance and acceptable time consumption.

All-trans retinoic acid (ATRA) inhibits insufficient radiofrequency ablation (IRFA)-induced enrichment of tumor-initiating cells in hepatocellular carcinoma.

OBJECTIVE: Local recurrence of hepatocellular carcinoma (HCC) after radiofrequency ablation (RFA) treatment remains a serious problem. Tumor-initiating cells (TICs) are thought to be responsible for tumor relapse. Here, we investigated the effect of the TIC differentiation inducer, all-trans retinoic acid (ATRA), on RFA and explored the potential molecular mechanisms. METHODS: The proportions of CD133+ and epithelial cell adhesion molecule (EpCAM)+ TICs in recurrent HCC after RFA and primary HCC were first determined in clinic. Then, the effect of heat intervention or insufficient RFA (IRFA) on the malignant potential of HCC cells, including cell migration, sphere formation ability, tumor growth, the proportion of CD133+ and EpCAM+ TICs and expression of stem cell-related genes, was evaluated in vitro andin vivo. Finally, the effect of ATRA on the tumor growth and the proportion of TICs was evaluated. RESULTS: In clinical data, a higher proportion of CD133+ and EpCAM+ TICs was found in recurrent tumors than in primary tumors. In vitro heat intervention promoted the cell migration and sphere formation ability. Additionally, it increased the proportion of CD133+ and EpCAM+ TICs and the expression of stem cell-related genes. In addition, after IRFA the residual tumors in xenografts grew faster and had more TICs than untreated tumors. ATRA remarkably inhibited residual tumor growth after IRFA by elimination of TICs though the PI3K/AKT pathway. Combination treatment with ATRA resulted in longer survival outcomes in mouse xenografts than RFA alone. CONCLUSIONS: ATRA, as a TIC differentiation inducer, could help to improve the effect of RFA treatment, which was partially attributed to its effect against TICs. The data indicated its potential as an alternative drug in the development of better therapeutic strategies for use in combination with RFA.

Large SARS-CoV-2 Outbreak Caused by Asymptomatic Traveler, China.

An asymptomatic person infected with severe acute respiratory syndrome coronavirus 2 returned to Heilongjiang Province, China, after international travel. The traveler's neighbor became infected and generated a cluster of >71 cases, including cases in 2 hospitals. Genome sequences of the virus were distinct from viral genomes previously circulating in China.

Effects of shell sand burial on seedling emergence, growth and stoichiometry of Periploca sepium Bunge.

BACKGROUND: Sand burial plays an irreplaceable and unique role in the growth and distribution of vegetation on the Shell Dike Island in the Yellow River Delta. There are still some unknown on the effects of sand burial on the morphology, biomass, and especially the stoichiometry of Periploca sepium, as well as the relationship between these factors. RESULTS: Shell sand burial depth had a significant influence on seedling emergence, growth, and biomass of P. sepium. Shallow sand burial shortened the emergence time and improved the emergence rate, morphological and biomass of P. sepium compared to deep burial and the control. Burial depth significantly affected the nitrogen (N) and phosphorus (P) contents of the leaves. With deep burial, the carbon/nitrogen (C/N) and carbon/phosphorus (C/P) ratios decreased firstly and then increased with depth, while the nitrogen/phosphorus ratio (N/P) presented the contrary trend. Correlation analysis showed that the stoichiometry of N/P was positively correlated to morphology and biomass of P. sepium at different burial depths. Structural equation model analysis revealed that N was the largest contributor to P. sepium biomass. CONCLUSIONS: Optimal burial depth is beneficial to the seedling emergence, growth and nutritional accumulation of P. sepium. Stoichiometry has an important influence on the morphological formation and biomass accumulation.

Photoluminescence characterization of wetting layer and carrier dynamics for coupled InGaAs/GaAs surface quantum dot pair structures.

The optical properties are investigated by spectroscopic characterizations for bilayer InGaAs/GaAs quantum dot (QD) structures consisting of a layer of surface quantum dots (SQDs) separated from a layer of buried quantum dots (BQDs) by different GaAs spacers with thicknesses of 7 nm, 10.5 nm and 70 nm. The coupling from the BQDs to SQDs leads to carrier transfer for the two samples with thin spacers, 7 nm and 10.5 nm, in which QD pairs are obtained while not for the 70 nm spacer sample. The carrier tunneling time is measured to be 0.145 ns and 0.275 ns from BQDs to SQD through the 7 nm and 10.5 nm spacers, respectively. A weak emission band can be observed at the wavelength of ∼ 960 nm, while the excitation intensity dependent PL and PLE spectra show that this is from the wetting layer (WL) of the SQDs. This WL is very important for carrier dynamics in bilayer structures of BQDs and SQDs, including for carrier generation, capture, relaxation, tunneling, and recombination. These results provide useful information for understanding the optical properties of InGaAs SQDs and for using such hybrid structures as building blocks for surface sensing devices.

Early fluid loading for septic patients: Any safety limit needed?

Early adequate fluid loading was the corner stone of hemodynamic optimization for sepsis and septic shock. Meanwhile, recent recommended protocol for fluid resuscitation was increasingly debated on hemodynamic stability vs risk of overloading. In recent publications, it was found that a priority was often given to hemodynamic stability rather than organ function alternation in the early fluid resuscitation of sepsis. However, no safety limits were used at all in most of these reports. In this article, the rationality and safety of early aggressive fluid loading for septic patients were discussed. It was concluded that early aggressive fluid loading improved hemodynamics transitorily, but was probably traded off with a follow-up organ function impairment, such as worsening oxygenation by reduction of lung aeration, in a part of septic patients at least. Thus, a safeguard is needed against unnecessary excessive fluids in early aggressive fluid loading for septic patients.

RNAi-Induced Electrophysiological and Behavioral Changes Reveal two Pheromone Binding Proteins of Helicoverpa armigera Involved in the Perception of the Main Sex Pheromone Component Z11-16:Ald.

Pheromone binding proteins (PBPs) are thought to play key roles in insect sex pheromone recognition; however, there is little in vivo evidence to support this viewpoint in comparison to abundant biochemical data in vitro. In the present study, two noctuid PBP genes HarmPBP1 and HarmPBP2 of the serious agricultural pest, Helicoverpa armigera were selected to be knocked down by RNA interference, and then the changes in electrophysiological and behavioral responses of male mutants to their major sex pheromone component (Z)-11-hexadecenal (Z11-16:Ald) were recorded. There were no significant electrophysiological or behavioral changes of tested male moths in response to Z11-16:Ald when either single PBP gene was knocked down. However, decreased sensitivity of male moths in response to Z11-16:Ald was observed when both HarmPBP1 and HarmPBP2 genes were silenced. These results reveal that both HarmPBP1 and HarmPBP2 are required for the recognition of the main sex pheromone component Z11-16:Ald in H. armigera. Furthermore, these findings may help clarify physiological roles of moth PBPs in the sex pheromone recognition pathway, which in turn could facilitate pest control by exploring sex pheromone blocking agents.

Dissecting and engineering of the TetR family regulator SACE_7301 for enhanced erythromycin production in Saccharopolyspora erythraea.

BACKGROUND: Saccharopolyspora erythraea was extensively utilized for the industrial-scale production of erythromycin A (Er-A), a macrolide antibiotic commonly used in human medicine. Yet, S. erythraea lacks regulatory genes in the erythromycin biosynthetic gene (ery) cluster, hampering efforts to enhance Er-A production via the engineering of regulatory genes. RESULTS: By the chromosome gene inactivation technique based on homologous recombination with linearized DNA fragments, we have inactivated a number of candidate TetR family transcriptional regulators (TFRs) and identified one TFR (SACE_7301) positively controlling erythromycin biosynthesis in S. erythraea A226. qRT-PCR and EMSA analyses demonstrated that SACE_7301 activated the transcription of erythromycin biosynthetic gene eryAI and the resistance gene ermE by interacting with their promoter regions with low affinities, similar to BldD (SACE_2077) previously identified to regulate erythromycin biosynthesis and morphological differentiation. Therefore, we designed a strategy for overexpressing SACE_7301 with 1 to 3 extra copies under the control of PermE* in A226. Following up-regulated transcriptional expression of SACE_7301, eryAI and ermE, the SACE_7301-overexpressed strains all increased Er-A production over A226 proportional to the number of copies. Likewise, when SACE_7301 was overexpressed in an industrial S. erythraea WB strain, Er-A yields of the mutants WB/7301, WB/2×7301 and WB/3×7301 were respectively increased by 17%, 29% and 42% relative to that of WB. In a 5 L fermentor, Er-A accumulation increased to 4,230 mg/L with the highest-yield strain WB/3×7301, an approximately 27% production improvement over WB (3,322 mg/L). CONCLUSIONS: We have identified and characterized a TFR, SACE_7301, in S. erythraea that positively regulated erythromycin biosynthesis, and overexpression of SACE_7301 in wild-type and industrial S. erythraea strains enhanced Er-A yields. This study markedly improves our understanding of the unusual regulatory mechanism of erythromycin biosynthesis, and provides a novel strategy towards Er-A overproduction by engineering transcriptional regulators of S. erythraea.

Effects of salt-drought stress on growth and physiobiochemical characteristics of Tamarix chinensis seedlings.

The present study was designed to clarify the effects of salinity and water intercross stresses on the growth and physiobiochemical characteristics of Tamarix chinensis seedlings by pots culture under the artificial simulated conditions. The growth, activities of SOD, POD, and contents of MDA and osmotic adjusting substances of three years old seedlings of T. chinensis were studied under different salt-drought intercross stress. Results showed that the influence of salt stress on growth was greater than drought stress, the oxidation resistance of SOD and POD weakened gradually with salt and drought stresses intensified, and the content of MDA was higher under severe drought and mild and moderate salt stresses. The proline contents increased with the stress intensified but only significantly higher than control under the intercross stresses of severe salt-severe drought. It implied that T. chinensis could improve its stress resistance by adjusted self-growth and physiobiochemical characteristics, and the intercross compatibility of T. chinensis to salt and drought stresses can enhance the salt resistance under appropriate drought stress, but the dominant factors influencing the physiological biochemical characteristics of T. chinensis were various with the changing of salt-drought intercross stresses gradients.

Protein expression of nucleolar protein 12 in the retina and its implication in protection of retina from UV irradiation damage.

Nucleolar protein 12 (NOL12), one of the nucleolar proteins which are primarily expressed in the nucleolus and play key roles in RNA metabolism, cell proliferation, cell cycle, and cell survival, is widely expressed in various species and multiple organs. Although it has been reported that the mRNA of Drosophila NOL12 homolog viriato is expressed in the eyes of Drosophila, the protein expression of NOL12 in mammalian eyes remains to be elucidated. In this study, we showed through immunohistochemistry that NOL12 was present in the rat retina, with predominant distribution in the cytoplasm of the retinal neuronal cells. In the human retinoblastoma cell line WERI-Rb1, we found that altering NOL12 expression led to a change in WERI-Rb1 cell viability. Knocking down NOL12 expression decreased cell viability. In contrast, overexpressing NOL12 increased cell viability. Furthermore, increasing NOL12 expression inhibited ultraviolet (UV)-induced apoptosis. These findings demonstrated that NOL12 may play an important protective role in retinal cells. In the WERI-Rb1 cells exposed to UV irradiation, we detected that NOL12 was degraded, but this degradation could be attenuated by a pan-Caspase inhibitor. Notably, the inhibitory effect of NOL12 against UV-induced apoptosis could be restrained by increasing the expression of ATR serine/threonine kinase (ATR), a kinase that, when activated by severe DNA damage, can result in apoptosis. We also found that upregulating NOL12 inhibited the activation of ATR caused by UV irradiation. Additionally, inhibiting ATR activity reduced apoptosis resulting from both silencing NOL12 expression and UV exposure. Thus, NOL12 may protect against UV irradiation-induced retinal damage by inhibiting ATR activity.

The significance of CD4+ and CD8+ T lymphocyte infiltration in esophageal squamous cell carcinoma.

PURPOSE: To investigate the relationship between the abundance of CD4+ and CD8+ T cells in the tumor microenvironment and the prognosis of patients with esophageal squamous cell carcinoma, and to analyze their correlation and explore its clinical value. MATERIALS AND METHODS: In total, we enrolled 120 cases of esophageal squamous cell carcinoma diagnosed. The abundance of CD4+ and CD8+ T lymphocytes in the tissue specimens of esophageal cancer was examined by immunohistochemistry. We measured the correlation between the abundance of CD4+ and CD8+ T lymphocytes and the clinical and pathological characteristics and prognosis of esophageal squamous cell carcinoma. RESULTS: The tissue abundance of CD4+ T lymphocytes was closely related to tumor prognosis (P < 0.05). Similarly, there was a statistically significant relationship between the tissue abundance of CD8+ T lymphocytes and patients' prognosis (P < 0.05), indicating that a high abundance of CD8+ T lymphocytes predicts better prognosis in esophageal squamous cell carcinoma. Surprisingly, we found that a higher CD4+/CD8+ ratio predicted a better prognosis of esophageal squamous cell carcinoma. CONCLUSIONS: The tissue abundance of CD4+ and CD8+ T lymphocytes can serve as an important indicator for predicting the long-term survival of patients with esophageal squamous cell carcinoma. A high CD4+/CD8+ ratio may improve patients' prognosis through several pathways. The association of this ratio with clinical and pathological characteristics may explain the poor efficacy of immunotherapy in patients with esophageal cancer. These findings may help us find new targets for immunotherapy by exploring the immune microenvironment of esophageal squamous cell carcinoma.

Single-cell RNA sequencing reveals aberrant sphingolipid metabolism in non-small cell lung cancer impacts tumor-associated macrophages and stimulates angiogenesis via macrophage inhibitory factor signaling.

BACKGROUND: Sphingolipids not only serve as structural components for maintaining cell membrane fluidity but also function as bioactive molecules involved in cell signaling and the regulation of various biological processes. Their pivotal role in cancer cell development, encompassing cancer cell proliferation, migration, angiogenesis, and metastasis, has been a focal point for decades. However, the contribution of sphingolipids to the complexity of tumor microenvironment promoting cancer progression has been rarely investigated. METHODS: Through the integration of publicly available bulk RNA-seq and single-cell RNA-seq data, we conducted a comprehensive analysis to compare the transcriptomic features between tumors and adjacent normal tissues, thus elucidating the intricacies of the tumor microenvironment (TME). RESULTS: Disparities in sphingolipid metabolism (SLM)-associated genes were observed between normal and cancerous tissues, with the TME characterized by the enrichment of sphingolipid signaling in macrophages. Cellular interaction analysis revealed robust communication between macrophages and cancer cells exhibiting low SLM, identifying the crucial ligand-receptor pair, macrophage inhibitory factor (MIF)-CD74. Pseudo-time analysis unveiled the involvement of SLM in modulating macrophage polarization towards either M1 or M2 phenotypes. Categorizing macrophages into six subclusters based on gene expression patterns and function, the SPP1+ cluster, RGS1+ cluster, and CXCL10+ cluster were likely implicated in sphingolipid-induced M2 macrophage polarization. Additionally, the CXCL10+, AGER+, and FABP4+ clusters were likely to be involved in angiogenesis through their interaction with endothelial cells. CONCLUSION: Based on multiple scRNA-seq datasets, we propose that a MIF-targeted strategy could potentially impede the polarization from M1 to M2 and impair tumor angiogenesis in low-SLM non-small cell lung cancer (NSCLC), demonstrating its potent antitumor efficacy.

Primary Alveolar Soft-Part Sarcoma of the Lung: A Case Report.

Alveolar soft-part sarcoma is a rare type of soft tissue malignant tumor. Although the tumor can occur in many parts of the body, primary alveolar soft-part sarcoma of the lung is extremely rare. According to previous literature, only 3 cases of primary alveolar soft-part sarcoma of the lung were reported, and no comprehensive analysis was conducted on these cases. Here, we describe another case of alveolar soft-part sarcoma in the lung, where the negative results of immunohistochemical staining cause extreme difficulty in distinguishing this lesion from other tumors. A 30-year-old Chinese male presented with chest pain and dyspnea. Computed tomography revealed a pulmonary mass, and biopsy results showed vacuolar tumor cells with abundant eosinophilic cytoplasm. A number of immunohistochemical markers were negative, but the tumor cells were positive for TFE3 and ASPSCR1::TFE3 fusion gene. No other tumor masses were found in the patient after whole-body scanning. The final diagnosis was primary alveolar soft-part sarcoma of the lung. Pathologists should consider the possibility of alveolar soft-part sarcoma in lung tumors with typical "organ like" or "acinar like" cell nests, where the tumor cells are large, vacuolated, and the nucleolus is obvious. After excluding metastasis from other sites, TFE3 immunohistochemical staining and ASPSCR1::TFE3 fusion gene detection are recommended for the diagnosis of primary alveolar soft-part sarcoma.