Base-Promoted Nucleophilic Phosphorylation of Benzyl Fluorides via C(sp3)-F Cleavage.

Herein, a transition-metal-free phosphorylation of benzyl fluorides with P(O)-H compounds is disclosed. In the presence of tBuOK, various benzyl fluorides react with P(O)-H compounds to produce the corresponding benzyl phosphine oxides, phosphinates, and phosphonates in good to high yields. This base-promoted phosphorylation reaction offers a facile and general strategy for the construction of a C(sp3)-P bond.

Embedded finite element modeling of the mechanics of brain axonal fiber tracts under head impact conditions.

Investigating and understanding the biomechanical kinematics and kinetics of human brain axonal fibers during head impact process is crucial to study the mechanisms of Traumatic Axonal Injury (TAI). Such a study may require the explicit incorporation of brain fiber tracts into the host brain in order to distinguish the mechanical states of axonal fibers and brain tissue. Herein we extend our previously developed human head model by using an embedded element method to include fiber tracts reconstructed from diffusion tensor images in a host brain with the purpose of numerically tracking the deformation state of axonal fiber tracts during a head impact simulation. The updated model is validated by comparing its prediction of intracranial pressures with experimental data, followed by a thorough study of the effects of element types used for fiber tracts and the stiffness ratios of fiber to host brain. The validated model is also used to predict and visualize the damaged region of fiber tracts during the head impact process based on different injury criteria. The model is promising in tracking the state of fiber tracts and can add more objective functions such as axonal fiber deformation if used in the future design optimization of head protective equipment such as a football helmet.

Adverse complications of cervical spinal fusion in patients with different types of diabetes mellitus: A retrospective nationwide inpatient sample database cross-sectional study.

BACKGROUND: Diabetes mellitus (DM) is a prevalent chronic condition that influences spine surgery outcomes. The impact of type Ⅰ and type Ⅱ DM on adverse postoperative outcomes, mortality, prolonged length of stay (LOS), and increased in-hospital costs following cervical fusion surgery remains unclear in the past decade. This study aims to determine the specific effect of different classifications of DM on postoperative complications in patients experiencing cervical fusion surgery. METHOD: Data from the Nationwide Inpatient Sample database was acquired between 2010 and 2019. Patients experiencing cervical fusion were included and classified as having type I DM, type II DM, or neither. Patient demographics, hospital characteristics, operative variables, comorbidities, complications, and other postoperative outcomes were assessed. Propensity score matching analysis was used to balance baseline differences. Univariate and multivariate logistic regression were employed to determine the risk of postoperative outcomes in patients with different classifications of DM. RESULT: A total of 267,174 cervical spinal fusions were identified (224,255 were patients without DM, 670 patients had type I DM, and 42,249 patients had type II DM). After propensity score matching, the multivariate analysis of non-DM and type I DM patients shows significant difference in pneumonia (P=0.020). However, type Ⅱ DM served as an independent predictor of an increased risk of acute cerebrovascular disease (P=0.001), acute myocardial infarction (P=0.014), pneumonia (P=0.045), continuous trauma ventilation (P=0.016), chest pain (P<0.001), urinary tract infection (P<0.001), transfusion (P=0.005) and dysphagia (P=0.013), prolonged LOS (P<0.001) and increased costs (P=0.008). CONCLUSION: Using non-DM patients as a reference, type II DM group demonstrated a higher risk of postoperative complications than type I DM group among patients receiving cervical fusion surgery. This vital distinction could enhance risk stratification and guidance for patients diagnosed with DM before cervical fusion surgery.

A leaf age-dependent light use efficiency model for remote sensing the gross primary productivity seasonality over pantropical evergreen broadleaved forests.

Tropical and subtropical evergreen broadleaved forests (TEFs) contribute more than one-third of terrestrial gross primary productivity (GPP). However, the continental-scale leaf phenology-photosynthesis nexus over TEFs is still poorly understood to date. This knowledge gap hinders most light use efficiency (LUE) models from accurately simulating the GPP seasonality in TEFs. Leaf age is the crucial plant trait to link the dynamics of leaf phenology with GPP seasonality. Thus, here we incorporated the seasonal leaf area index of different leaf age cohorts into a widely used LUE model (i.e., EC-LUE) and proposed a novel leaf age-dependent LUE model (denoted as LA-LUE model). At the site level, the LA-LUE model (average R2 = .59, average root-mean-square error [RMSE] = 1.23 gC m-2 day-1) performs better than the EC-LUE model in simulating the GPP seasonality across the nine TEFs sites (average R2 = .18; average RMSE = 1.87 gC m-2 day-1). At the continental scale, the monthly GPP estimates from the LA-LUE model are consistent with FLUXCOM GPP data (R2 = .80; average RMSE = 1.74 gC m-2 day-1), and satellite-based GPP data retrieved from the global Orbiting Carbon Observatory-2 (OCO-2) based solar-induced chlorophyll fluorescence (SIF) product (GOSIF) (R2 = .64; average RMSE = 1.90 gC m-2 day-1) and the reconstructed TROPOspheric Monitoring Instrument SIF dataset using machine learning algorithms (RTSIF) (R2 = .78; average RMSE = 1.88 gC m-2 day-1). Typically, the estimated monthly GPP not only successfully represents the unimodal GPP seasonality near the Tropics of Cancer and Capricorn, but also captures well the bimodal GPP seasonality near the Equator. Overall, this study for the first time integrates the leaf age information into the satellite-based LUE model and provides a feasible implementation for mapping the continental-scale GPP seasonality over the entire TEFs.

[Analysis of Heavy Metal Sources in Farmland Soil of Sewage Irrigation and Industrial Complex Area Based on APCS-MLR and PMF].

The contents of eight heavy metals （Cr, Ni, Cu, Zn, Cd, Pb, As, and Hg） were determined based on the surface soil samples of sewage irrigation and industrial complex in Kaifeng City. The absolute factor analysis-multiple linear regression （APCS-MLR） model and positive matrix factorization （PMF） model were used to analyze the sources and contribution rates of heavy metals in soil combined with correlation analysis and systematic cluster analysis. The results showed that： ① The average values of ω（Cr）, ω（Ni）, ω（Cu）, ω（Zn）, ω（Cd）, ω（Pb）, ω（As）, and ω（Hg） in the study area were 52.19, 25.00, 42.03, 323.53, 1.79, 53.45, 9.43, and 0.20 mg·kg-1, respectively, and Cr, Ni, and As are lower than the background values of tidal soil. Cu, Zn, Cd, Pb, and Hg are higher than the background values of the tidal soil. ② There were four sources of the eight heavy metals： natural sources, agricultural sewage irrigation sources, industrial atmospheric sedimentation sources, and transportation sources. Cr and Ni were mainly from natural sources； Cu, Zn, Cd, and Pb were mainly from agricultural sewage irrigation and transportation sources； As was mainly from natural sources and agricultural sewage irrigation； and Hg was mainly from industrial atmospheric sedimentation. ③ The APCS-MLR and PMF source analysis results indicated that industrial and agricultural activities were the main sources of heavy metals in the soil of the study area. The average contribution rates of APCS-MLR in the nine sampling areas of the research area were 76.01% （natural sources and agricultural sewage irrigation sources）, 22.71% （industrial atmospheric sedimentation sources and transportation sources）, and 1.28% （unknown sources）. The average contribution rates of PMF were 59.66% （natural sources and agricultural sewage irrigation sources） and 40.34% （industrial atmospheric sedimentation sources and transportation sources）. The source analysis results of the LZ, XZ, NLT, PT, YLZ, and BC models were basically consistent, and WL was better in the APCS-MLR model, whereas SG and QT were better in the PMF model. The research results can provide a scientific basis for the prevention and control of soil heavy metal pollution and environmental remediation.

Dominant role of the non-forest woody vegetation in the post 2015/16 El Niño tropical carbon recovery.

The extreme dry and hot 2015/16 El Niño episode caused large losses in tropical live aboveground carbon (AGC) stocks. Followed by climatic conditions conducive to high vegetation productivity since 2016, tropical AGC are expected to recover from large losses during the El Niño episode; however, the recovery rate and its spatial distribution remain unknown. Here, we used low-frequency microwave satellite data to track AGC changes, and showed that tropical AGC stocks returned to pre-El Niño levels by the end of 2020, resulting in an AGC sink of 0.18 0.14 0.26 $$ {0.18}_{0.14}^{0.26} $$ Pg C year-1 during 2014-2020. This sink was dominated by strong AGC increases ( 0.61 0.49 0.84 $$ {0.61}_{0.49}^{0.84} $$ Pg C year-1) in non-forest woody vegetation during 2016-2020, compensating the forest AGC losses attributed to the El Niño event, forest loss, and degradation. Our findings highlight that non-forest woody vegetation is an increasingly important contributor to interannual to decadal variability in the global carbon cycle.

Selective and stable CO2 electroreduction at high rates via control of local H2O/CO2 ratio.

Controlling the concentrations of H2O and CO2 at the reaction interface is crucial for achieving efficient electrochemical CO2 reduction. However, precise control of these variables during catalysis remains challenging, and the underlying mechanisms are not fully understood. Herein, guided by a multi-physics model, we demonstrate that tuning the local H2O/CO2 concentrations is achievable by thin polymer coatings on the catalyst surface. Beyond the often-explored hydrophobicity, polymer properties of gas permeability and water-uptake ability are even more critical for this purpose. With these insights, we achieve CO2 reduction on copper with Faradaic efficiency exceeding 87% towards multi-carbon products at a high current density of -2 A cm-2. Encouraging cathodic energy efficiency (>50%) is also observed at this high current density due to the substantially reduced cathodic potential. Additionally, we demonstrate stable CO2 reduction for over 150 h at practically relevant current densities owning to the robust reaction interface. Moreover, this strategy has been extended to membrane electrode assemblies and other catalysts for CO2 reduction. Our findings underscore the significance of fine-tuning the local H2O/CO2 balance for future CO2 reduction applications.

Case report: Formation and recurrence of inflammatory pseudotumor after metal-on-metal hip arthroplasty.

The metal-on-metal (MoM) artificial hip joint is a prosthesis used in early hip arthroplasty, particularly for hip resurfacing and total hip arthroplasty. However, abrasion and corrosion of MoM bearings result in the production of metal ions, such as cobalt and chromium, thereby inducing several complications such as inflammatory pseudotumor, aseptic inflammation, and allergy to metal ions (delayed type IV hypersensitivity). In this case report, we present a patient who was hospitalized for recurrence of a mass in the right inguinal area. In 2010, the patient underwent right MoM total hip arthroplasty for right femoral head necrosis and exhibited a good postoperative recovery. In 2019, the patient experienced pain in the right hip with activity limitation without any evident triggers, and a palpable mass was observed in the right inguinal area. A large periprosthetic mass was resected under general anesthesia, and the patient recovered well after the operation. Based on post-surgery imaging and pathological examinations, the mass was diagnosed as a periprosthetic inflammatory pseudotumor. In 2021, the inflammatory pseudotumor recurred at the same site. He then underwent right total hip revision surgery under epidural anesthesia and recovered well after surgery. No recurrence was noted at moderate follow-up. The incidence of inflammatory pseudotumors is high in MoM hip arthroplasty. Early revision is necessary in patients who meet the indications for revision, while regular postoperative follow-up is crucial.

Comparison of Left Ventricular Function Derived from Subject-Specific Inverse Finite Element Modeling Based on 3D ECHO and Magnetic Resonance Images.

Three-dimensional echocardiography (3D ECHO) and magnetic resonance (MR) imaging are frequently used in patients and animals to evaluate heart functions. Inverse finite element (FE) modeling is increasingly applied to MR images to quantify left ventricular (LV) function and estimate myocardial contractility and other cardiac biomarkers. It remains unclear, however, as to whether myocardial contractility derived from the inverse FE model based on 3D ECHO images is comparable to that derived from MR images. To address this issue, we developed a subject-specific inverse FE model based on 3D ECHO and MR images acquired from seven healthy swine models to investigate if there are differences in myocardial contractility and LV geometrical features derived using these two imaging modalities. We showed that end-systolic and end-diastolic volumes derived from 3D ECHO images are comparable to those derived from MR images (R2=0.805 and 0.969, respectively). As a result, ejection fraction from 3D ECHO and MR images are linearly correlated (R2=0.977) with the limit of agreement (LOA) ranging from -17.95% to 45.89%. Using an inverse FE modeling to fit pressure and volume waveforms in subject-specific LV geometry reconstructed from 3D ECHO and MR images, we found that myocardial contractility derived from these two imaging modalities are linearly correlated with an R2 value of 0.989, a gradient of 0.895, and LOA ranging from -6.11% to 36.66%. This finding supports using 3D ECHO images in image-based inverse FE modeling to estimate myocardial contractility.

Molecular Mechanisms of Plant Extracts in Protecting Aging Blood Vessels.

Plant Extracts (PE) are natural substances extracted from plants, rich in various bioactive components. Exploring the molecular mechanisms and interactions involved in the vascular protective effects of PE is beneficial for the development of further strategies to protect aging blood vessels. For this review, the content was obtained from scientific databases such as PubMed, China National Knowledge Infrastructure (CNKI), and Google Scholar up to July 2024, using the search terms "Plant extracts", "oxidative stress", "vascular aging", "endothelial dysfunction", "ROS", and "inflammation". This review highlighted the effects of PE in protecting aging blood vessels. Through pathways such as scavenging reactive oxygen species, activating antioxidant signaling pathways, enhancing respiratory chain complex activity, inhibiting mitochondrial-reactive oxygen species generation, improving nitric oxide bioavailability, downregulating the secretion of inflammatory factors, and activating sirtuins 1 and Nrf2 signaling pathways, it can improve vascular structural and functional changes caused by age-related oxidative stress, mitochondrial dysfunction, and inflammation due to aging, thereby reducing the incidence of age-related cardiovascular diseases.

A prospective phase 2 study of combination epigenetic therapy against relapsed/refractory peripheral T cell lymphoma.

BACKGROUND: Peripheral T cell lymphomas (PTCLs) are prototypical epigenetic malignancies with invariably poor prognoses. Novel and effective therapeutic strategies are needed to improve clinical outcomes, particularly in relapsed/refractory patients. METHODS: We conducted a multicenter phase 2 study to evaluate the therapeutic efficacy of azacitidine and chidamide, alone or in combination with gemcitabine and oxaliplatin (GemOx), in patients with relapsed/refractory PTCLs (registration number: ChiCTR2000037232). The primary endpoint was the best overall response rate. FINDINGS: As of May 1st, 2024, thirty patients were evaluable for efficacy and toxicity. The best overall response rate was 53.3%, meeting its primary endpoint. Among the patients with angioimmunoblastic T cell lymphoma (AITL; N = 19), a numerically higher response rate was observed, regardless of whether chemotherapy was combined, compared to patients with non-AITL. After a median follow-up of 36.6 months, median progression-free survival and overall survival were 7.1 and 8.7 months, respectively. Patients with AITL who received combination chemotherapy (N = 12) achieved the most promising response rates (overall response rate, 91.7%; complete remission rate, 66.7%) and survival outcomes (median progression-free survival, 17.2 months; median overall survival, 38.8 months). The most common grade 3-4 toxicities were neutropenia (40.0%) and thrombocytopenia (30.0%). CONCLUSIONS: The combination of epigenetic therapy with GemOx was well tolerated and highly effective in patients with relapsed/refractory PTCLs. Patients with AITL, in particular, may benefit more from this combination treatment and should be the focus of future studies. FUNDING: This work was funded by the Natural Science Foundation of Jiangsu Province (BK20232039).

Reconstructing high-resolution gridded precipitation data in the southwest China highland canyon area using an improved (MGWR) downscaling method.

High-spatiotemporal-resolution rainfall data are vital for investigating local terrestrial water cycles. Although remote-sensing satellite retrieval of precipitation products effectively reproduces spatial patterns of rainfall, it suffers from low spatial resolution. To overcome such limitations, a two-step downscaling approach is proposed here. First, 80 % of the meteorological-station data is utilized to calibrate the original Global Precipitation Measurement (GPM) data, enhancing the correlation between GPM and station data. Subsequently, utilizing elevation, slope, aspect, the normalized difference vegetation index (NDVI), wind direction, water vapor, and land surface temperature, as well as slope and aspect correction factors, as independent variables, multiscale geographically weighted regression (MGWR) and temporal lag MGWR (TL-MGWR) models were constructed. Through the aforementioned steps, downscaled monthly and daily precipitation data for the geographic region under investigation in 2022 at a spatial resolution of 0.01° were obtained. Our findings indicate that selectively employing suitable MGWR or TL-MGWR models on a monthly basis can effectively downscale monthly GPM rainfall data. The downscaled (original) monthly precipitation data exhibited a correlation of 0.94 (0.768), with a mean absolute error (MAE) of 16.233 mm/month, root-mean-square error (RMSE) of 27.106 mm/month, and bias of -0.043. Similar enhancement was likewise noted in daily precipitation, displaying a correlation coefficient of 0.863 (0.318) for downscaled (original) data, and a RMSE of 3.209 mm/day, MAE of 1.082 mm/day, and bias of -0.06. The downscaled results show a correlation increase of 0.172 monthly and 0.545 daily, with MAE reductions of 18.43 mm/month and 1.658 mm/day, RMSE reductions of 26.172 mm/month and 4.183 mm/day, and bias reductions of 82.7 % and 56.8 %. In summary, the data after downscaling, both for monthly and daily datasets, was markedly improved in accuracy. The proposed downscaling method is applicable for reconstructing high-resolution grid data in the complex terrain of the southwest China highland canyon area.

Thrombocytopenia in SFTS due to platelets with altered function undergoing cell death pathways.

BACKGROUND: Thrombocytopenia is the major clinical feature associated with the severity of SFTS, but the mechanism by which it occurs remains unclear. METHODS: RNA transcriptome analyses were performed on platelets purified from SFTS patients and SFTSV-infected mice. The functions of differentially expressed genes (DEGs) in the platelets were characterized. ELISA, flow cytometry, and qRT-PCR were used to measure the levels of platelet activation, SFTSV infection in platelets, formation of neutrophil extracellular traps (NETs), transcription of DEGs and percent of platelets undergoing cell death. RESULTS: Enhanced neutrophil activation and interferon (IFN) signaling involved in the viral life cycle were common platelet responses in SFTS, which may consume increasing numbers of platelets. Other functional changes may be associated with different outcomes of SFTS. SFTSV infection led to platelet destruction by pyroptosis, apoptosis, necroptosis, and autophagy. In contrast to SFTS patients, platelets in SFTSV-infected mice mainly play a role in adaptive immunity, and platelet death was not as severe as in humans. CONCLUSIONS: The altered functions of platelets, such as mediating leukocyte activation and undergoing cell death, contribute to thrombocytopenia in SFTS patients. The different mechanisms of thrombocytopenia in mice, suggest that platelet functions should be considered in experimental animal models.

The Association Between Elevated Myocardial Injury-Related Biomarker (TnI) and Increased Mortality in Patients With Severe Fever With Thrombocytopenia Syndrome.

OBJECTIVES: The objective of this study was to investigate the dynamic profiles of myocardial injury biomarkers and their association with mortality in patients with severe fever with thrombocytopenia syndrome (SFTS). DESIGN: A retrospective cohort study. SETTINGS: Union Hospital in Wuhan, China. PATIENTS: A total of 580 patients with SFTS, observed between May 2014 and December 2021, were included in the final analysis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In total, 580 patients with SFTS were enrolled in the study, comprised of 469 survivors and 111 nonsurvivors, with a 21-day fatality rate of 19.1%. The elevation of troponin I (TnI) was observed in 61.6% patients (357/580) with SFTS upon admission, and 68.4% patients (397/580) developed an abnormal TnI level during hospitalization. Multivariate logistic regression identified age, viral load, platelet count, creatinine level, and TnI level as potential risk factors for mortality in patients with SFTS. The results of restricted cubic splines revealed that when the TnI level (baseline TnI: 1.55 [lg (ng/L+1)], peak value: TnI 1.90 [lg (ng/L+1)]) exceeded a certain threshold, the predicted mortality of patients with SFTS increased alongside the rise in TnI levels. Mortality rate surpassed 40% among patients with SFTS with TnI greater than or equal to 10 times the upper limit of normal at admission (43.8%) or during hospitalization (41.7%). Older age, a history of cardiovascular disease, and higher d-dimer levels were potential risk factors for elevated TnI levels in patients with SFTS. CONCLUSIONS: Elevated TnI levels were prevalent among patients with SFTS and were strongly associated with an increased risk of mortality.

The difference of addictive behavior of freebase nicotine and nicotine salts in mice base on an aerosol self-administration model.

INTRODUCTION: The distinctions in the biological impacts of distinct forms of nicotine have become a prominent subject of current research. However, relatively little research has been done on the addictive effects of different forms of nicotine. METHODS: The aerosol self-administration device was briefly characterized by determining aerosol concentration, particle size, and distributional diffusion of the aerosol. And the aerosol self-administration model was constructed at 1, 5, and 10 mg/mL of nicotine to select the appropriate nicotine concentration. Subsequently, the model was used to explore the differences in aerosol self-administration behavior of freebase nicotine and nicotine salts and the behavioral differences after withdrawal. RESULTS: We successfully constructed mouse aerosol self-administration models at 1, 5, and 10 mg/mL nicotine concentrations. In the study of the difference in addictive behaviors between freebase nicotine and nicotine salts, mice with freebase nicotine and different nicotine salts showed varying degrees of drug-seeking behavior, with nicotine benzoate showing the strongest reinforcement. During the withdrawal phase, nicotine salts mice showed more robust anxiety-like behaviors. CONCLUSIONS: These results confirm the successful development and stability of the nicotine aerosol self-administration model. Furthermore, they demonstrated that nicotine salts enhance drug-seeking behavior to a greater extent than freebase nicotine, with nicotine benzoate exhibiting the most significant effects. IMPLICATIONS: In this study, an aerosol self-administered model of mice was constructed, which can be used not only for comparing the effects of freebase nicotine and nicotine salts on the behavior, but also for other addictive drugs, such as fentanyl and cannabis. In addition, this study shows that nicotine salts may be more addictive compared to freebase nicotine, which is a reference for the future use of nicotine salts in tobacco products such as e-cigarettes.

Solitary pulmonary capillary hemangioma - An underrecognized rare tumor. Report of 32 new cases with literature review.

OBJECTIVE: To explore the clinical, imaging, pathologic characteristics and differential diagnosis of solitary pulmonary capillary hemangioma (SPCH). METHODS: Thirty two cases of SPCH were collected and studied, with literature review. RESULTS: This study included 13 males and 19 females, with a male-to-female ratio of 1:1.5. The age ranged from 26 to 70 years (median age of 43 years). All patients were asymptomatic at presentation. Lung nodules were incidentally discovered during chest computed tomography (CT). Imaging features included 21 cases with partial solid nodules (PSN), 7 cases with ground-glass nodules (GGN), and 4 cases with solid nodules (SN). Eleven cases were in the left lung lower basal segment, 11 cases in the right lung lower basal segment, 6 cases in the right lung upper anterior segment, and 4 cases in the right lung middle lateral segment. The lower basal segments of the lungs were involved in 22 (11 in each lung) cases (22/32, 68 %). The tumors ranged from 6 to 18 mm (average 10 mm). Macroscopically, 16 cases had clear boundaries, while 16 cases had unclear boundaries, and gray-red or dark brown on cut surfaces. Intraoperative frozen section was performed in 27 cases, with diagnosis of SPCH in 12 and pneumonia or inflammatory lesion in 15. Microscopically, the nodules were composed of densely proliferated and dilated capillaries. The capillary walls were lined with a single layer of flat endothelial cells, without atypical features. Collapsed alveolar septa were replaced by a large number of capillaries. All cases showed proliferating capillaries spreading into the walls of small veins/arteries and bronchi, with 3 cases showing dilated capillaries protruding into the bronchiolar lumens as polyp-like structures. Twenty-six cases (26/32, 81 %) showed proliferating capillaries passed over the interlobular septa. Twenty-six cases (26/32, 81 %) showed irregular intimal thickening of small muscular arteries in the peripheral areas of the lesions, with the thickened intima being cellular or fibrous. In twenty-seven cases (27/32, 84 %) the lesions were located in the subpleura, with 6 cases involving the pleura. CONCLUSION: SPCH is a rare benign lung tumor that mostly occurs in the lung lower basal segments with predominance in females. It usually appears as a ground-glass nodule on CT and is very similar to early-stage lung cancer. Accurate diagnosis requires collaboration of radiologists, surgeons, and pathologists. SPCH should be regarded as an important differential diagnosis of small incidental lung nodules.

Refractory pure red cell aplasia associated with T-cell large granular lymphocyte leukemia treated by ruxolitinib.

Acquired pure red cell aplasia (PRCA) is a rare syndrome characterized by normocytic normochromic anemia with severe reticulocytopenia and absence of erythroid precursors in the bone marrow. For refractory PRCA patients, the low response rate and high toxicity of alternative therapies pose a great challenge. T-cell large granular lymphocyte (T-LGL) leukemia is one of the most common conditions in secondary PRCA and also the most difficult form to manage with an inferior treatment response to other secondary PRCA forms. T-LGL leukemia exhibits sustained activation of the intracellular JAK-STAT signaling pathway. We herein report a case of PRCA associated with T-LGL leukemia that had been refractory to multiple lines of therapies and was successfully treated by ruxolitinib. The patient achieved complete remission and tolerated ruxolitinib well without occurrence of neutropenia or thrombocytopenia. This preliminary finding favors ruxolitinib as a potential salvage therapy for refractory PRCA associated with T-LGL leukemia.

Pan-cancer analysis of LRRC59 with a focus on prognostic and immunological roles in hepatocellular carcinoma.

BACKGROUND: LRRC59 is a leucine-rich repeats-containing protein located in the endoplasmic reticulum (ER), it serves as a prognostic marker in several cancers. However, there has been no systematic analysis of its role in the tumor immune microenvironment, nor its predictive value of prognosis and immunotherapy response in different cancers. METHODS: A comprehensive pan-cancer analysis of LRRC59 was conducted from various databases to elucidate the associations between its expression and the prognosis of cancer, genetic alterations, tumor metabolism, and tumor immunity. Additionally, further functional assays were performed in hepatocellular carcinoma (HCC) to study its biological role in regulating cell proliferation, migration, apoptosis, cell cycle arrest, and sensitivity to immunotherapy. RESULTS: The pan-cancer analysis reveals a significant upregulation of LRRC59 in pan-cancer, and its overexpression is correlated with unfavorable prognosis in cancer patients. LRRC59 is negatively correlated with immune cell infiltration, tumor purity estimation, and immune checkpoint genes. Finally, the validation in HCC demonstrates LRRC59 is significantly overexpressed in cancer tissue and cell lines, and its knockdown inhibits cell proliferation and migration, promotes cell apoptosis, induces cell cycle arrest, and enhances the sensitivity to immunotherapy in HCC cells. CONCLUSIONS: LRRC59 emerges as a novel potential prognostic biomarker across malignancies, offering promise for anti-cancer drugs and immunotherapy.

Dynamic Single-Cell RNA-Seq reveals mechanism of Selinexor-Resistance in Chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is a type of hematologic malignancies caused by BCR-ABL chimeric oncogene. Resistance to tyrosine kinase inhibitors (TKIs) leads to the progression of CML into advanced stages. Selinexor is a small molecule inhibitor that targets a nuclear transporter called Exportin 1. Combined with imatinib, selinexor has been shown to disrupt nuclear-cytoplasmic transport signal of leukemia stem cells, resulting in cell death. The objective of this study was to investigate the mechanism of drug resistance to selinexor in CML. We established K562 cell line resistant to selinexor and conducted single cell dynamic transcriptome sequencing to analyze the heterogeneity within the parental and selinexor resistant cell populations. We identified specific gene expression changes associated with resistance to selinexor. Our results revealed differential expression patterns in genes such as MT2A, TFPI, MTND3, and HMGCS1 in the total RNA, as well as MT-TW, DNAJB1, and HSPB1 in the newly synthesized RNA, between the parental and drug-resistant groups. By applying pseudo-time analysis, we discovered that a specific cluster of cells exhibited characteristics of tumor stem cells. Furthermore, we observed a gradual decrease in the expression of ferroptosis-related molecules as drug resistance developed. In vitro experiments confirmed that the combination of a ferroptosis inducer called RSL3 effectively overcame drug resistance. In conclusion, this study revealed the resistance mechanism of selinexor in CML. In conclusion, we identified a subgroup of CML cells with tumor stem cell properties and demonstrated that ferroptosis inducer improved the efficacy of selinexor in overcoming drug resistance.

A study on construction of a prognosis model for liver cancer based on analgesic targets and screening therapeutic drugs.

BACKGROUND: Liver cancer is one of the most malignant liver diseases in the world, and the 5-year survival rate of such patients is low. Analgesics are often used to cure pain prevalent in liver cancer. The expression changes and clinical significance of the analgesic targets (ATs) in liver cancer have not been deeply understood. OBJECTIVE: The purpose of this study is to clarify the expression pattern of ATs gene in liver cancer and its clinical significance. Through the comprehensive analysis of transcriptome data and clinical parameters, the prognosis model related to ATs gene is established, and the drug information sensitive to ATs is mined. METHODS: The study primarily utilized transcriptomic data and clinical information from liver cancer patients sourced from The Cancer Genome Atlas (TCGA) database. These data were employed to analyze the expression of ATs, conduct survival analysis, gene set variation analysis (GSVA), immune cell infiltration analysis, establish a prognostic model, and perform other bioinformatic analyses. Additionally, data from liver cancer patients in the International Cancer Genome Consortium (ICGC) were utilized to validate the accuracy of the model. Furthermore, the impact of analgesics on key genes in the prognostic model was assessed using data from the Comparative Toxicogenomics Database (CTD). RESULTS: The study investigated the differential expression of 58 ATs genes in liver cancer compared to normal tissues. Patients were stratified based on ATs expression, revealing varied survival outcomes. Functional enrichment analysis highlighted distinctions in spindle organization, centrosome, and spindle microtubule functions. Prognostic modeling identified low TP53 expression as protective, while elevated CCNA2, NEU1, and HTR2C levels posed risks. Commonly used analgesics, including acetaminophen and others, were found to influence the expression of these genes. These findings provide insights into potential therapeutic strategies for liver cancer and shed light on the molecular mechanisms underlying its progression. CONCLUSIONS: The collective analysis of gene signatures associated with ATs suggests their potential as prognostic predictors in hepatocellular carcinoma patients. These findings not only offer insights into cancer therapy but also provide novel avenues for the development of indications for analgesics.