The aminophospholipid transporter, ATP8B3, as a potential biomarker and target for enhancing the therapeutic effect of PD-L1 blockade in colon adenocarcinoma.

BACKGROUND: Colon adenocarcinoma (COAD) is a prevalent malignant tumor globally, contributing significantly to cancer-related mortality. COAD guidelines label MSI (Microsatellite instability) and MSS (Microsatellite stability) subtypes as global classification criteria and treatment strategy selection criteria for COAD. Various combination therapies involving PD-L1 inhibitors and adjuvant therapy to enhance anti-tumor efficacy. METHODS: Datasets from single-cell RNA sequencing and bulk RNA sequencing in the TCGA and GEO databases were utilized to identify differentially expressed genes (DEGs). Furthermore, the correlation between ATP8B3 and PD-L1 was validated using siRNA, shRNA, and western blot analysis. Additionally, the association between ATP8B3 and immune checkpoint blockade (ICB) therapy was investigated through immune infiltration analysis and flow cytometry in both in vivo and in vitro assays. RESULTS: In the COAD patient group, ATP8B3 significantly contributed to the establishment of an immunosuppressive microenvironment. Inhibiting ATP8B3 led to a reduction in PD-L1 expression in colon cancer cell lines. Additionally, ATP8B3 expression levels could serve as a potential guide for PD-L1 treatment in MSI-H COAD patients, with higher ATP8B3 expression associated with increased sensitivity to PD-L1 therapy. However, due to the lack of immuno-killer cells in the microenvironment of MSS subtypes, elevated ATP8B3 expression couldn't increase the sensitivity of MSS COAD patients to PD-L1 inhibitors. CONCLUSION: Our research results support that Inhibiting ATP8B3 could enhance TIL (tumor-infiltrating lymphocyte) infiltration by reducing PD-L1 expression in MSI-H COAD, thereby serving as an effective strategy to improve PD-L1 blocker efficacy. The treatment strategy of combining ATP8B3 inhibitors and immunotherapy for MSI/MSS COAD patients will be the best choice.

Metabolic and Immunological Implications of MME+CAF-Mediated Hypoxia Signaling in Pancreatic Cancer Progression: Therapeutic Insights and Translational Opportunities.

Pancreatic cancer is a devastating malignancy with a high mortality rate, poor prognosis, and limited treatment options. The tumor microenvironment (TME) plays a crucial role in tumor progression and therapy resistance. Multiple subpopulations of cancer-associated fibroblasts (CAFs) within the TME can switch between different states, exhibiting both antitumorigenic and protumorigenic functions in pancreatic cancer. It seems that targeting fibroblast-related proteins and other stromal components is an appealing approach to combat pancreatic cancer. This study employed single-cell transcriptome sequencing to identify MME (Membrane Metalloendopeptidase)-expressing CAFs in pancreatic cancer. Systematic screening was conducted based on tumor differentiation, lymph node metastasis, and T-stage parameters to identify and confirm the existence of a subpopulation of fibroblasts termed MME+CAFs. Subsequent analyses included temporal studies, exploration of intercellular communication patterns focusing on the hypoxia signaling pathway, and investigation of MME+CAF functions in the pancreatic cancer microenvironment. The pathway enrichment analysis and clinical relevance revealed a strong association between high MME expression and glycolysis, hypoxia markers, and pro-cancer inflammatory pathways. The role of MME+CAFs was validated through in vivo and in vitro experiments, including high-throughput drug screening to evaluate potential targeted therapeutic strategies. Single-cell transcriptome sequencing revealed tumor-associated fibroblasts with high MME expression, termed MME+CAF, exhibiting a unique end-stage differentiation function in the TME. MME+CAF involvement in the hypoxia signaling pathway suggested the potential effects on pancreatic cancer progression through intercellular communication. High MME expression was associated with increased glycolysis, hypoxia markers (VEGF), and pro-cancer inflammatory pathways in pancreatic cancer patients, correlating with lower survival rates, advanced disease stage, and higher oncogene mutation rates. Animal experiments confirmed that elevated MME expression in CAFs increases tumor burden, promotes an immunosuppressive microenvironment, and enhances resistance to chemotherapy and immunotherapy. The developed MME+CAF inhibitor IOX2 (a specific prolyl hydroxylase-2 (PHD2) inhibitor), combined with AG (Paclitaxel + Gemcitabine) and anti-PD1 therapy, demonstrated promising antitumor effects, offering a translational strategy for targeting MME in CAFs of pancreatic cancer. The study findings highlighted the significant role of MME+CAF in pancreatic cancer progression by shaping the TME and influencing key pathways. Targeting MME presented a promising strategy to combat the disease, with potential implications for therapeutic interventions aimed at disrupting MME+CAF functions and enhancing the efficacy of pancreatic cancer treatments.

Association between obesity and systemic immune inflammation index, systemic inflammation response index among US adults: a population-based analysis.

BACKGROUND: Obesity is characterized by a chronic low-grade inflammatory condition. Two emerging inflammatory biomarkers, the systemic immune-inflammation index (SII) and the systemic inflammation response index (SIRI), have gained attention. However, the relationships between obesity and SII/SRI remain unclear. METHODS: In this study, we analyzed data from the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2018 among adults. SII-SIRI/SII/SIRI were categorized into three groups based on tertiles. The association between obesity and SII-SIRI/SII/SIRI was assessed by multivariable logistic regression models. Restricted cubic spline (RCS) plots were used to examine the nonlinear association between obesity and SII/SIRI. Finally, potential independent associations between obesity and SII/SIRI were further explored using subgroup analyses. RESULTS: The study included 20,011 adults, of whom 7,890 (39.32%) were obesity. In model 1, participants in the high (Q3) level of SII-SIRI had a significantly association with obesity than those in the low (Q1) level group. The high level of SII and SIRI were positively associated with obesity as compared to low levels. Model 2 revealed a positive association between obesity and high levels of SII-SIRI/SII/SIRI. Model 3 demonstrated a similar trend. RCS curves revealed a nonlinear association linking obesity to SII/SIRI. Subgroup analysis showed an interaction between SII/SIRI and age. CONCLUSIONS: Our research suggested that obesity was positively associated with SII-SIRI/SII/SIRI in U.S. adults. SII/SIRI may represent a cost-effective and direct approach to assessing obesity.

Deterministic distribution of multipartite entanglement in a quantum network by continuous-variable polarization states.

Quantum network plays a vitally important role in the practical application of quantum information, which requires the deterministic entanglement distribution among multiple remote users. Here, we propose a feasible scheme to deterministically distribute quadripartite entanglement by continuous-variable (CV) polarization states. The quantum server prepares the quadripartite CV polarization entanglement and distributes them to four remote users via optical fiber. In this way, the measurement of CV polarization entanglement is local oscillation free, which makes the long distance entanglement distribution in commercial optical fiber communication networks possible. Furthermore, both the Greenberger-Horne-Zeilinger-like (GHZ-like) and cluster-like polarization entangled states can be distributed among four users by controlling the beam splitter network in quantum server, which are confirmed by the extended criteria for polarization entanglement of multipartite optical modes. The protocol provides the direct reference for experimental implementation and can be directly extended to quantum network with more users, which is essential for a metropolitan quantum network.

Stabilization improvement of the squeezed optical fields using a high signal-to-noise ratio bootstrap photodetector.

High-precision cavity locking is crucial for squeezing optical fields. Here, a bootstrapped low-noise photodetector is utilized in the generation process of the squeezed state of light. This process is based on a combination of a modified trans-impedance amplifier (TIA) circuit and a two-stage bootstrap amplifier circuit. This not only achieves high-precision and long-term stable locking of the optical cavity, but it also improves the degree to which the light field is squeezed. The experiment results show that the detector has a high signal-to-noise ratio (SNR) of 26.7 dB at the analysis frequency of 3 MHz when measuring the shot noise with an injection optical power of 800 µW, and the equivalent optical power noise level is lower than 2.4 pW/Hz in the frequency range of 1-30 MHz. Moreover, the squeezing degree of the quadrature amplitude squeezed state light field can be improved by more than 34.9% when the detector is used for optical cavity locking. The photodetector is useful in continuous variable (CV) quantum information research.

Enhancing regioselectivity of sucrose phosphorylase by loop engineering for glycosylation of L-ascorbic acid.

Sucrose phosphorylase (SPase) has a remarkable capacity to synthesize numerous glucosides from abundantly available sucrose under mild conditions but suffers from specificity and regioselectivity issues. In this study, a loop engineering strategy was introduced to enhance the regioselectivity and substrate specificity of SPase for the efficient synthesis of 2-O-α-D-glucopyranosyl-L-ascorbic acid (AA-2G) via L-ascorbic acid (L-AA). P134, L341, and L343 were identified as "hotspots" for modulating the flexibility of loops, which significantly influenced the H-bonding network of L-AA in the active site, as well as the entrance of the substrate channel, thereby altering the regioselectivity and substrate specificity. Finally, the mutant L341V/L343F, with near-perfect control of the selectivity synthesis of the 2-OH group of L-AA (> 99%), was obtained. The AA-2G production by the mutant reached 244 g L-1 in a whole-cell biotransformation system, and the conversion rate of L-AA reached 64%, which is the highest level reported to date. Our work also provides a successful loop engineering case for modulating the regioselectivity and specificity of sucrose phosphorylase. KEY POINTS: • "Hotspots" were identified in the flexible loops of sucrose phosphorylase. • Mutants exhibited improved regioselectivity and specificity against L-ascorbic acid. • Synthesized AA-2G with high yield and regioselectivity by whole-cell of mutant.

The optimized biocatalytic synthesis of (S)-methyl 2-chlorobutanoate by Acinetobacter sp. lipase.

Epilepsy is a chronic disease caused by sudden abnormal discharge of brain neurons, leading to transient brain dysfunction. Levetiracetam, developed by the UCB company in Belgium, is an effective drug for the treatment of epilepsy. (S)-Methyl 2-chlorobutanoate is an important chiral building block of levetiracetam, which has attracted a great deal of attention. In this study, a strain of lipase-produced Acinetobacter sp. zjutfet-1 was screened from soil samples. At optimized conditions for fermentation and biocatalysis, the bacterial lipase exhibited high catalytic activity for hydrolysis and stereoselectivity toward racemic methyl 2-chlorobutanoate. When the enzymatic reaction was carried out in 6% of racemic substrate, the enantiomeric excess (e.e.s ) reached more than 95%, with a yield of over 86%. Therefore, this lipase can efficiently resolve racemic methyl 2-chlorobutanoate and obtain (S)-methyl 2-chlorobutanoate, which presents great potential in the industrial production of levetiracetam.

Batch-feeding whole-cell catalytic synthesis of α-arbutin by amylosucrase from Xanthomonas campestris.

α-Arbutin is an effective skin-whitening cosmetic ingredient and can be synthesized through hydroquinone glycosylation. In this study, amylosucrase (Amy-1) from Xanthomonas campestris pv. campestris 8004 was newly identified as a sucrose-utilizing glycosylating hydroquinone enzyme. Its kinetic parameters showed a seven-time higher affinity to hydroquinone than maltose-utilizing α-glycosidase. The glycosylation of HQ can be quickly achieved with over 99% conversion when a high molar ratio of glycoside donor to acceptor (80:1) was used. A batch-feeding catalysis method was designed to eliminate HQ inhibition with high productivity (> 36.4 mM h-1). Besides, to eliminate the serious inhibition caused by the accumulated hydroquinone oxidation products, the whole-cell catalysis was further proposed. 306 mM of α-arbutin was finally achieved with 95% molar conversion rate within 15 h. Hence, the batch-feeding whole-cell biocatalysis by Amy-1 is a promising technology for α-arbutin production with enhanced yield and molar conversion rate.

Quantum Secret Sharing Among Four Players Using Multipartite Bound Entanglement of an Optical Field.

Secret sharing is a conventional technique for realizing secure communications in information networks, where a dealer distributes to n players a secret, which can only be decoded through the cooperation of k (n/2

An intensive study on aerosol optical properties and affecting factors in Nanjing, China.

The optical properties of aerosol as well as their impacting factors were investigated at a suburb site in Nanjing during autumn from 14 to 28 November 2012. More severe pollution was found together with lower visibility. The average scattering and absorption coefficients (Bsca and Babs) were 375.7 ± 209.5 and 41.6 ± 18.7 Mm(-1), respectively. Higher Ångström absorption and scattering exponents were attributed to the presence of more aged aerosol with smaller particles. Relative humidity (RH) was a key factor affecting aerosol extinction. High RH resulted in the impairment of visibility, with hygroscopic growth being independent of the dry extinction coefficient. The hygroscopic growth factor was 1.8 ± 1.2 with RH from 19% to 85%. Light absorption was enhanced by organic carbon (OC), elemental carbon (EC) and EC coatings, with contributions of 26%, 44% and 75% (532 nm), respectively. The Bsca and Babs increased with increasing N100 (number concentration of PM2.5 with diameter above 100 nm), PM1 surface concentration and PM2.5 mass concentration with good correlation.

Curcumin Modulates Macrophage Polarization Through the Inhibition of the Toll-Like Receptor 4 Expression and its Signaling Pathways.

BACKGROUND: Curcumin, the active ingredient in curcuma rhizomes, has a wide range of therapeutic effects. However, its atheroprotective activity in human acute monocytic leukemia THP-1 cells remains unclear. We investigated the activity and molecular mechanism of action of curcumin in polarized macrophages. METHODS: Phorbol myristate acetate (PMA)-treated THP-1 cells were differentiated to macrophages, which were further polarized to M1 cells by lipopolysaccharide (LPS; 1 µg/ml) and interferon (IFN)-γ (20 ng/ml) and treated with varying curcumin concentrations. [3H]thymidine (3H-TdR) incorporation assays were utilized to measure curcumin-induced growth inhibition. The expression of tumor necrosis factor-α (TNF-α), interleukin (IL-6), and IL-12B (p40) were measured by quantitative real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA). Macrophage polarization and its mechanism were evaluated by flow cytometry and western blot. Additionally, toll-like receptor 4 (TLR4) small interfering RNA and mitogen-activated protein kinase (MAPK) inhibitors were used to further confirm the molecular mechanism of curcumin on macrophage polarization. RESULTS: Curcumin dose-dependently inhibited M1 macrophage polarization and the production of TNF-α, IL-6, and IL-12B (p40). It also decreased TLR4 expression, which regulates M1 macrophage polarization. Furthermore, curcumin significantly inhibited the phosphorylation of ERK, JNK, p38, and nuclear factor (NF)-κB. In contrast, SiTLR4 in combination with p-JNK, p-ERK, and p-p38 inhibition reduced the effect of curcumin on polarization. CONCLUSIONS: Curcumin can modulate macrophage polarization through TLR4-mediated signaling pathway inhibition, indicating that its effect on macrophage polarization is related to its anti-inflammatory and atheroprotective effects. Our data suggest that curcumin could be used as a therapeutic agent in atherosclerosis.

Activated phosphatidylinositol 3-kinase/Akt inhibits the transition of endothelial progenitor cells to mesenchymal cells by regulating the forkhead box subgroup O-3a signaling.

BACKGROUND AND AIMS: Endothelial progenitor cells (EPCs) differentiate into mature endothelial cells and may thus be candidates for ischemic disease therapy; however, the transition of EPCs to mesenchymal cells is not fully understood. We explored the role of phosphatidylinositol 3-kinase (PI3K)/Akt signaling in endothelial-to-mesenchymal transition (EndMT) induced by transforming growth factor beta 1 (TGF-ß1). METHODS: Rat bone marrow-derived EPCs were isolated by using Ficoll-Isopaque Plus density-gradient centrifugation. EndMT was induced by TGF-ß1 (5 ng/mL). PI3K/Akt signaling was activated by IGF-1 or Lenti-PIK3R2 shRNA. Additionally, FoxO3a expression was suppressed by a lentiviral vector (Lenti-FoxO3a shRNA). Smad3 and FoxO3a co-localization was detected by confocal immunofluorescence microscopy. The expressions of molecules involved in EndMT were exmined by using Western-blot analysis. RESULTS: EndMT of EPCs was fully developed after TGF-ß1 treatment (5 ng/mL) for 7 days. PIK3R2 expression in EPCs was driven by TGF-ß1. Lenti-PIK3R2 shRNA blocked alpha-smooth muscle actin (α-SMA) expression in EPCs treated with TGF-ß1, drove PI3K/Akt activation, and increased expression of phosphorylated FoxO3a instead of phosphorylated Smad3. The effect of Lenti-PIK3R2 shRNA was reduced by LY294002, a specific inhibitor of PI3K. IGF-1 attenuated α-SMA protein expression in EPCs treated with TGF-ß1. Similar to Lenti-PIK3R2 shRNA, IGF-1 also inhibited and elevated the phosphorylation of Smad3 and FoxO3a, respectively. IGF-1 disrupted the co-localization of these proteins in EPCs treated with TGF-ß1. Lenti-FoxO3a shRNA transfection of EPCs suppressed expression of FoxO3a as well as that of the mesenchymal markers SM22α and α-SMA. CONCLUSIONS: Activation of PI3K/Akt signaling by Lenti-PIK3R2 shRNA or by exogenous IGF-1 inhibits EndMT in EPCs via negative regulation of FoxO3a-dependent signaling.

Experimental generation of 8.4 dB entangled state with an optical cavity involving a wedged type-II nonlinear crystal.

Entangled state of light is one of the essential quantum resources in quantum information science and technology. Especially, when the fundamental principle experiments have been achieved in labs and the applications of continuous variable quantum information in the real world are considered, it is crucial to design and construct the generation devices of entangled states with high entanglement and compact configuration. We have designed and built an efficient and compact light source of entangled state, which is a non-degenerate optical parametric amplifier (NOPA) with the triple resonance of the pump and two subharmonic modes. A wedged type-II KTP crystal inside the NOPA is used for implementing frequency-down-conversion of the pump field to generate the optical entangled state and achieving the dispersion compensation between the pump and the subharmonic waves. The EPR entangled state of light with quantum correlations of 8.4 dB for both amplitude and phase quadratures are experimentally produced by a single NOPA under the pump power of 75 mW.

A multi-objective brain storm optimization for integrated distributed flexible job shop and distribution problems.

Production and distribution are critical components of the furniture supply chain, and achieving optimal performance through their integration has become a vital focus for both the academic and business communities. Moreover, as economic globalization progresses, distributed manufacturing has become a pioneering production technique. Via leveraging a distributed flexible manufacturing system, mass flexible production at lower costs can be achieved. To this end, this study presents an integrated distributed flexible job shop and distribution problem to minimize makespan and total tardiness. In our research, a set of custom furniture orders from different customers are processed among flexible job shops and then delivered by vehicles to customers as the due date. To distinctly show the presented problem, a mixed integer mathematical programming model is created, and a multi-objective brain storm optimization method is introduced considering the problem's features. In comparison to the other three advanced methods, the superiority of the algorithm created is showcased. The findings of the experiments demonstrate that the constructed model and the introduced algorithm have remarkable competitiveness in addressing the problem being examined.

Antiphospholipid syndrome presenting as extensive skin ulcers on unilateral lower extremity: a case report.

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by recurrent arterial and venous thrombosis, habitual fetal miscarriages, often accompanied by mild to moderate thrombocytopenia, and persistent moderate-to-high titer positivity for antiphospholipid antibodies (aPLs). However, patients with antiphospholipid antibodies may also present with several nonthrombotic clinical manifestations, such as thrombocytopenia, cardiac valve disease, nephropathy, skin ulcers, or cognitive dysfunction, which are collectively referred to as nonstandard manifestations of APS. Of these, for APS with predominantly cutaneous ulcers, previous reports have focused on APS with combined cutaneous vasculitis, and its medical treatment, rather than cutaneous ulcers with predominantly fatty inflammatory lesions, and the associated surgical treatment. Here, we admitted a relatively rare case of primary APS with extensive skin ulceration of the right lower extremity, without cutaneous vasculitis, in the presence of extensive and severe inflammatory lipoatrophy, carrying anti-ß2-glycoprotein I and lupus anticoagulant, which is reported as follows, with a view to raising awareness of this disease.

Tropical cyclone FANTALA's three turnbacks in the northeast of Madagascar Island.

The unique Tropical cyclone (TC) Fantala appeared in the central Indian Ocean (12.4°S, 73.5°E) at 00Z on April 11 in 2016 and moved northwestward along the northeast of Madagascar at 18 Z on April 15. Then, two incomprehensible turnbacks formed a unique TC track. The dynamic mechanisms of the three turnbacks were first studied based on remote sensing and multisource reanalysis data. The results reveal that the wind field with upper divergence and lower convergence promotes the development of Fantala. The anticyclone high pressure on the middle level atmosphere is an important factor for TC turnbacks. On 15 April, the TC made the first turnback to turn northwest due to the southward anticyclone weakened to moving northwest. On 18 April, the TC made the second turnback along the anticyclone edge due to the northern high-pressure and southern low-pressure trough. On 22 April, the TC made the third turnback because the anticyclonic high press center broke into two small independent anticyclonic centers in the southwest and northeast, which created a barrier band and pushed the northern TC to move to the northwest. Meanwhile, the vertical wind shear (VWS) also provides favorable conditions for TC turnbacks. On April 18, the middle atmosphere of the TC was affected by strong easterly shear and weak southerly shear, and the second turnback was completed. On April 22, the middle level environment was affected by strong westerly shear and weak north shear, and the third turnback was completed. Additionally, heat transport from the ocean to the atmosphere provides favorable conditions for TC development. On April 18, The maximum mean latent heat flux over northeastern Madagascar was 112.94 W/m2, Tropical Cyclone Heat Potential was 39.05 kJ/cm2, and the maximum wind speed at the center of the TC was 155 kts. On April 22, The heat transfer from the equator increased by 18.08 W/m2 compared with the latent heat on 21 April, the Tropical Cyclone Heat Potential was 33.30 kJ/cm2, the maximum wind speed in the TC center was 90 kts, the high PV centerspread down from 850 mb to 900 mb. This study deepens the understanding of track forecasting during the development of a TC.

Schisandra chinensis Bee Pollen Ameliorates Colitis in Mice by Modulating Gut Microbiota and Regulating Treg/Th17 Balance.

Colitis is a chronic disease associated with alterations in the composition of gut microbiota. Schisandra chinensis bee pollen extract (SCPE) has been proved to be rich in phenolic compounds and effective in modulating gut microbiota, but its effect on colitis and the underlying mechanism remains unclear. This study investigates the relationship between colitis amelioration and the gut microbiota regulation of SCPE via fecal microbial transplantation (FMT). The results showed that administration of 20.4 g/kg BW of SCPE could primely ameliorate colitis induced by dextran sulfate sodium (DSS) in mice, showing as more integration of colon tissue structure and the colonic epithelial barrier, as well as lower oxidative stress and inflammation levels compared with colitis mice. Moreover, SCPE supplement restored the balance of T regulatory (Treg) cells and T helper 17 (Th17) cells. Gut microbiota analysis showed SCPE treatment could reshape the gut microbiota balance and improve the abundance of gut microbiota, especially the beneficial bacteria (Akkermansia and Lactobacillus) related to the production of short-chain fatty acids and the regulation of immunity. Most importantly, the protection of 20.4 g/kg BW of SCPE on colitis can be perfectly transmitted by fecal microbiota. Therefore, the gut microbiota-SCFAS-Treg/Th17 axis can be the main mechanism for SCPE to ameliorate colitis. This study suggests that SCPE can be a new promising functional food for prevention and treatment of colitis by reshaping gut microbiota and regulating gut immunity.

Targeting treatment resistance: unveiling the potential of RNA methylation regulators and TG-101,209 in pan-cancer neoadjuvant therapy.

BACKGROUND: Tumor recurrence and mortality rates remain challenging in cancer patients despite comprehensive treatment. Neoadjuvant chemotherapy and immunotherapy aim to eliminate residual tumor cells, reducing the risk of recurrence. However, drug resistance during neoadjuvant therapy is a significant hurdle. Recent studies suggest a correlation between RNA methylation regulators (RMRs) and response to neoadjuvant therapy. METHODS: Using a multi-center approach, we integrated advanced techniques such as single-cell transcriptomics, whole-genome sequencing, RNA sequencing, proteomics, machine learning, and in vivo/in vitro experiments. Analyzing pan-cancer cohorts, the association between neoadjuvant chemotherapy/immunotherapy effectiveness and RNA methylation using single-cell sequencing was investigated. Multi-omics analysis and machine learning algorithms identified genomic variations, transcriptional dysregulation, and prognostic relevance of RMRs, revealing distinct molecular subtypes guiding pan-cancer neoadjuvant therapy stratification. RESULTS: Our analysis unveiled a strong link between neoadjuvant therapy efficacy and RNA methylation dynamics, supported by pan-cancer single-cell sequencing data. Integration of omics data and machine learning algorithms identified RMR genomic variations, transcriptional dysregulation, and prognostic implications in pan-cancer. High-RMR-expressing tumors displayed increased genomic alterations, an immunosuppressive microenvironment, poorer prognosis, and resistance to neoadjuvant therapy. Molecular investigations and in vivo/in vitro experiments have substantiated that the JAK inhibitor TG-101,209 exerts notable effects on the immune microenvironment of tumors, rendering high-RMR-expressing pan-cancer tumors, particularly in pancreatic cancer, more susceptible to chemotherapy and immunotherapy. CONCLUSIONS: This study emphasizes the pivotal role of RMRs in pan-cancer neoadjuvant therapy, serving as predictive biomarkers for monitoring the tumor microenvironment, patient prognosis, and therapeutic response. Distinct molecular subtypes of RMRs aid individualized stratification in neoadjuvant therapy. Combining TG-101,209 adjuvant therapy presents a promising strategy to enhance the sensitivity of high-RMR-expressing tumors to chemotherapy and immunotherapy. However, further validation studies are necessary to fully understand the clinical utility of RNA methylation regulators and their impact on patient outcomes.

Association between trajectories in cardiac damage and clinical outcomes after transcatheter aortic valve replacement.

BACKGROUND: There is little evidence of evolution in cardiac damage after transcatheter aortic valve replacement (TAVR) in aortic stenosis (AS) patients. Less is known about the prognostic value and potential utility of different cardiac damage trajectories following TAVR. OBJECTIVES: This study aims to investigate the cardiac damage trajectories following TAVR and explore their association with subsequent clinical outcomes. METHODS: AS patients undergoing TAVR were enrolled and classified into five cardiac damage stages (0-4) based on the echocardiographic staging classification retrospectively. They were further grouped into early stage (stage 0-2) and advanced stage (stage 3-4). The cardiac damage trajectories in TAVR recipients were evaluated according to their trend between baseline and 30 days after TAVR. RESULTS: A total of 644 TAVR recipients were enrolled, with four distinct trajectories identified. Compared to patients with early-early trajectory, patients with early-advanced trajectory were at 30-fold risk of all-cause death (HR 30.99, 95% CI 13.80-69.56; p < 0.001). In multivariable analyses, early-advanced trajectory was associated with higher 2-year all-cause death (HR 24.08, 95% CI 9.07-63.90; p < 0.001), cardiac death (HR 19.34, 95% CI 3.06-122.34; p < 0.05), and cardiac rehospitalization (HR 4.19, 95% CI 1.49-11.76; p < 0.05) after TAVR. CONCLUSIONS: This investigation provided insight into four cardiac damage trajectories in TAVR recipients and confirmed the prognostic value of distinct trajectories. Early-advanced trajectory was associated with poor clinical prognosis following TAVR.

Impact of early changes in cardiac damage following transcatheter aortic valve implantation.

BACKGROUND: The staging classification of aortic stenosis (AS) which characterises the extent of cardiac damage has been validated in patients undergoing transcatheter aortic valve implantation (TAVI). Short-term changes in cardiac damage after TAVI and their association with long-term prognosis remain unknown. AIMS: This study aims to investigate the early evolution of cardiac damage after TAVI and the association of residual cardiac damage with clinical outcomes in TAVI recipients. METHODS: AS patients undergoing TAVI were consecutively enrolled and classified into five stages of cardiac damage (0-4). Early change in cardiac damage was defined as any change of stage at 30 days (Δcardiac damage between baseline pre-TAVI and 30 days post-TAVI). RESULTS: Within 30 days post-TAVI, the baseline cardiac damage stage had changed in 22.2% of 644 TAVI recipients, accompanied by improvements in the degree of dyspnoea and left ventricular ejection fraction (LVEF). Two-year mortality was associated with residual cardiac damage within 30 days post-TAVI (hazard ratio [HR] 2.97, 95% confidence interval [CI]: 2.07-4.25; p<0.001). Compared to unchanged cardiac damage post-TAVI, further cardiac damage within 30 days was associated with a higher crude risk of 2-year mortality (HR 22.04, 95% CI: 9.87-49.20; p<0.001). Cardiac deterioration within 30 days post-TAVI was an independent risk factor for 2-year mortality (HR 19.564, 95% CI: 8.047-47.565; p<0.001). CONCLUSIONS: This investigation provided insight into the early evolution of cardiac damage in TAVI recipients and confirmed the predictive value of both residual and early changes in cardiac damage post-TAVI. Cardiac deterioration within 30 days is associated with poor clinical prognosis.