Comprehensive Target Engagement by the EZH2 Inhibitor Tulmimetostat Allows for Targeting of ARID1A Mutant Cancers.

Recurrent somatic mutations in the BAF chromatin remodeling complex subunit ARID1A occur frequently in advanced urothelial carcinoma, endometrial cancers, and ovarian clear cell carcinoma, creating an alternative chromatin state that may be exploited therapeutically. The histone methyltransferase EZH2 has previously been identified as targetable vulnerability in the context of ARID1A mutations. Here, we describe the discovery of tulmimetostat, an orally available, clinical stage EZH2 inhibitor and elucidate its therapeutic potential for treating ARID1A mutant tumors. Tulmimetostat administration achieved efficacy in multiple ARID1A mutant bladder, ovarian, and endometrial tumor models and improved cisplatin response in chemotherapy-resistant models. Consistent with its comprehensive and durable level of target coverage, tulmimetostat demonstrated greater efficacy than other PRC2-targeted inhibitors at comparable or lower exposures in a bladder cancer xenograft mouse model. Tulmimetostat mediated extensive changes in gene expression in addition to a profound reduction in global H3K27me3 levels in tumors. Phase I clinical pharmacokinetic and pharmacodynamic data indicated that tulmimetostat exhibits durable exposure and profound target engagement. Importantly, a tulmimetostat controlled gene expression signature identified in whole blood from a cohort of 32 cancer patients correlated with tulmimetostat exposure, representing a pharmacodynamic marker for the assessment of target coverage for PRC2-targeted agents in the clinic. Collectively, this data suggests that tulmimetostat has the potential to achieve clinical benefit in solid tumors as a monotherapy but also in combination with chemotherapeutic agents and may be beneficial in various indications with recurrent ARID1A mutations.

A fluorescence probe for imaging lipid droplet and visualization of diabetes-related polarity variations.

Diabetes mellitus is a disorder that affects lipid metabolism. Abnormalities in the lipid droplets (LDs) can lead to disturbances in lipid metabolism, which is a significant feature of diabetic patients. Nevertheless, the correlation between diabetes and the polarity of LDs has received little attention in the scientific literature. In order to detect LDs polarity changes in diabetes illness models, we created a new fluorescence probe LD-DCM. This probe has a stable structure, high selectivity, and minimal cytotoxicity. The probe formed a typical D-π-A molecular configuration with triphenylamine (TPA) and dicyanomethylene-4H-pyran (DCM) as electron donor and acceptor parts. The LD-DCM molecule has an immense solvatochromic effect (λem = 544-624 nm), fluorescence enhancement of around 150 times, and a high sensitivity to polarity changes within the linear range of Δf = 0.28 to 0.32, all due to its distinctive intramolecular charge transfer effect (ICT). In addition, LD-DCM was able to monitor the accumulation of LDs and the reduction of LDs polarity in living cells when stimulated by oleic acid, lipopolysaccharide, and high glucose. More importantly, LD-DCM has also been used effectively to detect polarity differences in organs from diabetic, drug-treated, and normal mice. The results showed that the liver polarity of diabetic mice was lower than that of normal mice, while the liver polarity of drug-treated mice was higher than that of diabetic mice. We believe that LD-DCM has the potential to serve as an efficient instrument for the diagnosis of disorders that are associated with the polarity of LDs.

Defects in Halide Perovskites: Does It Help to Switch from 3D to 2D?

Two-dimensional (2D) organic-inorganic hybrid iodide perovskites have been put forward in recent years as stable alternatives to their three-dimensional (3D) counterparts. Using first-principles calculations, we demonstrate that equilibrium concentrations of point defects in the 2D perovskites PEA2PbI4, BA2PbI4, and PEA2SnI4 (PEA, phenethylammonium; BA, butylammonium) are much lower than in comparable 3D perovskites. Bonding disruptions by defects are more destructive in 2D than in 3D networks, making defect formation energetically more costly. The stability of 2D Sn iodide perovskites can be further enhanced by alloying with Pb. Should, however, point defects emerge in sizable concentrations as a result of nonequilibrium growth conditions, for instance, then those defects likely hamper the optoelectronic performance of the 2D perovskites, as they introduce deep traps. We suggest that trap levels are responsible for the broad sub-bandgap emission in 2D perovskites observed in experiments.

Phase-separated porous nanocomposite with ultralow percolation threshold for wireless bioelectronics.

Realizing the full potential of stretchable bioelectronics in wearables, biomedical implants and soft robotics necessitates conductive elastic composites that are intrinsically soft, highly conductive and strain resilient. However, existing composites usually compromise electrical durability and performance due to disrupted conductive paths under strain and rely heavily on a high content of conductive filler. Here we present an in situ phase-separation method that facilitates microscale silver nanowire assembly and creates self-organized percolation networks on pore surfaces. The resultant nanocomposites are highly conductive, strain insensitive and fatigue tolerant, while minimizing filler usage. Their resilience is rooted in multiscale porous polymer matrices that dissipate stress and rigid conductive fillers adapting to strain-induced geometry changes. Notably, the presence of porous microstructures reduces the percolation threshold (Vc = 0.00062) by 48-fold and suppresses electrical degradation even under strains exceeding 600%. Theoretical calculations yield results that are quantitatively consistent with experimental findings. By pairing these nanocomposites with near-field communication technologies, we have demonstrated stretchable wireless power and data transmission solutions that are ideal for both skin-interfaced and implanted bioelectronics. The systems enable battery-free wireless powering and sensing of a range of sweat biomarkers-with less than 10% performance variation even at 50% strain. Ultimately, our strategy offers expansive material options for diverse applications.

Comparison of the coverage and rotation of asymmetrical and symmetrical tibial components: a systematic review and meta-analysis.

BACKGROUND: An optimized fit of the tibial component to the resection platform and correct rotational alignment are critical for successful total knee arthroplasty (TKA). However, there remains controversy regarding the superiority of symmetric tibial component versus asymmetric tibial component. The objective of this systematic review and meta-analysis was to evaluate the current evidence for comparing the coverage and rotation of asymmetrical and symmetrical tibial component. METHODS: We searched potentially relevant studies form PubMed, Web of science, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and China National Knowledge Infrastructure (CNKI), up to 1 March 2023. Data extraction and quality assessment were performed by two independent reviewers. Meta-analysis was conducted using Review Manager 5.4. RESULTS: Sixteen articles were identified. Compared to symmetric tibial component, asymmetric tibial component increased the coverage of the proximal tibial cut surface (MD, -2.87; 95%CI, -3.45 to -2.28; P < 0.00001), improved the prevalence of tibial baseplate underhang (OR, 0.16; 95%CI, 0.07 to 0.33; P < 0.00001) and malrotation (OR, 0.13; 95%CI, 0.02 to 0.90; P = 0.04), and reduced the degree of tibial component rotation (MD, -3.11; 95%CI, -5.76 to -0.47; P = 0.02). But there was no statistical significance for improving tibial baseplate overhang (OR, 0.58; 95%CI, 0.08 to 3.97; P = 0.58). Additionally, no revision had occurred for the two tibial components in the included studies. CONCLUSION: The current evidence shows asymmetric tibial component offer advantages in terms of coverage and rotation compared with symmetric tibial component in TKA.

[Structure motif guided mining of MHET hydrolase and development of a two-enzyme cascade for plastics depolymerization at mild temperature].

The utilization of polyethylene terephthalate (PET) has caused significant and prolonged ecological repercussions. Enzymatic degradation is an environmentally friendly approach to addressing PET contamination. Hydrolysis of mono(2-hydroxyethyl) terephthalate (MHET), a competitively inhibited intermediate in PET degradation, is catalyzed by MHET degrading enzymes. Herein, we employed bioinformatic methods that combined with sequence and structural information to discover an MHET hydrolase, BurkMHETase. Enzymatic characterization showed that the enzyme was relatively stable at pH 7.5-10.0 and 30-45 ℃. The kinetic parameters kcat and Km on MHET were (24.2±0.5)/s and (1.8±0.2) µmol/L, respectively, which were similar to that of the well-known IsMHETase with higher substrate affinity. BurkMHETase coupled with PET degradation enzymes improved the degradation of PET films. Structural analysis and mutation experiments indicated that BurkMHETase may have evolved specific structural features to hydrolyze MHET. For MHET degrading enzymes, aromatic amino acids at position 495 and the synergistic interactions between active sites or distal amino acids appear to be required for MHET hydrolytic activity. Therefore, BurkMHETase may have substantial potential in a dual-enzyme PET degradation system while the bioinformatic methods can be used to broaden the scope of applicable MHETase enzymes.

Enhancing Urban Mobility with Self-Tuning Fuzzy Logic Controllers for Power-Assisted Bicycles in Smart Cities.

In smart cities, bicycle-sharing systems have become an essential component of the transportation services available in major urban centers around the globe. Due to environmental sustainability, research on the power-assisted control of electric bikes has attracted much attention. Recently, fuzzy logic controllers (FLCs) have been successfully applied to such systems. However, most existing FLC approaches have a fixed fuzzy rule base and cannot adapt to environmental changes, such as different riders and roads. In this paper, a modified FLC, named self-tuning FLC (STFLC), is proposed for power-assisted bicycles. In addition to a typical FLC, the presented scheme adds a rule-tuning module to dynamically adjust the rule base during fuzzy inference processes. Simulation and experimental results indicate that the presented self-tuning module leads to comfortable and safe riding as compared with other approaches. The technique established in this paper is thought to have the potential for broader application in public bicycle-sharing systems utilized by a diverse range of riders.

Development and validation of a nomogram for Siewert II esophagogastric junction adenocarcinoma: a retrospective analysis.

Background: Due to the complex histological type and anatomical structures, there has been considerable debate on the classification of adenocarcinoma of the esophagogastric junction (AEG), especially Siewert II AEG. Furthermore, neither the American Joint Committee on Cancer (AJCC) 7th tumor-node-metastasis (TNM) [esophageal adenocarcinoma (E) or gastric cancer (G)] nor the AJCC 8th TNM (E or G) accurately predicted the prognosis of patients with Siewert II AEG. Objective: This study aimed to investigate the factors influencing the survival and prognosis of patients with Siewert II AEG and establish a new and better prognostic predictive model. Design: A retrospective study. Methods: Patients with Siewert II AEG, retrieved from the Surveillance, Epidemiology, and End Results (SEER) databases, were assigned to the training set. Patients retrieved from a single tertiary medical center were assigned to the external validation set. Significant variables were selected using univariate and multivariate Cox regression analyses to construct the nomogram. Nomogram models were assessed using the concordance index (C-index), a calibration plot, decision curve analysis (DCA), and external validation. Results: Age, tumor grade, and size, as well as the T, N, and M stages, were included in the nomograms. For the SEER training set, the C-index of the nomogram was 0.683 (0.665-0.701). The C-index of the nomogram for the external validation set was 0.690 (0.653-0.727). The calibration curve showed good agreement between the nomogram estimations and actual observations in both the training and external validation sets. The DCA showed that the nomogram was clinically useful. Conclusion: The new predictive model showed significant accuracy in predicting the prognosis of Siewert II AEG.

Origin of the Nonmonotonic Pressure Dependence of the Band Gap in the Orthorhombic Perovskite CsPbBr3.

The perovskite CsPbBr3 exhibits an unusual nonmonotonic dependence of the band gap on increasing pressure to about 2.0 GPa as compared to conventional semiconductors. Using the first-principles calculation method, we show that under pressure, isotropic volume deformation induces considerable compression of the Pb-Br bond length and thus an enhanced interaction between atomic orbitals of the antibonding valence band maximum states and the mostly nonbonding conduction band minimum states, resulting in a monotonic decrease in the band gap. On the other hand, structural relaxation tends to reduce the strain energy by decompressing the Pb-Br bond length and simultaneously compressing the Pb-Br-Pb bond angle, which increases the band gap energy. We find that the competition between the volume deformation effect and structural relaxation effect is the origin of the nonmonotonic behavior of the dependence of the band gap on pressure.

Development of a machine learning finite-range nonlocal density functional.

Kohn-Sham density functional theory has been the most popular method in electronic structure calculations. To fulfill the increasing accuracy requirements, new approximate functionals are needed to address key issues in existing approximations. It is well known that nonlocal components are crucial. Current nonlocal functionals mostly require orbital dependence such as in Hartree-Fock exchange and many-body perturbation correlation energy, which, however, leads to higher computational costs. Deviating from this pathway, we describe functional nonlocality in a new approach. By partitioning the total density to atom-centered local densities, a many-body expansion is proposed. This many-body expansion can be truncated at one-body contributions, if a base functional is used and an energy correction is approximated. The contribution from each atom-centered local density is a single finite-range nonlocal functional that is universal for all atoms. We then use machine learning to develop this universal atom-centered functional. Parameters in this functional are determined by fitting to data that are produced by high-level theories. Extensive tests on several different test sets, which include reaction energies, reaction barrier heights, and non-covalent interaction energies, show that the new functional, with only the density as the basic variable, can produce results comparable to the best-performing double-hybrid functionals, (for example, for the thermochemistry test set selected from the GMTKN55 database, BLYP based machine learning functional gives a weighted total mean absolute deviations of 3.33 kcal/mol, while DSD-BLYP-D3(BJ) gives 3.28 kcal/mol) with a lower computational cost. This opens a new pathway to nonlocal functional development and applications.

Revolutionizing early-stage green tide monitoring: eDNA metabarcoding insights into Ulva prolifera and microecology in the South Yellow Sea.

Green tides, characterized by excessive Ulva prolifera blooms, pose significant ecological and economic challenges, especially in the South Yellow Sea. We successfully employed 18S environmental DNA (eDNA) metabarcoding to detect Ulva prolifera micropropagules, confirming the technique's reliability and introducing a rapid green tide monitoring method. Our investigation revealed notable disparities in the eukaryotic microbial community composition within Ulva prolifera habitats across different regions. Particularly, during the early stages of the South Yellow Sea green tide outbreak, potential interactions emerged between Ulva prolifera micropropagules and certain previously undocumented microorganisms from neighboring waters. These findings enhance our comprehension of early-stage green tide ecosystem dynamics, underscoring the value of merging advanced molecular techniques with conventional ecological methods to gain a comprehensive understanding of the impact of green tide on the local ecosystem. Overall, our study advances our understanding of green tide dynamics, offering novel avenues for control, ecological restoration, and essential scientific support for sustainable marine conservation and management.

Transcranial Direct Current Stimulation for Knee Osteoarthritis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: The effects of transcranial direct current stimulation (tDCS) in the treatment of knee osteoarthritis (KOA) is still unclear. The objective is to evaluate the efficacy and safety of tDCS in improving symptoms in patients with KOA. METHODS: The following electronic databases were searched for eligible randomized controlled trials (RCTs): PubMed, Embase, Web of Science, and the Cochrane Library. The search was performed from the inception dates to April 30, 2023. Data extraction and quality assessment were performed by two independent reviewers. Standard mean differences (SMDs) with 95% confidence intervals (95% CIs) for pooled data were calculated. A random-effects model was used for the data analyses. The primary outcomes were pain and physical function. Secondary outcomes included stiffness, mobility performance, quality of life, pressure pain tolerance, and plasma levels of brain-derived neurotrophic factor (BDNF). RESULTS: This meta-analysis included 13 RCTs. tDCS was significantly associated with pain decrease compared with sham tDCS (SMD = -0.62, 95% CI -0.87 to -0.37, P < 0.00001). When comparing tDCS plus other non-tDCS with sham tDCS plus other non-tDCS, there was no longer a significant association with pain decrease (SMD = -0.45, 95% CI -1.08 to 0.17, P = 0.16). The changes in physical function were not significantly different between the tDCS and sham tDCS groups (SMD = -0.09, 95% CI -0.56 to 0.38, P = 0.71). When comparing tDCS plus other non-tDCS with sham tDCS plus other non-tDCS, there was still no significant association with improvement in physical function (SMD = -0.66, 95% CI -1.63 to 0.30, P = 0.18). There was no significant difference with improvement in stiffness (SMD = -0.21, 95% CI -0.77 to 0.34, P = 0.45), mobility performance (SMD = 4.58, 95% CI -9.21 to 18.37, P = 0.51), quality of life (SMD = -7.01, 95% CI -22.61 to 8.59, P = 0.38), and pressure pain tolerance (SMD = 0.30, 95% CI -0.09 to 0.69, P = 0.13). There was a statistically significant reduction in plasma levels of BDNF (SMD = -13.57, 95% CI -24.23 to -2.92, P = 0.01). CONCLUSION: In conclusion, tDCS could significantly alleviate pain, but it might have no efficacy in physical function, stiffness, mobility performance, quality of life, and pressure pain tolerance among patients with KOA.

Systematic Investigation of Novel, Controlled Low-Temperature Sintering Processes for Inkjet Printed Silver Nanoparticle Ink.

Functional inks enable manufacturing of flexible electronic devices by means of printing technology. Silver nanoparticle (Ag NP) ink is widely used for printing conductive components. A sintering process is required to obtain sufficient conductivity. Thermal sintering is the most commonly used method, but the heat must be carefully applied to avoid damaging low-temperature substrates such as polymer films. In this work, two alternative sintering methods, damp heat sintering and water sintering are systematically investigated for inkjet-printed Ag tracks on polymer substrates. Both methods allow sintering polyvinyl pyrrolidone (PVP) capped Ag NPs at 85°C. In this way, the resistance is significantly reduced to only 1.7 times that of the samples on polyimide sintered in an oven at 250°C. The microstructure of sintered Ag NPs is analyzed. Taking the states of the capping layer under different conditions into account, the explanation of the sintering mechanism of Ag NPs at low temperatures is presented. Overall, both damp heat sintering and water sintering are viable options for achieving high conductivity of printed Ag tracks. They can broaden the range of substrates available for flexible electronic device fabrication while mitigating substrate damage risks. The choice between them depends on the specific application and the substrate used.

Incidence of cancer for patients after bariatric surgery: evidence from 33 cohort studies.

BACKGROUND: With the rising prevalence of severe obesity, bariatric surgery has emerged as a crucial treatment option. As the number of surgeries performed worldwide increases, there has been growing interest in the impact of bariatric surgery on cancer incidence. While several studies have examined this relationship, the topic remains controversial. OBJECTIVES: We conducted this systematic review of cohort studies with meta-analysis to evaluate the effect of bariatric surgery versus nonsurgical treatment on overall cancer incidence. However, the effects may vary when focusing on specific cancer types, surgical procedures, or gender, so we conducted additional subgroup analyses. SETTING: A meta-analysis. University hospital. METHODS: The Cochrane, Embase, PubMed, and Web of Science databases were searched for studies from 1 January 2000 to 1 December 2022. Meta-analysis was conducted to evaluate the pooled effect and further implemented subgroup analysis stratified by cancer type, operation type, and sex. RESULTS: All cohort studies were included in this meta-analysis from 18,216 studies. The overall cancer incidence demonstrated a significant decrease in the group with bariatric surgery (odds ratios [OR] = .56, P = .000, 95% CI .46 to .68). In subgroup analysis, similar decrease effect was found in 9 cancers. Furthermore, the incidence of cancer decreased significantly in male (OR = .66, P = .001, 95% CI .51 to .85) and female patients (OR = .63, P = .000, 95% CI .57 to .69) and patients undergoing gastric bypass (OR = .46, P = .000, 95% CI .33 to .63) or sleeve gastrectomy (OR = .44, P = .001, 95% CI .27 to .70). CONCLUSIONS: In the overall analysis, bariatric surgery could reduce the incidence of cancer significantly. Further large-scale well-matched studies are needed to verify the protective effect of bariatric surgery on cancer incidence.

Vibrational Spectra of Highly Anharmonic Water Clusters: Molecular Dynamics and Harmonic Analysis Revisited with Constrained Nuclear-Electronic Orbital Methods.

Vibrational spectroscopy is widely used to gain insights into structural and dynamic properties of chemical, biological, and materials systems. Thus, an efficient and accurate method to simulate vibrational spectra is desired. In this paper, we justify and employ a microcanonical molecular simulation scheme to calculate the vibrational spectra of three challenging water clusters: the neutral water dimer (H4O2), the protonated water trimer (H7O3+), and the protonated water tetramer (H9O4+). We find that with the accurate description of quantum nuclear delocalization effects through the constrained nuclear-electronic orbital framework, including vibrational mode coupling effects through molecular dynamics simulations can additionally improve the vibrational spectrum calculations. In contrast, without the quantum nuclear delocalization picture, conventional ab initio molecular dynamics may even lead to less accurate results than harmonic analysis.

[Relationship between intramuscular fat content in the quadriceps muscle and clinical severity in patients with knee osteoarthritis].

OBJECTIVE: To explore relationship between intramuscular fat content of quadriceps femoris and clinical severity of knee osteoarthritis (KOA). METHODS: Totally 30 KOA patients were selected from February 2021 to June 2021, including 6 males and 24 females, aged with an average of (64.20±9.19) years old, and body mass index (BMI) was (24.92±3.35) kg·m-2. Patients were divided into relative severe leg (RSL) and relative moderate leg (RML) according to severity of pain on visual analogue scale(VAS). Musculoskeletal ultrasound was used to collect muscle images of quadriceps muscles on both sides of the patient, and Image J was used to analyze echo intensity (EI) of each muscle. Both VAS and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) were used to assess pain and function. Quadriceps muscle EI on both sides of patients was compared. Pearson correlation analysis was conducted to analyze correlation between quadriceps muscle EI value between RSL and RML, and linear regression was used to analyze relationship between each muscle EI and VAS and WOMA scores of patients. RESULTS: The EI of RSL lateral vastus lateralis (VL) was 123.78±36.25 and RSL vastus medialis (VM) was 109.46±30.36 which were significantly higher than those of 108.03±31.34 and 93.32±26.04 of RML (P<0.05), but there was no statistical significance in EI values of rectus femoris (RF) on both sides (P>0.05). EI values of VL and VM on both sides were significantly correlated (P<0.05). There was a significant positive correlation between VM EI value and VAS score in RSL and RML (P<0.05). VM EI values in RSL were positively correlated with total WOMAC (P<0.05), and VM VL EI values in RML were positively correlated with total WOMAC score (P<0.05). CONCLUSION: Intramuscular fat content of quadriceps is closely related to severity of clinical symptoms in KOA patients, and the most obvious one is VM. Therefore, the intramuscular fat content of quadriceps may be an objective indicator to evaluate severity of KOA patients. At the same time, reducing intramuscular fat content of the quadriceps muscle of KOA patients may be a new direction for the prevention and treatment of KOA.

Strategy for Fluorescence/Photoacoustic Signal Maximization Using Dual-Wavelength-Independent Excitation.

Dual-mode imaging of fluorescence-photoacoustics has emerged as a promising technique for biomedical applications. However, conventional dual-mode imaging is based on single-wavelength excitation, which often results in opposing fluorescence and photoacoustic signals due to competing photophysical processes in one agent, rendering the maximization of both signals infeasible. To meet this challenge, we herein propose a new strategy by using the dual-excitation approach, where one excitation wavelength generates a fluorescence signal and the other produces a photoacoustic signal, thus achieving simultaneous maximization of both signals in one fluorescence-photoacoustic molecule. Based on this strategy, three dye molecules were employed for comparison, and it was surprising to find that QHD dye with two types of excitation wavelengths could generate fluorescence and photoacoustic signals, respectively. Furthermore, this strategy was successfully implemented in dual-mode imaging of rheumatoid arthritis mice. Importantly, this study emphasizes a new design guideline for the maximization of fluorescence-photoacoustic signals by using dual-wavelength-independent excitation.

Association between IL-6 and prognosis of gastric cancer: a retrospective study.

Background: Gastric cancer (GC) is one of the common and fatal cancers. Even though the Tumor, Node, Metastasis (TNM) staging system is the most classical staging system recognized worldwide, it has been controversial because there are various factors affecting the prognosis of GC patients. Objectives: The study aims to evaluate the relationship between interleukin-6 (IL-6) and several clinical indicators and construct a prognostic model to better predict the prognosis of GC. Design: A retrospective study. Methods: Data of 249 patients with GC diagnosed in GC center of West China Hospital were collected. Clinicopathological characteristics were analyzed to determine whether there were differences between IL-6 HIGH group and IL-6 LOW group. Besides, the association between the two groups and tumor marker levels was clarified. The K-M curves of 3- and 5-year were plotted with log-rank test. Afterward, we conducted univariate and multivariate analysis and a predicting nomogram. Significantly, C-index, and calibration were used to evaluate the value of nomogram in predicting prognosis. Results: The overall survival of GC in the IL-6 HIGH and IL-6 LOW groups were 47.8 months (95% CI: 42.1-53.4) and 57.9 months (95% CI: 54.1-61.7), respectively, with significant differences (p = 0.0046). Average tumor size of GC (p = 0.000) and nerve invasion (p = 0.018) were statistically significant between two groups. Multivariate analysis revealed that the factors affecting prognosis were IL-6 (<5.51 and ⩾5.51 pg/ml) (Hazard Ratio(HR): 1.665, 95% CI: 1.026-2.703, p = 0.039), N stage (HR: 1.336, 95% CI: 1.106-1.615, p = 0.003), and T stage (HR: 1.268, 95% CI: 0.998-1.611, p = 0.052), which were included in the nomogram with a C-index of 0.71. The current data calculated TNM staging C-index was 0.68, and the p-value for the difference between the two models was 0.08. Internal validation revealed that the predicted overall survival did not differ significantly from the actual observed patient survival. Conclusion: The differential expression of IL-6 has a tendency to differentiate the prognosis of GC patients. IL-6, N stage, and T stage are independent prognostic factors, and the new survival prognostic model consisting of the above three indicators is better than the classical TNM staging system. Trial registration: This study is a retrospective study, which does not require clinical registration.

Volumetric Compression Shifts Rho GTPase Balance and Induces Mechanobiological Cell State Transition.

During development and disease progression, cells are subject to osmotic and mechanical stresses that modulate cell volume, which fundamentally influences cell homeostasis and has been linked to a variety of cellular functions. It is not well understood how the mechanobiological state of cells is programmed by the interplay of intracellular organization and complex extracellular mechanics when stimulated by cell volume modulation. Here, by controlling cell volume via osmotic pressure, we evaluate physical phenotypes (including cell shape, morphodynamics, traction force, and extracellular matrix (ECM) remodeling) and molecular signaling (YAP), and we uncover fundamental transitions in active biophysical states. We demonstrate that volumetric compression shifts the ratiometric balance of Rho GTPase activities, thereby altering mechanosensing and cytoskeletal organization in a reversible manner. Specifically, volumetric compression controls cell spreading, adhesion formation, and YAP nuclear translocation, while maintaining cell contractile activity. Furthermore, we show that on physiologically relevant fibrillar collagen I matrices, which are highly non-elastic, cells exhibit additional modes of cell volume-dependent mechanosensing that are not observable on elastic substrates. Notably, volumetric compression regulates the dynamics of cell-ECM interactions and irreversible ECM remodeling via Rac-directed protrusion dynamics, at both the single-cell level and the multicellular level. Our findings support that cell volume is a master biophysical regulator and reveal its roles in cell mechanical state transition, cell-ECM interactions, and biophysical tissue programming.

Adaptation to volumetric compression drives hepatoblastoma cells to an apoptosis-resistant and invasive phenotype.

Liver cancer involves tumor cells rapidly growing within a packed tissue environment. Patient tumor tissues reveal densely packed and deformed cells, especially at tumor boundaries, indicative of physical crowding and compression. It is not well understood how these physical signals modulate tumor evolution and therapeutic susceptibility. Here we investigate the impact of volumetric compression on liver cancer (HepG2) behavior. We find that conditioning cells under a highly compressed state leads to major transcriptional reprogramming, notably the loss of hepatic markers, the epithelial-to-mesenchymal transition (EMT)-like changes, and altered calcium signaling-related gene expression, over the course of several days. Biophysically, compressed cells exhibit increased Rac1-mediated cell spreading and cell-extracellular matrix interactions, cytoskeletal reorganization, increased YAP and ß-catenin nuclear translocation, and dysfunction in cytoplasmic and mitochondrial calcium signaling. Furthermore, compressed cells are resistant to chemotherapeutics and desensitized to apoptosis signaling. Apoptosis sensitivity can be rescued by stimulated calcium signaling. Our study demonstrates that volumetric compression is a key microenvironmental factor that drives tumor evolution in multiple pathological directions and highlights potential countermeasures to re-sensitize therapy-resistant cells. Significance statement: Compression can arise as cancer cells grow and navigate within the dense solid tumor microenvironment. It is unclear how compression mediates critical programs that drive tumor progression and therapeutic complications. Here, we take an integrative approach in investigating the impact of compression on liver cancer. We identify and characterize compressed subdomains within patient tumor tissues. Furthermore, using in vitro systems, we induce volumetric compression (primarily via osmotic pressure but also via mechanical force) on liver cancer cells and demonstrate significant molecular and biophysical changes in cell states, including in function, cytoskeletal signaling, proliferation, invasion, and chemoresistance. Importantly, our results show that compressed cells have impaired calcium signaling and acquire resistance to apoptosis, which can be countered via calcium mobilization.