MASLD-Related HCC: A Comprehensive Review of the Trends, Pathophysiology, Tumor Microenvironment, Surveillance, and Treatment Options.

Hepatocellular carcinoma (HCC) represents a significant burden on global healthcare systems due to its considerable incidence and mortality rates. Recent trends indicate an increase in the worldwide incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) and a shift in the etiology of HCC, with MASLD replacing the hepatitis B virus as the primary contributor to new cases of HCC. MASLD-related HCC exhibits distinct characteristics compared to viral HCC, including unique immune cell profiles resulting in an overall more immunosuppressive or exhausted tumor microenvironment. Furthermore, MASLD-related HCC is frequently identified in older age groups and among individuals with cardiometabolic comorbidities. Additionally, a greater percentage of MASLD-related HCC cases occur in noncirrhotic patients compared to those with viral etiologies, hindering early detection. However, the current clinical practice guidelines lack specific recommendations for the screening of HCC in MASLD patients. The evolving landscape of HCC management offers a spectrum of therapeutic options, ranging from surgical interventions and locoregional therapies to systemic treatments, for patients across various stages of the disease. Despite ongoing debates, the current evidence does not support differences in optimal treatment modalities based on etiology. In this study, we aimed to provide a comprehensive overview of the current literature on the trends, characteristics, clinical implications, and treatment modalities for MASLD-related HCC.

Development of automated proteomic workflows utilizing silicon-based coupling agents.

Automated methods for enzyme immobilization via 4-triethoxysilylbutyraldehyde (TESB) derived silicone-based coupling agents were developed. TESB and its oxidized derivative, 4-triethoxysilylbutanoic acid (TESBA), were determined to be the most effective. The resulting immobilized enzyme particles (IEPs) displayed robustness, rapid digestion, and immobilization efficiency of 51 ± 8%. Furthermore, we automated the IEP procedure, allowing for multiple enzymes, and/or coupling agents to be fabricated at once, in a fraction of the time via an Agilent Bravo. The automated trypsin TESB and TESBA IEPs were shown to rival a classical in-gel digestion method. Moreover, pepsin IEPs favored cleavage at leucine (>50%) over aromatic and methionine residues. The IEP method was then adapted for an in-situ immobilized enzyme microreactor (IMER) fabrication. We determined that TESBA could functionalize the silica capillary's inner wall while simultaneously acting as an enzyme coupler. The IMER digestion of bovine serum albumin (BSA), mirroring IEP digestion conditions, yielded a 33-40% primary sequence coverage per LC-MS/MS analysis in as little as 15 min. Overall, our findings underscore the potential of both IEP and IMER methods, paving the way for automated analysis and a reduction in enzyme waste through reuse, thereby contributing to a more cost-effective and timely study of the proteome. SIGNIFICANCE: This research introduces 4-triethoxysilylbutyraldehyde (TESB) and its derivatives as silicon-based enzyme coupling agents and an automated liquid handling method for bottom-up proteomics (BUP) while streamlining sample preparation for high-throughput processing. Additionally, immobilized enzyme particle (IEP) fabrication and digestion within the 96-well plate allows for flexibility in protocol where different enzyme-coupler combinations can be employed simultaneously. By enabling the digestion of entire microplates and reducing manual labor, the proposed method enhances reproducibility and offers a more efficient alternative to classical in-gel techniques. Furthermore, pepsin IEPs were noted to favor cleavage at leucine residues which represents an interesting finding when compared to the literature that warrants further study. The capability of immobilized enzyme microreactors (IMER) for rapid digestion (in as little as 15 min) demonstrated the system's efficiency and potential for rapid proteomic analysis. This advancement in BUP not only improves efficiency, but also opens avenues for a fully automated, mass spectrometry-integrated proteomics workflow, promising to expedite research and discoveries in complex biological studies.

Stretching Bonds without Breaking Symmetries in Density Functional Theory.

Kohn-Sham density functional theory (KS-DFT) stands out among electronic structure methods due to its balance of accuracy and computational efficiency. However, to achieve chemically accurate energies, standard density functional approximations in KS-DFT often need to break underlying symmetries, a long-standing "symmetry dilemma". By employing fragment spin densities as the main variables in calculations (rather than total molecular densities, as in KS-DFT), we present an embedding framework in which this symmetry dilemma is understood and partially resolved. The spatial overlap between fragment densities is used as the main ingredient to construct a simple, physically motivated approximation to a universal functional of the fragment densities. This "overlap approximation" is shown to significantly improve semilocal KS-DFT binding energies of molecules without artificially breaking either charge or spin symmetries. The approach is shown to be applicable to covalently bonded molecules and to systems of the "strongly correlated" type.

Strong electron correlation from partition density functional theory.

Standard approximations for the exchange-correlation functional in Kohn-Sham density functional theory (KS-DFT) typically lead to unacceptably large errors when applied to strongly correlated electronic systems. Partition-DFT (PDFT) is a formally exact reformulation of KS-DFT in which the ground-state density and energy of a system are obtained through self-consistent calculations on isolated fragments, with a partition energy representing inter-fragment interactions. Here, we show how typical errors of the local density approximation (LDA) in KS-DFT can be largely suppressed through a simple approximation, the multi-fragment overlap approximation (MFOA), for the partition energy in PDFT. Our method is illustrated on simple models of one-dimensional strongly correlated linear hydrogen chains. The MFOA, when used in combination with the LDA for the fragments, improves LDA dissociation curves of hydrogen chains and produces results that are comparable to those of spin-unrestricted LDA, but without breaking the spin symmetry. MFOA also induces a correction to the LDA electron density that partially captures the correct density dimerization in strongly correlated hydrogen chains. Moreover, with an additional correction to the partition energy that is specific to the one-dimensional LDA, the approximation is shown to produce dissociation energies in quantitative agreement with calculations based on the density matrix renormalization group method.

Retrospective Outcomes of a New Acupuncture Service at a Comprehensive Cancer Center.

Introduction: Among cancer centers, patients' interest in acupuncture is growing, in addition to clinical research in the intervention. Their National Cancer Institute-designated comprehensive cancer center piloted an acupuncture service. Their aim was to assess whether acupuncture impacted patient self-reported symptoms as delivered clinically and discuss their implementation strategy. Methods: Patients undergoing acupuncture at a comprehensive cancer center from June 2019 to March 2020 were asked to complete a modified Edmonton Symptom Assessment Scale (ESAS) before and after each session. The authors evaluated symptom changes after acupuncture in both outpatient and inpatient settings. A change of ≥1 U, on the 0-10 scale, was considered clinically significant. Results: Three hundred and nine outpatient and 394 inpatient acupuncture sessions were provided to patients at the comprehensive cancer center during this period, of which surveys from 186 outpatient (34 patients) and 124 inpatient (57 patients) sessions were available for analysis. The highest pretreatment symptoms reported by outpatients were neuropathy (5.78), pain (5.58), and tiredness (5.59). Outpatients receiving acupuncture reported clinically significant improvements in pain (ESAS score change of -2.97), neuropathy (-2.68), decreased lack of well-being (-2.60), tiredness (-1.85), nausea (-1.83), anxiety (-1.56), activities of daily living issues (-1.32), depression (-1.23), anorexia (-1.19), insomnia (-1.14), and shortness of breath (-1.14). The most severe pretreatment symptoms reported by inpatients were pain (6.90), insomnia (6.16), and constipation (5.44). Inpatients receiving acupuncture reported clinically significant improvements in anxiety (-3.69), nausea (-3.61), insomnia (-3.26), depression (-2.98), pain (-2.77), neuropathy (-2.68), anorexia (-2.20), constipation (-1.95), and diarrhea (-1.26). Conclusion: Both outpatient and inpatient participants in this pilot acupuncture program reported clinically significant improvements in symptoms after a single acupuncture treatment. Some differences between the outpatient and inpatient settings warrant further investigation.

Inverse Kohn-Sham Density Functional Theory: Progress and Challenges.

Inverse Kohn-Sham (iKS) methods are needed to fully understand the one-to-one mapping between densities and potentials on which density functional theory is based. They can contribute to the construction of empirical exchange-correlation functionals and to the development of techniques for density-based embedding. Unlike the forward Kohn-Sham problems, numerical iKS problems are ill-posed and can be unstable. We discuss some of the fundamental and practical difficulties of iKS problems with constrained-optimization methods on finite basis sets. Various factors that affect the performance are systematically compared and discussed, both analytically and numerically, with a focus on two of the most practical methods: the Wu-Yang method (WY) and the partial differential equation constrained optimization (PDE-CO). Our analysis of the WY and PDE-CO highlights the limitation of finite basis sets. We introduce new ideas to make iKS problems more tractable, provide an overall strategy for performing numerical density-to-potential inversions, and discuss challenges and future directions.

Impact of Phytoplankton Blooms on Concentrations of Antibiotics in Sediment and Snails in a Subtropical River, China.

The present three-year field investigation on sediment in the eutrophic Pearl River in South China showed that concentrations of sulfonamides (SAs), fluoroquinolones (FQs), and macrolides (MLs) in the river areas where blooms occurred were 4.6, 2.4, and 3.4 times higher than those without blooms, respectively, but the respective concentrations of tetracycline (TC) and oxytetracycline (OTC) in the areas with blooms were 2.6 and 3.8 times lower than those without. Significant positive correlations were found between concentrations of chlorophyll a in water and most antibiotics in sediment. Further investigation in each season suggested that lower diffusion but higher sinking were possible reasons driving the burial of sulfapyridine (SPD), sulfamethoxazole (SMX), and trimethoprim (TMP) in sediment from areas where blooms occurred, with burial rates up to 14.86, 48.58, and 52.19 g month-1, respectively. Concentrations of TCs in both water and sediment were inversely correlated with phytoplankton biomass, which might be related to the enhanced biodegradation capacity of bacteria caused by phytoplankton blooms. Phytoplankton also affected concentrations of antibiotics in the snail, Bellamya purificata, with higher values in March but lower values in September. The concentration of antibiotics in snails positively correlated with that in sediment when snails were dormant but with antibiotics in water after dormancy.

Purification and Identification of Pine Nut (Pinus yunnanensis Franch.) Protein Hydrolysate and Its Antioxidant Activity in Vitro and in Vivo.

In this study, the pine nut (Pinus yunnanensis Franch.) protein was hydrolyzed by alkaline protease and trypsin to prepare pine nut protein hydrolysate (PNPH). The chemical, intracellular and in vivo antioxidant capacity of PNPH were evaluated. PNPH owned the ability of scavenging free radicals, and it could protect the HepG2 cells from oxidative damage by preserving cell viability. Moreover, PNPH could reduce the malondialdehyde (MDA) content and improved the superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in serum, heart and liver of aging mice induced by D-galactose. Further, the PNPH was stepwise purified and identified, and 15 peptides were identified from purified fraction in PNPH. The three-dimension structures of identified peptides were predicted. Among all identified peptides, peptide 3, 7, 8 and 11 were presumed to possess good antioxidant activity. Overall, PNPH and purified peptides isolated from PNPH have potential application prospects in the field of natural antioxidants and anti-aging functional foods.

Nucleoporin 153 links nuclear pore complex to chromatin architecture by mediating CTCF and cohesin binding.

Nucleoporin proteins (Nups) have been proposed to mediate spatial and temporal chromatin organization during gene regulation. Nevertheless, the molecular mechanisms in mammalian cells are not well understood. Here, we report that Nucleoporin 153 (NUP153) interacts with the chromatin architectural proteins, CTCF and cohesin, and mediates their binding across cis-regulatory elements and TAD boundaries in mouse embryonic stem (ES) cells. NUP153 depletion results in altered CTCF and cohesin binding and differential gene expression - specifically at the bivalent developmental genes. To investigate the molecular mechanism, we utilize epidermal growth factor (EGF)-inducible immediate early genes (IEGs). We find that NUP153 controls CTCF and cohesin binding at the cis-regulatory elements and POL II pausing during the basal state. Furthermore, efficient IEG transcription relies on NUP153. We propose that NUP153 links the nuclear pore complex (NPC) to chromatin architecture allowing genes that are poised to respond rapidly to developmental cues to be properly modulated.

Clinical efficacy and safety in telbivudine- or tenofovir-treated hepatitis B e antigen-positive pregnant women.

BACKGROUND: Telbivudine (LdT) and tenofovir (TDF) are widely used in pregnant women to prevent vertical transmission; however, limited data are available on the differences in clinical efficacy and safety between the two drugs. METHODS: A total of 307 hepatitis B e antigen (HBeAg)-positive pregnant women with complete follow-up data were enrolled, the patients with alanine aminotransferase (ALT) levels <1×ULN at baseline were enrolled to cohort 1 for treatment from 28 ±4 weeks gestation to delivery, while ALT levels >1×ULN at baseline were enrolled to cohort 2 for treatment from 28 ±4 weeks gestation and continued after delivery. The clinical efficacy and safety was compared in LdT- and TDF-treated patients. In addition, 32 patients in cohort 1 were analysed for nucleoside analogue (NA)-related resistance mutations at baseline and after delivery. RESULTS: The results showed that HBV DNA levels were significantly lower at delivery than at baseline (P<0.001), but the decreases in HBV DNA, ALT, total bilirubin and total bile acid levels did not differ between the LdT- and TDF-treated patients at different time points (P>0.05) in the two cohorts. However, gastrointestinal adverse effects (vomiting) occurred more frequently in TDF-treated than LdT-treated patients (6.6% versus 0.0%; P=0.001). The results of NA-related resistance mutations analysis in cohort 1 revealed that short-term LdT or TDF treatment did not significantly change the NA-related resistance mutations (P>0.05). CONCLUSIONS: This study revealed that the clinical efficacy in LdT- or TDF-treated HBeAg-positive Chinese pregnant women is similar, and gastrointestinal adverse effects occurred more frequently in TDF-treated patients.

Evaluation of factors influencing annual occurrence, bioaccumulation, and biomagnification of antibiotics in planktonic food webs of a large subtropical river in South China.

Biological pump is important to control the fate and distribution of organic contaminants, particularly in temperate and cold oligotrophic waters. However, it remains largely unknown how factors affect the long-term occurrence and fate of ionogenic organic compounds in subtropical eutrophic waters. The present study aimed to assess biogeochemical and physical factors affecting the annual occurrence, bioaccumulation, and trophic transfer of 14 antibiotics through planktonic food webs in the Pearl River, a large subtropical eutrophic river in China. This was done by carrying out 1-year simultaneous field observations of antibiotic concentrations in five water column compartments and assessing the variability of bioconcentration (BCF), bioaccumulation (BAF), and biomagnification (BMF) factors, which were influenced by plankton biomass, pH and temperature of water columns. The annual mean antibiotic concentration per site ranged from 1014.66 ±â€¯535.66 ng L-1 to 1464.63 ±â€¯1075.91 ng L-1, and was positively correlated with phytoplankton biomass, but independent of the proximity of the sites to urban areas. Antibiotic occurrences in both phytoplankton and zooplankton were greatly influenced by a biodilution effect. The annual occurrence of antibiotics in the water column was modulated by biological pumps as well as their equilibrium partitioning, and indirectly influenced of eutrophication with pH increased with phytoplankton biomass and phytoplankton life cycling. BAF of antibiotics by plankton had biphasic correlations with temperature (n = 150, R2 = 0.17-0.60, p < 0.001) and decreased with plankton biomass (n = 105-147, R2 = 0.10-0.22, p < 0.001). The trophic transfer of antibiotics from phytoplankton to zooplankton (BMFs) were positively correlated with both phytoplankton biomass (n = 30, R2 = 0.58, p < 0.001) and temperature (n = 132-150, R2 = 0.12-0.43, p < 0.001). Mean BMFs of ciprofloxacin, lomefloxacin, ofloxacin, oxytetracycline, and tetracycline ranged between 0.18 and 2.25, implying these chemicals can undergo biomagnification along planktonic food webs. The present research demonstrates the important role of biogeochemical and physical factors in the environmental fate of antibiotics at large spatiotemporal scales.

The Nuclear Pore Complex in Cell Type-Specific Chromatin Structure and Gene Regulation.

Nuclear pore complex (NPC)-mediated nucleocytoplasmic trafficking is essential for key cellular processes, such as cell growth, cell differentiation, and gene regulation. The NPC has also been viewed as a nuclear architectural platform that impacts genome function and gene expression by mediating spatial and temporal coordination between transcription factors, chromatin regulatory proteins, and transcription machinery. Recent findings have uncovered differential and cell type-specific expression and distinct chromatin-binding patterns of individual NPC components known as nucleoporins (Nups). Here, we examine recent studies that investigate the functional roles of NPCs and Nups in transcription, chromatin organization, and epigenetic gene regulation in the context of development and disease.

Effects of Erythromycin on the Proliferation and Apoptosis of Cultured Nasal Polyp-Derived Cells and the Extracellular Signal-Regulated Kinase (ERK)/Mitogen-Activated Protein Kinase (MAPK) Signaling Pathway.

BACKGROUND Erythromycin and its derivatives have been used to treat nasal polyposis and reduce inflammation, but the mechanism of action remains unclear. The extracellular signal-regulated kinase (ERK) and mitogen-activated protein kinase (MAPK) pathway proteins are expressed in nasal polyps. The aim of this study was to investigate the effects of erythromycin on cell proliferation, apoptosis, and the expression of p-MEK1 and p-ERK1 on cultured nasal polyp-derived cells. MATERIAL AND METHODS Nasal polyp-derived cells (n=32) and control cells from normal inferior turbinate tissue (n=32) were divided into four groups: the control group; the erythromycin-treated (100 µM) group; the selumetinib-treated (2 nM) group; and the erythromycin + selumetinib-treated group. Western blot was used to detect p-MEK1 and p-ERK1 proteins. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect mRNA expression of BCL-2 and BAX. Flow cytometry detected expression of Ki-67 and cell apoptosis. Cell apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL). Spectrophotometry assessed caspase-3 activity. RESULTS The expression of Ki-67 was significantly increased, and cell apoptosis was significantly reduced in untreated nasal polyp-derived cells compared with controls. Erythromycin treatment significantly decreased cell proliferation and the expression of p-MEK1 and p-ERK1, and increased apoptosis in nasal polyp-derived cells compared with control cells. Selumetinib treatment had a synergistic effect with erythromycin to reduce the expression of p-MEK1 and p-ERK1, reduce cell proliferation, and increase cell apoptosis. CONCLUSIONS In cultured cells derived from nasal polyps, erythromycin treatment reduced cell proliferation and increased apoptosis by inhibiting the activation of the ERK/MAPK signaling pathway.

Heterogeneous conversion of CO2 into cyclic carbonates at ambient pressure catalyzed by ionothermal-derived meso-macroporous hierarchical poly(ionic liquid)s.

Meso-macroporous hierarchical poly(ionic liquid)s (MPILs) with extremely high ionic site densities and tunable pore structures were ionothermally synthesized through the free radical self-polymerization of our newly designed rigid bis-vinylimidazolium salt monomer. The synthesis avoided the use of any templates, gave a high yield (>99%) and allowed recycling of the IL solvent; thus it is facile, atom-efficient, environmentally friendly and sustainable. The synthesized MPILs possessed distinctive features of polycation matrices, abundant halogen anions, and large surface areas. They not only presented enhanced CO2 capture, but led to breakthroughs in the heterogeneous catalytic conversion of CO2 into cyclic carbonates: (1) unprecedented high activity at atmospheric pressure and low temperature; (2) good substrate compatibility, even being active towards the extremely inert aliphatic long carbon-chain alkyl epoxides. This result renders the first occasion of a metal-solvent-additive free recyclable heterogeneous cycloaddition of CO2 at such mild conditions.

Clinical studies on the treatment of cancer cachexia with megestrol acetate plus thalidomide.

BACKGROUND: The management of cancer-related anorexia/cachexia syndrome (CACS) is a great challenge in clinical practice. To date, practice guidelines for the prevention and treatment of CACS are lacking. The authors conducted a randomized study to confirm the effectiveness and safety of treatment of CACS utilizing megestrol acetate (MA) plus thalidomide. METHODS: One hundred and two candidates with CACS were randomly assigned to two treatment groups (trial group and control group): the trial group received MA (160 mg po, bid) plus thalidomide (50 mg po, bid), while the control group received MA (160 mg po, bid) alone. Treatment duration was 8 weeks. RESULTS: Analysis of the trial group demonstrated a significant increase from baseline in body weight (<0.01), quality of life (p = 0.02), appetite (p = 0.01), and grip strength (p = 0.01), and a significant decrease in fatigue, Glasgow Prognostic Score (p = 0.05), Eastern Cooperative Oncology Group performance status (p = 0.03), IL-6 (p < 0.01), and tumor necrosis factor-α (p = 0.02). In contrast, in the control group, endpoints with a significant improvement from baseline included body weight (p < 0.02) and appetite (p = 0.02). The mean changes in the endpoints from baseline in the trial group were significantly greater compared with the control group: in the primary endpoints, body weight (p = 0.05), fatigue (p < 0.01) and quality of life (p = 0.01), and in the secondary endpoints, grip strength (p = 0.05), Glasgow Prognostic Score (p = 0.02), Eastern Cooperative Oncology Group performance status (p = 0.02), IL-6 (p < 0.01) and tumor necrosis factor-α (p = 0.01). Toxicity was found to be relatively negligible in both groups. CONCLUSION: A combination regimen of MA and thalidomide is more effective than MA alone in the treatment of CACS.

[Treatment of nasopharyngeal atresia with dual U-shaped mucosal flap repair and local dilatation].

OBJECTIVE: The aim of current work was to investigate the methodology and effect of dual U-shaped mucosal flap repair plus local dilatation for the treatment of nasopharyngeal atresia. METHOD: Nine patients with nasopharyngeal stenosis were treated with dual U-shaped flap to repair the wound of retropharyngeal and soft palate mucosa. and then dilated by implanting a silicone tube. RESULT: The silicone tube was removed 6 months after the operation. The transverse diameter of nasopharynx maintained at about 2.0 - 2.5 cm, and anteroposterior diameter at about 1.0 cm. All cases had good nasal patency except velopharyngeal insufficiency and nasal regurgitation of food. After a 2 years follow-up, all cases had a good result except one still had the nasal regurgitation of food. CONCLUSION: U-shaped mucosal flap repair with local dilatation is an effective method for treatment of nasopharyngeal atresia.

Introduction to anti-control of discrete chaos: theory and applications.

In this paper, the notion of anti-control of chaos (or chaotification) is introduced, which means to make an originally non-chaotic dynamical system chaotic or enhance the existing chaos of a chaotic system. The main interest in this paper is to employ the classical feedback control techniques. Only the discrete case is discussed in detail, including both finite-dimensional and infinite-dimensional settings.

[Analysis of mortal risk factors in 12 patients with severe acute respiratory syndrome].

OBJECTIVE: To investigate the risk factors in the dead patients with severe acute respiratory syndrome (SARS). METHODS: The retrospective analyses were made on 12 dead cases and 32 recovered cases with SARS. RESULTS: The mean age was 67 years old in 12 dead cases with SARS and was 42 in recovered control group. There were 1-5 other basic diseases in 5 cases of death group. The states of dead patients were severe and the deterioration of patients' condition was rapid. The CD 4 and CD 8 T lymphocytes in peripheral blood were (416.6+/-235.0) cells/microl and (296.1+/-181.5)cells/microl in survival patients and (143.8+/-78.1)cells/microl, (103.6+/-63.2) cells/microl in dead patients, they often decreased compared to the normal values, especially in dead cases. Five cases were infected with bacteria in 12 dead cases, among them 3 were infected with fungus and 2 were septicemia. In dead group, the occurrence rates of electrolyte maladjustment and kidney injury were 41.67 percent. Invasive ventilation was used in 10 cases and death rate was 80.0 percent, among them 5 patients were infected with bacteria. None was dead in the patients with non-invasive ventilation. CONCLUSION: The age and basic diseases are the main mortal risk factors in SARS. Other risk factors include the decline of immune function, secondary infection, complications and use of invasive ventilation.