Insights into wheat-starch biosynthesis from two-dimensional macromolecular structure.

Starch structure is often characterized by the chain-length distribution (CLD) of the linear molecules formed by breaking each branch-point. More information can be obtained by expanding into a second dimension: in the present case, the total undebranched-molecule size. This enables answers to questions unobtainable by considering only one variable. The questions considered here are: (i) are the events independent which control total size and CLD, and (ii) do ultra-long amylopectin (AP) chains exist (these chains cannot be distinguished from amylose chains using simple size separation). This was applied here to characterize the structures of one normal (RS01) wheat and two high-amylose (AM) mutant wheats (an SBEIIa knockout and an SBEIIa and SBEIIb knockout). Absolute ethanol was used to precipitate collected fractions, then size-exclusion chromatography for total molecular size and for the size of branches. The SBEIIa and SBEIIb mutations significantly increased AM and IC contents and chain length. The 2D plots indicated the presence of small but significant amounts of long-chain amylopectin, and the asymmetry of these plots shows that the corresponding mechanisms share some causal effects. These results could be used to develop plants producing improved starches, because different ranges of the chain-length distribution contribute independently to functional properties.

Using molecular fine structure to identify optimal methods of extracting fungal glycogen.

Glycogen is a highly branched glucose polymer that is an energy storage material in fungi and animals. Extraction of glycogen from its source in a way that minimizes its molecular degradation is essential to investigate its native structure. In this study, the following extraction methods were compared: sucrose gradient density ultracentrifugation, thermal alkali, hot alcohol and hot water extractions. Molecular-size and chain-length distributions of glycogen were measured by size-exclusion chromatography and fluorophore-assisted carbohydrate electrophoresis, respectively. These two fine-structure features are the most likely structural characteristics to be degraded during extraction. The results show that the thermal alkali, hot alcohol and hot water extractions degrade glycogen molecular size and/or chain-length distributions, and that sucrose gradient density ultracentrifugation with neither high temperature nor alkaline treatment is the most suitable method for fungal glycogen extraction.

Process Mass Intensity (PMI): A Holistic Analysis of Current Peptide Manufacturing Processes Informs Sustainability in Peptide Synthesis.

Small molecule therapeutics represent the majority of the FDA-approved drugs. Yet, many attractive targets are poorly tractable by small molecules, generating a need for new therapeutic modalities. Due to their biocompatibility profile and structural versatility, peptide-based therapeutics are a possible solution. Additionally, in the past two decades, advances in peptide design, delivery, formulation, and devices have occurred, making therapeutic peptides an attractive modality. However, peptide manufacturing is often limited to solid-phase peptide synthesis (SPPS), liquid phase peptide synthesis (LPPS), and to a lesser extent hybrid SPPS/LPPS, with SPPS emerging as a predominant platform technology for peptide synthesis. SPPS involves the use of excess solvents and reagents which negatively impact the environment, thus highlighting the need for newer technologies to reduce the environmental footprint. Herein, fourteen American Chemical Society Green Chemistry Institute Pharmaceutical Roundtable (ACS GCIPR) member companies with peptide-based therapeutics in their portfolio have compiled Process Mass Intensity (PMI) metrics to help inform the sustainability efforts in peptide synthesis. This includes PMI assessment on 40 synthetic peptide processes at various development stages in pharma, classified according to the development phase. This is the most comprehensive assessment of synthetic peptide environmental metrics to date. The synthetic peptide manufacturing process was divided into stages (synthesis, purification, isolation) to determine their respective PMI. On average, solid-phase peptide synthesis (SPPS) (PMI ≈ 13,000) does not compare favorably with other modalities such as small molecules (PMI median 168-308) and biopharmaceuticals (PMI ≈ 8300). Thus, the high PMI for peptide synthesis warrants more environmentally friendly processes in peptide manufacturing.

International consensus guidelines for the definition, detection, and interpretation of autophagy-dependent ferroptosis.

Macroautophagy/autophagy is a complex degradation process with a dual role in cell death that is influenced by the cell types that are involved and the stressors they are exposed to. Ferroptosis is an iron-dependent oxidative form of cell death characterized by unrestricted lipid peroxidation in the context of heterogeneous and plastic mechanisms. Recent studies have shed light on the involvement of specific types of autophagy (e.g. ferritinophagy, lipophagy, and clockophagy) in initiating or executing ferroptotic cell death through the selective degradation of anti-injury proteins or organelles. Conversely, other forms of selective autophagy (e.g. reticulophagy and lysophagy) enhance the cellular defense against ferroptotic damage. Dysregulated autophagy-dependent ferroptosis has implications for a diverse range of pathological conditions. This review aims to present an updated definition of autophagy-dependent ferroptosis, discuss influential substrates and receptors, outline experimental methods, and propose guidelines for interpreting the results.Abbreviation: 3-MA:3-methyladenine; 4HNE: 4-hydroxynonenal; ACD: accidentalcell death; ADF: autophagy-dependentferroptosis; ARE: antioxidant response element; BH2:dihydrobiopterin; BH4: tetrahydrobiopterin; BMDMs: bonemarrow-derived macrophages; CMA: chaperone-mediated autophagy; CQ:chloroquine; DAMPs: danger/damage-associated molecular patterns; EMT,epithelial-mesenchymal transition; EPR: electronparamagnetic resonance; ER, endoplasmic reticulum; FRET: Försterresonance energy transfer; GFP: green fluorescent protein;GSH: glutathione;IF: immunofluorescence; IHC: immunohistochemistry; IOP, intraocularpressure; IRI: ischemia-reperfusion injury; LAA: linoleamide alkyne;MDA: malondialdehyde; PGSK: Phen Green™ SK;RCD: regulatedcell death; PUFAs: polyunsaturated fatty acids; RFP: red fluorescentprotein;ROS: reactive oxygen species; TBA: thiobarbituricacid; TBARS: thiobarbituric acid reactive substances; TEM:transmission electron microscopy.

The role of metal ions in the occurrence, progression, drug resistance, and biological characteristics of gastric cancer.

Metal ions exert pivotal functions within the human body, encompassing essential roles in upholding cell structure, gene expression regulation, and catalytic enzyme activity. Additionally, they significantly influence various pathways implicated in divergent mechanisms of cell death. Among the prevailing malignant tumors of the digestive tract worldwide, gastric cancer stands prominent, exhibiting persistent high mortality rates. A compelling body of evidence reveals conspicuous ion irregularities in tumor tissues, encompassing gastric cancer. Notably, metal ions have been observed to elicit distinct contributions to the progression, drug resistance, and biological attributes of gastric cancer. This review consolidates pertinent literature on the involvement of metal ions in the etiology and advancement of gastric cancer. Particular attention is directed towards metal ions, namely, Na, K, Mg, Ca, Fe, Cu, Zn, and Mn, elucidating their roles in the initiation and progression of gastric cancer, cellular demise processes, drug resistance phenomena, and therapeutic approaches.

Impact of body composition on the prognosis of hepatocellular carcinoma patients treated with transarterial chemoembolization: A systematic review and meta-analysis.

Objectives: To summarize current evidence about the influence of body composition on the prognosis of patients with hepatocellular carcinoma (HCC) after transarterial chemoembolization (TACE) treatment. Methods: Public databases were systematically searched to identify relevant studies published from the inception of the database up to May 2023. Studies that evaluated the association between body composition and clinical outcomes in HCC patients who underwent TACE were included. A pre-designed table was applied to summarize relevant information. Meta-analysis was performed to estimate the association of body composition with overall survival. Results: Fourteen studies were included in this review, including 3631 patients (sample size range: 56-908, median 186). All body composition measurements (including skeletal muscle area, visceral and subcutaneous adipose area, and bone mineral density) were based on computer tomography. The commonly used parameter was skeletal muscle index at 3rd lumbar vertebra level (8/14). Three studies evaluated the correlations of body composition changes with the prognosis after TACE. Most studies (12/14) identified body composition parameters as an independent indicator for overall survival, progression-free survival, and treatment response rate. The hazard ratio of different body composition parameters ranged from 1.01 to 2.88, and hazard ratio of body composition changes ranged from 1.88 to 5.93. The pooled hazard ratio of sarcopenia for overall survival was 1.38 (95 %CI: 1.20-1.58). Conclusions: Body composition seems to be an important prognostic factor for a poorer clinical outcome after TACE treatment in patients with hepatocellular carcinoma. Future prospective studies with a larger sample size are required to confirm these findings. Registration study: This study has been prospectively registered at the PROSPERO platform (https://www.crd.york.ac.uk/prospero/) with the registration No. CRD42022345602.

Efficacy and safety of stem cell therapy for Crohn's disease: a meta-analysis of randomized controlled trials.

PURPOSE: Small-scale clinical trials have provided evidence suggesting the effectiveness of stem-cell therapy (SCT) for patients diagnosed with Crohn's disease (CD). The objective of the research was to systematically assess the effectiveness and safety of SCT for individuals diagnosed with CD through a comprehensive review and meta-analysis. METHODS: A search was conducted in Medline (PubMed), CENTER (Cochrane Library), and Embase (Ovid) to find randomized controlled trials (RCTs) that assessed the impact of SCT on the occurrence of clinical remission (CR) and severe adverse events (SAE) among patients diagnosed with CD. The Cochrane Q test and estimation of I2 were used to assess heterogeneity among studies. After incorporating heterogeneity, a random-effects model was employed for data pooling. RESULTS: Overall, 12 RCTs involving 632 adult patients with medically refractory CD or CD-related fistula were included. In comparison with placebo or no treatment, SCT showed a greater likelihood of CR (odds ratio [OR] 2.08, 95% CI 1.39-3.12, p < 0.001) without any notable heterogeneity (I2 = 0%). Consistent results were observed in subgroup analyses based on study design, patient diagnosis, source and type of stem cells, and follow-up durations, with all p-values for subgroup analyses being greater than 0.05. The occurrence of SAE was similar among patients assigned to SCT and the placebo/no treatment cohorts (OR 0.70, 95% CI 0.37-1.33, p = 0.28; I2 = 0%). CONCLUSIONS: For patients with medically refractory CD or CD-related fistula, SCT may be an alternatively effective and safe treatment.

A guideline on the molecular ecosystem regulating ferroptosis.

Ferroptosis, an intricately regulated form of cell death characterized by uncontrolled lipid peroxidation, has garnered substantial interest since this term was first coined in 2012. Recent years have witnessed remarkable progress in elucidating the detailed molecular mechanisms that govern ferroptosis induction and defence, with particular emphasis on the roles of heterogeneity and plasticity. In this Review, we discuss the molecular ecosystem of ferroptosis, with implications that may inform and enable safe and effective therapeutic strategies across a broad spectrum of diseases.

Characterization of the Disinfectant Resistance Genes qacEΔ1 and cepA in Carbapenem-Resistant Klebsiella pneumoniae Isolates.

The emergence and wide global spread of carbapenem-resistant Klebsiella pneumoniae (CRKP) isolates are of great concern. This multicenter study aimed to investigate the molecular characteristics of CRKP isolates from inpatients in Wuhan, China. From June 2018 to March 2019, 74 nonduplicated CRKP clinical isolates were collected from six hospitals in Wuhan. We determined the minimum inhibitory concentrations of 18 antibiotics and used real-time polymerase chain reaction to detect the presence of disinfectant resistance genes qacEΔ1 and cepA. Pulsed-field gel electrophoresis was conducted to assess the genetic relatedness of isolates. Among the 74 CRKP isolates, the rates of resistance to carbapenems were high: 93.2% to ertapenem, 90.5% to imipenem, and 87.8% to meropenem. All isolates were resistant to at least one carbapenem antibiotic. Of the 74 isolates, 64.9% (48/74) were positive for qacEΔ1 and 93.2% (69/74) for cepA. QacEΔ1 and cepA were detected concomitantly in 46 isolates (62.2%), whereas only 4.1% (3/74) had no disinfectant resistance genes. Pulsed-field gel electrophoresis analysis clustered the 46 CRKP strains co-producing qacEΔ1 and cepA into 15 different clonal clusters (Types A to O). The most common clonal clusters were Type C (41.3%), Type E (13.0%), and Type J (8.7%). The study showed high rates of resistance to most antibiotics and high frequency of qacEΔ1 and cepA in CRKP isolates. Specific clonal dissemination of CRKP was detected within the same hospital or between different hospitals. Therefore, medical institutions should choose and use disinfectants correctly to prevent the spread of CRKP.

A radiomics model based on preoperative gadoxetic acid-enhanced magnetic resonance imaging for predicting post-hepatectomy liver failure in patients with hepatocellular carcinoma.

Background: Post-hepatectomy liver failure (PHLF) is a fatal complication after liver resection in patients with hepatocellular carcinoma (HCC). It is of clinical importance to estimate the risk of PHLF preoperatively. Aims: This study aimed to develop and validate a prediction model based on preoperative gadoxetic acid-enhanced magnetic resonance imaging to estimate the risk of PHLF in patients with HCC. Methods: A total of 276 patients were retrospectively included and randomly divided into training and test cohorts (194:82). Clinicopathological variables were assessed to identify significant indicators for PHLF prediction. Radiomics features were extracted from the normal liver parenchyma at the hepatobiliary phase and the reproducible, robust and non-redundant ones were filtered for modeling. Prediction models were developed using clinicopathological variables (Clin-model), radiomics features (Rad-model), and their combination. Results: The PHLF incidence rate was 24% in the whole cohort. The combined model, consisting of albumin-bilirubin (ALBI) score, indocyanine green retention test at 15 min (ICG-R15), and Rad-score (derived from 16 radiomics features) outperformed the Clin-model and the Rad-model. It yielded an area under the receiver operating characteristic curve (AUC) of 0.84 (95% confidence interval (CI): 0.77-0.90) in the training cohort and 0.82 (95% CI: 0.72-0.91) in the test cohort. The model demonstrated a good consistency by the Hosmer-Lemeshow test and the calibration curve. The combined model was visualized as a nomogram for estimating individual risk of PHLF. Conclusion: A model combining clinicopathological risk factors and radiomics signature can be applied to identify patients with high risk of PHLF and serve as a decision aid when planning surgery treatment in patients with HCC.

Critical examination of the characterization techniques, and the evidence, for the existence of extra-long amylopectin chains.

It has been suggested that amylopectin can contain small but significant amounts of extra-long chains (ELCs), which could affect functional properties, and also would have implications for the mechanism of starch biosynthesis. However, current evidence for the existence of ELCs is ambiguous. The amylose/amylopectin separation and the characterization techniques used for the investigation of ELCs are reviewed, problems in those techniques are examined, and studies of ELCs of amylopectin are discussed. A model for the biosynthesis of amylopectin chains in terms of conventional biosynthesis enzymes, which provides an excellent fit to a large amount of experimental data, is used to provide a rigorous definition of ELCs. In addition, current investigations of ELCs, involving separation, is hindered by the lack of a method to quantitatively separate all the amylopectin from starch without any traces of residual amylose (which would have long chains). Unambiguous evidence for the existence of ELCs can be obtained using two-dimensional (2D) characterization, these dimensions being the degree of polymerization of a chain and the size of the whole molecule. Available 2D data indicate that there are no ELCs present in currently detectable quantities in native rice starches. However, concluding this more rigorously requires improvements in the resolution of current 2D methods.

Boosting Interfacial Polarization Through Heterointerface Engineering in MXene/Graphene Intercalated-Based Microspheres for Electromagnetic Wave Absorption.

Multi-layer 2D material assemblies provide a great number of interfaces beneficial for electromagnetic wave absorption. However, avoiding agglomeration and achieving layer-by-layer ordered intercalation remain challenging. Here, 3D reduced graphene oxide (rGO)/MXene/TiO2/Fe2C lightweight porous microspheres with periodical intercalated structures and pronounced interfacial effects were constructed by spray-freeze-drying and microwave irradiation based on the Maxwell-Wagner effect. Such approach reinforced interfacial effects via defects introduction, porous skeleton, multi-layer assembly and multi-component system, leading to synergistic loss mechanisms. The abundant 2D/2D/0D/0D intercalated heterojunctions in the microspheres provide a high density of polarization charges while generating abundant polarization sites, resulting in boosted interfacial polarization, which is verified by CST Microwave Studio simulations. By precisely tuning the 2D nanosheets intercalation in the heterostructures, both the polarization loss and impedance matching improve significantly. At a low filler loading of 5 wt%, the polarization loss rate exceeds 70%, and a minimum reflection loss (RLmin) of -67.4 dB can be achieved. Moreover, radar cross-section simulations further confirm the attenuation ability of the optimized porous microspheres. These results not only provide novel insights into understanding and enhancing interfacial effects, but also constitute an attractive platform for implementing heterointerface engineering based on customized 2D hierarchical architectures.

Unsupervised Machine Learning of MRI Radiomics Features Identifies Two Distinct Subgroups with Different Liver Function Reserve and Risks of Post-Hepatectomy Liver Failure in Patients with Hepatocellular Carcinoma.

OBJECTIVE: To identify subgroups of patients with hepatocellular carcinoma (HCC) with different liver function reserves using an unsupervised machine-learning approach on the radiomics features from preoperative gadoxetic-acid-enhanced MRIs and to evaluate their association with the risk of post-hepatectomy liver failure (PHLF). METHODS: Clinical data from 276 consecutive HCC patients who underwent liver resections between January 2017 and March 2019 were retrospectively collected. Radiomics features were extracted from the non-tumorous liver tissue at the gadoxetic-acid-enhanced hepatobiliary phase MRI. The reproducible and non-redundant features were selected for consensus clustering analysis to detect distinct subgroups. After that, clinical variables were compared between the identified subgroups to evaluate the clustering efficacy. The liver function reserve of the subgroups was compared and the correlations between the subgroups and PHLF, postoperative complications, and length of hospital stay were evaluated. RESULTS: A total of 107 radiomics features were extracted and 37 were selected for unsupervised clustering analysis, which identified two distinct subgroups (138 patients in each subgroup). Compared with subgroup 1, subgroup 2 had significantly more patients with older age, albumin-bilirubin grades 2 and 3, a higher indocyanine green retention rate, and a lower indocyanine green plasma disappearance rate (all p < 0.05). Subgroup 2 was also associated with a higher risk of PHLF, postoperative complications, and longer hospital stays (>18 days) than that of subgroup 1, with an odds ratio of 2.83 (95% CI: 1.58-5.23), 2.41(95% CI: 1.15-5.35), and 2.14 (95% CI: 1.32-3.47), respectively. The odds ratio of our method was similar to the albumin-bilirubin grade for postoperative complications and length of hospital stay (2.41 vs. 2.29 and 2.14 vs. 2.16, respectively), but was inferior for PHLF (2.83 vs. 4.55). CONCLUSIONS: Based on the radiomics features of gadoxetic-acid-enhanced MRI, unsupervised clustering analysis identified two distinct subgroups with different liver function reserves and risks of PHLF in HCC patients. Future studies are required to validate our findings.

Esophageal papillomatosis: an exceedingly rare disease.

If esophageal papilloma (EP) is a rare condition, esophageal papillomatosis (EPS) is a distinct rarity. To date, only 53 well documented cases have been described in English literature. However, the number of reports on EPS significantly increased to over 40 cases during the past 20 years. Perhaps, this is due to the broad use of endoscopy and related research achievements. Most of the cases are individual and it seems that there are no associations between them. And up to now no guidelines can be followed. To further understand this exceedingly rare disease, we had a comprehensive review of the epidemiology, etiology, clinical manifestations, pathogenesis, treatment, and clinical course of EPS.

Development and External Validation of a Radiomics Model Derived from Preoperative Gadoxetic Acid-Enhanced MRI for Predicting Histopathologic Grade of Hepatocellular Carcinoma.

Histopathologic grade of hepatocellular carcinoma (HCC) is an important predictor of early recurrence and poor prognosis after curative treatments. This study aims to develop a radiomics model based on preoperative gadoxetic acid-enhanced MRI for predicting HCC histopathologic grade and to validate its predictive performance in an independent external cohort. Clinical and imaging data of 403 consecutive HCC patients were retrospectively collected from two hospitals (265 and 138, respectively). Patients were categorized into poorly differentiated HCC and non-poorly differentiated HCC groups. A total of 851 radiomics features were extracted from the segmented tumor at the hepatobiliary phase images. Three classifiers, logistic regression (LR), support vector machine, and Adaboost were adopted for modeling. The areas under the curve of the three models were 0.70, 0.67, and 0.61, respectively, in the external test cohort. Alpha-fetoprotein (AFP) was the only significant clinicopathological variable associated with HCC grading (odds ratio: 2.75). When combining AFP, the LR+AFP model showed the best performance, with an AUC of 0.71 (95%CI: 0.59-0.82) in the external test cohort. A radiomics model based on gadoxetic acid-enhanced MRI was constructed in this study to discriminate HCC with different histopathologic grades. Its good performance indicates a promise in the preoperative prediction of HCC differentiation levels.

The association of serum folate and homocysteine on venous thromboembolism in patients with colorectal cancer: a cross-sectional study.

Background: Venous thromboembolism is a common complication in patients with colorectal cancer who exhibit high homocysteine and low folate levels. However, whether venous thrombosis is the result of a direct effect of folic acid or the presence of a homocysteine-mediated mediating effect cannot be determined. This study aimed to explore the association and mediating effects of serum folate and homocysteine on venous thromboembolism in patients with colorectal cancer. Methods: This study included patients with colorectal cancer who were admitted to the First Hospital of Shanxi Medical University from May 2020 to May 2022. The patients' medical records were reviewed to collect information on general demographic characteristics, the prevalence of venous thromboembolism on admission, laboratory blood indices, serum folate, and serum homocysteine. SPSS 26.0 software was used for data collation and statistical analysis; the χ2 test was utilized for univariate analysis and unconditional logistic regression was applied for multivariate analysis. R 4.1.2 was used to perform the mediating effect test. Results: A total of 236 colorectal cancer patients were investigated. The prevalence of colorectal cancer combined with venous thromboembolism was 15.3%; serum folate was <10.75 nmol/L in 25.4% of patients; and serum homocysteine was ≥22 µmol/L in 30.5% of patients. After controlling for confounding factors, the risk of venous thromboembolism was 2.48 times greater [95% confidence interval (CI): 1.04 to 5.94] in patients with low serum folate (<10.75 nmol/L) than in those with high serum folate (≥10.75 nmol/L). Also, the risk of venous thromboembolism was greater in those with high serum homocysteine (≥22 µmol/L) [odds ratio (OR) =2.99. 95% CI: 1.11 to 8.08]. The mediating effect test showed no direct effect of serum folate on venous thromboembolism combined with colorectal cancer, and a full mediating effect of serum homocysteine between serum folate and venous thromboembolism combined with colorectal cancer, with a mediating effect value of 0.002 and a total effect value of 0.0054. Conclusions: Serum folate influences the formation of venous thromboembolism through serum homocysteine. It is recommended that the nutritional supplementation of patients be enhanced to control serum folate and serum homocysteine levels.

Long-term efficacy of no-touch radiofrequency ablation in the treatment of single small hepatocellular carcinoma: A single center long-term follow-up study.

OBJECTIVE: To evaluate the long-term efficacy of no-touch radiofrequency ablation (NT-RFA) for treating single hepatocellular carcinoma (HCC) less than 3 cm. METHODS: A total of 331 patients with HCC less than 3 cm undergoing RFA in Southwest Hospital from 2015 to 2020 were analyzed retrospectively. All patients were divided into NT-RFA group (n = 113) and conventional RFA (C-RFA) group (n = 218). The survival rate, local tumor progression (LTP) and intrahepatic distant recurrence (IDR) of the two groups were calculated and compared. RESULTS: A significant difference was observed in ablation range (p = 0.000) and safety margin (p = 0.000) between the two groups. The 1-, 2-, 3-, 4-and 5-year overall survival (OS) rates in NT-RFA and C-RFA group were 99.12%, 93.73%, 76.18%, 57.00%, 45.17% and 99.08%, 89.91%, 71.26%, 54.28%, 41.77%, respectively. There was no significant difference between the two groups (p = 0.281). The 1-, 2-, 3-, 4-and 5-year recurrence-free survival (RFS) rates in NT-RFA and C-RFA group were 78.51%, 52.59%, 41.02%, 34.36%, 30.92% and 68.81%, 44.95%, 30.88%, 23.73%, 22.88%, respectively. The two groups differed significantly (p = 0.044). The 1-, 3-and 5-year LTP-free survival rates in NT-RFA and C-RFA group were 87.12%, 74.99%, 72.32% and 75.75%, 65.52%, 65.52%, respectively. The two groups also differed significantly (p = 0.024). Furthermore, the RFS rates of D ≤ 2 cm subgroups in NT-RFA and C-RFA groups differed significantly (p = 0.037), while the RFS rates of 2 cm < D ≤ 3 cm subgroups in two groups showed no significant difference (p = 0.578). CONCLUSIONS: The RFS rates of single HCC less than 3 cm treated by NT-RFA was significantly higher than that of C-RFA. Due to a larger ablation range and safety margin, NT-RFA could significantly reduce LTP and improve RFS. Dual-electrode NT-RFA can significantly improve the RFS rate of patients with HCC less than 2 cm, but there is no obvious advantage compared with C-RFA in the treatment of HCC over 2 cm.

TMEM164 is a new determinant of autophagy-dependent ferroptosis.

Macroautophagy (hereafter "autophagy") is a membrane-mediated biological process that involves engulfing and delivering cytoplasmic components to lysosomes for degradation. In addition to autophagy's pro-survival effect during nutrient starvation, excessive activation of autophagy machinery can also cause regulated cell death, especially iron-dependent ferroptosis. Here, we report a key role of TMEM164 (transmembrane protein 164) in selectively mediating ATG5 (autophagy related 5)-dependent autophagosome formation during ferroptosis, rather than during starvation. In contrast, the membrane protein ATG9A (autophagy-related 9A) is dispensable for the formation of autophagosomes during ferroptosis. TMEM164-mediated autophagy degrades ferritin, GPX4 (glutathione peroxidase 4), and lipid droplets to increase iron accumulation and lipid peroxidation, thereby promoting ferroptotic cell death. Consequently, the loss of TMEM164 limits the anticancer activity of ferroptosis-mediated cytotoxicity in mice. High TMEM164 expression is associated with improved survival and increased immune cell infiltration in patients with pancreatic cancer. These findings establish a new mode of autophagy-dependent ferroptosis.

One-pot synthesis and enzyme-responsiveness of amphiphilic doxorubicin prodrug nanomicelles for cancer therapeutics.

In this study, we report a one-pot synthesis and enzyme-responsiveness of polyethylene glycol (PEG) and glutamic acid (Glu)-based amphiphilic doxorubicin (DOX) prodrug nanomicelles for cancer therapeutics. The nanomicelles were accomplished by esterification and amidation reactions. The nuclear magnetic resonance (NMR) and Fourier transform infrared (FTIR) data confirmed the structure of nanomicelles. The DOX-loaded nanomicelles showed a DLS-measured average size of 107 nm and excellent stability in phosphate-buffered saline (PBS) for 7 days. The drug loading and cumulative release rates were measured by ultraviolet-visible (UV-vis) spectrophotometry at 481 nm. The cumulative release rate could reach 100% in an enzyme-rich environment. Further, the therapeutic efficiency of nanomicelles to cancer cells was determined by cell viability and cellular uptake and distribution using HeLa cells. The cell viability study showed that the DOX-loaded nanomicelles could effectively inhibit the HeLa cell proliferation. The cellular uptake study confirmed that the nanomicelles could be effectively ingested by HeLa cells and distributed into cell nuclei. Based on the collective experimental data, this study demonstrated that the synthesized nanomicellar prodrug of DOX is a potential candidate for cancer therapeutics.