Structural analysis of the full-length human LRRK2.

Mutations in leucine-rich repeat kinase 2 (LRRK2) are commonly implicated in the pathogenesis of both familial and sporadic Parkinson's disease (PD). LRRK2 regulates critical cellular processes at membranous organelles and forms microtubule-based pathogenic filaments, yet the molecular basis underlying these biological roles of LRRK2 remains largely enigmatic. Here, we determined high-resolution structures of full-length human LRRK2, revealing its architecture and key interdomain scaffolding elements for rationalizing disease-causing mutations. The kinase domain of LRRK2 is captured in an inactive state, a conformation also adopted by the most common PD-associated mutation, LRRK2G2019S. This conformation serves as a framework for structure-guided design of conformational specific inhibitors. We further determined the structure of COR-mediated LRRK2 dimers and found that single-point mutations at the dimer interface abolished pathogenic filamentation in cells. Overall, our study provides mechanistic insights into physiological and pathological roles of LRRK2 and establishes a structural template for future therapeutic intervention in PD.

Structural Basis of Human KCNQ1 Modulation and Gating.

KCNQ1, also known as Kv7.1, is a voltage-dependent K+ channel that regulates gastric acid secretion, salt and glucose homeostasis, and heart rhythm. Its functional properties are regulated in a tissue-specific manner through co-assembly with beta subunits KCNE1-5. In non-excitable cells, KCNQ1 forms a complex with KCNE3, which suppresses channel closure at negative membrane voltages that otherwise would close it. Pore opening is regulated by the signaling lipid PIP2. Using cryoelectron microscopy (cryo-EM), we show that KCNE3 tucks its single-membrane-spanning helix against KCNQ1, at a location that appears to lock the voltage sensor in its depolarized conformation. Without PIP2, the pore remains closed. Upon addition, PIP2 occupies a site on KCNQ1 within the inner membrane leaflet, which triggers a large conformational change that leads to dilation of the pore's gate. It is likely that this mechanism of PIP2 activation is conserved among Kv7 channels.

Cryo-EM Structure of a KCNQ1/CaM Complex Reveals Insights into Congenital Long QT Syndrome.

KCNQ1 is the pore-forming subunit of cardiac slow-delayed rectifier potassium (IKs) channels. Mutations in the kcnq1 gene are the leading cause of congenital long QT syndrome (LQTS). Here, we present the cryoelectron microscopy (cryo-EM) structure of a KCNQ1/calmodulin (CaM) complex. The conformation corresponds to an "uncoupled," PIP2-free state of KCNQ1, with activated voltage sensors and a closed pore. Unique structural features within the S4-S5 linker permit uncoupling of the voltage sensor from the pore in the absence of PIP2. CaM contacts the KCNQ1 voltage sensor through a specific interface involving a residue on CaM that is mutated in a form of inherited LQTS. Using an electrophysiological assay, we find that this mutation on CaM shifts the KCNQ1 voltage-activation curve. This study describes one physiological form of KCNQ1, depolarized voltage sensors with a closed pore in the absence of PIP2, and reveals a regulatory interaction between CaM and KCNQ1 that may explain CaM-mediated LQTS.

The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity.

KRAS is the most frequently mutated oncogene in cancer and encodes a key signalling protein in tumours1,2. The KRAS(G12C) mutant has a cysteine residue that has been exploited to design covalent inhibitors that have promising preclinical activity3-5. Here we optimized a series of inhibitors, using novel binding interactions to markedly enhance their potency and selectivity. Our efforts have led to the discovery of AMG 510, which is, to our knowledge, the first KRAS(G12C) inhibitor in clinical development. In preclinical analyses, treatment with AMG 510 led to the regression of KRASG12C tumours and improved the anti-tumour efficacy of chemotherapy and targeted agents. In immune-competent mice, treatment with AMG 510 resulted in a pro-inflammatory tumour microenvironment and produced durable cures alone as well as in combination with immune-checkpoint inhibitors. Cured mice rejected the growth of isogenic KRASG12D tumours, which suggests adaptive immunity against shared antigens. Furthermore, in clinical trials, AMG 510 demonstrated anti-tumour activity in the first dosing cohorts and represents a potentially transformative therapy for patients for whom effective treatments are lacking.

Structural basis of DNA polymerase θ mediated DNA end joining.

DNA polymerase θ (Pol θ) plays an essential role in the microhomology-mediated end joining (MMEJ) pathway for repairing DNA double-strand breaks. However, the mechanisms by which Pol θ recognizes microhomologous DNA ends and performs low-fidelity DNA synthesis remain unclear. Here, we present cryo-electron microscope structures of the polymerase domain of Lates calcarifer Pol θ with long and short duplex DNA at up to 2.4 Šresolution. Interestingly, Pol θ binds to long and short DNA substrates similarly, with extensive interactions around the active site. Moreover, Pol θ shares a similar active site as high-fidelity A-family polymerases with its finger domain well-closed but differs in having hydrophilic residues surrounding the nascent base pair. Computational simulations and mutagenesis studies suggest that the unique insertion loops of Pol θ help to stabilize short DNA binding and assemble the active site for MMEJ repair. Taken together, our results illustrate the structural basis of Pol θ-mediated MMEJ.

Blocking CHOP-dependent TXNIP shuttling to mitochondria attenuates albuminuria and mitigates kidney injury in nephrotic syndrome.

Albuminuria is a hallmark of glomerular disease of various etiologies. It is not only a symptom of glomerular disease but also a cause leading to glomerulosclerosis, interstitial fibrosis, and eventually, a decline in kidney function. The molecular mechanism underlying albuminuria-induced kidney injury remains poorly defined. In our genetic model of nephrotic syndrome (NS), we have identified CHOP (C/EBP homologous protein)-TXNIP (thioredoxin-interacting protein) as critical molecular linkers between albuminuria-induced ER dysfunction and mitochondria dyshomeostasis. TXNIP is a ubiquitously expressed redox protein that binds to and inhibits antioxidant enzyme, cytosolic thioredoxin 1 (Trx1), and mitochondrial Trx2. However, very little is known about the regulation and function of TXNIP in NS. By utilizing Chop-/- and Txnip-/- mice as well as 68Ga-Galuminox, our molecular imaging probe for detection of mitochondrial reactive oxygen species (ROS) in vivo, we demonstrate that CHOP up-regulation induced by albuminuria drives TXNIP shuttling from nucleus to mitochondria, where it is required for the induction of mitochondrial ROS. The increased ROS accumulation in mitochondria oxidizes Trx2, thus liberating TXNIP to associate with mitochondrial nod-like receptor protein 3 (NLRP3) to activate inflammasome, as well as releasing mitochondrial apoptosis signal-regulating kinase 1 (ASK1) to induce mitochondria-dependent apoptosis. Importantly, inhibition of TXNIP translocation and mitochondrial ROS overproduction by CHOP deletion suppresses NLRP3 inflammasome activation and p-ASK1-dependent mitochondria apoptosis in NS. Thus, targeting TXNIP represents a promising therapeutic strategy for the treatment of NS.

Layered Ferromagnetic Structure Caused by the Proximity Effect and Interlayer Charge Transfer for LaNiO3/LaMnO3 Superlattices.

Magnetic proximity-induced magnetism in paramagnetic LaNiO3 (LNO) has spurred intensive investigations in the past decade. However, no consensus has been reached so far regarding the magnetic order in LNO layers in relevant heterostructures. This paper reports a layered ferromagnetic structure for the (111)-oriented LNO/LaMnO3 (LMO) superlattices. It is found that each period of the superlattice consisted of an insulating LNO-interfacial phase (five unit cells in thickness, ∼1.1 nm), a metallic LNO-inner phase, a poorly conductive LMO-interfacial phase (three unit cells in thickness, ∼0.7 nm), and an insulating LMO-inner phase. All four of these phases are ferromagnetic, showing different magnetizations. The Mn-to-Ni interlayer charge transfer is responsible for the emergence of a layered magnetic structure, which may cause magnetic interaction across the LNO/LMO interface and double exchange within the LMO-interfacial layer. This work indicates that the proximity effect is an effective means of manipulating the magnetic state and associated properties of complex oxides.

CRL4DCAF4 E3 ligase-mediated degradation of MEN1 transcriptionally reactivates hTERT to sustain immortalization in colorectal cancer cells.

Telomerase reactivation is implicated in approximately 85% of human cancers, yet its underlying mechanism remains elusive. In this study, we elucidate that the Cullin RING Ubiquitin Ligase 4 (CRL4) complex drives the reactivation of human telomerase reverse transcriptase (hTERT) in colorectal cancer (CRC) by degrading the tumor suppressor, menin 1 (MEN1). Our data show that, in noncancerous intestinal epithelial cells, the transcription factor specificity protein 1 (Sp1) recruits both the histone acetyltransferase p300 and MEN1 to suppress hTERT expression, thus maintaining telomere shortness post-cell division. Inflammation-induced microenvironments trigger an activation of the CRL4DCAF4 E3 ligase, leading to MEN1 ubiquitination and degradation in CRC cells. This process nullifies MEN1's inhibitory action, reactivates hTERT expression at the transcriptional level, interrupts telomere shortening, and spurs uncontrolled cellular proliferation. Notably, MEN1 overexpression in CRC cells partially counteracts these oncogenic phenotypes. NSC1517, an inhibitor of the CRL4DCAF4 complex identified through high-throughput screening from a plant-derived chemical pool, hinders MEN1 degradation, attenuates hTERT expression, and suppresses tumor growth in mouse xenograft models. Collectively, our research elucidates the transcriptional mechanism driving hTERT reactivation in CRC. Targeting the CRL4DCAF4 E3 ligase emerges as a promising strategy to counteract cancer cell immortalization and curb tumor progression.

Broad-spectrum resistance gene RPW8.1 balances immunity and growth via feedback regulation of WRKYs.

Arabidopsis RESISTANCE TO POWDERY MILDEW 8.1 (RPW8.1) is an important tool for engineering broad-spectrum disease resistance against multiple pathogens. Ectopic expression of RPW8.1 leads to enhanced disease resistance with cell death at leaves and compromised plant growth, implying a regulatory mechanism balancing RPW8.1-mediated resistance and growth. Here, we show that RPW8.1 constitutively enhances the expression of transcription factor WRKY51 and activates salicylic acid and ethylene signalling pathways; WRKY51 in turn suppresses RPW8.1 expression, forming a feedback regulation loop. RPW8.1 and WRKY51 are both induced by pathogen infection and pathogen-/microbe-associated molecular patterns. In ectopic expression of RPW8.1 background (R1Y4), overexpression of WRKY51 not only rescues the growth suppression and cell death caused by RPW8.1, but also suppresses RPW8.1-mediated broad-spectrum disease resistance and pattern-triggered immunity. Mechanistically, WRKY51 directly binds to and represses RPW8.1 promoter, thus limiting the expression amplitude of RPW8.1. Moreover, WRKY6, WRKY28 and WRKY41 play a role redundant to WRKY51 in the suppression of RPW8.1 expression and are constitutively upregulated in R1Y4 plants with WRKY51 being knocked out (wrky51 R1Y4) plants. Notably, WRKY51 has no significant effects on disease resistance or plant growth in wild type without RPW8.1, indicating a specific role in RPW8.1-mediated disease resistance. Altogether, our results reveal a regulatory circuit controlling the accumulation of RPW8.1 to an appropriate level to precisely balance growth and disease resistance during pathogen invasion.

Mast cell stabilizer, an anti-allergic drug, reduces ventricular arrhythmia risk via modulation of neuroimmune interaction.

Mast cells (MCs) are important intermediates between the nervous and immune systems. The cardiac autonomic nervous system (CANS) crucially modulates cardiac electrophysiology and arrhythmogenesis, but whether and how MC-CANS neuroimmune interaction influences arrhythmia remain unclear. Our clinical data showed a close relationship between serum levels of MC markers and CANS activity, and then we use mast cell stabilizers (MCSs) to alter this MC-CANS communication. MCSs, which are well-known anti-allergic agents, could reduce the risk of ventricular arrhythmia (VA) after myocardial infarction (MI). RNA-sequencing (RNA-seq) analysis to investigate the underlying mechanism by which MCSs could affect the left stellate ganglion (LSG), a key therapeutic target for modulating CANS, showed that the IL-6 and γ-aminobutyric acid (GABA)-ergic system may be involved in this process. Our findings demonstrated that MCSs reduce VA risk along with revealing the potential underlying antiarrhythmic mechanisms.

Causal relationship between prostatic diseases and prostate cancer: a mendelian randomization study.

BACKGROUND: Although it is thought that prostatitis or benign prostatic hyperplasia (BPH) is related to prostate cancer (PCa), the underlying causal effects of these diseases are unclear. METHODS: We assessed the causal relationship between prostatitis or BPH and PCa using a two-sample Mendelian randomization (MR) approach. The data utilized in this study were sourced from genome-wide association study. The association of genetic variants from cohorts of prostatitis or BPH and PCa patients was determined using inverse-variance weighted and MR Egger regression techniques. The direction of chance was determined using independent genetic variants with genome-wide significance (P < 5 × 10-6). The accuracy of the results was confirmed using sensitivity analyses. RESULTS: MR analysis showed that BPH had a significant causal effect on PCa (Odds Ratio = 1.209, 95% Confidence Interval: 0.098-0.281, P = 5.079 × 10- 5) while prostatitis had no significant causal effect on PCa (P > 0.05). Additionally, the pleiotropic test and leave-one-out analysis showed the two-sample MR analyses were valid and reliable. CONCLUSIONS: This MR study supports that BPH has a positive causal effect on PCa, while genetically predicted prostatitis has no causal effect on PCa. Nonetheless, further studies should explore the underlying biochemical mechanism and potential therapeutic targets for the prevention of these diseases.

Genomic and transcriptomic analyses provide new insights into the allelochemical degradation preference of a novel Acinetobacter strain.

A novel n-alkane- and phenolic acid-degrading Acinetobacter strain (designated C16S1T) was isolated from rhizosphere soil. The strain was identified as a novel species named Acinetobacter suaedae sp. nov. using a polyphasic taxonomic approach. Strain C16S1T showed preferential degradation of three compounds: p-hydroxybenzoate (PHBA) > ferulic acid (FA) > n-hexadecane. In a medium containing two or three of these allelochemicals, coexisting n-hexadecane and PHBA accelerated each other's degradation and that of FA. FA typically hindered the degradation of n-hexadecane but accelerated PHBA degradation. The upregulated expression of n-hexadecane- and PHBA-degrading genes induced, by their related substrates, was mutually enhanced by coexisting PHBA or n-hexadecane; in contrast, expression of both gene types was reduced by FA. Coexisting PHBA or n-hexadecane enhanced the upregulation of FA-degrading genes induced by FA. The expressions of degrading genes affected by coexisting chemicals coincided with the observed degradation efficiencies. Iron shortage limited the degradation efficiency of all three compounds and changed the degradation preference of Acinetobacter. The present study demonstrated that the biodegradability of the chemicals, the effects of coexisting chemicals on the expression of degrading genes and the strain's growth, the shortage of essential elements, and the toxicity of the chemicals were the four major factors affecting the removal rates of the coexisting allelochemicals.

Allosteric Activation of Ubiquitin-Specific Proteases by ß-Propeller Proteins UAF1 and WDR20.

Ubiquitin-specific proteases (USPs) constitute the largest family of deubiquitinating enzymes, whose catalytic competency is often modulated by their binding partners through unknown mechanisms. Here we report on a series of crystallographic and biochemical analyses of an evolutionarily conserved deubiquitinase, USP12, which is activated by two ß-propeller proteins, UAF1 and WDR20. Our structures reveal that UAF1 and WDR20 interact with USP12 at two distinct sites far from its catalytic center. Without increasing the substrate affinity of USP12, the two ß-propeller proteins potentiate the enzyme through different allosteric mechanisms. UAF1 docks at the distal end of the USP12 Fingers domain and induces a cascade of structural changes that reach a critical ubiquitin-contacting loop adjacent to the catalytic cleft. By contrast, WDR20 anchors at the base of this loop and remotely modulates the catalytic center of the enzyme. Our results provide a mechanistic example for allosteric activation of USPs by their regulatory partners.

Direct Observation of Magnetic Skyrmions and Their Current-Induced Dynamics in Epitaxial Single-Crystal Oxide Films.

Magnetic skyrmions are scarcely investigated for single-crystal quality films, for which skyrmions may have a remarkable performance. Even in the limited studies in this aspect, the skyrmions are usually probed by the topological Hall effect, missing important information on dynamic properties. Here, we present a comprehensive investigation on the generation/manipulation of magnetic skyrmions in La0.67Ba0.33MnO3 single-crystal films. Using the technique of magnetic force microscopy, the current-driven skyrmion dynamics are directly observed. Unlike isolated skyrmions produced by magnetic field alone, closely packed skyrmions can be generated by electric pulses in a magnetic background, with a high density (∼60/µm2) and a small size (dozens of nanometers). The threshold current moving skyrmions is ∼2.3 × 104 A/cm2, 2-3 orders of magnitude lower than that required by metallic multilayers or van der Waals ferromagnetic heterostructures. Our work demonstrates the great potential of single-crystal oxide films in developing skyrmion-based devices.

Genome-wide identification and expression analysis of the AUX/IAA gene family in turnip (Brassica rapa ssp. rapa).

BACKGROUND: Auxin/indoleacetic acid (AUX/IAA) genes encoding short-lived proteins participate in AUX signaling transduction and play crucial roles in plant growth and development. Although the AUX/IAA gene family has been identified in many plants, a systematic analysis of AUX/IAA genes in Brassica rapa ssp. rapa has not yet been reported. RESULTS: We performed a comprehensive genome-wide analysis and found 89 AUX/IAA genes in turnip based on the conserved AUX/IAA domain (pfam02309). Phylogenetic analysis of AUX/IAA genes from turnip, Arabidopsis, and cabbage revealed that these genes cluster into six subgroups (A1, A2, A3, A4, B1, and B2). The motif distribution was also conservative among the internal members of the clade. Enhanced yellow fluorescent protein (EYFP) signals of BrrIAA-EYFPs showed that BrrIAA members functioned as nucleoproteins. Moreover, transcriptional analysis revealed that the expression patterns of AUX/IAA genes in turnip were tissue-dependent. Because orthologs have similar biological functions and interaction networks in plant growth and development, BrrIAA66 in turnip possibly played a role in embryo axis formation, vascular development, lateral root formation, and floral organ development by interacting with BrrARF19 and BrrTIR1. CONCLUSION: These results provide a theoretical basis for further investigation of BrrAUX/IAA genes and lay the foundation for functional analysis of BrrIAA66 in turnip.

Isolation of Highly Reactive Cobalt Phthalocyanine via Electrochemical Activation for Enhanced CO2 Reduction Reaction.

Electrochemical CO2 -to-CO conversion offers an attractive and efficient route to recycle CO2 greenhouse gas. Molecular catalysts, like CoPc, are proved to be possible replacement for precious metal-based catalysts. These molecules, a combination of metal center and organic ligand molecule, may evolve into single atom structure for enhanced performance; besides, the manipulation of molecules' behavior also plays an important role in mechanism research. Here, in this work, the structure evolution of CoPc molecules is investigated via electrochemical-induced activation process. After numbers of cyclic voltammetry scanning, CoPc molecular crystals become cracked and crumbled, meanwhile the released CoPc molecules migrate to the conductive substrate. Atomic-scale HAADF-STEM proves the migration of CoPc molecules, which is the main reason for the enhancement in CO2 -to-CO performance. The as-activated CoPc exhibits a maximum FECO of 99% in an H-type cell and affords a long-term durability at 100 mA cm-2 for 29.3 h in a membrane electrode assembly reactor. Density-functional theory (DFT) calculation also demonstrates a favorable CO2 activation energy with such an activated CoPc structure. This work provides a different perspective for understanding molecular catalysts as well as a reliable and universal method for practical utilization.

Laparoscopic Anatomical Liver Resection of Segment VIII by Using ICG Fluorescence Positive Staining Under the Guidance of Laparoscopic Ultrasonography.

BACKGROUND: Anatomical segmentectomy is a surgical procedure that completely removes a territory (or territories) of the third-order portal venous branches of a Couinaud segment (Wakabayashi et al. in J Hepatobil Pancreat Sci 29(1):82-98, 2022. https://doi.org/10.1002/jhbp.899 ). Laparoscopic segmentectomy of S8 is considered technically challenging because of the Precise dissection of the Glissonean pedicle of S8, and exposure of the middle and right hepatic veins are required (Ome et al. in J Am Coll Surg 230(3):e13-e20, 2020; Wakabayashi et al. in Ann Surg 261(4):619-29, 2015. https://doi.org/10.1097/sla.0000000000001184 ; Monden et al. in J Hepatobil Pancreat Sci 29(1):66-81, 2022. https://doi.org/10.1002/jhbp.898 ). This report describes a new approach, which can reduce unwanted damage to normal tissues and complications. METHODS: A 53-year-old man who has suffered from hepatitis B for 10 years was admitted for the treatment of two nodular tumors located in segment VIII. The surgical procedure began with the percutaneous injection of 5 mL, 0.025 mg/mL of ICG into the S8 portal branch by using an 18G PTCD needle under the guidance of laparoscopic ultrasound (Xu et al. in Surg Endosc 34(10):4683-4691, 2020. https://doi.org/10.1007/s00464-020-07691-5 ; Wang et al. in Ann Surg 274(1):97-106, 2021. https://doi.org/10.1097/sla.0000000000004718 ; Aoki et al. in J Am Coll Surg 230(3):e7-e12, 2020. https://doi.org/10.1016/j.jamcollsurg.2019.11.004 ), followed by liver transection on the cranial side of the liver, which used the ICG fluorescence images for exposing the roots of the middle and right hepatic veins and dissecting and ligating S8 portal pedicle. The excision specimen was sent for histopathological diagnosis. RESULTS: It took 200 min for the operation and 60 min for the total Pringle maneuver. The estimate of blood loss was 110 mL. The final histopathologic results of the two nodules were hepatocellular carcinoma (HCC). The patient was discharged on postoperative Day 6 with no complications. CONCLUSIONS: Laparoscopic anatomical liver resection of S8 has been demonstrated to be feasible. Under the guidance of laparoscopic ultrasonography, ICG positive staining was proven to be optimal for Anatomical segmentectomy.

Identification of key somatic oncogenic mutation based on a confounder-free causal inference model.

Abnormal cell proliferation and epithelial-mesenchymal transition (EMT) are the essential events that induce cancer initiation and progression. A fundamental goal in cancer research is to develop an efficient method to detect mutational genes capable of driving cancer. Although several computational methods have been proposed to identify these key mutations, many of them focus on the association between genetic mutations and functional changes in relevant biological processes, but not their real causality. Causal effect inference provides a way to estimate the real induce effect of a certain mutation on vital biological processes of cancer initiation and progression, through addressing the confounder bias due to neutral mutations and unobserved latent variables. In this study, integrating genomic and transcriptomic data, we construct a novel causal inference model based on a deep variational autoencoder to identify key oncogenic somatic mutations. Applied to 10 cancer types, our method quantifies the causal effect of genetic mutations on cell proliferation and EMT by reducing both observed and unobserved confounding biases. The experimental results indicate that genes with higher mutation frequency do not necessarily mean they are more potent in inducing cancer and promoting cancer development. Moreover, our study fills a gap in the use of machine learning for causal inference to identify oncogenic mutations.

Nomogram Model Based on Iodine Nutrition and Clinical Characteristics of Papillary Thyroid Carcinoma to Predict Lateral Lymph Node Metastasis.

OBJECTIVE: Preoperative evaluation of lateral lymph node metastasis (LLNM) in patients with papillary thyroid carcinoma (PTC) has been one of the major clinical challenges. This study aims to develop and validate iodine nutrition-related nomogram models to predict lateral cervical lymph node metastasis in patients with PTC. METHODS: This is a retrospective study. Urinary iodine concentration (UIC) and serum iodine concentration (SIC) were measured in 187 LLNM patients and 289 non-LLNM (NLLNM) patients. All patients were randomized 3:1 into the training cohort (n = 355) and the validation cohort (n = 121). Using logistic regression analysis, we analyzed the influence of iodine nutrition-related factors and clinicopathological characteristics on LLNM in PTC patients. Lasso regression method was used to screen risk factors and construct a nomogram for predicting LLNM. The receiver operating characteristic curve (ROC curve), calibration curve, and decision curve analysis (DCA) of the nomogram models were carried out for the training and validation cohorts. RESULTS: Gender, SIC, smoking history, drinking history, family history of PTC, multifocality, bilateral or unilateral tumors, TSH, Tg, and tumor size were included in the nomogram model predicting LLNM, with an area under the curve (AUC) of .795. The nomogram model showed good calibration and clinical benefit in both the training and validation cohorts. CONCLUSION: The nomogram model based on iodine nutrition and other clinicopathological features is effective for predicting the lateral lymph node metastasis in PTC patients.

MTM-HCC at Previous Liver Resection as a Predictor of Overall Survival in Salvage Liver Transplantation.

OBJECTIVES: Salvage liver transplantation (sLT) is considered an effective method to treat hepatocellular carcinoma (HCC) recurrence. This multicenter research aimed to identify the prognostic factors associated with recurrence-free survival (RFS) and overall survival (OS) after sLT. MATERIAL AND METHODS: A retrospective analysis of 114 patients who had undergone sLT for recurrent HCC between February 2012 and September 2020 was performed. The baseline and clinicopathological data of the patients were collected. RESULTS: The 1-, 3-, and 5-year RFS rates after sLT were 88.9%, 75.2%, and 69.2%, respectively, and the OS rates were 96.4%, 78.3%, and 70.8%. A time from liver resection (LR) to recurrence < 1 year, disease beyond the Milan criteria at sLT and macrotrabecular massive (MTM)-HCC were identified as risk factors for RFS and were further identified as independent risk factors. A time from LR to recurrence < 1 year, disease beyond the Milan criteria at sLT and MTM-HCC were also risk factors for OS and were further identified as independent risk factors. CONCLUSIONS: Compared with primary liver transplantation (pLT), more prognostic factors are available from patients who had undergone LR. We suggest that in cases of HCC recurrence within 1 year after LR, disease beyond the Milan criteria at sLT and MTM-HCC patients, sLT should be used with caution.