Influence of intraoperative blood salvage and autotransfusion on tumor recurrence after deceased donor liver transplantation: a large nationwide cohort study.

BACKGROUND AND AIMS: The practice of intraoperative blood salvage and autotransfusion (IBSA) during deceased donor liver transplantation (DDLT) for hepatocellular carcinoma (HCC) can potentially reduce the need for allogeneic blood transfusion. However, implementing IBSA remains debatable due to concerns about its possible detrimental effects on oncologic recurrence. METHODS: This study retrospectively enrolled nationwide recipients of DDLT for HCC between 2015 and 2020. The focus was on comparing the cumulative recurrence rate and the recurrence-free survival rate. Propensity score matching was conducted repeatedly for further subgroup comparison. Recipients were categorized based on the Milan criteria, macrovascular invasion, and pre-transplant α-Fetoprotein (AFP) level to identify subgroups at risk of HCC recurrence. RESULTS: A total of 6196 and 329 patients were enrolled in the non-IBSA and IBSA groups in this study. Multivariable competing risk regression analysis identified IBSA as independent risk factors for HCC recurrence (P<0.05). Post-matching, the cumulative recurrence rate and recurrence-free survival rate revealed no significant difference in the IBSA group and non-IBSA group (22.4% vs. 16.5%, P=0.12; 60.3% vs. 60.9%, P=0.74). Recipients beyond Milan criteria had higher, albeit not significant, risk of HCC recurrence if receiving IBSA (33.4% vs. 22.5%, P=0.14). For recipients with macrovascular invasion, the risk of HCC recurrence has no significant difference between the two groups (32.2% vs. 21.3%, P=0.231). For recipients with an AFP level<20 ng/mL, the risk of HCC recurrence was comparable in the IBSA group and the non-IBSA group (12.8% vs. 18.7%, P=0.99). Recipients with an AFP level ≥20 ng/mL, the risk of HCC recurrence was significantly higher in the IBSA group. For those with an AFP level≥400 ng/mL, the impact of IBSA on the cumulative recurrence rate was even more pronounced (49.8% vs. 21.9%, P=0.011). CONCLUSIONS: IBSA does not appear to be associated with worse outcomes for recipients with HCC exceeding the Milan criteria or with macrovascular invasion. IBSA could be confidently applied for recipients with a pre-transplant AFP level<20 ng/mL. For recipients with AFP levels≥20 ng/mL, undertaking IBSA would increase the risk of HCC recurrence.

Advancements of Macrophages Involvement in Pathological Progression of Colitis-Associated Colorectal Cancer and Associated Pharmacological Interventions.

Intestinal macrophages play crucial roles in both intestinal inflammation and immune homeostasis. They can adopt two distinct phenotypes, primarily determined by environmental cues. These phenotypes encompass the classically activated pro-inflammatory M1 phenotype, as well as the alternatively activated anti-inflammatory M2 phenotype. In regular conditions, intestinal macrophages serve to shield the gut from inflammatory harm. However, when a combination of genetic and environmental elements influences the polarization of these macrophages, it can result in an M1/M2 macrophage activation imbalance, subsequently leading to a loss of control over intestinal inflammation. This shift transforms normal inflammatory responses into pathological damage within the intestines. In patients with ulcerative colitis-associated colorectal cancer (UC-CRC), disorders related to intestinal inflammation are closely correlated with an imbalance in the polarization of intestinal M1/M2 macrophages. Therefore, reinstating the equilibrium in M1/M2 macrophage polarization could potentially serve as an effective approach to the prevention and treatment of UC-CRC. This paper aims to scrutinize the clinical evidence regarding Chinese medicine (CM) in the treatment of UC-CRC, the pivotal role of macrophage polarization in UC-CRC pathogenesis, and the potential mechanisms through which CM regulates macrophage polarization to address UC-CRC. Our objective is to offer fresh perspectives for clinical application, fundamental research, and pharmaceutical advancement in UC-CRC.

[Comparative study of external fixator combined with Kirschner wire fixation and Kirschner wires fixation in treatment of cubitus varus deformity in children].

Objective: To analyze the effectiveness comparison of external fixator combined with Kirschner wire fixation and Kirschner wire fixation in the treatment of cubitus varus deformity in children. Methods: A retrospective case-control study was conducted to collect 36 children of postoperative supracondylar humerus fracture complicating cubitus varus deformity between January 2018 and July 2022. Among them, 17 cases were treated with distal humeral wedge osteotomy external fixation combined with Kirschner wire fixation (observation group), and 19 cases were treated with distal humeral wedge osteotomy and Kirschner wire fixation (control group). The baseline data including age, gender, deformity side, time from fracture to operation, carrying angle of the healthy side and preoperative carrying angle of the affected side, elbow flexion and extension range of motion, and lateral condylar prominence index (LCPI) showed no significant difference between the two groups ( P>0.05). The operation time, hospitalization cost, healing time of osteotomy, postoperative complications, and the carrying angle, LCPI, and elbow flexion and extention range of motion were recorded and compared between the two groups. The elbow function was assessed by Oppenheim score at 3 months after operation and at last follow-up. Results: The children in both groups were followed up 13-48 months, with an average of 26.7 months. There was 1 case of needle tract infection in the observation group and 2 cases in the control group, and no nerve injury occurred, the difference in the incidence of complication (5.88% vs 10.53%) between the two groups was not significant ( χ 2=0.502, P=0.593). There was no significant difference in the operation time and fracture healing time between the two groups ( P>0.05); the hospitalization cost of the observation group was significantly higher than that of the control group ( P<0.05). The Oppenheim score of the observation group was significantly better than that of the control group at 3 months after operation ( P<0.05), but there was no significant difference in the Oppenheim score between the two groups at last follow-up ( P>0.05). At last follow-up, the carrying angle of affected side significantly improved in both groups when compared with preoperative ones ( P<0.05); the differences of the pre- and post-operative carrying angle of affected side and elbow flexion and extension range of motion showed no significant differences between the two groups ( P>0.05), but the difference in pre- and post-operative LCPI of the observation group was significantly better than that of the control group ( P<0.05). Conclusion: External fixator combined with Kirschner wire fixation and Kirschner wire fixation both can achieve satisfactory correction of cubitus varus deformity in children, and the former can achieve better short-term functional recovery of elbow joint and reduce the incidence of humeral lateral condyle protrusion.

Phyllanthus emblica Linn: A comprehensive review of botany, traditional uses, phytonutrients, health benefits, quality markers, and applications.

Phyllanthus emblica Linn is not only an edible fruit with high nutritional value, but also a medicinal plant with multiple bioactivities. It is widely used in clinical practice with functions of clearing heat, cooling blood, digesting food, strengthening stomach, promoting fluid production, and relieving cough. This review summarized a wide variety of phytonutrients, including nutritional components (mineral elements, amino acids, vitamins, polysaccharides, unsaturated free fatty acids) and functional components (phenolic acids (1-34), tannins (35-98), flavonoids (99-141), sterols (142-159), triterpenoids (160-175), lignans (176-183), alkaloids (184-197), alkanes (198-212), aromatic micromolecules (213-222), other compounds (223-239)). The isolated compounds and the various extracts of P. emblica Linn presented a diverse spectrum of biological activities such as anti-oxidant, anti-cancer, anti-inflammatory, anti-bacterial, hepatoprotective, hypoglycemic, anti-atherosclerosis, neuroprotective, enhancing immunity, anti-fatigue, anti-myocardial fibrosis. The quality markers of P. emblica Linn were predicted and analyzed based on traditional medicinal properties, traditional efficacy, plant genealogy and chemical component characteristics, biogenic pathway of chemical components, measurability of chemical components, transformation characteristics of polyphenolic components, homologous characteristics of medicine and food, compound compatibility environment, and clinical applications. This review also summarized and prospected applications of P. emblica Linn in beverages, preserved fruits, fermented foods, etc. However, the contents of mechanism, structure-activity relationship, quality control, toxicity, extraction, processing of P. emblica Linn are not clear, and are worth further studies in the future.

KIF18A inactivates hepatic stellate cells and alleviates liver fibrosis through the TTC3/Akt/mTOR pathway.

Activation of hepatic stellate cells (HSCs) has been demonstrated to play a pivotal role in the process of liver fibrogenesis. In this study, we observed a decrease in the expression of KIF18A in fibrotic liver tissues compared to healthy liver tissues, which exhibited a negative correlation with the activation of HSCs. To elucidate the molecular mechanisms underlying the involvement of KIF18A, we performed in vitro proliferation experiments and established a CCl4-induced liver fibrosis model. Our results revealed that KIF18A knockdown enhanced HSCs proliferation and reduced HSCs apoptosis in vitro. Mouse liver fibrosis grade was evaluated with Masson's trichrome and alpha-smooth muscle actin (α-SMA) staining. In addition, the expression of fibrosis markers Col1A1, Stat1, and Timp1 were detected. Animal experiments demonstrated that knockdown of KIF18A could promote liver fibrosis, whereas overexpression of KIF18A alleviated liver fibrosis in a CCl4-induced mouse model. Mechanistically, we found that KIF18A suppressed the AKT/mTOR pathway and exhibited direct binding to TTC3. Moreover, TTC3 was found to interact with p-AKT and could promote its ubiquitination and degradation. Our findings provide compelling evidence that KIF18A enhances the protein binding between TTC3 and p-AKT, promoting TTC3-mediated ubiquitination and degradation of p-AKT. These results refine the current understanding of the mechanisms underlying the pathogenesis of liver fibrosis and may offer new targets for treating this patient population.

Heparanase inhibitor OGT 2115 induces prostate cancer cell apoptosis via the downregulation of MCL­1.

Heparanase (HPSE), an endo-ß-D-glucuronidase, cleaves heparan sulfate and serves an important role in the tumor microenvironment and thus in tumorigenesis. HPSE is known to promote tumor cell evasion of apoptosis. However, the underlying mechanism of this requires further study. In the present study, the results demonstrated that myeloid cell leukemia-1 (MCL-1), an antiapoptotic protein, and HPSE were upregulated in prostate cancer tissues compared with adjacent normal tissues. In addition, the HPSE inhibitor, OGT 2115, inhibited PC-3 and DU-145 prostate cancer cell viability in a dose-dependent manner, with IC50 values of 20.2 and 97.2 µM, respectively. Furthermore, annexin V/PI double-staining assays demonstrated that OGT 2115 induced apoptosis in prostate cancer cells. OGT 2115 treatment markedly decreased MCL-1 protein expression levels, whereas RNA interference-mediated downregulation of MCL-1 and OGT 2115 drug treatment synergistically induced apoptosis in PC-3 and DU-145 cells. In vivo, OGT 2115 40 mg/kg (ig) significantly inhibited PC-3 cell xenograft growth in nude mice and increased the positive TUNEL staining rate of xenograft tissues. It was therefore hypothesized that MCL-1 was an important signaling molecule in OGT 2115-induced apoptosis. The results of the present study also demonstrated that the proteasome inhibitor, MG-132, markedly inhibited the downregulation of MCL-1 protein expression levels induced by OGT 2115. However, the protein synthesis inhibitor, cycloheximide, did not affect the role of OGT 2115 in regulating MCL-1. In summary, the results of the present study demonstrated that the proapoptotic activity of OGT 2115 was achieved by downregulating MCL-1.

[Clinical observation of virtual reality technology combined with isokinetic strength training for patients after anterior cruciate ligament reconstruction].

OBJECTIVE: To explore application value and effectiveness of virtual reality technology combined with isokinetic muscle strength training in the rehabilitation of patients after anterior cruciate ligament (ACL) reconstruction surgery. METHODS: Forty patients who underwent ACL reconstruction surgery from December 2021 to January 2023 were selected and divided into control group and observation group according to treatment methods, 20 patients in each group. Control group was received routine rehabilitation training combined with isokinetic muscle strength training, including 15 males and 5 females, aged from 17 to 44 years old, with an average of (29.10±8.60) years old. Observation group was performed virtual reality technology combined with isokinetic muscle strength training, including 16 males and 4 females, aged from 17 to 45 years old with an average of (30.95±9.11) years old. Lysholm knee joint score, knee extension peak torque, and knee flexion peak torque between two groups at 12 (before training) and 16 weeks (after training) after surgery were compared. RESULTS: All patients were followed up for 1 to 6 months with an average of (3.30±1.42) months. There were no statistically significant difference in Lysholm knee joint score, peak knee extension peak torque, and peak knee flexion peak torque between two groups (P>0.05) before training. After training, Lysholm knee joint score, knee extension peak torque, and knee flexion peak torque of both groups were improved compared to before training (P<0.05);there were significant difference in Lysholm knee joint score, knee extension peak torque, and knee flexion peak torque between two groups(P<0.05). CONCLUSION: The application of virtual reality technology combined with isokinetic muscle strength training could promote recovery of knee joint function and enhance muscle strength in patients after ACL reconstruction surgery in further.

MELK promotes HCC carcinogenesis through modulating cuproptosis-related gene DLAT-mediated mitochondrial function.

Cuproptosis caused by copper overload is mediated by a novel regulatory mechanism that differs from previously documented mechanisms regulating cell death. Cells dependent on mitochondrial respiration showed increased sensitivity to a copper ionophore elesclomol that induced cuproptosis. Maternal embryonic leucine zipper kinase(MELK) promotes tumorigenesis and tumor progression through the PI3K/mTOR pathway, which exerts its effects partly by targeting the pyruvate dehydrogenase complex(PDHc) and reprogramming the morphology and function of mitochondria. However, the role of MELK in cuproptosis remains unclear. Here, we validated that elevated MELK expression enhanced the activity of PI3K/mTOR signaling and subsequently promoted Dihydrolipoamide S-Acetyltransferase (DLAT) expression and stabilized mitochondrial function. This regulatory effect helped to improve mitochondrial respiration, eliminate excessive intracellular reactive oxygen species (ROS), reduce intracellular oxidative stress/damage and the possibility of mitochondria-induced cell fate alternations, and ultimately promote the progression of HCC. Meanwhile, elesclomol reduced translocase of outer mitochondrial membrane 20(TOM 20) expression and increased DLAT oligomers. Moreover, the above changes of MELK to HCC were abolished by elesclomol. In conclusion, MELK enhanced the levels of the cuproptosis-related signature(CRS) gene DLAT (especially the proportion of DLAT monomer) by activating the PI3K/mTOR pathway, thereby promoting elesclomol drug resistance, altering mitochondrial function, and ultimately promoting HCC progression.

Clinical Effect of Platelet-Rich Fibrin Combined with BIO-GENE Artificial Bone Meal in Bone Defects After Jaw Cyst Surgery.

Purpose: To compare the clinical repair effects of leaving the defect empty and using Platelet-Rich Fibrin (PRF) combined with BIO-GENE artificial bone powder in patients with bone defects 6 months after jaw cystectomy. Patients and Methods: From June 2021 to June 2022, 70 patients who were admitted to the Department of Stomatology, Affiliated Hospital of Yanbian University, and were diagnosed with jaw cysts postoperatively were selected. All of the patients were divided into two groups according to random method, among which 35 patients who underwent cystectomy alone were recorded as group A, which served as blank control; 35 patients who underwent cystectomy and PRF combined with BIO-GENE artificial bone meal repaired bone defects during the same period were recorded as group B. 3D Slicer 5.0.3 software was used to reconstruct Cone Beam Computed Tomography (CBCT) after operation. In this study, the preoperative and postoperative CBCT data of the patients were analyzed using 3D Slicer 5.0.3 software in DICOM format to calculate the cleft volume before surgery and the newly formed bone volume after surgery. The osteogenesis rate was measured based on these calculations.The bone formation percentage in the bone defect area was recorded at 6 months, and the clinical curative effects of the two groups were compared. Results: After 6 months of surgery, the patients showed varying degrees of restoration in the jaw cyst area.The osteogenesis rate at 6 months in group A was 76.06±13.38%, while group B had a rate of 92.87±5.72%.The CBCT values in group B were higher than those in group A at 6 months post-surgery (P<0.05), t=-6.84.Group A and Group B showed a statistically significant difference. Conclusion: Compared with simple cystectomy, PRF combined with BIO-GENE artificial bone powder has a better effect on the speed of bone repair after cystectomy within 6 months and provides more favorable effects for the repair of postoperative dentition defects, and provides support to repair teeth after defects such as dental implants.

pH-Responsive and Actively Targeted Metal-Organic Framework Structures for Multimodal Antitumor Therapy and Inhibition of Tumor Invasion and Metastasis.

Multimodal treatment is an important tool to overcome tumor drug resistance. The reactive oxygen species (ROS) generated by photodynamic therapy (PDT) can directly play a killing role on tumor cells, which has the advantages of repeatable treatment and no drug resistance. However, its therapeutic oxygen consumption and destruction of tumor microvessels lead to hypoxia in tumor tissues, and hypoxia leads to overexpression of the receptor tyrosine kinase (c-MET) and vascular endothelial growth factor receptor (VEGFR). Overexpression of these two receptors leads to increased tumor invasiveness and metastasis. The molecularly targeted drug cabozantinib (CAB) has multiple targets, including anti-c-MET and VEGFR, to inhibit the development of hepatocellular carcinoma (HCC). In this study, our team designed a pH-sensitive nanoparticle CAB/Ce6@ZIF-8@PEG-FA (CCZP) loaded with CAB and Ce6, which exerted a multimodal therapeutic effect of PDT and molecularly targeted therapy by laser irradiation, and the PDT-induced overexpression of MET and VEGFR could also be inhibited by the target of CAB, thus reducing the invasive tumor cells metastasis. In summary, CCZP gives full play to the advantages of both drugs, exerting multimodal treatment while reducing HCC invasion and metastasis, providing a safe, potential approach to clinical treatment.

NOP2-mediated m5C Modification of c-Myc in an EIF3A-Dependent Manner to Reprogram Glucose Metabolism and Promote Hepatocellular Carcinoma Progression.

Mitochondrial dysfunction and glycolysis activation are improtant hallmarks of hepatocellular carcinoma (HCC). NOP2 is an S-adenosyl-L-methionine-dependent methyltransferase that regulates the cell cycle and proliferation activities. In this study, found that NOP2 contributes to HCC progression by promoting aerobic glycolysis. Our results revealed that NOP2 was highly expressed in HCC and that it was associated with unfavorable prognosis. NOP2 knockout in combination with sorafenib enhanced sorafenib sensitivity, which, in turn, led to marked tumor growth inhibition. Mechanistically, we identified that NOP2 regulates the c-Myc expression in an m5C-modification manner to promote glycolysis. Moreover, our results revealed that m5C methylation induced c-Myc mRNA degradation in an eukaryotic translation initiation factor 3 subunit A (EIF3A)-dependent manner. In addition, NOP2 was found to increase the expression of the glycolytic genes LDHA, TPI1, PKM2, and ENO1. Furthermore, MYC associated zinc finger protein (MAZ) was identified as the major transcription factor that directly controlled the expression of NOP2 in HCC. Notably, in a patient-derived tumor xenograft (PDX) model, adenovirus-mediated knockout of NOP2 maximized the antitumor effect and prolonged the survival of PDX-bearing mice. Our cumulative findings revealed the novel signaling pathway MAZ/NOP2/c-Myc in HCC and uncovered the important roles of NOP2 and m5C modifications in metabolic reprogramming. Therefore, targeting the MAZ/NOP2/c-Myc signaling pathway is suggested to be a potential therapeutic strategy for the treatment of HCC.

Development and validation of prognostic risk prediction models for hepatocellular carcinoma patients treated with immune checkpoint inhibitors based on a systematic review and meta-analysis of 47 cohorts.

Objective: To identify the risk factors associated with prognosis in patients with hepatocellular carcinoma (HCC) treated with immune checkpoint inhibitors (ICI) via meta-analysis. And to construct prediction models to aid in the prediction and improvement of prognosis. Methods: We searched PubMed, Embase, Web of Science and Cochrane Library for relevant studies from inception to March 29, 2023. After completing literature screening and data extraction, we performed meta-analysis, sensitivity analysis, and subgroup analysis to identify risk factors associated with OS and PFS. Using the pooled hazard ratio value for each risk factor, we constructed prediction models, which were then validated using datasets from 19 centers in Japan and two centers in China, comprising a total of 204 patients. Results: A total of 47 studies, involving a total of 7649 ICI-treated HCC patients, were included in the meta-analysis. After analyzing 18 risk factors, we identified AFP, ALBI, NLR, ECOG performance status, Child-Pugh stage, BCLC stage, tumor number, vascular invasion and combination therapy as predictors for OS prediction model, while AFP, ALBI, NLR, ECOG performance status, Child-Pugh stage, BCLC stage, tumor number and vascular invasion were selected as predictors for PFS model. To validate the models, we scored two independent cohorts of patients using both prediction models. Our models demonstrated good performance in these cohorts. In addition, in the pooled cohort of 204 patients, Our models also showed good performance with area under the curve (AUC) values of 0.712, 0.753, and 0.822 for the OS prediction model at 1-year, 2-year, and 3-year follow-up points, respectively, and AUC values of 0.575, 0.749 and 0.691 for the PFS prediction model Additionally, the calibration curve, decision curve analysis, and Kaplan-Meier curves in the pooled cohort all supported the validity of both models. Conclusion: Based on the meta-analysis, we successfully constructed the OS and PFS prediction models for ICI-treated HCC patients. We also validated the models externally and observed good discrimination and calibration. The model's selected indicators are easily obtainable, making them suitable for further application in clinical practice.

LRP1B suppresses HCC progression through the NCSTN/PI3K/AKT signaling axis and affects doxorubicin resistance.

Accumulating evidence supports the association of somatic mutations with tumor occurrence and development. We aimed to identify somatic mutations with important implications in hepatocellular carcinoma (HCC) and explore their possible mechanisms. The gene mutation profiles of HCC patients were assessed, and the tumor mutation burden was calculated. Gene mutations closely associated with tumor mutation burden and patient overall survival were identified. In vivo and in vitro experiments were performed to verify the effects of putative genes on proliferation, invasion, drug resistance, and other malignant biological behaviors of tumor cells. Fourteen genes with a high mutation frequency were identified. The mutation status of 12 of these genes was closely related to the mutation burden. Among these 12 genes, LRP1B mutation was closely associated with patient prognosis. Nine genes were associated with immune cell infiltration. The results of in vivo and in vitro experiments showed that the knockdown of LRP1B promotes tumor cell proliferation and migration and enhances the resistance of tumor cells to liposomal doxorubicin. LRP1B could directly bind to NCSTN and affect its protein expression level, thereby regulating the PI3K/AKT pathway. Our mutational analysis revealed complex and orchestrated liposomal alterations linked to doxorubicin resistance that may also render cancers less susceptible to immunotherapy and also provides new treatment alternatives.

Therapeutic advances targeting tumor angiogenesis in pancreatic cancer: Current dilemmas and future directions.

Pancreatic cancer (PC) is one of the most lethal malignancies, which is generally resistant to various treatments. Tumor angiogenesis is deemed to be a pivotal rate-determining step for tumor growth and metastasis. Therefore, anti-angiogenetic therapy is a rational strategy to treat various cancers. However, numerous clinical trials on anti-angiogenetic therapies for PC are overwhelmingly disappointing. The unique characteristics of tumor blood vessels in PC, which are desperately lacking and highly compressed by the dense desmoplastic stroma, are reconsidered to explore some optimized strategies. In this review, we mainly focus on its specific characteristics of tumor blood vessels, discuss the current dilemmas of anti-angiogenic therapy in PC and their underlying mechanisms. Furthermore, we point out the future directions, including remodeling the abnormal vasculature or even reshaping the whole tumor microenvironment in which they are embedded to improve tumor microcirculation, and then create therapeutic vulnerabilities to the current available therapeutic strategies.

Erratum: KLF5 downregulation desensitizes castration-resistant prostate cancer cells to docetaxel by increasing BECN1 expression and inducing cell autophagy: Erratum.

[This corrects the article DOI: 10.7150/thno.33282.].

Loss of LncRNA DUXAP8 synergistically enhanced sorafenib induced ferroptosis in hepatocellular carcinoma via SLC7A11 de-palmitoylation.

BACKGROUND: Ferroptosis is an important iron-dependent form of cell death in hepatocellular carcinoma (HCC). Sorafenib, a potent ferroptosis inducer, is used to treat advanced HCC but its efficacy is limited by the development of drug resistance. METHODS: The effects of DUXAP8 expression on HCC progression were evaluated by TCGA database, Kaplan-Meier analysis, and in situ hybridization analysis. Sorafenib resistant HCC cell lines were modeled in vitro to study the regulation of DUXAP8 on ferroptosis in HCC induced by sorafenib. We used RNA pull-down, immunofluorescence assays, acyl-biotinyl exchange assay and mass spectrometry analysis to assess the molecular mechanism of ferroptosis regulation by DUXAP8. Syngeneic subcutaneous and orthotopic CDX models were used to assess whether DUXAP8 inhibition improves HCC in vivo. RESULTS: LncRNA DUXAP8, which is highly expressed in liver cancer and associated with poor prognosis, contributes to sorafenib resistance through suppression of ferroptosis. In vitro tests revealed that DUXAP8 reduced the sensitivity of HCC to sorafenib-induced ferroptosis by acting on SLC7A11, a subunit of the amino acid antiporter system xc-. DUXAP8 facilitates SLC7A11 palmitoylation and impedes its lysosomal degradation, thereby enhancing SLC7A11 action and suppressing ferroptosis. RNA pull-down and immunofluorescence assays confirmed that DUXAP8 decreased membrane translocation and promoted sorting of de-palmitoylated SLC7A11 to lysosomes by binding of DUXAP8 to SLC7A11. In addition, mass spectrometric analysis found that the Cys414 residue of SLC7A11 might be the predominant mutant site responsible for molecular masking of SLC7A11 lysosomal sorting. Further, the antitumor effect of DUXAP8 knockdown was verified in orthotopic and subcutaneous CDX models. CONCLUSIONS: Our findings suggest that a novel translational strategy combining sorafenib with DUXAP8 silencing to overcome drug resistance may improve treatment efficacy in patients with advanced HCC.

Epidemiological Trends of Kidney Cancer Along with Attributable Risk Factors in China from 1990 to 2019 and Its Projections Until 2030: An Analysis of the Global Burden of Disease Study 2019.

Background: Understanding the past and future burden of kidney cancer in China over years provides essential references for optimizing the prevention and management strategies. Methods: The data on incidence, mortality, disability-adjusted life-years (DALYs) and age-standardized rates of kidney cancer in China, 1990-2019, were collected from the database of Global Burden of Disease Study 2019. The estimated annual percentage change (EAPC) was calculated to depict the trends of kidney cancer burden, and Bayesian age-period-cohort analysis was used to predict the incidence and mortality in the next decade. Results: Over the past 30 years, the number of new kidney cancer cases sharply increased from 11.07 thousand to 59.83 thousand, and the age-standardized incidence rate (ASIR) tripled from 1.16/100,000 to 3.21/100,000. The mortality and DALYs also presented an increasing pattern. Smoking and high body mass index were mainly risk factors for kidney cancer. We predicted that by 2030, the incident cases and deaths of kidney cancer would increase to 126.8 thousand and 41.8 thousand, respectively. Conclusion: In the past 30 years, the kidney cancer burden gradually increased in China, and it will continue to rise in the next decade, which reveals more targeted intervention measures are necessary.

MARS-GAN: Multilevel-Feature-Learning Attention-Aware Based Generative Adversarial Network for Removing Surgical Smoke.

Surgical smoke caused poor visibility during laparoscopic surgery, the smoke removal is important to improve the safety and efficiency of the surgery. We propose the Multilevel-feature-learning Attention-aware based Generative Adversarial Network for Removing Surgical Smoke (MARS-GAN) in this work. MARS-GAN incorporates multilevel smoke feature learning, smoke attention learning, and multi-task learning together. Specifically, the multilevel smoke feature learning adopts the multilevel strategy to adaptively learn non-homogeneity smoke intensity and area features with specific branches and integrates comprehensive features to preserve both semantic and textural information with pyramidal connections. The smoke attention learning extends the smoke segmentation module with the dark channel prior module to provide the pixel-wise measurement for focusing on the smoke features while preserving the smokeless details. And the multi-task learning strategy fuses the adversarial loss, cyclic consistency loss, smoke perception loss, dark channel prior loss, and contrast enhancement loss to help the model optimization. Furthermore, a paired smokeless/smoky dataset is synthesized for elevating smoke recognition ability. The experimental results show that MARS-GAN outperforms the comparative methods for removing surgical smoke on both synthetic/real laparoscopic surgical images, with the potential to be embedded in laparoscopic devices for smoke removal.