Platelets promote primary hepatocellular carcinoma metastasis through TGF-ß1-mediated cancer cell autophagy.

Previous research has revealed that platelets promote tumor metastasis by binding to circulating tumor cells (CTCs). However, the role of platelets in epithelial-mesenchymal transition (EMT) of cancer cells at the primary tumor site, the crucial initial step of tumor metastasis, remains to be elucidated. Here, we found that platelet releasate enhanced EMT and motility of hepatocellular carcinoma (HCC) cells via AMPK/mTOR-induced autophagy. RNA-seq indicated that platelet releasate altered TGF-ß signaling pathway of cancer cells. Inhibiting TGFBR or deleting platelet TGF-ß1 suppressed AMPK/mTOR pathway activation and autophagy induced by platelet releasate. Compared with Pf4cre-; Tgfb1fl/fl mice, HCC orthotopic models established on Pf4cre+; Tgfb1fl/fl mice showed reduced TGF-ß1 in primary tumors, which corresponded with decreased cancer cell EMT, autophagy, migration ability and tumor metastasis. Inhibition of autophagy via Atg5 knockdown in cancer cells negated EMT and metastasis induced by platelet-released TGF-ß1. Clinically, higher platelet count correlated with increased TGF-ß1, LC3 and N-cad expression in primary tumors of HCC patients, suggesting a link between platelets and HCC progression. Our study indicates that platelets promote cancer cell EMT in the primary tumor and HCC metastasis through TGF-ß1-induced HCC cell autophagy via the AMPK/mTOR pathway. These findings offer novel insights into the role of platelets in HCC metastasis and the potential therapeutic targets for HCC metastasis.

Oral Decoctions Based on Qi-Yin Syndrome Differentiation After Adjuvant Chemotherapy in Resected Stage ΙΙΙA Non-Small Cell Lung Cancer: A Randomized Controlled Trial.

OBJECTIVE: Powerful adjuvant strategies are required to improve the survival of patients with completely resected stage ΙΙΙA non-small cell lung cancer (NSCLC). We aimed to compare the efficacy of traditional Chinese medicine (TCM) treatment versus observation after adjuvant chemotherapy in these patients. METHODS: Eligible patients were randomized 1:1 to receive either oral decoctions based on Qi-Yin syndrome differentiation (TCM group) or observation (observation group). The intervention lasted for 12 months. The primary endpoint was 1-year disease-free survival (DFS). Secondary endpoints were DFS, quality of life, regulatory T cells (Tregs), and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) on the surface of Tregs in peripheral blood. We used EORTC QLQ-LC43 to evaluate quality of life. RESULTS: Between Apr 29, 2019, and Nov 11, 2021, 75 patients were randomly assigned to oral decoctions based on Qi-Yin syndrome differentiation (n = 38) or observation (n = 37). The full analysis set included 35 patients in the TCM group and 35 in the observation group. After a median follow-up of 24.2 months, oral decoctions based on Qi-Yin syndrome differentiation improved DFS compared with observation (HR 0.378, 95% CI: 0.157-0.912; P = .03). One-year DFS was 82.1% in the TCM group and 61.9% in the observation group (P = .06). Three months after randomization, scores of total health, role function, emotional function, and social function in the TCM group were higher than those in the observation group (P < .01 for all), scores of fatigue, pain, insomnia, appetite loss, constipation, cough, and chest pain were lower than those in the observation group (P < .05 for all); there was no significant difference in the proportion of Tregs between the TCM group and the observation group (P = .58); the proportion of CTLA-4+Tregs in the TCM group was lower than that in the observation group (P = .046). There were no adverse events that occurred in both groups. CONCLUSIONS: Oral decoctions based on Qi-Yin syndrome differentiation after adjuvant chemotherapy prolonged DFS, reduced the risk of disease recurrence and metastasis, improved quality of life, and down-regulated the proportion of CTLA-4+Tregs in completely resected stage ΙΙΙA NSCLC patients. TRIAL REGISTRATION: Chinese Clinical Trial Register, No. ChiCTR1800019396. Date of registration: 9 November 2018.

A combined pre- and intra-operative nomogram in evaluation of degrees of liver cirrhosis predicts post-hepatectomy liver failure: a multicenter prospective study.

Background: Adequate evaluation of degrees of liver cirrhosis is essential in surgical treatment of hepatocellular carcinoma (HCC) patients. The impact of the degrees of cirrhosis on prediction of post-hepatectomy liver failure (PHLF) remains poorly defined. This study aimed to construct and validate a combined pre- and intra-operative nomogram based on the degrees of cirrhosis in predicting PHLF in HCC patients using prospective multi-center's data. Methods: Consecutive HCC patients who underwent hepatectomy between May 18, 2019 and Dec 19, 2020 were enrolled at five tertiary hospitals. Preoperative cirrhotic severity scoring (CSS) and intra-operative direct liver stiffness measurement (DSM) were performed to correlate with the Laennec histopathological grading system. The performances of the pre-operative nomogram and combined pre- and intra-operative nomogram in predicting PHLF were compared with conventional predictive models of PHLF. Results: For 327 patients in this study, histopathological studies showed the rates of HCC patients with no, mild, moderate, and severe cirrhosis were 41.9%, 29.1%, 22.9%, and 6.1%, respectively. Either CSS or DSM was closely correlated with histopathological stages of cirrhosis. Thirty-three (10.1%) patients developed PHLF. The 30- and 90-day mortality rates were 0.9%. Multivariate regression analysis showed four pre-operative variables [HBV-DNA level, ICG-R15, prothrombin time (PT), and CSS], and one intra-operative variable (DSM) to be independent risk factors of PHLF. The pre-operative nomogram was constructed based on these four pre-operative variables together with total bilirubin. The combined pre- and intra-operative nomogram was constructed by adding the intra-operative DSM. The pre-operative nomogram was better than the conventional models in predicting PHLF. The prediction was further improved with the combined pre- and intra-operative nomogram. Conclusions: The combined pre- and intra-operative nomogram further improved prediction of PHLF when compared with the pre-operative nomogram. Trial Registration: Clinicaltrials.gov Identifier: NCT04076631.

Tetrabromobisphenol-A/S and their derivatives in surface particulates from workshop floors of three representative e-waste recycling sites in China.

Surface particulates collected from the workshop floors of three major e-waste recycling sites (Taizhou, Qingyuan, and Guiyu) in China were analyzed for tetrabromobisphenol A/S (TBBPA/S) and their derivatives to investigate the environmental pollution caused by e-waste recycling activities. Mean concentrations of total TBBPA/S analogs in surface particulates were 31,471-116,059 ng/g dry weight (dw). TBBPA, TBBPA-BGE, and TBBPA-BDBPE were the most frequently detected in particulates with average concentration ranges of 17,929-78,406, 5601-15,842, and 5929-21,383 ng/g dw, respectively. Meanwhile, TBBPA, TBBPA-BGE, and TBBPA-BDBPE were the most abundant TBBPA/S analogs, accounting for around 96% of the total. The composition profiles of TBBPA/S analogs differed significantly among three e-waste sites. Similarly, principal component analysis uncovered different pollution patterns among different sites. The discrepancy in the profiles of TBBPA/S analogs largely relied on the e-waste types recycled in different areas. E-waste recycling led to the release of TBBPA/S analogs, and TBBPA/S analogs produced differentiation during migration from source (surface particulates) to nearby soil. More researches are necessary to find a definite relationship between pollution status and e-waste types and study differentiation behavior of TBBPA/S analogs in migration and diffusion from source to environmental medium.

A deep-learning-based genomic status estimating framework for homologous recombination deficiency detection from low-pass whole genome sequencing.

Genome-wide sequencing allows for prediction of clinical treatment responses and outcomes by estimating genomic status. Here, we developed Genomic Status scan (GSscan), a long short-term memory (LSTM)-based deep-learning framework, which utilizes low-pass whole genome sequencing (WGS) data to capture genomic instability-related features. In this study, GSscan directly surveys homologous recombination deficiency (HRD) status independent of other existing biomarkers. In breast cancer, GSscan achieved an AUC of 0.980 in simulated low-pass WGS data, and obtained a higher HRD risk score in clinical BRCA-deficient breast cancer samples (p = 1.3 × 10-4, compared with BRCA-intact samples). In ovarian cancer, GSscan obtained higher HRD risk scores in BRCA-deficient samples in both simulated data and clinical samples (p = 2.3 × 10-5 and p = 0.039, respectively, compared with BRCA-intact samples). Moreover, HRD-positive patients predicted by GSscan showed longer progression-free intervals in TCGA datasets (p = 0.0011) treated with platinum-based adjuvant chemotherapy, outperforming existing low-pass WGS-based methods. Furthermore, GSscan can accurately predict HRD status using only 1 ng of input DNA and a minimum sequencing coverage of 0.02 × , providing a reliable, accessible, and cost-effective approach. In summary, GSscan effectively and accurately detected HRD status, and provide a broadly applicable framework for disease diagnosis and selecting appropriate disease treatment.

Thermal ablation for hepatic tumors in high-risk locations.

Thermal ablative techniques such as radiofrequency and microwave ablation are minimally invasive and cost-effective approaches that are currently being adopted as alternatives to surgical resection for primary and metastatic liver malignancies. However, they are considered to be relatively contraindicated for tumors in high-risk locations due to technical difficulties and a perceived increased risk of perioperative complications. Several techniques, including artificial ascites, non-touch multibipolar ablation, and laparoscopically assisted ablation, can be used to improve the outcomes of ablation for high-risk tumors. This review aims to provide a comprehensive summary of the techniques currently used to improve thermal ablation outcomes for high-risk liver tumors.

Acupuncture for cervical dystonia associated with anxiety and depression: A case report.

BACKGROUND: Cervical dystonia (CD) is a type of muscle tone disorder that usually occurs in the neck muscles. Due to the intermittent or continuous involuntary contraction of the neck muscles, the head and neck are twisted and skewed and some postural abnormalities occur. Long-term abnormal posture or pain can cause negative emotions in patients, which can affect their quality of life. CASE SUMMARY: This case report included a 37-year-old woman who was diagnosed with CD associated with anxiety and depression; the accompanying symptoms were head and neck tilt of approximately 90° to the right and mental abnormality. After two courses of acupuncture treatment, the patient's head and neck can be maintained in a normal position, and the negative emotions can be relieved. CONCLUSION: This case indicates that acupuncture can effectively improve CD and the emotional state and quality of life of patients, making it an effective alternative treatment for the condition.

Direct interaction of platelet with tumor cell aggravates hepatocellular carcinoma metastasis by activating TLR4/ADAM10/CX3CL1 axis.

Metastasis is the main culprit of cancer-related death and account for the poor prognosis of hepatocellular carcinoma. Although platelets have been shown to accelerate tumor cell metastasis, the exact mechanism remained to be fully understood. Here, we found that high blood platelet counts and increased tumor tissue ADAM10 expression indicated the poor prognosis of HCC patients. Meanwhile, blood platelet count has positive correlation with tumor tissue ADAM10 expression. In vitro, we revealed that platelet increased ADAM10 expression in tumor cell through TLR4/NF-κB signaling pathway. ADAM10 catalyzed the shedding of CX3CL1 which bound to CX3CR1 receptor, followed by inducing epithelial to mesenchymal transition and activating RhoA signaling in cancer cells. Moreover, knockdown HCC cell TLR4 (Tlr4) or inhibition of ADAM10 prevented platelet-increased tumor cell migration, invasion and endothelial permeability. In vivo, we further verified in mice lung metastatic model that platelet accelerated tumor metastasis via cancer cell TLR4/ADAM10/CX3CL1 axis. Overall, our study provides new insights into the underlying mechanism of platelet-induced HCC metastasis. Therefore, targeting the TLR4/ADAM10/CX3CL1 axis in cancer cells hold promise for the inhibition of platelet-promoted lung metastasis of HCC.

Clinical efficacy and biomarker analysis of neoadjuvant camrelizumab plus chemotherapy for early-stage triple-negative breast cancer: a experimental single-arm phase II clinical trial pilot study.

BACKGROUND: Triple-negative breast cancer (TNBC) is associated with a dismal prognosis. Immune checkpoint inhibitors have shown promising antitumor activity in neoadjuvant settings. This single-arm, phase II trial aimed to evaluate the efficacy and safety of camrelizumab plus chemotherapy as the neoadjuvant therapy (NAT) in early TNBC. METHODS: Patients received eight cycles of camrelizumab plus nonplatinum-based chemotherapy. The primary endpoint was total pathological complete response (pCR). Secondary endpoints included the breast pathological complete response (bpCR), adverse events (AEs). Multiomics biomarkers were assessed as exploratory objective. RESULTS: Twenty of 23 TNBC patients receiving NAT underwent surgery, with the total pCR rate of 65% (13/20) and bpCR rate of 70% (14/20). Grade ≥3 treatment-related AEs were observed in 14 (60.9%) patients, with the most common AE being neutropenia (65.2%). Tumor immune microenvironment was analyzed between pCR and non-pCR samples before and after the NAT. Gene expression profiling showed a higher immune infiltration in pCR patients than non-pCR patients in pre-NAT samples. Through establishment of a predictive model for the NAT efficacy, TAP1 and IRF4 were identified as the potential predictive biomarkers for response to the NAT. Gene set enrichment analysis revealed the glycolysis and hypoxia pathways were significantly activated in non-pCR patients before the NAT, and this hypoxia was aggravated after the NAT. CONCLUSION: Camrelizumab plus nonplatinum-based chemotherapy shows a promising pCR rate in early-stage TNBC, with an acceptable safety profile. TAP1 and IRF4 may serve as potential predictive biomarkers for response to the NAT. Aggravated hypoxia and activated glycolysis after the NAT may be associated with the treatment resistance.

NHC-Silyliumylidene Cation-Catalyzed Hydroboration of Isocyanates with Pinacolborane.

The low-oxidation-state silicon-catalyzed hydroboration of isocyanates with pinacolborane (HBpin) using the NHC-silyliumylidene cation catalyst [(IMe)2SiH]I (1, IMe = :C{N(Me)C(Me)}2) is described. In the catalysis, the Si lone pair electrons activate isocyanates, and the latter react with HBpin to form N-boryl formamides at room temperature. Catalyst 1 further activates N-boryl formamides at 70 °C, the intermediates of which react with HBpin to form N-boryl methylamines and (pinB)2O.

Effects of microcystin on protein profile in hepatopancreas of Litopenaeus vannamei.

For intensive aquaculture in freshwater ponds, microcystin (MC-LR) generated from cyanobacterial blooms is one of the bottlenecks for the healthy and sustainable development of shrimp aquaculture industry. In this study, we measured the MC-LR content in the hepatopancreas and muscles of Litopenaeus vannamei stressed by MC-LR, and analyzed protein expression in the hepatopancreas using DIA high-throughput proteomics technology. The results showed that MC-LR content in the hepatopancreas and muscles reached the highest at 1 h after MC-LR injection, which was (6.12±0.45) µg·kg-1 and (5.00±0.19) µg·kg-1, respectively. Then, it decreased gra-dually, with that in the hepatopancreas being significantly higher than in muscles. We identified 820 differential expressed proteins, including 586 up-regulated and 234 down-regulated ones. Results of bioinformatics analysis showed that MC-LR stress significantly affected immune-related pathways such as lysosome, RIG-Ⅰ receptor signals and interleukin-2. It also altered energy metabolisms including citrate cycle, metabolism of starch and sucrose, and interconversion of pentose and glucoronate, which in turn led to the disorder of carbohydrate metabolism. In addition, MC-LR significantly upregulated 19 cytoskeleton-related blood shadow proteins and damaged the hepatopancreas cytoskeleton. It was concluded that MC-LR mainly affected the physiological processes associated with immunity, energy metabolism, and cytoskeleton in the hepatopancreas of L. vannamei.

m6A-regulated tumor glycolysis: new advances in epigenetics and metabolism.

Glycolytic reprogramming is one of the most important features of cancer and plays an integral role in the progression of cancer. In cancer cells, changes in glucose metabolism meet the needs of self-proliferation, angiogenesis and lymphangiogenesis, metastasis, and also affect the immune escape, prognosis evaluation and therapeutic effect of cancer. The n6-methyladenosine (m6A) modification of RNA is widespread in eukaryotic cells. Dynamic and reversible m6A modifications are widely involved in the regulation of cancer stem cell renewal and differentiation, tumor therapy resistance, tumor microenvironment, tumor immune escape, and tumor metabolism. Lately, more and more evidences show that m6A modification can affect the glycolysis process of tumors in a variety of ways to regulate the biological behavior of tumors. In this review, we discussed the role of glycolysis in tumor genesis and development, and elaborated in detail the profound impact of m6A modification on different tumor by regulating glycolysis. We believe that m6A modified glycolysis has great significance and potential for tumor treatment.

[Observation of the long-term clinical efficacy of "Fuyang Guben" acupuncture-moxibustion therapy on perennial allergic rhinitis and its effects on the total IgE and IL-4 in the serum].

OBJECTIVE: To investigate the long-term clinical efficacy and safety of "Fuyang Guben" (supporting yang and consolidating root) acupuncture-moxibustion therapy on perennial allergic rhinitis (PAR), and to explore its functioning mechanism. METHODS: The patients with PAR were randomly divided into acupuncture + western medicine group (n=30) and western medicine group (n=30). In the western medicine group, fluticasone propionate nasal spray was administered, one spray in each nostril in one treatment, once a day, for 6 weeks. On the basis of the western medicine group, fuyangguben acupuncture-moxibustion therapy was supplemented. Acupuncture was applied to Shangxing (GV23), Yintang (GV24+), and bilateral Yingxiang (LI20), Shangyingxiang (EX-HN8), Sibai (ST2), Hegu (LI4) and Chize (LU5); warm needling was applied at Dazhui (GV14). The patients of this group received 30 min of acupuncture-moxibustion therapy 3 times weekly during the first 4 weeks and twice a week in the last 2 weeks, totally for 6 weeks. Before treatment, after treatment, in week 10, 18 and 30 of follow-up visits, the reflective total nasal symptom score (rTNSS), the total non-nasal symptom score (TNNSS), the total ophthalmic symptom score (TOSS), and the score of the rhinitis quality of life (RQLQ) scale were compared in the patients of the two groups separately. Using ELISA, the serum concentrations of total immunoglobulin E (IgE) and interleukin-4 (IL-4) were detected before and after treatment. RESULTS: After treatment, the rTNSS, TNNSS, TOSS, as well as RQLQ score were lower in comparison with those before treatment in each group (P<0.05).The rTNSS, TNNSS, TOSS and the score of RQLQ in the week 10, 18 and 30 of follow-up visits were reduced when compared with those before treatment in each group (P<0.05), and these scores in the acupuncture + western medicine group were remarkably lower than those of the western medicine group (P<0.05). After treatment, the serum contents of total IgE and IL-4 were significantly decreased when compared with those before treatment in the acupuncture + western medicine group (P<0.05), and these indicators in the acupuncture + western medicine group were lower than those of the western medicine group (P<0.05). CONCLUSION: On the base of treatment with fluticasone propionate nasal spray, "Fuyang Guben" acupuncture-moxibustion therapy is safe and effective on PAR, presenting a remarkably long-term efficacy. The functioning mechanism may be related to the down-regulation of total IgE and IL-4 in serum.

Case Report: Solitary metastasis to the appendix after curative treatment of HCC.

Background: Liver cancer is now the fourth most common cancer in China. The most important factor in decreasing the overall survival is recurrence. Nearly 40%-70% of patients would be detected with intrahepatic or extrahepatic recurrence in 5 years after R0 resection. The intestine is not a usual site for extrahepatic metastasis. Only one case of hepatocellular carcinoma (HCC) metastasis to the appendix has been reported so far. So, it poses a difficulty for us to develop treatment plan. Case presentation: Here, we report a very rare case of a recurrent HCC patient. R0 resection was first performed on this 52-year-old men who was diagnosed with Barcelona Clinic Liver Cancer stage A HCC. Different from other cases, a solitary metastasis to the appendix was detected 5 years after the R0 resection. After discussing with the multidisciplinary team, we decided to perform surgical resection again. The final postoperative pathology confirmed HCC. Complete responses were detected in this patient after the combined treatment of transarterial chemoembolization, angiogenesis inhibitors, and immune checkpoint inhibitors. Conclusion: Because solitary metastasis to the appendix in HCC is very rare, this case might be the first reported in HCC patients after R0 resection. This case report highlights the efficacy of the combination of surgery, local regional therapy, angiogenesis inhibitors, and immune treatment in HCC patients with solitary metastasis to the appendix.

[Moxibustion improves learning-memory ability by regulating apoptosis related proteins of hippocampus in diabetic rats with cognitive impairment].

OBJECTIVE: To investigate the effect of moxibustion on the proteins related with apoptosis and nuclear transcription factor kappa B (NF-κB) in hippocampus of diabetic rats with cognitive impairment (CI), so as to explore its mechanism underlying improvement of learning-memory ability. METHODS: Thirty SD rats were randomly divided into normal, model and moxibustion groups (n=10 rats/group). The diabetic model was established by i.p. injection of streptozotocin solution (25 mg·kg-1·d-1), followed by high-fat diet raising for 4 weeks, and the CI model was confirmed by Morris water maze test. The rats in the moxibustion group were given moxibustion at "Shenting" (GV24), "Baihui" (GV20) and "Dazhui" (GV14) for 20 min each time, the treatment was conducted 6 times a week for 4 weeks. The learning-memory ability was detected by Morris water maze test, the random blood glucose of rats was measured by glucometer and test strips. The protein and mRNA expression levels of Bcl-2, Bax, Caspase-3 and NF-κB p65 in hippocampus were detected by Western blot and quantitative real-time PCR, separately. RESULTS: After modeling, the random blood glucose, escape latency, and the expression levels of Bax, Caspase-3 and NF-κB p65 proteins and mRNAs in the model group were significantly increased, while the expression levels of Bcl-2 protein and mRNA were decreased (P<0.001，P<0.01, P<0.05) in comparison with the normal group. Following the treatment, the modeling induced increase of blood glucose, escape latency, and the expression levels of Bax, Caspase-3 and NF-κB p65 proteins and mRNAs, as well as decrease of Bcl-2 protein and mRNA expression levels were reversed (P<0.05, P<0.01, P<0.001). CONCLUSION: Moxibustion can improve learning-memory ability in diabetic rats with cognitive impairment, which may be related to its function in regulating the expression levels of hippocampal Bcl-2, Bax, Caspase-3 and NF-κB.

Hydroxyethyl starch stabilized copper-diethyldithiocarbamate nanocrystals for cancer therapy.

Cancer stem cells (CSCs) have been recognized as the culprit for tumor progression, treatment resistance, metastasis, and recurrence while redox homeostasis represents the Achilles' Heel of CSCs. However, few drugs or formulations that are capable of elevating oxidative stress have achieved clinical success for eliminating CSCs. Here, we report hydroxyethyl starch stabilized copper-diethyldithiocarbamate nanoparticles (CuET@HES NPs), which conspicuously suppress CSCs not only in vitro but also in numerous tumor models in vivo. Furthermore, CuET@HES NPs effectively inhibit CSCs in fresh tumor tissues surgically excised from hepatocellular carcinoma patients. Mechanistically, we uncover that hydroxyethyl starch stabilized copper-diethyldithiocarbamate nanocrystals via copper­oxygen coordination interactions, thereby promoting copper-diethyldithiocarbamate colloidal stability, cellular uptake, intracellular reactive oxygen species production, and CSCs apoptosis. As all components are widely used in clinics, CuET@HES NPs represent promising treatments for CSCs-rich solid malignancies and hold great clinical translational potentials. This study has critical implications for design of CSCs targeting nanomedicines.

A novel lonidamine derivative targeting mitochondria to eliminate cancer stem cells by blocking glutamine metabolism.

Cancer stem cells (CSCs) have been blamed as the main culprit of tumor initiation, progression, metastasis, chemoresistance, and recurrence. However, few anti-CSCs agents have achieved clinical success so far. Here we report a novel derivative of lonidamine (LND), namely HYL001, which selectively and potently inhibits CSCs by targeting mitochondria, with 380-fold and 340-fold lower IC50 values against breast cancer stem cells (BCSCs) and hepatocellular carcinoma stem cells (HCSCs), respectively, compared to LND. Mechanistically, we reveal that HYL001 downregulates glutaminase (GLS) expression to block glutamine metabolism, blunt tricarboxylic acid cycle, and amplify mitochondrial oxidative stress, leading to apoptotic cell death. Therefore, HYL001 displays significant antitumor activity in vivo, both as a single agent and combined with paclitaxel. Furthermore, HYL001 represses CSCs of fresh tumor tissues derived from liver cancer patients. This study provides critical implications for CSCs biology and development of potent anti-CSCs drugs.

MTDH-stabilized DDX17 promotes tumor initiation and progression through interacting with YB1 to induce EGFR transcription in Hepatocellular Carcinoma.

Metadherin (MTDH) is a well-established oncogene in various cancers including Hepatocellular Carcinoma (HCC). However, the precise mechanism through which MTDH promotes cancer-related signaling pathways in HCC remains unknown. In this study, we identified DDX17 as a novel binding partner of MTDH. Furthermore, MTDH increased the protein level of DDX17 by inhibiting its ubiquitination. We confirmed that DDX17 was a novel oncogene, with dramatically upregulated expression in HCC tissues. The increased expression of DDX17 was closely associated with vascular invasion, TNM stage, BCLC stage, and poor prognosis. In vitro and in vivo tests demonstrated that DDX17, a downstream target of MTDH, played a crucial role in tumor initiation and progression. Mechanistically, DDX17 acted as a transcriptional regulator that interacted with Y-box binding protein 1 (YB1) in the nucleus, which in turn drove the binding of YB1 to its target epidermal growth factor receptor (EGFR) gene promoter to increase its transcription. This in turn increased expression of EGFR and the activation of the downstream MEK/pERK signaling pathway. Our results identify DDX17, stabilized by MTDH, as a powerful oncogene in HCC and suggest that the DDX17/YB1/EGFR axis contributes to tumorigenesis and metastasis of HCC.

Pemigatinib in previously treated Chinese patients with locally advanced or metastatic cholangiocarcinoma carrying FGFR2 fusions or rearrangements: A phase II study.

OBJECTIVE: This study evaluated the antitumor activity and safety of pemigatinib in previously treated Chinese patients with advanced cholangiocarcinoma and fibroblast growth factor receptor 2 (FGFR2) fusions or rearrangements. BACKGROUND: Pemigatinib provided clinical benefits for previously treated patients with cholangiocarcinoma carrying FGFR2 fusions or rearrangements and was approved for this indication in multiple countries. METHODS: In this ongoing, multicenter, single-arm, phase II study, adult patients with locally advanced or metastatic cholangiocarcinoma carrying centrally confirmed FGFR2 fusions or rearrangements who had progressed on ≥1 systemic therapy received 13.5 mg oral pemigatinib once daily (3-week cycle; 2 weeks on, 1 week off) until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was objective response rate (ORR) assessed by an independent radiology review committee. RESULTS: As of January 29, 2021, 31 patients were enrolled. The median follow-up was 5.1 months (range, 1.5-9.3). Among 30 patients with FGFR2 fusions or rearrangements evaluated for efficacy, 15 patients achieved partial response (ORR, 50.0%; 95% confidence interval [CI], 31.3-68.7); 15 achieved stable disease, contributing to a disease control rate of 100% (95% CI, 88.4-100). The median time to response was 1.4 months (95% CI, 1.3-1.4), the median duration of response was not reached, and the median progression-free survival was 6.3 months (95% CI, 4.9-not estimable [NE]). Eight (25.8%) of 31 patients had ≥grade 3 treatment-emergent adverse events. Hyperphosphatemia, hypophosphatasemia, nail toxicities, and ocular disorders were mostly

A Prospective Study Using Propensity Score Matching to Compare Long-term Survival Outcomes After Robotic-assisted, Laparoscopic, or Open Liver Resection for Patients With BCLC Stage 0-A Hepatocellular Carcinoma.

OBJECTIVE: To compare the short- and long-term outcomes of robot-assisted (RALR), laparoscopic (LLR), or open liver resection (OLR) in the treatment of Barcelona Clinic Liver Cancer (BCLC) stage 0-A hepatocellular carcinoma (HCC). SUMMARY BACKGROUND DATA: Following the Balliol IDEAL classification, long-term oncological outcomes can be used to evaluate the value of minimally invasive techniques in the treatment of HCC, and to assess whether they should become a standard practice. METHODS: Data from prospective cohorts of patients with BCLC stage 0-A HCC who underwent curative liver resection using OLR, LLR, or RALR at Tongji Hospital were reviewed. The short-term and long-term oncological outcomes of these 3 different surgical approaches after adequate follow-up were compared using propensity score matching to reduce selection bias. RESULTS: Of 369 patients included in this study (71, RALR; 141, LLR; and 157, OLR), 56 patients in each of the 3 groups were chosen for further comparison, after propensity score matching. In the minimally invasive group (RALR+LLR), both the operative time and duration of Pringle's maneuver were significantly longer than those in the OLR group; however, the length of hospital stay was significantly shorter. There were no significant differences in the other intraoperative parameters and the incidence of postoperative complications among the 3 groups. HCC recurrence in the minimally invasive group when compared with the OLR group was characterized by a significantly higher proportion of single lesion or early-stage HCC. However, there were no significant differences in the 5-year disease-free survival (63.8%, 54.4%, and 50.6%) or overall survival rates (80.8%, 78.6%, and 75.7%, respectively) among the 3 groups. Clinically significant portal hypertension was the only risk factor that negatively affected the 5-year disease-free survival rate. Multivariate Cox regression analysis showed that clinically significant portal hypertension, serum alpha-fetoprotein level (≥400 ng/mL), and Edmondson-Steiner grading (III+IV) were independent risk factors for poor long-term survival. CONCLUSION: Both robotic and laparoscopic hepatectomies were safe and effective for patients with BCLC stage 0-A HCC when compared with open hepatectomy.